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.

Distinct Immunogenetic Profiles of Chronic Lymphocytic Leukemia in Asia: A Taiwan Cooperative Oncology Group Registry Study.

Asian patientswith chronic lymphocytic leukemia (CLL) exhibit immunoglobulin heavy variable (IGHV) gene repertoires that are distinct from those observed in Western populations, and a higher proportion of Asian CLL patients carry heavy loads of somatic hypermutations (SHM) within the B-cell receptor immunoglobulins (BcR IG). Due to the low regional incidence of CLL in Asia, only a limited number of studies had attempted to probe the phenomenon of BcR IG stereotypy in Asian populations. In this study, we analyzed the IGHV-IGHD-IGHJ gene rearrangements from a series of 255 CLL patients recruited in a nationwide, multicenter study in Taiwan. Our analysis revealed that the IGHV gene repertoire was characterized by evident biases, with IGHV3-7, IGHV4-34, and IGHV3-23 being the most frequent rearranged IGHV genes, and a higher proportion of cases carrying mutated IGHV. In terms of BcR stereotypy, the incidence of major subsets was less frequent in this cohort, with subsets #77 and #28A being the most common, while the incidence of minor subsets was approximately equivalent to that reported in the Western cohorts. With this study, we provide evidence that CLL in Asia is indeed associated with distinct immunogenetic characteristics regarding IGHV gene usage, SHM status, and BcR IG stereotypy.

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.

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.

The incidence and risk factors of hepatic veno-occlusive disease after hematopoietic stem cell transplantation in Taiwan.

Hepatic veno-occlusive disease (VOD) is a potentially fatal complication of hematopoietic stem cell transplantation (HSCT). We conducted this study to investigate the incidence and risk factors of hepatic VOD for patients receiving HSCT in Taiwan. We retrospectively analyzed the data from a nationwide registry for patients receiving HSCT, which was collected by the Taiwan Society of Blood and Marrow Transplantation. The data collection period was from 2009 to 2014. A total 2345 patients were reviewed and 39 patients among them were diagnosed as having hepatic VOD. The cumulative incidence of hepatic VOD in the whole cohort of 2345 patients was 1.66%. In multivariate analysis, disease diagnosis of myelodysplastic syndrome, chronic HCV infection, condition regimens of bulsulfan intravenously administered, and antithymocyte immunoglobulin were independent factors to predict higher risk of hepatic VOD. The overall mortality rate for patients with hepatic VOD was 79%. Patients with hepatic VOD had significant worse survival outcomes when compared with those without hepatic VOD (P = 0.00063). In conclusion, although the incidence is low, hepatic VOD remains a serious complication after HSCT in Taiwan. The findings of this study could be the basis for developing prophylactic or early treatment strategies for hepatic VOD.

The learning curve of robotic nipple sparing mastectomy for breast cancer: An analysis of consecutive 39 procedures with cumulative sum plot.

BACKGROUND: The preliminary experience and learning curve of robotic nipple sparing mastectomy (R-NSM) in the management of breast cancer were analyzed and reported. METHODS: The medical records of patients who underwent R-NSM for breast cancer during the period of March 2017 to June 2018 were collected from the same surgeon in a single institute. Data on clinicopathologic characteristics, type of surgery, method of breast reconstruction, and operation time were prospective collected. Learning curve of R-NSM was evaluated and analyzed by the cumulative sum (CUSUM) plot method. RESULTS: A total of 39 consecutive R-NSM procedures from 35 patients were analyzed. The time needed for "docking", "R-NSM", and "R-NSM and immediate prosthesis breast reconstruction (IPBR)" decreased after cases experience accumulated, and in mature phase procedures could finished within 10 min, 100mins, and 240 min, separately. In CUSUM plots analysis of learning curve, the cases needed to decrease operation time for "docking", "R-NSM", and "total time for R-NSM and IPBR" were 13th, 13th, and 12th procedures separately. Mastectomy weight and lymph node metastasis were factors related to operation time. The rate of total nipple areolar complex necrosis for R-NSM was 0%. One (2.9%, 1/35) R-NSM procedure was found to have positive margin involved in the final pathologic check-up. No implant loss, or local recurrence was observed during a mean follow-up of 8.6 ±â€¯4.5 (1.3-16.7) months. CONCLUSION: From our preliminary experience, R-NSM and IPBR (or R-NSM alone) is a safe procedure, and the operation time needed significantly decrease after cases experience accumulated.

Adjuvant radiotherapy after curative surgery for oral cavity squamous cell carcinoma and treatment effect of timing and duration on outcome-A Taiwan Cancer Registry national database analysis.

Conduct an accurate risk assessment of resected oral cavity squamous cell carcinoma (OSCC) patients by accessing a nationwide systemic investigation is pivotal to improve treatment outcomes. In this article, we tried to determine the impact of different prognostic factors for OSCC patients who received adjuvant radiotherapy (RT) after curative surgery, using Taiwan's national cancer registry database (TCR). A nationwide, large population-based study was conducted using TCR with patients identified from 2007 to 2015. The study variables included age, gender, cancer subsites, stage, histology grade, margin and extra-nodal extension (ENE) status, treatment type, surgery to RT interval (ORI), total RT treatment time (RTT), and RT dose. Univariate and multivariate analysis were performed to identify predictors of the variables associated with overall survival (OS), cause-specific survival (CSS), local-regional relapse-free survival (LRFS), and distant metastasis-free survival (DMFS). 8986 OSCC patients treated with surgery and adjuvant RT were analyzed. In multivariate analysis, worse outcomes were associated with males, older age, subsite in the oral tongue, advanced stage, higher histologic grade, involved margin, and positive ENE. ORI only showed an adverse trend in LRFS, when exceeding 7 weeks (P = .06). RTT >8 weeks was a significant poor predictor in OS, CSS and LRFS (P < .001). Extreme RT dose (>70 Gy or ≤50 Gy) also demonstrated an adverse impact on the outcomes. Prolonged RT treatment time and extreme RT doses were identified as significantly poor prognostic predictors in OSCC patients who received adjuvant RT after curative surgery.

Cancer-related pain: a nationwide survey of patients' treatment modification and satisfaction in Taiwan.

BACKGROUND: We have limited knowledge about cancer patients' pain control satisfaction in outpatient departments in Taiwan and doctors' practice of adjusting analgesics according to their pain status. This survey examined pain management and satisfaction among cancer outpatients with pain and obtained information on their quality of life and treatment management for different pain intensities. METHODS: The Short version of the Brief Pain Inventory was used as the outcome questionnaire. Participants comprised 2075 patients with different cancers and disease statuses at 14 oncological outpatient departments, of which 1051 reported pain within the week prior to testing. The impact of pain management on physical and psychological functioning, and satisfaction with doctors were evaluated. Information about doctors' prescriptions was collected. Logistic regression analyses were conducted to evaluate whether the interference scale performed identically in the different analgesic ladders. RESULTS: Pain was significantly linked to disease status and affected patients' physical and psychiatric functioning. Almost 100% of patients were satisfied with their pain control, but more than 70% of doctors did not change analgesics based on patients' current pain status. The results show that although patients were satisfied with their physicians, treatment of cancer pain was still suboptimal. CONCLUSION: Pain assessment and treatment need to be more thorough and management guidelines should be revised to improve pain control in patients with cancer.

Waldenström's macroglobulinemia-associated renal amyloidosis presenting as a solitary lung mass.

A single nodular lesion can be observed in various pulmonary diseases, including cancer, tuberculosis, and fungal infection. Waldenström's macroglobulinemia (WM) usually occurs in older adults and involves the lymph nodes, bone marrow, and spleen. Respiratory tract involvement is very rare. We reported a case of WM-associated renal amyloidosis. The patient was admitted with the initial presentation as a single mass in the lung and progression to renal involvement.

Efficacy and safety of tramadol/acetaminophen in the treatment of breakthrough pain in cancer patients.

OBJECTIVE: We evaluated the analgesic efficacy and safety of tramadol 37.5 mg/acetaminophen 325 mg combination tablet, for the treatment of breakthrough pain in cancer patients. METHODS: This study was conducted at Changhua Christian Hospital, Changhua, Taiwan from January 2006 to February 2007. The single-center and open-label study enrolled 59 opioid-treated cancer patients with at least moderate breakthrough pain (visual analog scale [VAS] score ≥40mm on a 100-mm scale). The efficacy measures included VAS scores and adverse effect assessment 10, 30, and 60 minutes after the administration of tramadol/acetaminophen. Visual analog scale score at time of pain relief was reported. RESULTS: The mean VAS score when the breakthrough pain episode began (0 minute) was 77.8. Analysis showed significant better mean pain VAS scores at 10, 30, and 60 minutes after the administration of tramadol/acetaminophen (p≤0.001 versus 0 min for all 3 time points). The mean time to pain relief was 597.2 seconds and the mean VAS score at time of relief was 43.4. The effective rates, defined by more than 30% reduction of the VAS score, after 10 minutes of administration was 74.6%, 30 minutes 86.4%, and one hour 94.9% (p≤0.001 versus 0 minute for all 3 time points). Two cases of drowsiness were reported. CONCLUSION: Tramadol/acetaminophen might be efficacious and safe in the treatment of breakthrough pain in cancer.

Identification and characterization of a putative dihydroorotase, KPN01074, from Klebsiella pneumoniae.

Dihydroorotase (DHO; EC 3.5.2.3) is an essential metalloenzyme in the biosynthesis of pyrimidine nucleotides. Here, we identified and characterized DHO from the pathogenic bacterium Klebsiella pneumoniae (Kp). The activity of KpDHO toward L: -dihydroorotate was observed with K (m) = 0.04 mM and V (max) = 8.87 mumol/(mg min). Supplementing the standard growth medium with Co2+, Mn2+, Mg2+, or Ni2+ increased enzyme activity. The catalytic activity of KpDHO was inhibited with Co2+, Zn2+, Mn2+, Cd2+, Ni2+, and phosphate ions. Substituting the putative metal binding residues His17, His19, Lys103, His140, His178, and Asp251 with Ala completely abolished KpDHO activity. However, the activity of the mutant D251E was fourfold higher than that of the wild-type protein. On the basis of these biochemical and mutational analyses, KpDHO (KPN01074) was identified as type II DHO.

Superwarfarin intoxication: hematuria is a major clinical manifestation.

Since superwarfarin is popular and readily available in stores, it may cause intoxication or overexposure, which can result in coagulopathy or abnormal bleeding in humans and, thus, is an important public health problem. We report our clinical experience with superwarfarin intoxication. Nine patients, including eight patients who had histories of ingesting superwarfarin, were studied. Of the patients, hematuria occurred in eight. Laboratory tests among the nine patients showed extremely prolonged prothrombin times and activated partial thromboplastin times, which could be corrected to normal by mixing 1:1 with normal pooled plasma; they also had very low functional levels of factor II, VII, IX, X, and proteins C and S, but normal functional levels of factors V, VIII, fibrinogen, and anti-thrombin III. Large doses of vitamin K1 were needed for 3 months or more to treat and correct the coagulopathy among the patients. The majority of the patients presented with gross hematuria, suggesting that hematuria is probably a major clinical manifestation of superwarfarin intoxication. Prolonged use of large doses of vitamin K1 is needed for the treatment of superwarfarin intoxication.

Phase I study of biweekly gemcitabine followed by oxaliplatin and simplified 48-h infusion of fluorouracil/leucovorin for advanced pancreatic cancer.

OBJECTIVES: To evaluate the feasibility and maximal tolerated dose (MTD) of oxaliplatin of a triplet regimen consisting of gemcitabine, oxaliplatin and infusional fluorouracil (5-FU)/leucovorin (LV) (GOFL) for advanced pancreatic cancer. PATIENTS AND METHODS: Patients with histologically proven metastatic or unresectable, locally advanced pancreatic adenocarcinoma were eligible to take part in the study. The treatment consisted of fixed-rate infusion (10 mg/m2/minute) of 800 mg/m2 gemcitabine followed by 2-h infusion of oxaliplatin and then 48-h infusion of 5-FU/LV day 1 and day 15 every 4 weeks. The oxaliplatin would be evaluated at three dose levels, 65, 75 and 85 mg/m2. RESULTS: A total of 15 patients were enrolled at three dose levels. Dose-limiting toxicity of neutropenic fever and grade 4 thrombocytopenia occurred in one of each six patients at oxaliplatin dose level of 65 mg/m2 and 85 mg/m2, respectively. The MTD of oxaliplatin for this combination was 85 mg/m2. After a median four cycles of treatment, grade 3/4 neutropenia occurred in 46.7% of patients and thrombocytopenia in 13.3%. Non-hematological toxicities were generally of grade 1/2. Objective tumor response was observed in five patients (33.3%, 95% confidence interval, 6.3-60.4%). CONCLUSION: Biweekly GOFL is a feasible regimen for advanced pancreatic cancer. For further phase II studies, the recommended dose of oxaliplatin is 85 mg/m2.

Phase II study of gemcitabine plus vinorelbine in the treatment of cisplatin-resistant nasopharyngeal carcinoma.

BACKGROUND: A phase II study was conducted to evaluate the safety and efficacy of a gemcitabine plus vinorelbine combination (GV) for patients with cisplatin-resistant nasopharyngeal carcinoma (NPC). METHODS: Thirty-nine eligible patients received vinorelbine, 20 mg/m(2), followed by gemcitabine, 1,000 mg/m(2), on days 1 and 8 of each 21-day cycle. RESULTS: Grade 3/4 neutropenia and thrombocytopenia occurred in 44% and 18% of patients, respectively, but there was only one episode of febrile neutropenia. Nonhematologic toxicities were mild and did not lead to any treatment withdrawal. The overall response rate was 36% (95% confidence interval [CI], 20% to 52%) in an intent-to-treat analysis, with one complete response (3%) and 13 partial responses (33%). The median response duration, progression-free survival, and overall survival were 5.1, 5.6, and 11.9 months, respectively. CONCLUSION: Given the moderately high activity and favorable toxicity profile, GV is a reasonable choice for patients with cisplatin-resistant NPC.

Generation of carcinoembryonic antigen (CEA)-specific T-cell responses in HLA-A*0201 and HLA-A*2402 late-stage colorectal cancer patients after vaccination with dendritic cells loaded with CEA peptides.

PURPOSE: We intranodally immunized metastatic colorectal carcinoma patients, who had failed standard chemotherapy, with dendritic cells (DCs) pulsed with HLA-A*0201- or HLA-A*2402-restricted carcinoembryonic antigen (CEA) peptides to evaluate the safety of this treatment and the immune response against CEA peptides before and after the treatment. EXPERIMENTAL DESIGN: Six patients with the HLA-A*2402 genotype and 4 patients with the HLA-A*0201 genotype were enrolled. A single CEA peptide (YLSGANLNL) or two CEA peptides (QYSWFVNGTF and TYACFVSNL) were used for patients with the HLA-A*0201 or HLA-A*2402 genotype, respectively. Autologous DCs were generated by culturing adherent mononuclear cells with interleukin 4 and granulocyte macrophage colony-stimulating factor for 6 days. Maturation of DCs was then induced with tumor necrosis factor alpha for 40 h. Mature DCs were pulsed with appropriate CEA peptides for 2 h. After washing, 1 million peptide-pulsed DCs were injected into one inguinal lymph node under sonographic guidance. Each patient received four injections. RESULTS: No grade II/III toxicity or autoimmunity was observed. An increase in the number of CEA-specific T cells after DC vaccination could be detected in 7 of 10 (70%) patients. Two (20%) patients had stable disease for at least 12 weeks. One of these 2 patients experienced a transient decrease in CEA levels during the treatment period and also had the most significant T-cell response against the immunizing CEA peptides. CONCLUSIONS: These results suggest that our vaccination procedure can generate or boost specific T-cell responses and may provide clinical benefit in certain cancer patients.