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Female reproductive timing and lifespan, with a close relation to long-term health outcomes, have been altered in U.S. women over the past decades. However, epidemiologic evidence of the potential causes was lacking. On the basis of 1981 naturally postmenopausal women from the National Health and Nutrition Examination Survey 1999–2020, this study aimed to investigate the associations of urinary heavy metals with age at menarche, age at menopause, and reproductive lifespan. Multivariate generalized linear regression and addictive models were used for single metal exposure analysis, and weighted quantile sum (WQS) and Bayesian kernel machine regression (BKMR) models were employed for mixed exposures. In the fully adjusted model, higher urinary antimony concentration was associated with earlier age at menarche of 0.137 years, while higher concentrations of cadmium, cesium, lead, antimony, and thallium were associated with delayed age at menopause of 0.396–0.687 years. Additionally, urinary barium, cesium, lead, antimony, and thallium levels were associated with longer reproductive lifespan ranging between 0.277 and 0.713 years. Both WQS and BKMR models showed significantly positive associations of metal mixtures with age at menopause (β: 0.667, 95 % CI: 0.120–1.213) and reproductive lifespan (β: 0.686, 95 % CI: 0.092–1.280), with cadmium and lead identified as principal contributors. In conclusion, heavy metal exposures were associated with reproductive timing and lifespan of U.S. women, highlighting the need for further prevention and intervention strategies.

ABSTRACTSynbiotics are increasingly used by the general population to boost immunity. However, there is limited evidence concerning the immunomodulatory effects of synbiotics in healthy individuals. Therefore, we conducted a double-blind, randomized, placebo-controlled study in 106 healthy adults. Participants were randomly assigned to receive either synbiotics (containing Bifidobacterium lactis HN019 1.5 × 108 CFU/d, Lactobacillus rhamnosus HN001 7.5 × 107 CFU/d, and fructooligosaccharide 500 mg/d) or placebo for 8 weeks. Immune parameters and gut microbiota composition were measured at baseline, mid, and end of the study. Compared to the placebo group, participants receiving synbiotic supplementation exhibited greater reductions in plasma C-reactive protein (P = 0.088) and interferon-gamma (P = 0.008), along with larger increases in plasma interleukin (IL)-10 (P = 0.008) and stool secretory IgA (sIgA) (P = 0.014). Additionally, synbiotic supplementation led to an enrichment of beneficial bacteria (Clostridium_sensu_stricto_1, Lactobacillus, Bifidobacterium, and Collinsella) and several functional pathways related to amino acids and short-chain fatty acids biosynthesis, whereas reduced potential pro-inflammatory Parabacteroides compared to baseline. Importantly, alternations in anti-inflammatory markers (IL-10 and sIgA) were significantly correlated with microbial variations triggered by synbiotic supplementation. Stratification of participants into two enterotypes based on pre-treatment Prevotella-to-Bacteroides (P/B) ratio revealed a more favorable effect of synbiotic supplements in individuals with a higher P/B ratio. In conclusion, this study suggested the beneficial effects of synbiotic supplementation on immune parameters, which were correlated with synbiotics-induced microbial changes and modified by microbial enterotypes. These findings provided direct evidence supporting the personalized supplementation of synbiotics for immunomodulation.

Background: Evidence on environmental exposure to perchlorate, nitrate, and thiocyanate, three thyroidal sodium iodine symporter (NIS) inhibitors, and thyroid function in the Chinese population remains limited. Objective: To investigate the associations of environmental exposure to perchlorate, nitrate, and thiocyanate with markers of thyroid function in Chinese adults. Methods: A total of 2441 non-pregnant adults (mean age 50.4 years and 39.1% male) with a median urinary iodine of 180.1 μg/L from four communities in Shenzhen were included in this cross-sectional study. Urinary perchlorate, nitrate, thiocyanate, and thyroid profiles, including serum free thyroxine (FT4), total thyroxine (TT4), free triiodothyronine (FT3), total triiodothyronine (TT3), and thyroid stimulating hormone (TSH), were measured. Generalized linear model was applied to investigate the single-analyte associations. Weighted quantile sum (WQS) regression and Bayesian kernel machine regression (BKMR) models were used to examine the association between the co-occurrence of three anions and thyroid profile. Results: The median levels of urinary perchlorate, nitrate, and thiocyanate were 5.8 μg/g, 76.4 mg/g, and 274.1 μg/g, respectively. After adjusting for confounders, higher urinary perchlorate was associated with lower serum FT4, TT4, and TT3, and higher serum FT3 and TSH (all P

BackgroundEpidemiologic studies on cruciferous vegetable (CV) intake and cardiovascular disease (CVD) were inconclusive.ObjectiveTo investigate the associations of urinary thiocyanate, a biomarker of CV intake, with CVD and all-cause mortality among non-smoking adults.MethodsThis prospective cohort study comprised 10,489 non-smoking adults (weighted mean age, 46.8 years; 43.4% male) from the National Health and Nutrition Examination Survey 2001–2014. Non-smokers were defined as subjects with serum cotinine < 3 ng/mL. Urinary thiocyanate was measured with ion chromatography tandem mass spectrometry at baseline, and CVD and all-cause mortality were identified through linkage to National Death Index until December 31, 2015. Cox proportional hazards model was applied to estimate the hazard ratios (HRs) with 95% confidence intervals (CIs) for CVD and all-cause mortality.ResultsA total of 800 deaths, of which 136 died of CVD, were ascertained within a median 7.8 years of follow-up. Urinary thiocyanate was positively correlated with total CV intake among non-smoking adults (rs = 0.088, P < 0.001). Comparing extreme quartiles, the multivariate-adjusted HRs for CVD and all-cause mortality were 0.50 (95% CI: 0.29–0.85) and 0.75 (95% CI: 0.60–0.92), respectively. Each 1 μg/g creatinine increment of log-transformed urinary thiocyanate was associated with a 25% (HR: 0.75; 95% CI: 0.62–0.91) reduced CVD mortality risk and 12% (HR: 0.88; 95% CI: 0.81–0.96) reduced all-cause mortality risk. The documented inverse associations persisted in sensitivity analyses.ConclusionIncreased levels of urinary thiocyanate, a candidate biomarker of CV intake, were associated with low risks of CVD and total mortality among non-smoking adults. This prospective biomarker-based study provided further evidence to support the cardiovascular benefits of CVs.

Background: Perchlorate, nitrate, and thiocyanate are three well-known sodium iodine symporter inhibitors, however, associations of their individual and concurrent exposure with central thyroid hormones sensitivity remain unclear. Objectives: To investigate the associations of urinary perchlorate, nitrate, thiocyanate, and their co-occurrence with central thyroid hormones sensitivity among US general adults. Methods: A total of 7598 non-pregnant adults (weighted mean age 45.9 years and 52.9% men) from National Health and Nutritional Examination Survey 2007–2012 were included in this cross-sectional study. Central sensitivity to thyroid hormones was estimated with the Parametric Thyroid Feedback Quantile-based Index (PTFQI). Ordinary least-squares regression, weighted quantile sum (WQS) regression, and Bayesian kernel machine regression (BKMR) models were performed to examine the associations of three anions and their co-occurrence with PTFQI. Results: The weighted mean values of urinary perchlorate, nitrate, thiocyanate, and perchlorate equivalent concentration (PEC) were 5.48 μg/L, 57.59 mg/L, 2.65 mg/L, and 539.8 μg/L, respectively. Compared with the lowest quartile, the least-square means difference (LSMD) of PTFQI was −0.0516 (LSMD ± SE: −0.0516 ± 0.0185, P

Purpose: We aimed to validate the Multinational Association for Supportive Care in Cancer (MASCC) risk index, and compare it with the Talcott model and artificial neural network (ANN) in predicting the outcome of febrile neutropenia in a Chinese population.Methods: We prospectively enrolled adult cancer patients who developed febrile neutropenia after chemotherapy and risk classified them according to MASCC score and Talcott model. ANN models were constructed and temporally validated in prospectively collected cohorts.Results: From October 2005 to February 2008, 227 consecutive patients were enrolled. Serious medical complications occurred in 22% of patients and 4% died. The positive predictive value of low risk prediction was 86% (95% CI = 81-90%) for MASCC score ≥ 21, 84% (79-89%) for Talcott model, and 85% (78-93%) for the best ANN model. The sensitivity, specificity, negative predictive value, and misclassification rate were 81%, 60%, 52%, and 24%, respectively, for MASCC score ≥ 21; and 50%, 72%, 33%, and 44%, respectively, for Talcott model; and 84%, 60%, 58%, and 22%, respectively, for ANN model. The area under the receiver-operating characteristic curve was 0.808 (95% CI = 0.717-0.899) for MASCC, 0.573 (0.455-0.691) for Talcott, and 0.737 (0.633-0.841) for ANN model. In the low risk group identified by MASCC score ≥ 21 (70% of all patients), 12.5% developed complications and 1.9% died, compared with 43.3%, and 9.0%, respectively, in the high risk group (p < 0.0001).Conclusions: The MASCC risk index is prospectively validated in a Chinese population. It demonstrates a better overall performance than the Talcott model and is equivalent to ANN model. [ABSTRACT FROM AUTHOR]

Abstract Background Interprofessional learning is gaining momentum in revolutionizing healthcare education. During the academic year 2015/16, seven undergraduate-entry health and social care programs from two universities in Hong Kong took part in an interprofessional education program. Based on considerations such as the large number of students involved and the need to incorporate adult learning principles, team-based learning was adopted as the pedagogy for the program, which was therefore called the interprofessional team-based learning program (IPTBL). The authors describe the development and implementation of the IPTBL program and evaluate the effectiveness of the program implementation. Methods Eight hundred and one students, who are predominantly Chinese, participated in the IPTBL. The quantitative design (a pretest-posttest experimental design) was utilized to examine the students’ gains on their readiness to engage in interprofessional education (IPE). Results Three instructional units (IUs) were implemented, each around a clinical area which could engage students from complementary health and social care disciplines. Each IU followed a team-based learning (TBL) process: pre-class study, individual readiness assurance test, team readiness assurance test, appeal, feedback, and application exercise. An electronic platform was developed and was progressively introduced in the three IUs. The students’ self-perceived attainment of the IPE learning outcomes was high. Across all four subscales of RIPLS, there was significant improvement in student’s readiness to engage in interprofessional learning after the IPTBL. A number of challenges were identified: significant time involvement of the teachers, difficulty in matching students from different programs, difficulty in making IPTBL count towards a summative assessment score, difficulty in developing the LAMS platform, logistics difficulty in managing paper TBL, and inappropriateness of the venue. Conclusions Despite some challenges in developing and implementing the IPTBL program, our experience showed that TBL is a viable pedagogy to be used in interprofessional education involving hundreds of students. The significant improvement in all four subscales of RIPLS showed the effects of the IPTBL program in preparing students for collaborative practice. Factors that contributed to the success of the use of TBL for IPE are discussed.

To document the magnetic resonance imaging (MRI) features of diffuse large B-cell lymphoma (DLBCL) in Waldeyer's ring (WR) and the sinonasal (SN) region, and to identify any differences between lymphatic and extra-lymphatic DLBCLs, and predictors of disease beyond the neck. Primary, nodal, and multifocal sites on head and neck MRI were compared between 31 WR and 15 SN DLBCL, and between 27 patients with disease confined to the head and neck and 16 patients with disease beyond the neck, using logistic regression. Compared to SN, WR DLBCLs had significantly smaller primary tumour volumes (p = 0.009), less deep invasion (p = 0.001), and more nodal disease (p = 0.016). Tumour site (WR vs. SN) was an independent predictor of deep invasion (p = 0.007). Nodal and multifocal diseases were predictors of disease beyond the neck (p = 0.027 and 0.011, respectively). Lymphatic WR DLBCLs were less locally aggressive but had greater propensity to nodal spread than extra-lymphatic SN DLBCLs. Nodal and multifocal diseases predicted disease beyond the neck.

Nasopharyngeal cancer (NPC) is a highly prevalent and invasive head and neck cancer in Asia. Disease recurrence and distant metastasis account for major NPC deaths. Therefore, more effective therapy is needed. Lapatinib, a dual tyrosine kinase inhibitor (TKI) against both EGFR and HER-2, has been known to exert potent antitumor activity against several cancer models. Given that both EGFR and HER-2 are co-expressed in NPC, we hypothesized that dual targeting of EGFR and HER-2 by this small molecule EGFR/HER-2 TKI would elicit anti-tumor activity in NPC. Using in vitro models of NPC, we demonstrated that lapatinib was able to efficiently inhibit the phosphorylation of both EGFR and HER-2. This was accompanied by significant growth inhibition of NPC cells (with maximal growth inhibition >90%). For the most lapatinib-sensitive cell line (HK1-LMP1, with IC(50) ∼ 600 nM), which harbored the highest levels of both EGFR and HER-2, inhibition of cell growth was associated G(0)/G(1) cell cycle arrest, marked PARP cleavage, caspase-3 cleavage, as well as significant downregulation of several important survival proteins (e.g. survivin, Mcl-1 and cyclin D1). NPC cells are intrinsically invasive. We found that lapatinib was able to inhibit cellular invasion of both HK1-LMP1 and HONE-1 cells. Furthermore, our data demonstrated for the first time that lapatinib harbored potent anoikis-sensitization activity (i.e. sensitizing cancer cells to detachment-induced apoptosis) in human cancer cells overexpressing both EGFR and HER-2 (HK1-LMP1 and HK1). Taken together, our findings suggest that lapatinib is a promising anti-cancer agent for NPC with anti-invasion and anoikis-sensitization activities.

1-(3-C-ethynyl-beta-d-ribo-pentofuranosyl)cytosine (ECyd) is a ribose-modified nucleoside analog of cytidine with potent anticancer activity in several cancers. The main antitumor mechanism of this promising RNA-directed nucleoside anti-metabolite is efficient blockade of RNA synthesis in cancer cells. Here, we examined the therapeutic potential of this RNA-directed anti-metabolite in in vitro models of nasopharyngeal cancer (NPC). In a panel of 6 NPC cell lines, ECyd effectively inhibited cellular proliferation at nM concentrations (IC(50): approximately 13-44nM). Moreover, cisplatin-resistant NPC cells were highly sensitive to ECyd (at nM concentration). The ECyd-mediated growth inhibition was associated with G(2)/M cell cycle arrest, PARP cleavage (a hallmark of apoptosis) and Bcl-2 downregulation, indicating induction of apoptosis by ECyd in NPC cells. Unexpectedly, ECyd-induced significant downregulation of TIGAR, a newly described dual regulator of apoptosis and glycolysis. More importantly, this novel action of ECyd on TIGAR was accompanied by marked depletion of NADPH, the major reducing power critically required for cell proliferation and survival. We hypothesized that ECyd-induced TIGAR downregulation was crucially involved in the antitumor activity of ECyd. Indeed, overexpression of TIGAR was able to rescue NPC cells from ECyd-induced growth inhibition, demonstrating a novel mechanistic action of ECyd on TIGAR. We demonstrated for the first time that an RNA-directed nucleoside analog, ECyd, exerts its antitumor activity via downregulation of a novel regulator of apoptosis, TIGAR. Moreover, ECyd may represent a novel therapy for NPC., (Copyright 2010 Elsevier Inc. All rights reserved.)

Objective: To identify clinical markers to predict which patients with advanced colorectal cancers are likely to benefit from cetuximab-chemotherapy., Design: Retrospective review., Setting: Oncology unit in a university teaching hospital in Hong Kong., Patients: A total of 102 patients with metastatic colorectal cancer treated with cetuximab-chemotherapy., Main Outcome Measures: Correlation of multiple potential clinical predictive factors with tumour response to cetuximab-chemotherapy., Results: The objective response rates to cetuximab plus chemotherapy were 53% in patients receiving first-line treatment and 17% in previously treated patients. The univariate analysis indicated that fewer prior lines of chemotherapy (odds ratio=0.36; 95% confidence interval, 0.21-0.63; P<0.01) and development of cetuximab-related grade 3 rash (5.52; 1.62-18.76; P<0.01) were associated with significantly higher response rates. Multivariate analysis confirmed the independent predictive value of the number of prior chemotherapy regimens (odds ratio=0.37; 95% confidence interval, 0.20-0.69; P<0.01) and grade 3 rash (4.65; 1.21-19.29; P=0.03)., Conclusions: In this cohort of Chinese patients with advanced colorectal cancer, the presence of grade 3 rash and the number of prior chemotherapy regimens were independent predictors of response to cetuximab-chemotherapy. The utility of these clinical markers in clinical practice should be further evaluated together with established biomarkers.

Purpose: To prospectively determine the diagnostic accuracy of diffusion-weighted magnetic resonance (MR) imaging for discrimination of malignant neck nodes due to lymphoma, squamous cell carcinoma (SCC), and undifferentiated nasopharyngeal carcinoma (NPC), with histologic findings and imaging criteria as reference standards., Materials and Methods: Ethics committee approval and informed consent were obtained. Patients with malignant lymphadenopathy underwent 1.5-T diffusion-weighted MR imaging. A region of interest was drawn around the malignant node on apparent diffusion coefficient (ADC) maps; ADC values were compared (Kruskal-Wallis test). Receiver operating characteristic analysis was employed to investigate whether ADC values could aid in discrimination among malignancies., Results: Forty-three patients (34 men, nine women; mean age, 54 years) with 43 nodes underwent imaging. Mean ADC values for lymphoma (n = 8), NPC (n = 17), and SCC (n = 18) were (0.664 +/- 0.071 [standard deviation]) x 10(-3) mm(2)/sec, (0.802 +/- 0.128) x 10(-3) mm(2)/sec, and (1.057 +/- 0.169) x 10(-3) mm(2)/sec, respectively, with significant differences between SCC and lymphoma or NPC (P < .001) and between NPC and lymphoma (P = .04). To optimize sensitivity and specificity with equal weighting, ADC threshold values for distinguishing between SCC and NPC, between SCC and lymphoma, and between NPC and lymphoma were 0.894 x 10(-3) mm(2)/sec, 0.824 x 10(-3) mm(2)/sec, and 0.694 x 10(-3) mm(2)/sec, respectively. To produce a 100% specificity while sensitivity is maximized, the following ADC threshold values were obtained for prediction of differentiation between malignancies: (a) SCC versus lymphoma, greater than 0.824 x 10(-3) mm(2)/sec (sensitivity, 94%), and lymphoma versus SCC, less than 0.767 x 10(-3) mm(2)/sec (sensitivity 88%); (b) NPC versus SCC, less than 0.764 x 10(-3) mm(2)/sec (sensitivity, 47%), and SCC versus NPC, greater than 1.093 x 10(-3) mm(2)/sec (sensitivity, 39%); (c) NPC versus lymphoma, greater than 0.788 x 10(-3) mm(2)/sec (sensitivity, 53%), and lymphoma versus NPC, no suitable threshold value., Conclusion: Diffusion-weighted MR imaging shows significant differences among malignant nodes of SCC, lymphoma, and NPC. ADC threshold values can help distinguish SCC from lymphoma., Supplemental Material: http://radiology.rsnajnls.org/cgi/content/full/2451061804/DC1.

Purpose: For cancer patients receiving cytotoxic chemotherapy, hepatitis B virus (HBV) reactivation is a well described complication resulting in varying degrees of liver damage. The objectives of this study were to assess the efficacy of the antiviral agent lamivudine in reducing the incidence of HBV reactivation and diminishing morbidity and mortality of cancer patients with chronic HBV infection during chemotherapy., Patients and Methods: Two groups were compared in this nonrandomized study. The prophylactic lamivudine group consisted of 65 patients in a phase II study who were treated with lamivudine before and until 8 weeks after discontinuing chemotherapy. The historical controls consisted of 193 consecutive patients who underwent chemotherapy without prophylactic lamivudine. Significant prognosticators for the development of HBV reactivation were determined based on data from the controls. Potential confounding factors were identified between the two groups. The outcomes were compared., Results: In the controls, lymphoma and anthracycline usage were factors identified to be associated with reactivation. The two groups were comparable in most baseline characteristics, although in the prophylactic lamivudine group, there were significantly more patients with lymphoma and receiving anthracyclines. In the prophylactic lamivudine group, there was significantly less HBV reactivation (4.6% v 24.4% in the controls; P <.001), fewer incidences of hepatitis (17.5% v 44.6%; P <.0001) that were less severe (4.8% v 18.7%; P =.0005), and less disruption of chemotherapy (15.4% v 34.6%; P =.0029). The reduction in overall mortality was not statistically different., Conclusion: Prophylactic lamivudine significantly reduced the incidence of HBV reactivation and the overall morbidity of cancer patients undergoing chemotherapy.

The aim of this study is to describe the imaging features of neck nodes in non-Hodgkin's lymphoma (NHL). The MR scans of 61 patients undergoing staging of a primary extranodal NHL of the head and neck were reviewed retrospectively. Those MR images with nodal disease were assessed for (a) the pattern of nodal disease, (b) presence of nodal necrosis and (c) presence of extracapsular neoplastic spread (ENS) and nodal matting. The features of the nodal disease were analysed in relationship to the sites of the primary NHL (palatine tonsil (PT) n=23, nasal cavity (NC) n=24, nasopharynx (NP) n=6, other extralymphatic sites (OES) n=8), and histology (natural killer/T-cell (NK/T) n=26, diffuse large cell (DLC) n=24, other subtypes (OS) n=11). Nodal disease was present in 26 patients (43%) and occurred in NHL of the PT n=16 (70%), NP n=3 (50%), NC n=5 (21%) and OES n=2 (25%) and in DLC n=15 (63%), NK/T n=6 (23%) and OS n=5 (45%). Nodal disease was significantly more frequent in DLC than NK/T lymphomas (p=0.0053). Nodal disease spread in a contiguous fashion in 25 (96%) patients with nodes. Necrosis was present in 7 of 26 (27%) being present in DLC of the PT in 5, NK/T of the NP in one and NK/T of the NC in one. ENS and matting were present in 19 (73%) and 13 (50%) patients with nodes, respectively. ENS was found in DLC, NK/T, OS, NC, NP, PT, OES (11, 4, 4,1, 2, 14, 2, respectively) and matting was found in DLC, NK/T, OS, NC, NP, PT, OES (9, 3, 1, 0, 2, 10, 1, respectively). Nodal NHL spreads in a contiguous fashion and is most commonly associated with DLC lymphoma of the NP and PT in Waldeyer's ring. Extracapsular nodal spread is frequent and found in most histological subtypes especially those arising from Waldeyer's ring. Necrosis is more common than previously believed.

Background and Purpose: Non-Hodgkin lymphoma (NHL) of the larynx is a rare tumor. The aim of this study was to report the CT and MR features of laryngeal NHL in four patients to determine if there are any features that might be helpful to distinguish NHL from other laryngeal tumors., Methods: The CT and MR images of four patients with laryngeal NHL were retrospectively reviewed for tumor volume and distribution, appearance, local invasion, and lymphadenopathy., Results: Tumor volume ranged from 4 to 45 mL(3). Tumor was based in the submucosal (2/4 [50%]), mucosal (1/4 [25%]), or both regions (1/4 [25%]) and was centered in the supraglottis (4/4 [100%]) but also involved the glottis (4/4 [100%]) and subglottis (2/4 [50%]). Laryngeal tumor involved the aryepiglottic folds (4/4 [100%)]), ventricles and false cords (4/4 [100%]), epiglottis (3/4 [75%]), paraglottis (3/4 [75%]), true cords (4/4 [100%]), anterior commissure (4/4 [100%]), and laryngeal cartilage (1/4 [25%]). The tumor extended into the hypopharynx (4/4 [100%]), strap muscles (1/4 [25%]), prevertebral muscles (1/4 [25%]), tongue base (1/4 [25%]), and walls of the oropharynx (1/4 [25%]) and nasopharynx (1/4 [25%]). Bilateral cervical lymphadenopathy with extracapsular tumor spread was present in one patient., Conclusion: Laryngeal NHL is a tumor that usually has a large submucosal component centered in the surpaglottis. The tumor extends into the glottis, with less frequent spread to the subglottis, laryngeal cartilage, and strap muscles. Laryngeal NHL also involves the hypopharynx, with large tumors extending superiorly into the tongue base, oropharynx, and nasopharynx. A laryngeal tumor with a large supraglottic submucosal component should alert the ragiologist to the possibility of NHL.

Objective: Nasopharyngeal (NP) non-Hodgkin's lymphoma (NHL) is an uncommon tumour. The aim of the study was to describe the appearances on CT and MR imaging, and identify the features which help to distinguish NPNHL from other NP tumours., Materials and Methods: The CT (n=8) and MR (n=10) images of 14 patients with NPNHL were reviewed retrospectively. Patients with NPNHL were divided into primary NPNHL, where the primary tumour was in the NP (n=7) and secondary NPNHL where the primary tumour was at another extranodal site in the head and neck (n=7). All NPNHL were assessed for tumour size and distribution, appearance and local tumour invasion, in addition lymphadenopathy was assessed in primary NPNHL., Results: The NPNHL ranged in size from 20-75 mm (mean of 55 mm for primary and 30 mm for secondary NHL) and were homogeneous on CT in eight (100%) and MR in seven (70%) and mildly heterogeneous on MR in three (30%) patients. NPNHL involved all walls of the NP in 10 (71%) (n=1). Primary NPNHL extended superficially in five (71%) to involve the nasal cavity (n=3) and oropharynx (n=2) and lymphadenopathy was present in five (71%) being bilateral and involving multiple nodal sites (n=4) with necrosis (n=2) and matting (n=3)., Conclusion: NPNHL is a homogeneous tumour that tends to diffusely involve all walls of the nasopharynx and spread in an exophytic fashion to fill the airway, rather than infiltrating into the deep tissues. Deep tumour infiltration, when it occurs, is found in those patients with primary NHL and is usually limited in extent and of small volume. and extended in an exophytic fashion to fill the NP cavity in six (43%). Deep tumour invasion was present in two (14%) both patients with primary NHL, the extent and volume of this tumour invasion was small and involved the prevertebral muscles (n=2), parapharyngeal fat space (n=1) and skull base Primary NHL more commonly spreads superficially to involve the nasal cavity or oropharynx, lymphadenopathy is frequent and extensive. A large tumour that fills the nasopharynx, with no or minimal invasion into deep structures, and a propensity to extend down into the tonsil, rather than up into the skull base, may suggest the diagnosis of NHL over nasopharyngeal carcinoma.

Despite the increasing clinical applications of circulating EBV DNA analysis as a tumor marker, the molecular nature of these EBV DNA molecules remains unclear. We subjected plasma/serum samples of nasopharyngeal carcinoma and lymphoma patients to DNase digestion and ultracentrifugation and showed that circulating EBV DNA molecules are "naked" DNA fragments instead of being contained inside virions. We further showed that these EBV DNA fragments were relatively short, and 87% of them were shorter than 181 bp. These results provide fundamental information that may improve our understanding of the release of tumor-derived nucleic acids into the blood of cancer patients.

Cytogenetic investigation of multiple myeloma (MM) has been difficult by conventional methods and most of the data have been derived from western population where incidence of MM is much higher as compared to that of Asians. The current study represents the first report of chromosomal aberrations of multiple myeloma in Chinese. We investigated 25 consecutive Chinese patients with MM for chromosomal aberrations at diagnosis using G-banding and multicolor spectral karyotyping (SKY). Of the 21 patients successfully analyzed by G-banding, 11 patients revealed cytogenetic abnormalities showing complex numerical and structural aberrations, which were further characterized with SKY. An abnormal karyotype significantly associated with blastic MM was observed. Consistent with the western literature, structural rearrangements involving chromosomes 1, 6, 8, 19, numerical abnormalities of gains in chromosomes 9, 3, and 5, and losses in chromosomes 13 and 14 were observed. However, there were notably higher incidences of -22/22q- (4/11) and structural aberrations of chromosome X but a lower incidence of -X. The biological implications of these findings, if confirmed, deserve further evaluation.

Purpose: Natural killer/T-cell (NK/T-cell) lymphoma is a highly aggressive tumor for which no serological tumor marker has yet been established to be useful clinically. We investigated the potential of circulating EBV DNA as a tumor marker for this malignancy., Experimental Design: A real-time quantitative PCR assay was used to measure circulating EBV DNA., Results: Plasma EBV DNA levels were measured in 18 patients with NK/T-cell lymphoma at presentation and during therapy. Plasma EBV DNA was detected in 17 of the 18 patients (median, 659 copies/ml; interquartile range, 181-17,042 copies/ml) but in none of 35 control subjects (p < 0.0001). Serial measurements of plasma EBV DNA levels during therapy showed a close correlation between clinical response and changes in plasma EBV DNA levels. Clinically responding patients showed a fall of plasma EBV DNA levels to low or undetectable levels, whereas those who failed therapy showed a rapid increase in plasma EBV DNA levels. Most importantly, patients with high baseline plasma EBV DNA levels (> or = 600 copies/ml) demonstrated a significantly inferior survival than those with low baseline plasma EBV DNA (< 600 copies/ml; 21% versus 78%; P = 0.024)., Conclusions: Plasma EBV DNA, as measured by real-time quantitative PCR, is a useful tumor marker for diagnosis, disease monitoring, and prediction of outcome in patients with NK/T-cell lymphoma.

Epstein-Barr virus (EBV) is a human lymphotrophic herpesvirus implicated in the development of several lymphoid malignancies. Recently, detection of cell-free EBV DNA in sera or plasma from patients with EBV-associated malignancies has been reported. However, most published studies are qualitative in nature, with only a few providing quantitative data. We have described the temporal changes of plasma EBV DNA levels in patients with EBV-associated lymphoid malignancies during therapy using quantitative real-time PCR. A close correlation between plasma EBV DNA levels and therapeutic response was observed. Our aim was to update our results and to assess the role of the plasma EBV DNA levels as a molecular marker for disease monitoring in patients with EBV-associated lymphoid malignancies.

Non-Hodgkin's lymphoma (NHL) arising primarily in the palatine tonsil is uncommon. The aims of the study were to describe the appearances on MRI and to identify the features that help to distinguish NHL from other tonsillar tumours. The clinical records and MR images of eight patients with primary NHL of the palatine tonsil were reviewed. Patients had a short duration of symptoms (mean 1 month). Systemic symptoms (fever, weight loss or night sweats) occurred in two patients. Tumours were round or lobulated and ranged in size from 30 mm to 70 mm. The signal intensity on T2 weighted, T1 weighted and T1 weighted contrast enhanced images was homogeneous and similar to that of normal tonsil in six patients. Two large tumours were mildly heterogeneous and one of these showed small foci of necrosis. NHL of the tonsil displaced rather than invaded local structures in seven patients and locally invaded the soft palate in only one patient. Lymphadenopathy was present in five patients and the nodes were of similar signal intensity to the primary tumour. There was involvement of the ipsilateral upper internal jugular chain in all cases of lymphadenopathy. The posterior triangle was involved in two patients, the periparotid node in one patient and the retro-oropharyngeal region in one patient. The presence of a large tumour without deep invasion together with homogeneous non-necrotic nodes suggests the diagnosis of NHL. As NHL frequently has similar signal intensity to normal tonsil, MRI may not be able to detect lymphomatous involvement in the non-enlarged tonsil.

Background: Hairy cell leukemia (HCL) is a unique chronic B cell lymphoproliferative disease (B-LPD), with distinct clinical and pathological features, and excellent treatment response to 2-chlorodeoxyadenosine (2-CDA) and pentostatin. There have been few reports of HCL from oriental countries., Patients and Methods: A retrospective survey of HCL in six major hematology units in Hong Kong over a 12-year period., Results: There were 18 cases of HCL identified. Most patients presented with fever, splenomegaly and monocytopenia. Lymphadenopathy was present in three patients, and open biopsy revealed tuberculosis infection in two cases. Seven cases received interferon and 12 cases received 2-CDA. Four patients died from bronchogenic carcinoma, cerebral vascular accident, fulminant hepatitis B virus reactivation and malignant melanoma. The remaining 14 patients are in clinical remission at a median of 6 years' follow-up; two are also surviving from second malignancies (thyroid papillary carcinoma and renal cell carcinoma)., Conclusions: Parallel to the low incidence of B-LPD in Chinese, the incidence of HCL (0.035/100000 population per year) is much lower than in Western series. Other clinical features such as male dominance, clinical presentation, response to 2-CDA treatment, and association with second malignancy are similar to Western reports. However, two common complications in the Chinese population are the fulminant reactivation of hepatitis B infection and disseminated tuberculosis infection.

Unlabelled: The addition of a brief alpha interferon regimen to each CHOP induction cycle, plus one year of alpha interferon thrice weekly maintenance therapy, has no early effect on response rates or survival in patients with Intermediate or High grade cell NHL., Background: The CHOP (Cyclophosphamide, Adriamycin. Vincristine, Prednisone) regimen is the most widely used first-line therapy for patients with Intermediate or High Grade (IG/HG) non-Hodgkin's lymphoma (NHL). Alpha 2b interferon (INF) enhances response rates and improves survival in low-grade NHL. The International Oncology Study Group (IOSG) conducted a prospective randomized study comparing CHOP alone or combined with INF in patients with IG/HG-NHL. The primary study aim was to compare the objective response rates in these patient cohorts., Patients and Methods: Patients with a confirmed diagnosis of measurable NHL of International Working Formulation (IWF) groups D to H histology were randomized to receive CHOP alone or CHOP with 5Mu INF s.c. for 5 days on days 22 to 26 of each 28 day cycle with INF 5 million units (Mu) given three times per week subcutaneously for 52 weeks in those patients who responded to CHOP plus INF., Results: The overall response rates were equivalent in both groups: CHOP alone (214 patients) 81% (complete 55%, partial 26%); CHOP plus INF (221 patients) 80% (complete 54%, partial 26%). At 36 months, the actuarial survival rate was equivalent in both groups., Conclusions: There is no apparent early advantage in terms of response or survival conferred by adding the study INF regimen to CHOP therapy for patients with IG/HG-NHL.

Cell-free Epstein-Barr virus (EBV) DNA has recently been detected in the plasma and serum of patients with Hodgkin's disease, post-transplant lymphoproliferative disease (PTLD) and acquired immunodeficiency syndrome-related lymphoma. However, no data are available on the temporal variation of plasma/serum EBV DNA levels in patients with EBV-associated lymphoid malignancies during the course of therapy. Using a real-time quantitative polymerase chain reaction assay, we studied the plasma EBV DNA levels in 13 patients with EBV-associated lymphoid malignancies (six patients with Hodgkin's disease, four with nasal natural killer/T-cell lymphoma, two cases of PTLD and one patient with Burkitt's lymphoma) at presentation and during therapy. Plasma EBV DNA was detected in 12 of the 13 patients (median 2,266 copies/ml; interquartile range 181-8,379 copies/ml), but not in any of 35 healthy control subjects (P < 0.0001). The EBV status in tumour cells was also examined in 12 of these patients using in situ hybridization for EBV-encoded small RNAs (EBERs). EBER positivity was observed in 11 patients, all of whom had EBV DNA detectable in plasma. The one patient who had no detectable plasma EBV DNA was also negative for EBERs in tumour tissue. Serial measurements of plasma EBV DNA levels were performed in nine of the patients during the course of therapy. All patients who responded to therapy demonstrated a significant reduction of plasma EBV DNA to low or undetectable levels, whereas in two patients with ineffective therapy, disease progression was associated with a rapid increase in plasma EBV DNA levels. We concluded that plasma EBV DNA is detectable in a wide range of EBV-associated lymphoid malignancies. As plasma EBV DNA levels correlate well with the therapeutic response, such analysis may be a valuable tool for monitoring clinical progress.

Background: Elevated levels of soluble intercellular adhesion molecules (sICAM)-1 in serum have been shown to be associated with poor prognosis in Hodgkin disease and non-Hodgkin lymphomas. However, little is known about the significance of serum sICAM-1 levels in extranodal lymphomas. The objective of this study was to examine the sICAM-1 levels in patients with extranodal lymphomas and the correlation with clinical features and outcome., Methods: The serum levels of sICAM-1 were measured in stored serum samples of 88 patients with primary extranodal lymphomas at presentation using enzyme-linked immunoassay. The correlation between serum sICAM-1 levels and clinical characteristics, pathologic features, and disease outcome were retrospectively analyzed., Results: Serum sICAM-1 levels in patients with extranodal lymphomas (mean, 372 +/- 198.8 ng/mL; interquartile range, 252-466 ng/mL) were significantly higher than that of healthy control subjects (mean, 214 +/- 78.5 ng/mL; interquartile range, 160-241 ng/mL; P < 0.0001). High serum sICAM-1 levels (>/= 371 ng/mL) were significantly associated with B-symptoms, elevated lactate dehydrogenase level, advanced stage (III/IV; Ann Arbor Staging System), and poor response to therapy. Univariate analysis demonstrated a significantly poorer 5-year disease free (41% vs. 64%; P = 0.01) and overall (44% vs. 73%; P = 0. 003) survival in patients with high serum sICAM-1 as compared with those with normal sICAM-1. In multivariate analysis, both disease free (P = 0.0085) and overall (P = 0.0003) survival were independently associated with high serum sICAM-1 levels., Conclusions: Serum sICAM-1 levels are elevated in patients with extranodal lymphomas. In these individuals, high serum sICAM-1 levels are associated with adverse disease features and poor outcome., (Copyright 2000 American Cancer Society.)

Objective: Nasal T-cell/natural killer cell lymphoma is a distinct clinicopathologic entity derived from natural killer cells. The purpose of the study was to describe the MR features of this rare nasal cavity tumor and correlate MR findings with stage of disease., Conclusion: Nasal T-cell/natural killer cell lymphoma frequently exhibits diffuse invasion of the nasal cavity with necrosis, midline destruction, and extension into the nasopharynx. These features may be seen in both early- and late-stage disease.

Primary nasal lymphoma (NSL) and nasopharyngeal lymphoma (NPL) are uncommon extranodal lymphomas that have often been grouped together in studies published in the literature. It is unclear whether or not NSL and NPL are biologically different entities. We reviewed the records of 25 NSL and 19 NPL patients who were managed between 1985 and 1995, to evaluate and compare their clinical characteristics and treatment outcome. Clinical variables, including age, sex, stage, tumour bulk and treatment modality, were assessed for their prognostic influence on survival. Nasal obstruction (80%), nasal discharge (64%) and epistaxis (60%) were the predominant symptoms in NSL patients; neck swelling/mass (42%), nasal obstruction (37%) and hearing impairment (32%) were common findings in NPL patients. Limited stage disease (I/II) was present in all NSL and in 80% of the NPL patients. Thirty-six per cent of the NSL and 32% of the NPL patients had bulky disease. The majority of the immunophenotyped NSLs were of T-cell lineage (75%, 12/16) and most immunophenotyped NPLs were of B-cell lineage (69%, 11/16). The patients were treated with radiotherapy alone (14%), chemotherapy alone (23%) or chemotherapy plus radiotherapy (64%). NSL patients showed a lower complete remission rate and higher relapse rate than NPL patients, although the difference did not reach statistical significance. Both the 5-year disease-free survival (36% versus 76%; P = 0.007) and overall survival (33% versus 82%; P = 0.003) were significantly worse in NSL compared with NPL patients. Advanced age (>60 years; P = 0.03) and bulky disease (P = 0.04) were also associated with inferior survival times. The analysis of sex, stage and type of therapy showed no evidence of significant impact on the survival. Despite the close anatomical relationship in origin, NSL and NPL were noted to behave as biologically distinct entities, in which the NSLs demonstrated a higher frequency of T-cell tumours and a much worse prognosis than NPL. In addition to the primary site, advanced age and bulky disease were also associated with reduced survival.

To gain insight into the real incidence of the numeric chromosomal aberrations and the cell lineage involvement of the neoplastic process in multiple myeloma (MM), we examined 18 Chinese MM patients by May-Grunwald-Giemsa (MGG) staining and fluorescence in situ hybridization using three DNA centromeric probes specific for chromosomes 3, 7, and 9. In this investigation, cytogenetic abnormalities were detected in plasma cells (PCs), myeloid cells (MCs), and lymphoid cells (LCs) in all of the MM patients studied. This is the first demonstration of the cytogenetic aberration involved in the myeloid series. Furthermore, the MCs and PCs of 16 MM patients had the same aneuploidies in one or more of the chromosomes analyzed. These data suggest that the neoplastic transformation of MM may occur early in the hematopoietic development. Chromosomal aberrations involving mainly subclones and considerable cellular heterogeneity with gain of a variety of copy numbers of the same chromosome were demonstrated within PCs, which may possibly be the result of an underlying defect of PCs in the control of their number of chromosomes. Whereas PCs showed evidence suggestive of increased polyploidization, MCs and LCs, which exhibited similar chromosomal patterns as the former, rarely did. Thus, the clonal evolution from LC to PC, if that happens in MM, is characterized by chromosomal instability favoring growth of tumor cells with polysomies and polyploidies.

Sarcoidosis is rare in the Chinese population and most patients with sarcoidosis present with asymptomatic mediastinal lymphadenopathy. We report on a 31-year-old woman who presented with bilateral hilar lymphadenopathy and pulmonary infiltration that spontaneously resolved without treatment, and we present a review of the literature on sarcoidosis among the Hong Kong Chinese population.

Primary non-Hodgkin's lymphoma of the liver is an extremely rare lymphoma subset that often presents with diagnostic difficulties to both clinicians and pathologists. Using MEDLINE search, 90 cases of primary hepatic lymphomas reported in the literature were reviewed. The epidemiology and etiology, clinical presentation, pathologic features, management, and outcome of these patients have been summarized and described. Results of this review show that middle-aged males are most often affected. Abdominal pain or discomfort, weight loss and fever are the most frequent presenting symptoms. Most cases have a solitary or multiple mass lesions in the liver, and are frequently misdiagnosed as having a primary liver tumor or metastatic cancer. Diffuse large cell lymphoma is the most commonly encountered histologic subtype. Surgery, chemotherapy and radiotherapy have been used alone or in combination as treatment but the outcome is generally poor. Although primary hepatic lymphoma is an aggressive disease, it is resectable, and responsive to chemotherapy and radiotherapy. Because of the profound therapeutic implications, it should be considered in the differential diagnosis for patients presenting with mass lesions in the liver or hepatic disease.

Fifteen computed tomography (CT) scans in nine patients with invasive thymoma are presented. The CT findings were an anterior mediastinal mass (89%), pleural deposits (78%), local infiltration of the mediastinum (100]), invasion of the cardiovascular structures (22%), lung invasion (11%) and diaphragmatic or subdiaphragmatic deposits (33%). Radiologic-pathologic correlation available in six patients showed a sensitivity of 89.5%, specificity of 87.5% and accuracy of 88.6% for CT. We conclude that CT is superior to plain radiography in the diagnosis of invasive thymoma. It provides an accurate pre-operative assessment by better demonstration of the full extent of abnormalities, and is useful in surgical planning, monitoring of therapeutic response and detecting recurrence.

A case of advanced leiomyosarcoma of the urinary bladder is reported in a 25-year old man who, in a short time, experienced a complete 'spontaneous' regression of his fatal illness. He first presented with severe haemoperitoneum resulting from an unresectable bleeding tumour of the urinary bladder. Debulking surgery was performed, followed by salvage chemotherapy. Histological and ultrastructural examinations of the tumour confirmed a poorly differentiated leiomyosarcoma. The residual disease failed to respond to salvage chemotherapy, but regressed 'spontaneously' 5 months after cessation of therapy. The patient is alive without evidence of disease 51 months after the diagnosis. This remarkable phenomenon and relatively long survival in a poor-risk leiomyosarcoma of the urinary bladder has never been reported previously.

An unusual case of aggressive Stage IIE(B) primary natural killer cell lymphoma of the caecum is described in a 16-year old Chinese girl. The immunophenotype of the tumour cells was CD2+, CD3-, CD4-, CD5-, CD7+, CD8-, CD45RO+, CD45RA-, CD56+, CD57-. Southern blot analysis showed a normal germline arrangements of the T-cell antigen receptor and immuno-globulin heavy chain genes. This lymphoma pursued a highly aggressive clinical course, with the rapid development of an extensive local recurrence after an apparently complete resection and combination cytotoxic therapy. The patient died 7 months after diagnosis, despite receiving salvage treatment. Given the aggressiveness and poor prognosis in this biologically distinct primary gastrointestinal lymphoma, a more vigorous systemic therapy should be considered in addition to surgery.

Background: Primary non-Hodgkin's lymphoma of the liver is rare. In this study, the presentation, pathologic features, and outcome of seven Chinese patients with primary hepatic lymphoma are described., Methods: From 1984 to 1994, the clinical records of 14 Chinese patients with non-Hodgkin's lymphoma and histologically proven liver involvement were reviewed. Seven (four males, three females; median age, 54 years) were considered to have primary hepatic lymphoma. Histologic and immunohistochemical studies were performed on paraffin embedded liver tissue., Results: "B" symptoms including fever (86%) and weight loss (57%) were the most striking presenting features. Hepatomegaly was present in all patients, splenomegaly in three (43%), and thrombocytopenia in six (86%). Only one patient was hepatitis B surface antigen-seropositive. None had preexisting liver disease. Histologic subtypes, though heterogeneous, were mostly unfavorable and consisted of diffuse large cell lymphoma (two patients), small lymphocytic lymphoma (one patient), lymphoblastic lymphoma (one case), mantle cell lymphoma (one patient), anaplastic large cell Ki-1 lymphoma (one patient), and hepatosplenic T-cell lymphoma (one patient). Three patients expressed B-cell and 2 expressed T-cell phenotypes. Six patients received cytotoxic chemotherapy. One had resection and one had splenectomy, but none achieved complete remission, and only one remained alive as of this writing. The median survival was 3.7 months (range, 8 days to 47.7 months)., Conclusion: Chinese patients with primary non-Hodgkin's lymphoma of the liver have prominent "B" symptoms, disease with a highly aggressive course, a poor response to local and systemic treatment, and short survival. Hepatitis B virus infection is not a major etiologic factor for these patients.

We describe an unusual occurrence of bilateral conjunctival tumours in a 25-year-old woman. This was the first sign of relapse of acute monoblastic leukaemia. There was also both marrow relapse and subsequent skin infiltration. No central nervous system involvement was detected. The tumours appeared as pink raised lesions in the upper conjunctivae of both eyes. They were not associated with pain or visual impairment. Conjunctival tumour biopsy revealed a dense mononuclear cell infiltration. Complete remission (conjunctival tumours, skin infiltration and bone marrow) was attained following systemic chemotherapy in combination with intrathecal chemotherapy.

Four of 12 Chinese patients receiving BACOP, in combination with recombinant human granulocyte colony-stimulating factor, for aggressive non-Hodgkin's lymphoma developed a rapidly progressive pneumonic illness characterised by diffuse pulmonary infiltrates and hypoxaemia. The condition proved fatal in three, and in none could an infective cause be identified. A retrospective analysis revealed only one episode of pneumonia in the previous 24 patients in whom the same BACOP regimen was administered without granulocyte colony-stimulating factor support. Granulocyte colony-stimulating factor, by augmenting white cell production, pulmonary sequestration and margination and production of toxic oxygen species, may exacerbate underlying subclinical bleomycin pulmonary toxicity. Caution should be exercised before using granulocyte-stimulating factors in bleomycin-containing regimens.