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Myelomatous pleural effusion (MPE) is a rare, often treatment-resistant complication of multiple myeloma. Intrapleural bortezomib shows promise but lacks standardized dosing. We report a 62-year-old woman with MPE treated with 1.3 mg/m 2 (2 mg) subcutaneous and 0.975 mg/m 2 (1.5 mg) intrapleural bortezomib on days 1 and 4. Despite MPE regression, significant toxicity occurred. Adjusted dosing to 0.65 mg/m 2 (1 mg) for both routes on days 11 and 14 consolidated the response without side effects. This case demonstrates the feasibility of intrapleural therapy and the importance of cautious dosing. Literature supports equal intrapleural and systemic bortezomib dosing for MPE management., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

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., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

Catalytic cross-coupling by transition metals has revolutionized the formation of C-C bonds in organic synthesis. However, the challenge of forming multiple alkyl-alkyl bonds in crowded environments remains largely unresolved. Here, we report the regioselective functionalization of olefins with sp 3 -hybridized organohalides and organozinc reagents using a simple (terpyridine)iron catalyst. Aliphatic groups of various sizes are successfully installed on either olefinic carbon, furnishing a diverse array of products with congested cores featuring C- or heteroatom-substituted stereocenters. The method enables access to valuable but synthetically challenging C(sp 3 )-rich molecules, including alicyclic compounds bearing multiple contiguous stereocenters through annulation cascades. Mechanistic and theoretical studies suggest a stepwise iron-mediated radical carbometallation pathway followed by outer-sphere C-C bond formation, which potentially opens the door to a broader scope of transformations and new chemical space.

Targeted therapy with Bruton tyrosine kinase (BTK) inhibitors have revolutionized the treatment of patients with various B-cell malignancies. BTK inhibitors such as ibrutinib, zanubrutinib, orelabrutinib, and acalabrutinib have shown good clinical efficacy and better safety profiles than those of traditional chemotherapy and chemoimmunotherapy regimens. Multiple studies on new BTK inhibitors are ongoing, which may provide more therapeutic options for the treatment of B-cell malignancies. Considering the unmet need of evidence on BTK inhibitors in all clinical settings and to standardize the use of BTK inhibitors available in mainland China, Taiwan, Hong Kong, and Macau regions, this consensus has been formulated for the treatment of various B-cell malignancies based on the clinical practice and available evidences on the use of BTK inhibitors. The recommendations of this consensus will provide guidance to physicians and clinical researchers on the effective treatment of B-cell malignancies with BTK inhibitors., (© 2023. YUMED Inc. and BioMed Central Ltd.)

In the past two decades, substantial advances have been made on the asymmetric alkyne functionalization by the activation of inert alkynes. However, these asymmetric transformations have so far been mostly limited to transition metal catalysis, and chiral Brønsted acid-catalyzed examples are rarely explored. Here, we report a chiral Brønsted acid-catalyzed dearomatization reaction of phenol- and indole-tethered homopropargyl amines, allowing the practical and atom-economical synthesis of a diverse array of valuable fused polycyclic enones and indolines bearing a chiral quaternary carbon stereocenter and two contiguous stereogenic centers in moderate to good yields with excellent diastereoselectivities and generally excellent enantioselectivities (up to >99% enantiomeric excess). This protocol demonstrates Brønsted acid-catalyzed asymmetric dearomatizations via vinylidene-quinone methides.

Mantle cell lymphoma (MCL) is a B-cell lymphoma featuring an aggressive course and a progressive relapsing pattern. International guidelines recommend early consolidative autologous stem cell transplant (auto-SCT) for eligible patients while reserving allogeneic SCT (allo-SCT) as therapy for refractory cases. Since data describing the implementation of transplants in the Asian population with MCL are limited, we aimed to analyze post-SCT outcomes of 99 MCL patients from the Taiwan Bone Marrow Transplant Registry database. The median age was 56 years, and 11% of the patients had blastoid variant MCL. Ninety-four patients received auto-SCT, while 13 patients received allo-SCT, eight of which received allo-SCT after failing auto-SCT. Before auto-SCT, 52% of the patients were in their first complete remission (CR1). Overall, 37 patients (39%) relapsed after auto-SCT. The median post-auto-SCT progression-free survival and overall survival (OS) were 43.6 months and not reached, respectively. Blastoid variant MCL, transplant not received in CR1, and disease progression within 12 months post-auto-SCT independently predicted inferior OS in multivariable analysis. The median post-allo-SCT OS was 74 months. Two patients (15%) died of MCL recurrence post-allo-SCT. Three patients with refractory diseases were salvaged with ibrutinib or venetoclax to allo-SCT. Treatment strategies incorporating novel agents warrant further optimization., (© 2022. The Author(s).)

Introduction: While Hodgkin lymphoma (HL) is mostly curable, outcomes for advanced-stage HL remain unsatisfactory. The International Prognostic Score and its modifications were developed to predict HL prognosis; however, more straightforward prognostic factors are needed. This study aimed to identify simpler prognostic factors for advanced-stage newly diagnosed HL (NDHL)., Methods: This retrospective study used the Taiwan National Health Insurance Research Database and the Taiwan Cancer Registry. Patients with advanced-stage NDHL receiving ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) or ABVD-like regimens between 2009 and 2016 were enrolled. Cox proportional hazards models were used to identify prognostic factors for the time to next treatment (TTNT) and overall survival (OS). We used the time-dependent area under the receiver operating characteristic curve (AUROC) to evaluate model performance., Results: The study included 459 patients with advanced-stage NDHL. A bimodal age distribution (peaks 20-44 and >65 years) was observed. Over a median follow-up of 4.7 years, the complete remission and OS rates were 52% and 76%, respectively. Age ≥60 years (adjusted hazard ratio [aHR]: 1.73, 95% confidence interval [CI]: 1.23-2.43), extranodal involvement (1.40, 1.05-1.87), B symptoms (1.53, 1.13-2.06), and Charlson Comorbidity Index (CCI) ≥1 (1.49, 1.08-2.06) were significantly associated with a shorter TTNT. The time-dependent AUROC was .65. With a time-dependent AUROC of .81, age ≥60 years (4.55, 2.90-7.15) and CCI ≥1 (1.86, 1.18-2.91) were risk factors for worse OS., Conclusion: Older age and more comorbidities were risk factors for an inferior OS in advanced-stage NDHL, while older age, extranodal involvement, B-symptoms, and higher CCI were significantly associated with disease relapse.

Background/purpose: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the curative therapy for acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS), but advanced age with multiple comorbidities limits the eligibility for allo-HSCT. We conducted a retrospective study to investigate the comorbidities assessments and prognostic factors that predict outcomes for these patients., Methods: Clinical data of patients older than 50 years who had received diagnoses of AML or MDS and underwent allo-HSCT were obtained. Information on patient characteristics, including age, gender, allogeneic transplant type, conditioning regimens, Charlson comorbidity index (CCI), and presence of acute graft-versus-host disease (GVHD) or chronic GVHD, were collected and analyzed., Results: Two hundred fifty-five elderly patients with a median age at allo-HSCT of 57 years were included. The significant prognostic factors associated with worse overall survival (OS) were CCI ≥3 (hazard ratio: 1.88) and grade III-IV acute GVHD (3.18). Similar findings were noted in the non-relapse mortality analysis. To investigate the effects of chronic GVHD on patient outcomes, OS analysis was performed for those with survival >100 days after transplantation. The results revealed CCI ≥3 (1.88) and grade III-IV acute GVHD (2.73) remained poor prognostic factors for OS, whereas mild chronic GVHD (0.43) was associated with better OS., Conclusion: This cohort study suggests that CCI ≥3 predicts poor outcomes, primarily due to a higher NRM risk. Careful management of GVHD after transplantation could improve outcomes in elderly patients with AML or MDS after allo-HSCT., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article., (Copyright © 2020 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Ynamides are electron-rich heteroatom-substituted alkynes with C-C triple bond directly tethered to the amide group. Over the past decades, ynamides have proven to be versatile reagents for organic synthesis and have received extensive attention. Compared with the well-established ionic reactions of ynamides, radical-based ynamide reactions have been exploited relatively seldom. Herein, radical reactions of ynamides, classified by radical attack at the α-position and β-position of ynamides, are reviewed by highlighting the reaction selectivity, scope, mechanism, and applicability. The aim of this review is to provide a comprehensive summarization of these advances, casting light on the further development of ynamide chemistry., (© 2020 Wiley-VCH GmbH.)

Lenalidomide with dexamethasone (Len/Dex) is considered to be an effective and well-tolerated regimen to treat multiple myeloma (MM) patients relapsing after bortezomib induction therapy. With the increase in novel agents targeting refractory and relapsed MM, the identification of clinical or laboratory variables that can predict the appropriate candidates of Len/Dex is essential. To address this question, we prospectively assessed 38 adult MM patients who received bortezomib-based induction therapy and were administered Len/Dex for their first relapse. These 38 patients were stratified into the symptomatic relapse group (n = 10) and biological relapse group (n = 28) according to the disease status when Len/Dex was initiated. The overall response rate in the symptomatic group and biological relapse group was 70.0% (7/10) and 60.7% (17/28), respectively (P = 0.964). These two groups harbored a comparable median Len/Dex treatment duration (139 vs. 225 days; P = 0.876) and progression-free survival 2 (PFS2) (501 vs. 1289 days; P = 0.410). Multivariate analyses failed to show that treating biological relapse (hazard ratio [HR]: 1.29; 95% confidence interval [CI]: 0.43-3.88; P = 0.648), PFS with bortezomib-based induction therapies ≥18 months (HR: 1.79; 95% CI: 0.64-5.01; P = 0.266), autologous hematopoietic stem cell transplantation (HR: 2.18; 95% CI: 0.56-8.55; P = 0.262), and high-risk cytogenetics (HR: 0.85; 95% CI: 0.18-3.93; P = 0.835) were attributed to depth of Len/Dex treatment. In conclusion, whether MM patients treated by Len/Dex for biological relapse would have a better outcome than those prescribed for symptomatic relapse remains inconclusive. Treating significant biological relapse and symptomatic relapse remains the current consensus., Competing Interests: None

Described herein is an organocatalytic enantioselective desymmetrizing cycloisomerization of arylsulfonyl-protected ynamide cyclohexanones, representing the first metal-free asymmetric Conia-ene-type carbocyclization. This method allows the highly efficient and atom-economical construction of a range of valuable morphans with wide substrate scope and excellent enantioselectivity (up to 97 % ee). In addition, such a cycloisomerization of alkylsulfonyl-protected ynamide cyclohexanones can lead to the divergent synthesis of normorphans as the main products with high enantioselectivity (up to 90 % ee). Moreover, theoretical calculations are employed to elucidate the origins of regioselectivity and enantioselectivity., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

We retrospectively analyzed the impact of initial positron emission tomography and computed tomography (PET-CT) complete remission (CR) and time to next treatment (TTNT) on patient outcome in follicular lymphoma. Between 2002 and 2014, 150 patients could be evaluated for treatment response and long-term outcome. The CR after first line treatment with either rituximab-cyclophosphamide, oncovin, and prednisolone (R-COP) or rituximab-cyclophosphamide, doxorubicin, oncovin, and prednisolone (R-CHOP) was 89% and partial response (PR) was 7%. The 5- and 10-year survival rates were 86.0% and 62.6%, respectively. In five years, 11% of patients had died of lymphoma and 3% from other causes. Forty-seven patients (31%) underwent a second line of treatment comprising 19 (40%) with a TTNT shorter than 24 months and 28 (60%) longer than 24 months. There was no difference in overall survival (OS) between R-COP (86%) and R-CHOP (77%) at 5 years, but there were more next treatment events in the R-COP compared with the R-CHOP group on longer follow-up (60% versus 35% at 8 years). For PET-CT response, there was a significant OS difference between initial CR and PR patients (88% versus 70%, p < 0.01), and a longer TTNT was seen in initial CR patients. Patients with a TTNT longer than 24 months had better OS compared with patients with a shorter TTNT (93% versus 54% at 5 years, p < 0.01). In conclusion, patients with initial PET-CT CR and TTNT longer than 24 months had better OS compared with those achieving only PR and shorter TTNT. PET-CT CR should be considered the treatment goal during initial treatment, and more aggressive treatment should be considered for patients with a TTNT of less than 24 months., Competing Interests: The authors have no other affiliations or financial involvement with any organization or entity apart from those disclosed. The authors have no financial interest in or financial conflict with the subject matter or materials discussed in the manuscript., (© 2019 International Academy for Clinical Hematology. Publishing services by Atlantis Press International B.V.)

Ultrasonic computed tomography based on back scattering theory is the most powerful and accurate tool in ultrasound based imaging approaches because it is capable of providing quantitative information about the imaged target and detects very small targets. The duple-frequency distorted Born iterative method (DF-DBIM), which uses density information along with sound contrast for imaging, is a promising approach for imaging targets at the level of biological tissues. With two frequencies f 1 (low) and f 2 (high) through N f 1 and N f 2 iterations respectively, this method is used to estimate target density along with sound contrast. The implications of duple-frequency fusion for the image reconstruction quality of density information along with sound contrast based ultrasound tomography have been analyzed in this paper. In this paper, we concentrate on the selection of parameters that is supposed to be the best to improve the reconstruction quality of ultrasound tomography. When there are restraints imposed on simulated scenarios to have control of the computational cost, the iteration number N f 1 is determined resulting in giving the best performance. The DF-DBIM is only effective if there are a moderate number of iterations, transmitters and receivers. In case that the number of transducers is either too large or too small, a result of reconstruction which is better than that of the single frequency approach is not produced by the implementation of DF-DBIM. A fixed sum N iter of N f 1 and N f 2 was given, the investigation of simulation results shows that the best value of N f 1 is N iter 2 - 1 . The error, when applying this way of choosing the parameters, will be normalized with the reduction of 56.11%, compared to use single frequency as used in the conventional DBIM method. The target density along with sound contrast is used to image targets in this paper. It is a fact that low-frequency offers fine convergence, and high-frequency offers fine spatial resolution. Wherefore, this technique can effectively expand DBIM's applicability to the problem of biological tissue reconstruction. Thanks to the usage of empirical data, this work will be further developed prior to its application in reality., Competing Interests: Conflict of interestThe authors declare that they have no conflict of interest., (© Korean Society of Medical and Biological Engineering 2019.)

A series of gold-catalysed intramolecular anti-Markovnikov hydroamination-initiated azidation, allylation and heteroarylation reactions of chiral homopropargyl sulfonamides have been developed. Various enantioenriched 2,5-disubstituted pyrrolidines are obtained in moderate to excellent yields with excellent enantioselectivities and generally high diastereoselectivities.

Catalytic cycloisomerization-initiated cascade cyclizations of terminal alkynes have received tremendous interest, and been widely used in the facile synthesis of a diverse array of valuable complex heterocycles. However, these tandem reactions have been mostly limited to noble-metal catalysis, and are initiated by an exo-cyclization pathway. Reported herein is an unprecedented copper-catalyzed endo-cyclization-initiated tandem reaction of indolyl homopropargyl amides, where copper catalyzes both the hydroamination and Friedel-Crafts alkylation process. This method allows the practical and atom-economical synthesis of valuable bridged aza-[n.2.1] skeletons (n=3-6) with wide substrate scope, and excellent diastereoselectivity and enantioselectivity by a chirality-transfer strategy. Moreover, the mechanistic rationale for this novel cascade cyclization is also strongly supported by control experiments, and is distinctively different from the related gold catalysis., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

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.

Background/purpose: Multiple myeloma (MM) is a monoclonal plasma cell malignancy. The primary choice of treatment for MM is induction therapy followed by autologous stem cell transplantation (ASCT). This study aimed to analyze the treatment efficacy of ASCT in a Taiwanese cohort and evaluate possible prognostic factors., Methods: From the database of the Taiwan Blood and Marrow Transplantation registry, data on 396 patients with MM who underwent ASCT were reviewed., Results: The average age of participants was 54.8 years, and there were more men than women (57.6% vs. 42.4%). Most patients were diagnosed with IgG-type myeloma (52.4%), followed by IgA-type (23.2%) and light-chain type (21.4%). Patients with Durie Salmon Staging System (DSS) III disease accounted for 61.9% of the study cohort, while 23.7% had stage II and 14.4% had stage I disease. The median progression-free survival (PFS) and overall survival (OS) after ASCT were 46.5 months and 70.4 months, respectively. DSS III was a poor prognostic factor affecting both PFS and OS with a duration of 35.9 months and 69.0 months, respectively, compared with the other two stages (p = 0.006 and p = 0.03, respectively). In addition, patients with better treatment response before ASCT had better PFS and OS compared with those who did not show a response (both p < 0.0001). The overall incidence of organ toxicities associated with transplantation was low., Conclusion: In conclusion, our cohort showed that myeloma patients with early DSS and better treatment response before ASCT had better long-term survival outcomes., (Copyright © 2018. Published by Elsevier B.V.)

A novel Brønsted acid-catalyzed oxidative C-H functionalization of alkynyl thioethers has been developed. This method allows the practical synthesis of valuable isothiochroman-3-ones in mostly moderate to good yields under mild reaction conditions and features a broad substrate scope and wide functional group tolerance. Moreover, this metal-free oxidation can also be used to promote formal N-H insertion involving an unexpected 1,2-sulfur migration, affording useful 1,4-benzothiazin-3-ones.

T-cell lymphomas are generally aggressive malignancies with poor prognosis. There are no standard treatment guidelines for T-cell lymphomas, and the timing of stem cell transplantation (SCT) is not well known. In this study, we investigated the outcomes of Taiwanese patients with T-cell lymphomas after SCT. We retrospectively analyzed 131 patients with T-cell lymphomas receiving SCT (autologous: 90, allogeneic: 41) from 2009 to 2014. More autologous SCT recipients were ALCL or in complete remission, and more allogeneic recipients had advanced disease. 56 patients who were sensitive to chemotherapy underwent SCT as upfront setting. The 2-year PFS and OS rates were 67.0 and 64.5%, respectively. Regarding disease status before transplantation, patients with CR1 had the best outcomes. Among different subtypes, patients with natural killer/T-cell lymphomas showed the worst outcomes, with 2-year OS rate of 23.5%. The OS rates for the other three major subtypes were as follows: 72.9% for ALCL; 75.0% for AITL; and 51.4% for PTCL-NOS. For more rare subtypes, such as ATLL and SPTCL, data from our study show that SCT can be beneficial. We concluded that upfront autologous SCT is feasible and effective for patients with low PIT, and disease status at transplant is the strong predictor of outcome.

Background: Nilotinib, a second-generation tyrosine kinase inhibitor (TKI), is approved for the treatment of patients with chronic myeloid leukemia (CML) in many countries, including Taiwan. Though a number of controlled clinical trials have demonstrated the safety and efficacy of nilotinib, studies assessing the safety and efficacy of nilotinib in routine clinical practice are limited., Methods: The current study was an open-label, single-arm study conducted across 12 centers in Taiwan in adult patients with CML in chronic or accelerated phase with confirmed Ph+ chromosome (or BCR-ABL) and resistant or intolerant to one or more previous TKIs. The primary objective was to collect the long-term safety data in patients treated with nilotinib 400 mg, twice daily for up to 2 years., Results: The study enrolled 85 patients with CML, including 76 in the chronic phase (CML-CP) and 9 in the accelerated phase (CML-AP). Overall, 1166 adverse events (AEs) were reported in 80 patients (94.1%), of which 70 AEs (6%) in 28 patients (32.9%) were serious and 336 AEs (28.8%) reported in 60 patients (70.6%) were drug-related. Common drug-related AEs were thrombocytopenia (21.2%), increased alanine aminotransferase (21.2%) and pruritus (17.7%). Of the 85 patients, 19 switched from imatinib due to intolerance - AEs were resolved in 16 of these 19 patients (84.2%). By 24 months, the cumulative rates of complete cytogenetic response (CCyR), major molecular response (MMR), MR4.0 ( BCR-ABL1 IS ⩽0.01%) and MR4.5 ( BCR-ABL1 IS ⩽0.0032%) were 75.3, 56.8, 16.2 and 7.4%, respectively. Patients with CML-CP at baseline had higher overall survival (OS) and progression-free survival (PFS) than those with CML-AP., Conclusion: This is the first study that demonstrated that nilotinib is effective and well-tolerated in patients resistant or intolerant to imatinib in the real-world setting in Taiwan, reflecting effective management of CML by physicians under routine clinical practice in Taiwan., Competing Interests: Conflict of interest statement: Ching-Yuan Kuo has received honoraria from Novartis, Roche, Celgene, Takeda and Janssen. Cheng-Shyong Chang has received fees for consulting from Novartis, Roche, Takeda, Celgene and Janssen, participated in a speakers’ bureau for Novartis, Janssen and Roche, and received honoraria from Novartis, Roche, Takeda, Celgene, Janssen, Kyrin and MSD. Chinjune Lin, Clinton Lai and Darko Miljkovic are employees of Novartis. Chih-Yi Hsieh was an employee of Novartis from January 2013 to June 2015. All other authors have no conflicts of interest to disclose.

Isoxazoles, as masked 1,3-dicarbonyl equivalents, have proven to be versatile building blocks and pivotal intermediates for the construction of a variety of useful azacycles with molecular complexity. As a result, a range of new reactions have been discovered based on isoxazoles in the past decade. However, the relevant reactions of isoxazoles with alkynes have seldom been explored. In this review, we will focus on the recent progress in the transition-metal-catalyzed formal annulations for the efficient synthesis of N-heterocycles between alkynes and isoxazoles by highlighting their specificity and applicability, and the mechanistic rationale is presented where possible.

An efficient yttrium-catalyzed tandem intermolecular hydroalkoxylation/Claisen rearrangement has been developed, providing various γ,δ-unsaturated amides in generally good to excellent yields. Importantly, high Z/E selectivity and diastereoselectivity were achieved. Other notable features of this method include widespread availability of the substrates, compatibility with a broad range of functional groups, and mild reaction conditions.

A novel dual gold/photoredox-catalyzed bis-arylative cyclization of chiral homopropargyl sulfonamides with diazonium salts has been developed, allowing the facile synthesis of various enantioenriched 2,3-dihydropyrroles in generally moderate to good yields with excellent enantioselectivities under very mild conditions without using any strong oxidants. The reaction is proposed to undergo an Au I /Au III redox cycle promoted by visible-light photoredox catalysis.

Gold-catalyzed nucleophilic addition to terminal alkynes has received considerable interest in the past decade, as this chemistry offers a highly efficient and regioselective way for CC, CH and CX bond formation. However, such a nucleophilic addition mainly involves a Markovnikov addition. In this short review, the recent progress of the gold-catalyzed 5-endo-dig cycloisomerization-initiated tandem reactions by utilizing the steric strain in ring formation to achieve an anti-Markovnikov regioselectivity was reviewed, including the scope of reactions, mechanism and synthetic applications., (Copyright © 2017 Science China Press. Published by Elsevier B.V. All rights reserved.)

A novel gold-catalyzed tandem cycloisomerization/hydrogenation of chiral homopropargyl sulfonamides has been developed. Various enantioenriched pyrrolidines can be obtained in excellent yields and excellent enantioselectivities by combination of chiral tert-butylsulfinimine chemistry with gold catalysis. Importantly, this represents the first example of a pyrrolidine synthesis from homopropargyl sulfonamide.

Iron overload is common in myelodysplastic syndrome (MDS) patients, and an accumulation of evidence shows that iron chelation may have benefits in these patients. However, discussion and consensus about iron chelation therapy (ICT) for MDS patients is lacking in Taiwan and other Southeast Asian countries. An Expert Panel in Taiwan was organized in 2011 to develop iron overload guidelines and provide a uniform reference for physicians treating MDS patients with iron overload, with specific regard to when to initiate ICT, in which patients, and the clinical and scientific rationale behind its use.

Alveolar rhabdomyosarcoma (ARMS) is remarkably rare in adults older than 45 years. Histologically, the tumor is composed of blue round cells with frequent expression of CD56 in addition to myogenic markers. Recent studies of ARMS have shown two specific recurrent translocations: PAX3-FKHR [t(2;13)(q35;q14)] or PAX7-FKHR [t(1;13)(p36;q14)]. Extranodal natural killer (NK)/T-cell lymphoma (ENKTL) occurs most frequently in the upper aerodigestive tract with a male preference in East Asia and Central and South Americas with neoplastic cells frequently expressing CD56. We report a 53-year-old Taiwanese man presenting with a nasopharyngeal mass, cervical lymphadenopathy, and multiple bone metastases. Histologically, the nasopharyngeal biopsy revealed diffuse sheets of small blue round tumor cells without obvious alveolar pattern, angioinvasion or tumor necrosis. An initial erroneous diagnosis of ENKTL was made due to CD56 expression using fresh tumor tissue with flow cytometric analysis and the patient was treated accordingly. Retrospective study showed that the tumor cells expressed CD56, desmin, and myogenin. Fluorescence in situ hybridization revealed that the tumor cells were positive for FKHR gene rearrangement, confirming the diagnosis of ARMS. Our case illustrates that a diagnosis of ENKTL based solely on CD56 expression can be misleading for a nasopharyngeal small blue round cell tumor. ARMS should be included as a differential diagnosis, and a correct diagnosis can be reached only after a high index of suspicion and a thorough histological examination with the aid of ancillary studies.

Purpose: The purpose of this study is to evaluate the performance of gallium-67 scan (GS) and F-18 fluorodeoxyglucose (FDG) PET scan in lymphoma staging and recurrence detection by comparing the 2 imaging studies in the same patient., Materials and Methods: A total of 42 patients from the period between July 2002 and May 2006 were included in this study. Of the 42 patients, 6 had Hodgkin disease and 36 had non-Hodgkin lymphomas. All of them underwent one or more FDG PET scans and also underwent corresponding GS performed within 7 days of FDG PET, for staging or detection of lymphoma recurrence. Among the non-Hodgkin lymphoma cases, 18 were diffuse large B-cell lymphoma, 10 were follicular center cell lymphoma, and 8 were of other types. Of the total 46 pairs of imaging performed in these 42 patients, 27 were for staging, and 19 for restaging after recurrence., Results: In all these studies, FDG PET detected 230 lesion sites, whereas GS detected 85 lesion sites. All of the lesions detected by GS were noted on FDG PET, whereas GS detected only 37.0% of the lesions detected by FDG PET. Among the 27 studies for staging, FDG PET detected 120 lesions, whereas GS detected 68 lesions (56.7%). In the 19 images taken for relapse, FDG PET detected 110 lesions, whereas GS detected only 17 (15.5%)., Conclusions: FDG PET is superior to GS in staging and detecting all types of lymphoma. The difference is notably more significant in recurrence detection.

Background: we compared the clinical efficacy and safety between a new injectable cyclooxygenase-2 selective inhibitor, parecoxib, and an old nonselective, ketorolac combined with morphine in patient-controlled analgesia (PCA) for management of post-cesarean delivery pain., Methods: in this randomized, open-label study, 66 parturients undergoing cesarean section were divided into two groups: In Group P the patients received an initial intravenous bolus of 40mg parecoxib as a loading dose post-operatively and then two bolus doses of 20mg parecoxib were subsequently given at intervals of 24h. Morphine was basically used in PCA manner during the 3-day study course; and in Group K patients received an intravenous loading bolus of 30mg ketorolac post-operatively and then 90mg ketorolac combined with morphine in PCA fashion throughout the study course. Efficacy was evaluated by Verbal ranking scale (0-10) for pain intensity, Ramsay sedation score (1-6), profile of mood state (0-3) and quality of sleep (0-3), and patient satisfaction (0-4) with the analgesia. Efficacy evaluations and adverse effects were recorded every 24h and at 72h after initial loading boluses. The duration of hospital stay and total dose of morphine used throughout the study were also recorded., Results: there were no significant differences of sedation scale, mood state, quality of sleep and satisfaction between two groups, except patients of Group P had a lower pain scores than those of the Group K at 24h (3.1, range 0-5 vs. 4.3, range 0-8, p = 0.005) and 72h (1.1, range 0-3 vs. 1.9, range 0-4, p = 0.005). Moreover, there were also no significant differences in the duration of hospital stay, but there was a lower total morphine requirement (22% reduction) in Group P in comparison with Group K (43.5 ± 19.2 vs. 55.5 ± 21.5, p = 0.02). Regarding adverse effects, there were no statistical differences between two groups., Conclusions: we noted that parecoxib with PCA morphine can be used for post-cesarean delivery analgesia with the same efficacy as ketorolac for an opioid-sparing effect., (Copyright © 2010. Published by Elsevier B.V.)

Objectives: Considering the difficulty of diagnosing catheter-related bloodstream infection (CRBSI), Koo Foundation Sun Yat-Sen Cancer Center uses differential time to positivity (DTP) as a hospital-wide approach to improve the diagnosis of CRBSI in febrile patients with indwelling central venous catheters (CVCs). This study describes the result of a hospital-wide use of DTP in a real practice setting., Methods: During January 2003-August 2007, 142 positive paired blood cultures from 125 patients without infection focus other than CVC were included. These were evaluated by DTP and semi-quantitative catheter culture (SQCC) to confirm the diagnosis of CRBSI, and were further divided into two groups: confirmed (either by DTP or SQCC) and non-confirmed CRBSI (neither DTP nor SQCC positive)., Results: Fifty-nine point two percent (84/142) of episodes were confirmed as CRBSI, of which DTP was positive in 83.3% (n=70). Non-confirmed CRBSI was associated with hematologic malignancy, neutropenia status, previous antibiotics exposure and a lower CVC removal rate., Conclusions: A hospital-wide approach of DTP was practical and feasible in improving the diagnosis of CRBSI in a real practice setting.

Background: Most acute leukemias are classified as lymphoid or myeloid lineages by standard microscopic morphology, cytochemistry and a panel of immunologic markers. The World Health Organization classification of acute leukemia incorporates morphologic, cytogenetic, immunologic and clinical features to define the entities that are biologically homogeneous and that have clinical relevance. The purpose of this study was to determine the clinicopathologic characteristics of acute myeloid leukemia (AML) in Taiwan., Methods: Archival tissues from 70AML patients during the period of 1995 to 2003 were retrieved. Histologic subtype was classified, defined by World Health Organization classification. Clinical data, including age, gender, treatment and outcome, were scrutinized., Results: There were 37 males and 33 females. The median age at onset of disease was 49 years (range, 2-78 years), which was younger in biphenotypic AML (23.5 years) and older in multilineage dysplasia-related AML (61 years). There were 9 cases (13%) with recurrent cytogenetic abnormality, 7 (10%) multilineage dysplasia-related, 7 (10%) therapy-related, 39 (56%) not other categorized and 8 (11%) of ambiguous lineage. The 2- and 5-year overall survival rates of AML were 26.5% and 20.6%, respectively. Histologic subtype was a significant parameter to determine survival (p < 0.05). The median survivals of therapyrelated, multilineage dysplasia-related and biphenotypic AML were 2 months, 9 months and 30.5 months, respectively., Conclusion: This was a clinicopathologic study of AML in Taiwan. Histologic subtype plays a significant prognostic role. Multilineage dysplasia- and therapy-related AML have worse prognosis. Biphenotypic AML may not be an aggressive subtype.

Purpose: This study established a prognostic scoring system for nasopharyngeal carcinoma (NPC), which estimates the probability of locoregional (LR) control following definitive conformal radiotherapy., Methods and Materials: Patients with nondisseminated NPC at initial presentation (n = 630) were enrolled in this study. All patients had magnetic resonance imaging of the head and neck and were treated with conformal radiotherapy. Among them, 93% had concurrent chemotherapy, and 76% had postradiation chemotherapy. The extent of the primary tumor, age at diagnosis, primary tumor size, tumor and nodal classification, histology, and serum lactate dehydrogenase (LDH) level before treatment were included in the analysis for building a prognostic scoring system. The end point for this study was LR control., Results: The prognostic score was defined as the number of adverse prognostic factors present at diagnosis. Four factors had similarly independent prognostic effects (hazard ratio, 2.0-2.6): age >40 years, histologic WHO type I-II, serum LDH level > or =410 U/L, and involvement of two or more sites of the following anatomic structures, i.e., sphenoid floor, clivus marrow, clivus cortex, prevertebral muscles, and petrous bone. The score predicted the 5-year probability of LR control as follows: 0 (15% of the patients), 100%; 1 (42% of the patients), 93%; 2 (29% of the patients), 83%; 3 or higher (13% of the patients), 71%., Conclusion: This scoring system is useful in the decision-making for individual patients and the design of clinical trials to improve LR control for advanced-stage NPC.

The clinicopathological characteristics of malignant lymphomas vary according to geography. The purpose of this study is to determine the distribution and clinicopathological characteristics of malignant lymphomas in Taiwan. Archival tissue from 598 malignant lymphomas during the period of 1995-2002 was retrieved. They were reclassified according to the World Health Organization classification system. Clinical data, including age, gender, clinical staging, and follow-up, were scrutinized. There were 330 males and 268 females. The median age at onset of disease was 56 years for B-cell lymphoma (BCL), 50 years for T/NK-cell lymphoma (TCL), and 26 years for Hodgkin's lymphoma (HL). BCL accounted for 80.6%, TCL for 12.4%, and HL for 7%. The major subtypes of non-HL were diffuse large B-cell lymphoma, follicular lymphoma, plasma cell myeloma, marginal zone lymphoma of mucosa-associated lymphoid tissue type, mantle cell lymphoma, unspecified peripheral TCL, and nasal type T/NK-cell lymphoma. Nodular sclerosing subtype was the most common in HL. The frequencies of TCL and HL were relatively low. For histological subtype, enteropathy-type TCL and primary bone marrow HL had higher frequency and poorer prognosis. The 5-year overall survival of BCL, TCL, and HL was 58.9, 34.7, and 83.5%, respectively. To the best of our knowledge, this is the largest series study of malignant lymphoma in Taiwan. Immunophenotype, histological subtype, and clinical stage play significant roles in prognosis (P < 0.05).

The incidence rate of Hodgkin's lymphoma (HL) in Asia is much lower than that of western countries. This study demonstrates the incidence rate and the clinico-pathological features of HL in a cancer center in Taiwan with respect to demographics, histological subtypes and clinical outcomes. We evaluated the clinical, morphological and immunohistochemical features of 42 patients with HL during the period of 1995-2002. Clinico-pathological features and follow-up were scrutinized. There were 21 males and 21 females. The incidence rate of HL in malignant lymphoma in our center was 7%. The median age was 26 years old. There was no apparent bimodal age distribution. The most prevalent histological subtype was nodular sclerosis (69%). Mixed cellularity, lymphocyte rich, lymphocyte depletion, nodular lymphocyte predominance and unclassified was 4.8%, 4.8%, 0%, 7% and 14% respectively. The most common site at presentation was the cervical lymph node (31 cases; 74%). Clinically, 1 (2%) had stage I disease, 23 (55%) stage II, 8 (19%) stage III and 10 (24%) stage IV. Two cases had rare primary bone marrow HL of stage IV. Both cases died within 1 month. Clinical stage (P=0.09) and age (P<0.001) were prognostic parameters determining the overall survival.

Objectives: The clinicopathological characteristics of malignant lymphomas vary according to geography, especially for the T-cell lymphoma (TCL). The aim of this study is to demonstrate the incidence and clinicopathological characteristics of TCL in Taiwan according to WHO classification., Methods: Archival tissue from 600 malignant lymphomas during the period of 1995-2002 was retrieved, there were 74 cases diagnosed with TCL. Hematoxylin and eosin slides stained and other special studies were reviewed. All cases were reclassified according to the WHO classification. Clinical data, including age, gender, clinical staging, and follow-up, were scrutinized., Results: There were 52 males and 22 females with male predilectation. The incidence of TCL in malignant lymphoma was 12.3%. The most prevalent histologic subtype was peripheral T-cell lymphoma (PTCL), followed by nasal T-cell/Natural killer- (T-/NK-) cell lymphoma, T-lymphoblastic lymphoma (LBL), anaplastic large cell lymphoma, and enteropathy-type intestinal lymphoma (ETCL). Clinically, 39 cases (49%) had higher clinical stage (III/IV). Overall 2-year and 5-year survival rate was 51.4% and 34.7%, respectively. It was noteworthy that ETCL had high incidence rate (8.1%) and high mortality. There was significant difference in survival rates in respect of clinical stages and histological subtypes., Conclusions: TCL is relatively less frequent in Taiwan, compared to other countries in Asian and western countries. The most common histological subtypes are PTCL, unspecified and T-/NK-cell lymphoma. Five-year survival rate is 34.7%. ETCL has higher incidence rate in Taiwan. The clinical stage and histological subtypes are prognostic parameters in determining the survival rates., (Copyright Blackwell Munksgaard 2005.)

Objective: The purpose of this prospective study was to investigate the toxicity and efficacy of integrating extended-field para-aortic and pelvic external radiation, high-dose-rate intracavity brachytherapy, and concurrent and adjuvant cisplatin-based chemotherapy for locally advanced cervical cancer., Method: A phase I/II study was performed from 1998 to 2003 including sixty-three patients with both clinical FIGO and MRI/CT-based TNM stage IIB-IVA cervical cancer. Patients were treated with extended-field external radiation to the para-aortic and pelvic regions with 45 Gy in 25 fractions, and an additional boost to the gross nodes to 50.4 Gy and the parametrium to 59.4 Gy. Patients also received a high-dose-rate (HDR) intracavity brachytherapy with doses of 22-31 Gy to point A in 4-6 fractions. Concurrently, two cycles of cisplatin (50-80 mg/m(2)) were administered in weeks 1 and 5 during radiotherapy, as well as two cycles of cisplatin (60-80 mg/m(2)) for 1 day and 5-fluorouracil (600-800 mg/m(2)) for 4 days at 1 and 2 months after completion of radiotherapy. The treatment-related acute and late side effects were evaluated using RTOG criteria, and the disease control and survival rate were calculated using the Kaplan-Meier method. The median follow-up interval was 36 months., Results: All sixty-three patients completed the planned extended-field radiotherapy and high-dose-rate brachytherapy with 2 concurrent cycles of cisplatin. Fifty-eight (92%) patients received 2 cycles of the post-radiation adjuvant chemotherapy of cisplatin and 5-fluorouracil. RTOG grade III acute toxicity was gastrointestinal (2%) and hematological (10%). No patient had grade IV acute toxicity. Late grades III-IV morbidity actuarial risk of 6% at 6.5 years primarily involved the injuries to the bowels requiring surgical intervention for intestinal obstruction or fistula formation. Initial sites of recurrence were locoregional failure alone (pelvic and para-aortic regions within the radiation field), 3%; distant metastases only, 8%; and locoregional failure plus distant metastases, 8%. The observed rates at 3-year and 5-year of locoregional control, freedom from distant metastasis, and overall survival were 86% and 86%, 81% and 81%, and 81% and 77%, respectively., Conclusion: Incorporating HDR brachytherapy into a regimen including concurrent chemotherapy and extended radiation appears safe and effective.

Purpose: To determine whether the parapharyngeal space venous plexus and marrow of the skull base bones are anatomic landmarks of the potential routes for the spread of disease for Stage I-III (American Joint Commission on Cancer 1997 staging system) nasopharyngeal carcinoma (NPC)., Methods and Materials: A total of 364 patients with NPC were enrolled in this study. The selection criteria were Stage I-III disease and primary radiotherapy at our hospital between 1990 and 2001. All patients had undergone MRI to evaluate the head-and-neck tumors. Patients who had undergone inadequate radiotherapy at a dose of <60 Gy and/or preradiotherapy chemotherapy before the imaging evaluation were excluded from the study., Results: Of the 364 patients treated between 1990 and 2001, 163 (44.8%) had low-risk Stage I-III NPC (without parapharyngeal space extension or T3 disease). The 5-year distant metastasis-free survival rate, with and without adjuvant chemotherapy, was 97% and 96%, respectively. The remaining 201 patients had Stage II-III with parapharyngeal space extension or T3 disease. Their 5-year recurrence-free survival rate, with and without adjuvant chemotherapy, was 76.8% and 53.2% (p = 0.01), respectively., Conclusion: Our findings suggest that the risk of distant metastasis in Stage I-III NPC patients without parapharyngeal space extension or T3 disease is extremely low. Invasion into the parapharyngeal space venous plexus and marrow of the skull base bones is associated with distant metastasis, and involvement of these anatomic sites is considered a potential route for hematogenous disease spread in patients with Stage I-III NPC.

We compared the clinical efficacy and safety of two doses of ropivacaine for spinal anesthesia in Chinese patients undergoing lower limb and lower abdominal surgery. In this randomized, open-label study, 40 patients were divided into two groups: group A received 3.5 mL (26.25 mg) of 0.75% glucose-free ropivacaine, and group B received 4.5 mL (33.75 mg). Sensory and motor blocks were assessed during and after surgery through to complete recovery. Seven standard measurements were taken: time to onset of sensory blocks; maximum sensory cephalad spread; time to maximum sensory block; maximum number of blocked segments; duration of sensory block at L3; time to onset of complete motor block; and duration until complete motor block recovery. Vital signs and any adverse effects related to spinal anesthesia were also recorded. No significant differences were found between the two groups: time to onset of sensory block at L3 in group A vs B (2.1 +/- 9.6 vs 1.7 +/- 7.3 minutes), maximum cephalad spread [T4-5 (C3-T11) vs T4 (C3-T8)], maximum number of blocked segments (18.0 +/- 3.4 vs 19.8 +/- 3.7), time to maximum sensory block (34.0 +/- 22.9 vs 26.8 +/- 17.9 minutes), duration of sensory block at L3 (251.2 +/- 34.7 vs 277.3 +/- 51.1 minutes), time to onset of complete motor block (13.4 +/- 6.4 vs 10.3 +/- 3.4 minutes), and time for complete recovery from motor block (264 +/- 52.1 vs 292.5 +/- 64.5 minutes). No significant differences in global hemodynamic changes were found during and after the operation. While shivering was more frequent in group B during the operation, the difference was not significant. Otherwise, there were no differences in adverse effects during and after surgery. We conclude that both doses of 0.75% glucose-free ropivacaine, 26.25 mg (3.5 mL) and 33.75 mg (4.5 mL), have the same efficacy and safety in Chinese patients undergoing spinal anesthesia for lower limb and lower abdominal surgery.

Background: We compared the clinical efficacy and safety between 2 doses of 2.5 ml (18.75 mg) and 3 ml (22.5 mg) of 0.75% glucose free spinal ropivacaine in Chinese parturients undergoing Cesarean section., Methods: In this randomized, open-label study, 40 parturients enrolled were divided into two groups: Group A received a 2.5 ml 0.75% ropivacaine as opposed to 3 ml in Group B. Sensory and motor blocks were assessed during and after surgery until complete recovery. Eight standard measurements were taken: time at onset of sensory block; maximum cephalic sensory spread; maximum number of blocked segments; time to maximum sensory block; duration of sensory block at L3; time at onset of complete motor block and duration until complete recovery. Vital signs and any adverse effects related to spinal anesthesia were also recorded., Results: Five of the 6 variables showed no significant difference between groups A and B: onset time of sensory block at L3 was 1.8 +/- 6.7 min vs. 2.3 +/- 9.8 min; maximum cephalic spread was T3-4 (C3-T7) vs. T3 (C2-T8); maximum number of blocked segments was 20.7 +/- 3.5 vs. 20.2 +/- 3.4; time to maximum sensory block 15.4 +/- 5.5 min vs. 20.3 +/- 15.1 min; time for regression to L3 was 200.8 +/- 59.5 min vs. 215.0 +/- 37.6 min and time for complete recovery of motor block 208.5 +/- 55.5 min vs. 226.5 +/- 461. min. Group B had a significantly faster onset time for complete motor block (P < 0.05) 15.4 +/- 5.6 min vs. 10.4 +/- 4.7 min. Moreover, there were no significant differences in global hemodynamic changes during and after the operation. Transient hypotension attacks were more frequent in group A at the beginning of anesthesia, perhaps due to inadequate prehydration. Otherwise, there were no differences in adverse effects during or after surgery., Conclusions: We conclude that for Cesarean section in Chinese parturients either 18.75 mg (2.5 ml) or 22.5 mg (3 ml) 0.75% glucose-free ropivacaine can provide a spinal anesthesia of the same efficacy and safety.

Purpose: When the primary tumor of nasopharyngeal carcinoma (NPC) is treated at the base of skull and intracranium with conventional radiotherapy, the result is generally poor. In this report, we investigated whether hyperfractionated radiotherapy (HFRT) and concomitant chemotherapy (CCT) could achieve better local control and survival in NPC patients with T3 and T4 lesions., Patients and Methods: Forty-eight patients (11 T3 and 37 T4 NPC) were treated with HFRT and CCT. HFRT was administered at 1.2 Gy per fraction, two fractions per day, Monday-Friday for 62 fractions for a total dose of 74.4 Gy. Concomitant chemotherapy consisting of cis-diamino-dichloroplatinum (CDDP) alone or CDDP and 5-fluorouracil was delivered simultaneously with radiotherapy during Weeks 1 and 6. Adjuvant chemotherapy consisted of CDDP and 5-fluorouracil for 2 to 3 cycles and was given monthly beginning 1 month after completion of radiation., Results: With a median follow-up of 57 months (range: 28-94 months), the 3-year locoregional control rate was 93%, the disease-free survival rate was 71%, and the overall survival rate was 72%. For T4 patients, the 3-year locoregional control rate was 91%, disease-free survival was 62%, and overall survival was 63%. The major acute toxicity was Grade 3 mucositis in 73% and Grade 2 weight loss in 31% of patients. Fifty percent of patients were tube fed. Most patients tolerated the combined modality treatments relatively well; 88% of patients completed their radiation treatment within 8 weeks., Conclusion: HFRT and CCT for T3 and T4 NPC were associated with excellent local control and improved survival. The treatment-related toxicity was acceptable and reversible. We would recommend using HFRT with CCT for advanced T-stage NPC if the three-dimensional conformal radiation planning shows a significant portion of the brainstem to be inside the treatment field.

Purpose: Concomitant chemotherapy and radiotherapy (CCRT), followed by adjuvant chemotherapy, has improved the outcome of nasopharyngeal carcinoma (NPC). However, the prognosis and patterns of failure after this combined-modality treatment are not yet clear. In this report, the prognostic factors and failure patterns we observed with CCRT may shed new light in the design of future trials., Methods and Patients: One hundred forty-nine (149) patients with newly diagnosed and histologically proven NPC were prospectively treated with CCRT followed by adjuvant chemotherapy between April 1990 and December 1997. One hundred and thirty-three (89.3%) patients had MRI of head and neck for primary evaluation before treatment. Radiotherapy was delivered either at 2 Gy per fraction per day up to 70 Gy or 1.2 Gy per fraction, 2 fractions per day, up to 74.4 Gy. Chemotherapy consisted of cisplatin and 5-fluorouracil. According to the AJCC 1997 staging system, 32 patients were in Stage II, 53 in Stage III, and 64 in Stage IV (M0)., Results: Univariate analysis revealed that WHO (World Health Organization) Type II histology, T4 classification, and parapharyngeal extension were poor prognostic factors for locoregional control. Multivariate analysis revealed that T4 disease was the most important adverse factor that affects locoregional control, the risk ratio being 5.965 (p = 0.02). Univariate analysis for distant metastasis revealed that T4 and N3 classifications, serum LDH level > 410 U/L (normal range, 180-460), parapharyngeal extension, and infiltration of the clivus were significantly associated with poor prognosis. Multivariate analysis, however, revealed that T4 classification and N3 category were the only two factors that predicted distant metastasis; the risk ratios were 3.994 (p = 0.02) and 3.390 (p = 0.01), respectively. Therefore, based on the risk factor analysis, we were able to identify low-, intermediate-, and high-risk patients. Low-risk patients were those without the risk factors mentioned above. They consisted of Stage II patients with T2aN0, T1N1, and T2aN1 categories and of Stage III patients with T1N2 and T2aN2 categories. Their risk of recurrence is low (4%). Intermediate-risk patients were those with at least one univariate risk factor. They are Stage II patients with T2bN0 and T2bN1 categories and Stage III patients with T2bN2 and T3N0-2 categories. The risk of recurrence is modest (18%). High-risk patients have risk factors by multivariate analysis. They are stage T4 or N3 patients. Their risk of recurrence is high (36%)., Conclusion: Low-risk patients have an excellent outcome. Future trials should focus on reducing treatment-associated toxicities and complications and reevaluate the benefit of sequential adjuvant chemotherapy. The recurrence in treatment of intermediate-risk patients is modest; CCRT and adjuvant chemotherapy may be the best standard for them. Patients with T4 and N3 disease have poorer prognosis. Hyperfractionated radiotherapy may be considered for the T4 patients. Future study in these high-risk patients should also address the problem of distant spread of the disease.

Purpose: The purpose of this study is to demonstrate long-term survival of nasopharyngeal carcinoma treated with concomitant chemotherapy and radiotherapy (CCRT) followed by adjuvant chemotherapy., Methods and Patients: One hundred and seven patients with Stage III and IV (American Joint Committee on Cancer, AJCC, 1988) nasopharyngeal carcinoma (NPC) were treated with concomitant chemotherapy and radiotherapy (CCRT) followed by adjuvant chemotherapy between April 1990 and December 1997 in Koo Foundation Sun Yat-Sen Cancer Center, Taipei. The dose of radiation was 70 Gray (Gy) given in 35 fractions, 5 fractions per week. Two courses of chemotherapy, consisting of cisplatin and 5-fluorouracil, were delivered simultaneously with radiotherapy in Weeks 1 and 6 and two additional monthly courses were given after radiotherapy. According to the AJCC 1997 staging system, 32 patients had Stage II disease, 44 had Stage III, and 31 had Stage IV disease., Results: With median follow-up of 44 months, the 5-year overall survival rate in all 107 patients was 84.1%, disease-free survival rate was 74.4%, and locoregional control rate was 89.8%. The 3-year overall survival for Stage II was 100%, for Stage III it was 92.8%, and for Stage IV, 69. 4% (p = 0.0002). The 3-year disease-free survival for Stage II was 96.9%, for Stage III it was 87.7%, and for Stage IV it was 51.9% (p = 0.0001)., Conclusion: CCRT and adjuvant chemotherapy is effective in Taiwanese patients with advanced NPC. The prognosis of AJCC 1997 Stage II and III disease is excellent, but, for Stage IV (M0), it is relatively poor. Future strategies of therapy should focus on high-risk AJCC 1997 Stage IV (M0) cohort.

Purpose: Early-stage nasopharyngeal carcinoma (NPC) continues to carry a failure rate of 15% to 30% when treated with radiotherapy alone; the benefit of concomitant radiotherapy and chemotherapy (CCRT) in early-stage NPC is unclear. The purpose of this report is to describe our efforts to improve treatment outcome in early-stage NPC after CCRT., Patients and Methods: Of 189 newly diagnosed NPC patients without evidence of distant metastases who were treated in our institution between 1990 and 1997, 44 presented with early-stage (stage I and II) disease according to the American Joint Committee on Cancer (AJCC) 1997 NPC staging system. Twelve of these patients were treated with radiotherapy alone and 32 with CCRT. Each patient's head and neck area was evaluated by magnetic resonance imaging or computed tomography. Radiotherapy was administered at 2 Gy per fraction per day, Monday through Friday, for 35 fractions for a total dose of 70 Gy. Chemotherapy consisting of cis-diamine-dichloroplatinum and fluorouracil was delivered simultaneously with radiotherapy in weeks 1 and 6 and sequentially for two monthly cycles after radiotherapy., Results: Patients who were treated with radiotherapy alone primarily had stage I disease, whereas none of those who were treated with CCRT had stage I disease (11 of 12 patients v none of 32 patients; P =.001). The locoregional control rate at 3 years for the radiotherapy group was 91.7% (median follow-up period, 34 months) and was 100% for the CCRT group (median follow-up period, 44 months) (P =.10). The 3-year disease-free survival rate in the radiotherapy group was 91.7% and was 96.9% in the CCRT group (P =.66)., Conclusion: Our results reveal excellent prognosis of AJCC 1997 stage II NPC treated with CCRT. Stage II patients with a greater tumor burden treated with CCRT showed an equal disease-free survival, compared with stage I patients treated with radiotherapy alone. A prospective randomized trial is underway to confirm the role of CCRT in stage II NPC.

Purpose: Concurrent chemotherapy and radiotherapy (CCRT) are effective in treatment of locoregionally advanced nasopharyngeal carcinoma (NPC). However, the prognostic factors after CCRT have not been evaluated. We therefore attempt to evaluate factors that influence treatment outcomes following CCRT., Methods and Materials: Seventy-four (5 in stage III and 69 in stage IV) patients with locoregionally advanced NPC were treated with CCRT. Radiotherapy was delivered either at 2 Gray (Gy) per fraction per day up to 70 Gy or 1.2 Gy, 2 fractions per day, up to 74.4 Gy. Concurrent chemotherapy consisted of cisplatin and 5-fluorouracil. Cox proportional-hazards model was used to analyze the prognostic factors which included age, gender, pathologic type, T, N, lactate dehydrogenase (LDH), and infiltration of the clivus., Results: The primary tumor control rate at 3 years was 96.7% (95% confidence interval [CI]: 92.5-100), distant metastasis-free survival 81.1% (95% CI: 70.6-91.6), disease-free survival 77.0% (95% CI: 65.3-88.7), and overall survival 79.8% (95% CI: 69.2-90.4) with a median follow-up interval of 29 months (range 15-74 months). Cox proportional-hazards model revealed that infiltration of the clivus and serum level of LDH before treatment were the most two important factors that predict distant metastases. Infiltration of the clivus and the serum LDH level greater than 410 U/L were strongly associated with distant metastasis-free survival (p = 0.0004 and p = 0.0002, respectively). When these two risk factors were considered together, no distant metastasis was observed in 40 patients with both intact clivus and LDH < or = 410 U/L. On the contrary, 13 of the remaining 34 patients with at least one risk factor developed distant metastasis (p = 0.0001)., Conclusion: Our study demonstrates that CCRT can improve the primary tumor control of 96.7% and disease-free survival of 77.0% at 3-year follow-up. Distant metastasis, however, is the major cause of failure. Infiltration of the clivus by the tumor and LDH greater than 410 U/L are the two independent and useful prognostic factors in patients with locoregionally advanced NPC who were treated with CCRT. Good- and poor-risk patients can be distinguished by virtue of their having both conditions.

Inhaled medication is commonly prescribed for the treatment of asthma and chronic obstructive pulmonary disease (COPD), but is often not properly used by patients. A total of 316 patients suffering from asthma or COPD took part in a study that evaluated how patients utilized their metered-dose inhaler (MDI) or dry powder inhaler, using a standardized inhaler checklist. Two hundred eighty-one patients (88.9%) made at least one mistake in the inhalation technique. The mistakes were classified into skill and nonskill mistakes. Two hundred patients made one or more skill mistakes and 81 patients only made one or more nonskill mistakes. The most common skill error was "not continuing to inhale slowly after activation of the canister" (69.6%). The nonskill item most patients had difficulties with was "exhale before the inhalation" (65.8%). Patients who used an MDI made significantly fewer nonskill mistakes than patients using a dry powder device. Older patients had more difficulty with the correct use of the inhaler than younger patients. There was no difference in errors between men and women. In this patient sample, most patients failed to use their inhaler correctly. Regular instructions and checkups of inhalation technique are the responsibility of the physician and should be a standard and routine procedure.

A case of cervical small cell carcinoma (SCC) with large cell neuroendocrine carcinoma (LCNC) differentiation is presented. A 35-year-old Taiwanese woman was diagnosed as having stage IIB bulky SCC confirmed by cervical biopsy and underwent induction combination chemoradiotherapy followed by hysterectomy. The pathology of the cervical tumor after the initial treatment showed the residual tumor to be LCNC instead of SCC. Histochemistry, immunohistochemistry, and electron microscopy demonstrated presence of neuroendocrine differentiation on both the biopsy and the surgical specimens. Following surgical resection a course of adjuvant chemotherapy and a local radiation boost were added. Despite complete local control, she developed brain metastasis 8 months later and vertebral spread soon thereafter. The pathology of the brain tumor showed pure SCC. The patient died 19 months after diagnosis and 13 months after completion of treatment. This case suggests that SCC with LCNC component has a similar clinical course as a pure SCC., (Copyright 1998 Academic Press.)

Background: Modern induction chemotherapy produce 60% to 80% complete remission in adults with newly diagnosed acute myelogenous leukemia (AML). A major challenge is to eradicate subclinical disease in remission and prevent leukemic relapse. Intensive post-remission chemotherapy was proved of comparable disease-free survival as BMT., Methods: From February 1992 to to March 1995, twelve patients with AML, aged 15 to 57 y/o, received intensive consolidation chemotherapy immediately after the first complete remission. The chemotherapy included either 4 courses of high dose Arac (HiDAC), 3 gm/m2 q12h x3 days, or 2 courses of HiDAC (4 days) plus mitoxantrone for 3 days and etoposide for 7 days (HiDAC-3-7). Granulocyte colony-stimulating factor (G-CSF) used used 24 hours after chemotherapy until absolute neutrophile count greater than 500/mm3., Results: Totally 24 courses of high dose chemotherapy were given. The median duration of severe neutropenia (absolute neutrophile count < or = 500/mm3) was 12 days, thrombocytopenia (< or = 50,000/mm3) 18 days, fever > or = 38 degrees C 6 days, and from severe neutropenia (absolute neutrophile count < or = 500/mm3) was 12 days, thrombocytopenia (< or = 50,000/mm3) 18 days, fever > or = 38 degrees C 6 days, and from severe neutropenia (< or = 500/mm3) to infection 4 days. Infection was the most frequent complication during HiDAC treatment. No toxic death was noted. After a median follow-up of 16 months, early relapse was noted in 3 patients (2, 4, and 5 months, respectively), and late relapse in two patients (11 and 20 months, respectively). Seven patients remained in complete remission status after a median follow-up of 14+ months (7+ to 37+ months)., Conclusions: Intensive consolidation chemotherapy is well tolerable and may prolong remission duration when used in the early post-remission phase of AML.