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Background: Over-expression of cyclooxygenase-2 (COX-2) enzyme has been reported in nasopharyngeal carcinoma (NPC). However, the prognostic significance of this has yet to be conclusively determined. Thus, from our randomized trial of radiation versus concurrent chemoradiation in endemic NPC, we analyzed a cohort of tumour samples collected from participants from one referral hospital.Methods: 58 out of 88 patients from this institution had samples available for analysis. COX-2 expression levels were stratified by immunohistochemistry, into negligible, weak, moderate and strong, and correlated with overall and disease specific survivals.Results: 58% had negligible or weak COX-2 expression, while 14% and 28% had moderate and strong expression respectively. Weak COX-2 expression conferred a poorer median overall survival, 1.3 years for weak versus 6.3 years for negligible, 7.8 years, strong and not reached for moderate. There was a similar trend for disease specific survival.Conclusion: Contrary to literature published on other malignancies, our findings seemed to indicate that over-expression of COX-2 confer a better prognosis in patients with endemic NPC. Larger studies are required to conclusively determine the significance of COX-2 expression in these patients. [ABSTRACT FROM AUTHOR]

Purpose: To report outcomes of using image-guided hybrid intra-cavitary/interstitial applicators under moderate sedation for locally advanced cervical cancer patients in our institution., Material and Methods: A total of 69 fractions of brachytherapy with hybrid applicators were performed in 33 patients from January 2017 to April 2021. All patients underwent MRI pelvis 1 week pre-brachytherapy to determine suitability for interstitial brachytherapy and pre-plan needle placement. All insertion of applicators were performed under moderate sedation with midazolam and/or fentanyl. Fifty-eight (84.1%) fractions were planned with CT alone. Clinical outcomes, dose volume parameters, and toxicities were analyzed., Results: The median follow-up was 28 months. A total of 320 needles (median, 5 needles per fraction) were implanted, with a median insertion depth of 3 cm (range, 1.5-4 cm). The median high-risk clinical target volume (HR-CTV) during initial brachytherapy was 34.5 cc (range, 17.8-74.7 cc). The median total EQD 2 D 2cc of the rectum, bladder, sigmoid, and small intestine colon was 71.8 Gy, 81.5 Gy, 69 Gy, and 58.3 Gy, respectively. The 2-year local control and overall survival were 80.7% and 77.7%, respectively. Larger volume HR-CTV was significantly associated with worse local control (HR = 1.08, p = 0.005) and overall survival (HR = 1.04, p = 0.015). None of the patients required in-patient admission or blood transfusion post-procedure. Late grade 3 gastrointestinal and genitourinary toxicities were observed in 4 patients (12.2%)., Conclusions: Hybrid applicators inserted under moderate sedation are feasible and safe. Image-guided interstitial brachytherapy with CT planning aided by MRI performed 1 week pre-brachytherapy is associated with favorable outcomes and modest toxicities., Competing Interests: The authors report no conflict of interest., (Copyright © 2023 Termedia.)

Replacing conventional fine aggregates with spent mushroom substrate (SMS) is aimed at developing a sustainable lightweight masonry mortar. It is also an alternative solution for the current improper mushroom waste disposals. Density, workability, compressive strength, specific strength, flexural strength, ultrasonic pulse velocity, water absorption, sorptivity, and equivalent CO 2 emission in relation to sand reduction in mortars containing 2.5-15.0% (by volume) SMS passing through a 4.75-mm sieve were investigated. As the percentages of replacement increased from 2.5 to 15.0%, the density of the SMS mortar reduced up to 34.8%, with corresponding compressive strengths of 24.96 to 3.37 MPa. Mixes with up to 12.5% SMS met the minimum compressive and flexural strengths as stated in the ASTM C129 standard. In addition, the equivalent CO 2 emission of the mixes reduced 15.09% as the SMS content increased while cost-effectiveness increases up to 98.15% until 7.5% SMS replacement. In conclusion, the use of SMS as fine aggregates up to 12.5% is a viable mix design strategy for producing sustainable lightweight mortar with a lower carbon emission., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Deep learning (DL) has been proposed to automate image segmentation and provide accuracy, consistency, and efficiency. Accurate segmentation of lipomatous tumors (LTs) is critical for correct tumor radiomics analysis and localization. The major challenge of this task is data heterogeneity, including tumor morphological characteristics and multicenter scanning protocols. To mitigate the issue, we aimed to develop a DL-based Super Learner (SL) ensemble framework with different data correction and normalization methods. Pathologically proven LTs on pre-operative T1-weighted/proton-density MR images of 185 patients were manually segmented. The LTs were categorized by tumor locations as distal upper limb (DUL), distal lower limb (DLL), proximal upper limb (PUL), proximal lower limb (PLL), or Trunk (T) and grouped by 80%/9%/11% for training, validation and testing. Six configurations of correction/normalization were applied to data for fivefold-cross-validation trainings, resulting in 30 base learners (BLs). A SL was obtained from the BLs by optimizing SL weights. The performance was evaluated by dice-similarity-coefficient (DSC), sensitivity, specificity, and Hausdorff distance (HD95). For predictions of the BLs, the average DSC, sensitivity, and specificity from the testing data were 0.72 [Formula: see text] 0.16, 0.73 [Formula: see text] 0.168, and 0.99 [Formula: see text] 0.012, respectively, while for SL predictions were 0.80 [Formula: see text] 0.184, 0.78 [Formula: see text] 0.193, and 1.00 [Formula: see text] 0.010. The average HD95 of the BLs were 11.5 (DUL), 23.2 (DLL), 25.9 (PUL), 32.1 (PLL), and 47.9 (T) mm, whereas of SL were 1.7, 8.4, 15.9, 2.2, and 36.6 mm, respectively. The proposed method could improve the segmentation accuracy and mitigate the performance instability and data heterogeneity aiding the differential diagnosis of LTs in real clinical situations., (© 2023. The Author(s).)

Introduction: Clinical outcomes of implantable port catheters (IPCs) placed via alternative veins such as the external jugular and cervical collaterals have not been well established. This investigation evaluates the short- and long-term outcomes of IPCs inserted via alternate cervical veins (ACV) compared to traditionally inserted IPCs via the internal jugular vein (IJV)., Materials and Methods: A total of 24 patients who received an IPC between 2010 and 2020 via an ACV-defined as the external jugular vein, superficial cervical vein, or unnamed collateral veins-were identified. Based on power analysis, a matched control group of 72 patients who received IPCs via the IJV was identified. Non-inferiority analysis for port complications was performed between the two groups based on the selected non-inferiority margin of 20%. Secondary end points included complication-free survival and comparison of complications by the time at which they occurred., Results: ACV access was non-inferior to traditional access for overall complications. Alternate access resulted in fewer complications than traditional access with an estimated reduction of - 7.0% [95% CI - 23.6%, 39.7%]. There was no significant difference in peri-procedural and post-procedural complications between the two groups. Complication-free survival was also equivalent between the two groups., Conclusion: IPC placement via ACVs was non-inferior to IPCs placed via traditional access through the IJV. When abnormal pathology obviates the use of IJV access, other cervical veins may be considered prior to seeking alternate locations such as femoral, translumbar, inferior vena cava, and hepatic veins., (© 2022. The Author(s).)

Palm oil clinker (POC) aggregates is a viable alternative to the naturally occurring sand and gravel in the manufacturing of concrete. The usage of POC aggregates assists in the reduction of solid waste and preserves the consumption of natural resources. Although researchers investigated the mechanical response of POC-containing concrete, limited research is available for its torsional behavior. In general, the torsional strength depends on the tensile strength of concrete. This research investigates the compressive, tensile, and torsional response of concrete with various ratios of POC-aggregates. Five batches of concrete were casted with POC-aggregate replacing granite at ratios of 0, 20, 40, 60, and 100%. The selection for the mixture proportions for the various batches was based on the design of experiments (DOE) methodology. The hard density, compressive strength, splitting tensile strength, and flexural strength of concrete with a 100% replacement of granite with POC-aggregates reduced by 8.80, 37.25, 30.94, and 14.31%, respectively. Furthermore, a reduction in initial and ultimate torque was observed. While cracks increased with the increase in POC-aggregates. Finally, the cracking of concrete subjected to torsional loads was monitored and characterized by acoustic emissions (AE). The results illustrate a sudden rise in AE activities during the initiation of cracks and as the ultimate cracks were developed. This was accompanied by a sudden drop in the torque/twist curve.

Purpose: We present the strategy of a comprehensive cancer center organized to make operations pandemic proof and achieve continuity of cancer care during the COVID-19 pandemic., Methods: Disease Outbreak Response (DORS) measures implemented at our center and its satellite clinics included strict infection prevention, manpower preservation, prudent resource allocation, and adaptation of standard-of-care treatments. Critical day-to-day clinical operations, number of persons screened before entry, staff temperature monitoring, and personal protection equipment stockpile were reviewed as a dashboard at daily DORS taskforce huddles. Polymerase chain reaction swab tests performed for patients and staff who met defined criteria for testing of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection were tracked. Descriptive statistics of outpatient attendances and treatment caseloads from February 3 to May 23, 2020, were compared with the corresponding period in 2019., Results: We performed COVID-19 swabs for 80 patients and 93 staff, detecting three cancer patients with community-acquired COVID-19 infections with no nosocomial transmission. Patients who required chemotherapy, radiotherapy, or surgery and patients who are on maintenance treatment continued to receive timely treatment without disruption. The number of intravenous chemotherapy treatments was maintained at 97.8% compared with 2019, whereas that of weekly radiotherapy treatments remained stable since December 2019. All cancer-related surgeries proceeded without delay, with a 0.3% increase in workload. Surveillance follow-ups were conducted via teleconsultation, accounting for a 30.7% decrease in total face-to-face clinic consultations., Conclusion: Through the coordinated efforts of a DORS taskforce, it is possible to avoid nosocomial SARS-CoV-2 transmissions among patients and staff without compromising on care delivery at a national cancer center.

The COVID-19 pandemic has disrupted current models of healthcare and adaptations will likely continue. With the gradual easing of lockdown measures worldwide, cancer centres must be prepared to implement novel means to prevent repeated waves of infection. There are two limitations unique to oncology - a higher susceptibility of patients to COVID-19 and the multidisciplinary approach required of cancer management. We describe the measures implemented in the largest cancer centre in Singapore to continue optimal cancer care in spite of the ongoing pandemic, with no nosocomial infections reported in our centre to date. We adopted a multipronged approach, with an overall committee supervising the entire COVID-19 management effort. A screening clinic was setup to triage patients prior to entry to the centre. Each Oncology Division within the cancer centre designed solutions tailored to the specific needs of their discipline. We explore in detail the screening criteria and workflow of the screening clinic, as well as modifications by individual divisions to reduce infection risk to patients and healthcare professionals. This approach can be modelled by other cancer centres during this prolonged COVID-19 pandemic., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2020 Elsevier Ltd. All rights reserved.)

In December 2019, pneumonia of unknown cause was reported by China to WHO. The outbreak was found to be caused by a coronavirus which was officially named "severe acute respiratory syndrome coronavirus 2" (SARS-CoV-2), and the disease caused by it was named 'COVID-19'. The first case in Singapore was confirmed on 23rd January 2020. With lessons learnt from the SARS epidemic in 2003 and the H1N1 flu pandemic in 2009, Singapore was much better prepared to deal with the virus outbreak. The government has taken swift measures to contain and break the chain of transmission. Healthcare workers face the challenge of keeping patients and staff safe from the disease. There is a higher risk of mortality of COVID-19 in cancer patients and hence unique considerations for a radiation oncology department operating in an infectious disease outbreak. This article is the recommendations and adapted workflow from the two National Cancer Centres in Singapore with the endorsement by the working committee of the Chapter of Radiation Oncology, Academy of Medicine, Singapore. It highlights the challenges that radiation oncology departments in Singapore face and the appropriate recommended responses. This includes interventions, business continuity plans and workflow in managing a COVID-19 positive patient on radiotherapy., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The aim of this retrospective national cohort study is to assess the association between various radiation heart dosimetric parameters (RHDPs), acute myocardial infarct (AMI) and overall survival (OS) outcomes in non-small cell lung cancer (NSCLC) patients treated with post-operative thoracic radiotherapy (PORT) using contemporary radiation techniques.We identified patients with stage I to III NSCLC treated with PORT at the 2 national cancer institutions from 2007 to 2014. We linked their electronic medical records to the national AMI and death registries. Univariable Cox regression was performed to assess the association between various RHDPs, AMI, and OS.We included 43 eligible patients with median follow-up of 36.6 months. Median age was 64 years. Majority of the patients had pathological stage III disease (72%). Median prescription dose was 60Gy. Median mean heart dose (MHD) was 9.4Gy. There were no AMI events. The 5-year OS was 34%. Univariable Cox regression showed that age was significantly associated with OS (hazard ratio, 1.06; 95% confidence interval, 1.01 to 1.10; P = .008). Radiation heart doses, including MHD, volume of heart receiving at least 5, 25, 30, 40, 50Gy and dose to 30% of heart volume, were not significantly associated with OS.There is insufficient evidence to conclude that RHDPs are associated with OS for patients with NSCLC treated with PORT in this study. Studies with larger sample size and longer term follow-up are needed to assess AMI outcome.

Background: The survival benefit of PCI in ES-SCLC reported by a European randomized trial (RCT) in 2007 was not replicated by a Japanese RCT published in 2017. This study aimed to evaluate the uptake of PCI before and after publication of the European RCT and its association with survival in ES-SCLC., Methods: We identified eligible patients in the only two Singapore national cancer centres from 2003 to 2010. We linked their electronic medical records to the national death registry. We described the utilization of PCI in patients diagnosed from 2003 to 2006 (pre-adoption cohort) with patients diagnosed from 2007 to 2010 (post-adoption cohort). We performed univariable and multivariable Cox regression analysis to assess the association between PCI and survival., Results: We identified 224 patients with ES-SCLC with no brain metastases. Among the 71 patients who had at least stable disease after first line chemotherapy, there was an increase in the use of PCI from the period 2007 to 2010 compared with 2003 to 2006 (32% versus 10%, P = 0.044). PCI was associated with improved OS (hazard ratio 0.22, 95% CI 0.10 to 0.47, P < 0.001) compared to no PCI in the multivariable analysis., Conclusion: There was an increase in the adoption of PCI for ES-SCLC since 2007. PCI was associated with improved survival in patients who did not have mandatory MRI brain imaging prior to PCI and had stable disease or better after first line chemotherapy, suggesting that the results of the European RCT are reproducible in the real-world practice.

Embryogenesis is an intricate process involving multiple genes and pathways. Some of the key transcription factors controlling specific cell types are the Sox trio, namely, Sox5 , Sox6 , and Sox9 , which play crucial roles in organogenesis working in a concerted manner. Much however still needs to be learned about their combinatorial roles during this process. A developmental genomics and systems biology approach offers to complement the reductionist methodology of current developmental biology and provide a more comprehensive and integrated view of the interrelationships of complex regulatory networks that occur during organogenesis. By combining cell type-specific transcriptome analysis and in vivo ChIP-Seq of the Sox trio using mouse embryos, we provide evidence for the direct control of Sox5 and Sox6 by the transcriptional trio in the murine model and by Morpholino knockdown in zebrafish and demonstrate the novel role of Tgfb2 , Fbxl18 , and Tle3 in formation of Sox5 , Sox6 , and Sox9 dependent tissues. Concurrently, a complete embryonic gene regulatory network has been generated, identifying a wide repertoire of genes involved and controlled by the Sox trio in the intricate process of normal embryogenesis.

This work pertains to GEO submission GSE36672, in vivo and in vitro genome wide binding (ChIP-Seq) of Bapx1/Nkx3.2 and Sox9 proteins. We have previously shown that data from a genome wide binding assay combined with transcriptional profiling is an insightful means to divulge the mechanisms directing cell type specification and the generation of tissues and subsequent organs [1]. Our earlier work identified the role of the DNA-binding homeodomain containing protein Bapx1/Nkx3.2 in midgestation murine embryos. Microarray analysis of EGFP-tagged cells (both wildtype and null) was integrated using ChIP-Seq analysis of Bapx1/Nkx3.2 and Sox9 DNA-binding proteins in living tissue.

Background: The assessment of bone marrow composition has recently gained significant attention due to its association with bone loss pathophysiology and cancer therapy-induced bone marrow damage. The purpose of our study was to investigate the anatomical variation of the vertebral bone marrow fat using chemical shift-encoding based water-fat MRI and to assess the repeatability of these measurements., Methods: Chemical shift-encoding based water-fat MRI of the whole spine was performed in 28 young, healthy subjects (17 males, 11 females, 26 ± 4 years). Six subjects were scanned three times with repositioning to assess the repeatability of these measurements. Proton density fat fraction (PDFF) maps were computed and manually segmented to obtain PDFF of C3-L5., Results: Mean PDFF of all subjects significantly increased from C3 to L5 (P < 0.05) with r = 0.88 (P < 0.05). PDFF averaged over C3-7, T1-6, T7-12, and L1-5 of males and females amounted to 31.7 ± 7.9% and 23.0 ± 7.8% (P = 0.002), 33.8 ± 6.8% and 24.6 ± 8.8% (P = 0.005), 33.8 ± 6.4% and 26.1 ± 6.4% (P = 0.023), and 38.8 ± 7.6% and 31.5 ± 12.4% (P = 0.063), respectively. The repeatability for PDFF measurements expressed as absolute precision error was 1.7% averaged over C3-L5., Conclusion: Whole spine vertebral bone marrow fat could be reproducibly assessed by using chemical shift-encoding based water-fat MRI and showed anatomical variations., (© 2015 Wiley Periodicals, Inc.)

The data described in this article refers to Chatterjee et al. (2015) "In vivo genome-wide analysis of multiple tissues identifies gene regulatory networks, novel functions and downstream regulatory genes for Bapx1 and its co-regulation with Sox9 in the mammalian vertebral column" (GEO GSE35649) [1]. Transcriptional profiling combined with genome wide binding data is a powerful tool to elucidate the molecular mechanism behind vertebrate organogenesis. It also helps to uncover multiple roles of a single gene in different organs. In the above mentioned report we reveal the function of the homeobox gene Bapx1 during the embryogenesis of five distinct organs (vertebral column, spleen, gut, forelimb and hindlimb) at a relevant developmental stage (E12.5), microarray analysis of isolated wildtype and mutant cells in is compared in conjunction with ChIP-Seq analysis. We also analyzed the development of the vertebral column by comparing microarray and ChIP-Seq data for Bapx1 with similarly generated data sets for Sox9 to generate a gene regulatory network controlling various facets of the organogenesis.

Objectives: This purpose of this study was to examine clinical-pathologic factors--particularly smoking and brain metastases--in EGFR mutation positive (M(+)) lung adenocarcinoma (ADC) to determine their impact on survival in patients treated with first line EGFR TKI., Methods: A retrospective review of EGFR mutation reflex testing experience for all ADC diagnosed at a tertiary Asian cancer centre from January 2009 to April 2013. Amongst this cohort, patients with advanced EGFR M(+) ADC treated with first line EGFR TKI were identified to determine factors that influence progression free and overall survival., Results: 444/742 (59.8%) ADC reflex tested for EGFR mutations were EGFR M(+.) Amongst never-smokers (n=468), EGFR M(+) were found in 74.5% of females and 76.3% of males, and amongst ever smokers (n=283), in 53.3% of females and 35.6% of males. Exon 20 mutations were found more commonly amongst heavy smokers (> 50 pack years and > 20 pack years, Pearson's chi square p=0.044, and p=0.038 respectively). 211 patients treated with palliative first line TKI had a median PFS and OS of 9.2 and 19.6 months respectively. 26% of patients had brain metastasis at diagnosis. This was significantly detrimental to overall survival (HR 1.85, CI 1.09-3.16, p=0.024) on multivariate analysis. There was no evidence that smoking status had a significant impact on survival., Conclusions: The high prevalence of EGFR M(+) in our patient population warrants reflex testing regardless of gender and smoking status. Smoking status and dosage did not impact progression free or overall survival in patients treated with first line EGFR TKI. The presence of brain metastasis at diagnosis negatively impacts overall survival.

Vertebral bone marrow fat quantification using single-voxel MRS is confounded by overlapping water-fat peaks and the difference in T2 relaxation time between water and fat components. The purposes of the present study were: (i) to determine the proton density fat fraction (PDFF) of vertebral bone marrow using single-voxel multi-TE MRS, addressing these confounding effects; and (ii) to investigate the implications of these corrections with respect to the age dependence of the PDFF. Single-voxel MRS was performed in the L5 vertebral body of 86 subjects (54 women and 32 men). To reliably extract the water peak from the overlying fat peaks, the mean bone marrow fat spectrum was characterized based on the area of measurable fat peaks and an a priori knowledge of the chemical triglyceride structure. MRS measurements were performed at multiple TEs. The T2 -weighted fat fraction was calculated at each TE. In addition, a T2 correction was performed to obtain the PDFF and the T2 value of water (T2w ) was calculated. The implications of the T2 correction were investigated by studying the age dependence of the T2 -weighted fat fractions and the PDFF. Compared with the PDFF, all T2 -weighted fat fractions significantly overestimated the fat fraction. Compared with the age dependence of the PDFF, the age dependence of the T2 -weighted fat fraction showed an increased slope and intercept as TE increased for women and a strongly increased intercept as TE increased for men. For women, a negative association between the T2 value of bone marrow water and PDFF was found. Single-voxel MRS-based vertebral bone marrow fat quantification should be based on a multi-TE MRS measurement to minimize confounding effects on PDFF determination, and also to allow the simultaneous calculation of T2w , which might be considered as an additional parameter sensitive to the composition of the water compartment., (Copyright © 2015 John Wiley & Sons, Ltd.)

Background: Vertebrate organogenesis is a highly complex process involving sequential cascades of transcription factor activation or repression. Interestingly a single developmental control gene can occasionally be essential for the morphogenesis and differentiation of tissues and organs arising from vastly disparate embryological lineages., Results: Here we elucidated the role of the mammalian homeobox gene Bapx1 during the embryogenesis of five distinct organs at E12.5 - vertebral column, spleen, gut, forelimb and hindlimb - using expression profiling of sorted wildtype and mutant cells combined with genome wide binding site analysis. Furthermore we analyzed the development of the vertebral column at the molecular level by combining transcriptional profiling and genome wide binding data for Bapx1 with similarly generated data sets for Sox9 to assemble a detailed gene regulatory network revealing genes previously not reported to be controlled by either of these two transcription factors., Conclusions: The gene regulatory network appears to control cell fate decisions and morphogenesis in the vertebral column along with the prevention of premature chondrocyte differentiation thus providing a detailed molecular view of vertebral column development.

Traditionally, conditional knockout studies in mouse have utilized the Cre or Flpe technology to activate the expression of reporter genes such as lacZ or PLAP. Employing these reporter genes, however, requires tissue fixation. To make way for downstream in vivo or in vitro applications, we have inserted enhanced green fluorescent protein (EGFP) into the endogenous Sox9 locus and generated a novel conditional Sox9 null allele, by flanking the entire Sox9 coding region with loxP sites and inserting an EGFP reporter gene into the 3'-UTR allowing for EGFP to be expressed upon Sox9 loss of function yet under the control of the endogenous Sox9 promoter. Mating this new allele to any Cre-expressing line, the fate of Sox9 null cells can be traced in the cell type of interest in vivo or in vitro after fluorescence-activated cell sorting.

The goal of this magnetic resonance (MR) imaging study was to quantify vertebral bone marrow fat content and composition in diabetic and nondiabetic postmenopausal women with fragility fractures and to compare them with nonfracture controls with and without type 2 diabetes mellitus. Sixty-nine postmenopausal women (mean age 63 ± 5 years) were recruited. Thirty-six patients (47.8%) had spinal and/or peripheral fragility fractures. Seventeen fracture patients were diabetic. Thirty-three women (52.2%) were nonfracture controls. Sixteen women were diabetic nonfracture controls. To quantify vertebral bone marrow fat content and composition, patients underwent MR spectroscopy (MRS) of the lumbar spine at 3 Tesla. Bone mineral density (BMD) was determined by dual-energy X-ray absorptiometry (DXA) of the hip and lumbar spine (LS) and quantitative computed tomography (QCT) of the LS. To evaluate associations of vertebral marrow fat content and composition with spinal and/or peripheral fragility fractures and diabetes, we used linear regression models adjusted for age, race, and spine volumetric bone mineral density (vBMD) by QCT. At the LS, nondiabetic and diabetic fracture patients had lower vBMD than controls and diabetics without fractures (p = 0.018; p = 0.005). However, areal bone mineral density (aBMD) by DXA did not differ between fracture and nonfracture patients. After adjustment for age, race, and spinal vBMD, the prevalence of fragility fractures was associated with -1.7% lower unsaturation levels (confidence interval [CI] -2.8% to -0.5%, p = 0.005) and +2.9% higher saturation levels (CI 0.5% to 5.3%, p = 0.017). Diabetes was associated with -1.3% (CI -2.3% to -0.2%, p = 0.018) lower unsaturation and +3.3% (CI 1.1% to 5.4%, p = 0.004) higher saturation levels. Diabetics with fractures had the lowest marrow unsaturation and highest saturation. There were no associations of marrow fat content with diabetes or fracture. Our results suggest that altered bone marrow fat composition is linked with fragility fractures and diabetes. MRS of spinal bone marrow fat may therefore serve as a novel tool for BMD-independent fracture risk assessment., (Copyright © 2013 American Society for Bone and Mineral Research.)

The primary goal of this study was to assess peripheral bone microarchitecture and strength in postmenopausal women with type 2 diabetes with fragility fractures (DMFx) and to compare them with postmenopausal women with type 2 diabetics without fractures (DM). Secondary goals were to assess differences in nondiabetic postmenopausal women with fragility fractures (Fx) and nondiabetic postmenopausal women without fragility fractures (Co), and in DM and Co women. Eighty women (mean age 61.3 ± 5.7 years) were recruited into these four groups (DMFx, DM, Fx, and Co; n = 20 per group). Participants underwent dual-energy X-ray absorptiometry (DXA) and high-resolution peripheral quantitative computed tomography (HR-pQCT) of the ultradistal and distal radius and tibia. In the HR-pQCT images volumetric bone mineral density and cortical and trabecular structure measures, including cortical porosity, were calculated. Bone strength was estimated using micro-finite element analysis (µFEA). Differential strength estimates were obtained with and without open cortical pores. At the ultradistal and distal tibia, DMFx had greater intracortical pore volume (+52.6%, p = 0.009; +95.4%, p = 0.020), relative porosity (+58.1%, p = 0.005; +87.9%, p = 0.011) and endocortical bone surface (+10.9%, p = 0.031; +11.5%, p = 0.019) than DM. At the distal radius DMFx had 4.7-fold greater relative porosity (p < 0.0001) than DM. At the ultradistal radius, intracortical pore volume was significantly higher in DMFx than DM (+67.8%, p = 0.018). DMFx also displayed larger trabecular heterogeneity (ultradistal radius: +36.8%, p = 0.035), and lower total and cortical BMD (ultradistal tibia: -12.6%, p = 0.031; -6.8%, p = 0.011) than DM. DMFx exhibited significantly higher pore-related deficits in stiffness, failure load, and cortical load fraction at the ultradistal and distal tibia, and the distal radius than DM. Comparing nondiabetic Fx and Co, we only found a nonsignificant trend with increase in pore volume (+38.9%, p = 0.060) at the ultradistal radius. The results of our study suggest that severe deficits in cortical bone quality are responsible for fragility fractures in postmenopausal diabetic women., (Copyright © 2013 American Society for Bone and Mineral Research.)

Background and Purpose: We sought to evaluate the nature and frequency of late toxicities in a cohort of nasopharyngeal cancer (NPC) patients treated with conventional radiotherapy alone., Methods and Materials: Seven-hundred and ninety-six consecutive NPC patients treated using conventional radiotherapy at a single center from 1992 to 1995 were retrospectively analyzed. Patients with histology proven, completely staged, Stage I-IVB World Health Organization Type I-III NPC and completed radical radiotherapy were included. Patients with incomplete staging investigations, distant metastases at diagnosis, previous treatment, and incomplete radiotherapy were excluded. Radiotherapy-related complications were categorized using the RTOG Late Radiation Morbidity Scoring Criteria., Results: Median follow-up was 7.2 years. The 5-year overall survival and disease free survival were 69% and 56%, respectively, and the corresponding 10-year rates were 52% and 44%. Among 771 patients with at least 3 months of follow-up post treatment, 565 (73%) developed RT-related complications. Diagnosed neurological complications were cranial nerve palsies (n=70; 9%), temporal lobe necrosis (n=37; 5%), Lhermitte's syndrome (n=7; 1%), and brachial plexopathy (n=2; 0.3%). Non-neurological complications included xerostomia (n=353; 46%), neck fibrosis (n=169; 22%), hypo-pituitarism (n=48; 6%), hearing loss (n=120; 16%), dysphagia (n=116; 15%), otorrhea (n=101; 13%), tinnitus (n=94; 12%), permanent tube feeding (n=61; 8%), trismus (n=45; 6%), second malignancies within treatment field (n=17; 2%), and osteo-radionecrosis (n=13; 2%)., Conclusions: While radiotherapy is curative in NPC, many patients suffer significant late treatment morbidities with conventional radiotherapy techniques., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Unlabelled: The molecular pathogenesis of natural killer/T-cell lymphoma (NKTCL) is not well understood. We conducted whole-exome sequencing and identified Janus kinase 3 (JAK3) somatic-activating mutations (A572V and A573V) in 2 of 4 patients with NKTCLs. Further validation of the prevalence of JAK3 mutations was determined by Sanger sequencing and high-resolution melt (HRM) analysis in an additional 61 cases. In total, 23 of 65 (35.4%) cases harbored JAK3 mutations. Functional characterization of the JAK3 mutations support its involvement in cytokine-independent JAK/STAT constitutive activation leading to increased cell growth. Moreover, treatment of both JAK3-mutant and wild-type NKTCL cell lines with a novel pan-JAK inhibitor, CP-690550, resulted in dose-dependent reduction of phosphorylated STAT5, reduced cell viability, and increased apoptosis. Hence, targeting the deregulated JAK/STAT pathway could be a promising therapy for patients with NKTCLs., Significance: Gene mutations causing NKTCL have not been fully identified. Through exome sequencing, we identified activating mutations of JAK3 that may play a significant role in the pathogenesis of NKTCLs. Our findings have important implications for the management of patients with NKTCLs.

Objective: The goal of this study was to compare the semi-quantitative Goutallier classification for fat infiltration with quantitative fat-fraction derived from a magnetic resonance imaging (MRI) chemical shift-based water/fat separation technique., Methods: Sixty-two women (age 61 ± 6 years), 27 of whom had diabetes, underwent MRI of the calf using a T1-weighted fast spin-echo sequence and a six-echo spoiled gradient-echo sequence at 3 T. Water/fat images and fat fraction maps were reconstructed using the IDEAL algorithm with T2* correction and a multi-peak model for the fat spectrum. Two radiologists scored fat infiltration on the T1-weighted images using the Goutallier classification in six muscle compartments. Spearman correlations between the Goutallier grades and the fat fraction were calculated; in addition, intra-observer and inter-observer agreement were calculated., Results: A significant correlation between the clinical grading and the fat fraction values was found for all muscle compartments (P < 0.0001, R values ranging from 0.79 to 0.88). Goutallier grades 0-4 had a fat fraction ranging from 3.5 to 19%. Intra-observer and inter-observer agreement values of 0.83 and 0.81 were calculated for the semi-quantitative grading., Conclusion: Semi-quantitative grading of intramuscular fat and quantitative fat fraction were significantly correlated and both techniques had excellent reproducibility. However, the clinical grading was found to overestimate muscle fat., Key Points: Fat infiltration of muscle commonly occurs in many metabolic and neuromuscular diseases. • Image-based semi-quantitative classifications for assessing fat infiltration are not well validated. • Quantitative MRI techniques provide an accurate assessment of muscle fat.

Background: In the field of mouse genetics the advent of technologies like microarray based expression profiling dramatically increased data availability and sensitivity, yet these advanced methods are often vulnerable to the unavoidable heterogeneity of in vivo material and might therefore reflect differentially expressed genes between mouse strains of no relevance to a targeted experiment. The aim of this study was not to elaborate on the usefulness of microarray analysis in general, but to expand our knowledge regarding this potential "background noise" for the widely used Illumina microarray platform surpassing existing data which focused primarily on the adult sensory and nervous system, by analyzing patterns of gene expression at different embryonic stages using wild type strains and modern transgenic models of often non-isogenic backgrounds., Results: Wild type embryos of 11 mouse strains commonly used in transgenic and molecular genetic studies at three developmental time points were subjected to Illumina microarray expression profiling in a strain-by-strain comparison. Our data robustly reflects known gene expression patterns during mid-gestation development. Decreasing diversity of the input tissue and/or increasing strain diversity raised the sensitivity of the array towards the genetic background. Consistent strain sensitivity of some probes was attributed to genetic polymorphisms or probe design related artifacts., Conclusion: Our study provides an extensive reference list of gene expression profiling background noise of value to anyone in the field of developmental biology and transgenic research performing microarray expression profiling with the widely used Illumina microarray platform. Probes identified as strain specific background noise further allow for microarray expression profiling on its own to be a valuable tool for establishing genealogies of mouse inbred strains.

Purpose: To show the feasibility of assessing the spatial distribution of skeletal muscle adipose tissue using chemical shift-based water/fat separation and to characterize differences in calf intermuscular adipose tissue (IMAT) compartmentalization in patients with type 2 diabetes mellitus (T2DM) compared to healthy age-matched controls., Materials and Methods: A chemical shift-based water/fat separation approach using a multiecho 3D spoiled gradient echo sequence was applied in a study of 64 patients, including 35 healthy controls and 29 subjects with T2DM. Masks were defined based on manual segmentations to compute fat volume within different compartments, including regions of subcutaneous adipose tissue (SAT) and six muscular regions. IMAT was divided into two compartments representing fat within the muscular regions (intraMF) and fat between the muscular regions (interMF). Two-sample Student's t-tests were used to compare fat volumes between the two groups., Results: The subjects with T2DM had a lower volume of SAT compared to the healthy controls (P = 4 × 10(-5) ). There was no statistically significant difference in the IMAT volume between the two groups. However, the intraMF volume normalized by the IMAT volume was higher in the diabetics compared to the controls (P = 0.006)., Conclusion: Chemical shift-based water/fat separation enables the quantification of fat volume within localized muscle regions, showing that the IMAT regional distribution is significantly different in T2DM compared to normal controls., (Copyright © 2011 Wiley Periodicals, Inc.)

To gain insight into the roles of various genes in development and to circumvent embryonic lethality that hinders genetic studies, lineage tracing and conditional knockout techniques have been widely performed on mice using the increasing numbers of gene-targeted Cre mouse lines. Employing the internal ribosome entry site (IRES) and the 2A peptide multicistronic expression strategies, we report two new Bapx1 mouse lines with functional Bapx1 whereby Cre and enhanced green fluorescence protein (EGFP) are expressed discretely under the control of the Bapx1 promoter. These mouse lines, when mated with the Rosa26R-lacZ reporter line, can be used to trace the lineage of Bapx1-expressing cells whereas stage-specific, spatial expression of Bapx1 can be visualized by the EGFP fluorescence. In addition, both of our Bapx1(Cre-EGFP) mouse lines can be used to enrich for Bapx1-specific cells and also serve as effective conditional knockout tools to investigate gene functions in the skeleton and/or visceral organs., (Copyright © 2011 Wiley-Liss, Inc.)

Cancer is a genetic disease, grows exponentially with the development of intrinsic and acquired treatment resistance. Past decade has witnessed a considerable progress towards the treatment and understanding of proposed hallmarks of cancer and together with advances in early detection and various treatment modalities. Radiation therapy is an integral part of cancer treatment armamentarium. In developed countries more than half of all cancer patients receive radiation therapy during their course of illness. Although radiation damages both cancer and normal cells, the goal of radiation therapy is to maximize the radiation dose to abnormal cancer cells while minimizing exposure to normal cells, which is adjacent to cancer cells or in the path of radiation. In recent years, life expectancy increases among cancer patients and this increase is due to the results of early diagnosis, screening efforts, improved treatments and with less late effects mostly secondary cancer development. Therefore, cancer survivorship issues have been gaining prominence in the area of radiation oncology research. Understanding the tradeoff between the expected decreases in normal tissue toxicity resulting from an improved radiation dose distribution to the targeted site is an increasingly pertinent, yet needed attention and research in the area of radiation oncology. In recent years, a number of potential molecular targets that involve either with radiation increased tumor cell killing or protecting normal cells have been identified. For clinical benefits, translating these findings to maximize the toxicity of radiation on tumor cells while safeguarding early or late normal cell toxicities using molecular targeted radioprotectors will be useful in radiation treatment.

Purpose: To compare vertebral bone marrow fat content quantified with proton MR spectroscopy ((1)H-MRS) with the volume of abdominal adipose tissue, lumbar spine volumetric bone mineral density (vBMD), and blood biomarkers in postmenopausal women with and without type 2 diabetes mellitus (T2DM)., Materials and Methods: Thirteen postmenopausal women with T2DM and 13 age- and body mass index-matched healthy controls were included in this study. All subjects underwent (1)H-MRS of L1-L3 to quantify vertebral bone marrow fat content (FC) and unsaturated lipid fraction (ULF). Quantitative computed tomography (QCT) was performed to assess vBMD of L1-L3. The volumes of abdominal subcutaneous/visceral/total adipose tissue were determined from the QCT images and adjusted for abdominal body volume (SAT(adj)/VAT(adj)/TAT(adj)). Fasting blood tests included plasma glucose and HbA1c., Results: Mean FC showed an inverse correlation with vBMD (r = -0.452; P < 0.05) in the whole study population. While mean FC was similar in the diabetic women and healthy controls (69.3 ± 7.5% versus 67.5 ± 6.1%; P > 0.05), mean ULF was significantly lower in the diabetic group (6.7 ± 1.0% versus 7.9 ± 1.6%; P < 0.05). SAT(adj) and TAT(adj) correlated significantly with mean FC in the whole study population (r = 0.538 and r = 0.466; P < 0.05). In contrast to the control group, significant correlations of mean FC with VAT(adj) and HbA1c were observed in the diabetic group (r = 0.642 and r = 0.825; P < 0.05)., Conclusion: This study demonstrated that vertebral bone marrow fat content correlates significantly with SAT(adj), TAT(adj), and lumbar spine vBMD in postmenopausal women with and without T2DM, but with VAT(adj) and HbA1c only in women with T2DM., (Copyright © 2011 Wiley Periodicals, Inc.)

Objective: Synchronous occurrence of endometrial and ovarian tumors is uncommon, and they affect less than 10% of women with endometrial or ovarian cancers. The aim of this study is to describe the epidemiological and clinical factors; and survival outcomes of women with these cancers., Methods: This is a retrospective cohort study in a large tertiary institution in Singapore. The sample consists of women with endometrial and epithelial ovarian cancers followed up over a period of 10 years from 2000 to 2009. The epidemiological and clinical factors include age at diagnosis, histology types, grade and stage of disease., Results: A total of 75 patients with synchronous ovarian and endometrial cancers were identified. However, only 46 patients met the inclusion criteria. The median follow-up was 74 months. The incidence rate for synchronous cancer is 8.7% of all epithelial ovarian cancers and 4.9% of all endometrial cancers diagnosed over this time frame. Mean age at diagnosis was 47.3 years old. The most common presenting symptom was abnormal uterine bleeding (36.9%) and 73.9% had endometrioid histology for both endometrial and ovarian cancers. The majority of the women (78%) presented were at early stages of 1 and 2. There were 6 (13.6%) cases of recurrence and the 5 year cumulative survival rate was at 84%., Conclusion: In our cohort, we found that majority of women afflicted with synchronous cancer of the endometrium and ovary were younger at age of diagnosis, had early stage of cancer and good survival.

Objective: The use of adjuvant radiotherapy for early stage node negative patients varies for different institutions. The recognized factors such as deep stromal invasion, lymph vascular space invasion, and size of tumor are the most common factors cited for adjuvant radiotherapy. Studies done have shown that this increases local control but may increase chronic toxicity rates. We report on our use of the GOG score to tailor our treatment decisions., Methods: A review of all patients staged IB-IIA who underwent Type 3 Radical Hysterectomy and pelvic lymph node dissection (RH) from 1997 to 2007. The GOG score proposed by Delgado et al. was applied, and patients were stratified into 3 groups; <40: no adjuvant treatment, 40-120: Small Field RT (SmRT), and >120: Standard Field RT (StRT) RESULTS: A total of 126 patients matched these criteria. Sixty one patients underwent either SmRT or StRT. There were only 2 known relapses and one death due to inter current illness. The median follow up was 57 months and the 5 year Disease Free Survival was 98.2%. There were no documented Grade 3 or 4 chronic toxicities. There were significantly less (p=0.025) patients with lower limb lymphedema in the SmRT group compared to StRT., Conclusion: Our study confirms the utility of the GOG score to tailor radiotherapy for this cohort of patients. This has been proven to be high in efficacy and low in morbidity., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Sox9 is expressed in multiple tissues during mouse development and adulthood. Mutations in the Sox9 gene or changes in expression levels can be attributed to many congenital diseases. Heterozygous loss-of-function mutations in the human SOX9 gene cause Campomelic dysplasia, a semi-lethal skeletal malformation syndrome. Disruption of Sox9 by conventional gene targeting leads to perinatal lethality in heterozygous mice, hence hampering the feasibility to obtain the homozygous Sox9 null mice for in vivo functional studies. In this study, we generated a conditional allele of Sox9 (Sox9 ( tm4.Tlu )) by flanking exon 1 with loxP sites. Homozygous mice for the Sox9 ( tm4.Tlu ) allele (Sox9 ( flox/flox )) are viable, fertile and indistinguishable from wildtype (WT) mice, indicating that the Sox9 ( tm4.Tlu ) allele is a fully functional Sox9 allele. Furthermore, we demonstrated that Cre-mediated recombination using a Col2a1-Cre line resulted in specific ablation of Sox9 activity in cartilage tissues.

While nonmyeloablative peripheral blood stem cell transplantation (NST) has shown efficacy against several solid tumors, it is untested in nasopharyngeal cancer (NPC). In a phase II clinical trial, 21 patients with pretreated metastatic NPC underwent NST with sibling PBSC allografts, using CY conditioning, thymic irradiation and in vivo T-cell depletion with thymoglobulin. Stable lymphohematopoietic chimerism was achieved in most patients and prophylactic CYA was tapered at a median of day +30. Seven patients (33%) showed partial response and three (14%) achieved stable disease. Four patients were alive at 2 years and three showed prolonged disease control of 344, 525 and 550 days. With a median follow-up of 209 (4-1147) days, the median PFS was 100 days (95% confidence interval (CI), 66-128 days), and median OS was 209 days (95% CI, 128-236 days). Patients with chronic GVHD had better survival-median OS 426 days (95% CI, 194-NE days) vs 143 days (95% CI, 114-226 days) (P=0.010). Thus, NST may induce meaningful clinical responses in patients with advanced NPC.

This retrospective study aimed to evaluate the clinical characteristics and prognostic factors of Asian patients with primary mediastinal large B-cell lymphoma (PMBCL) and to determine the role of rituximab in this entity. Forty-one consecutive patients from 1997 to 2009 were included: 14 received CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisolone), while 27 more recently treated patients received CHOP with rituximab (R-CHOP). All patients with a complete or partial response received consolidation involved field radiotherapy (RT). After a median follow-up of 31.2 months (104.4 months for CHOP and 28.8 months for R-CHOP), the overall survival (OS) and progression-free survival (PFS) for R-CHOP- and CHOP-treated patients were 87% vs. 57% and 88% vs. 36%, respectively. R-CHOP resulted in an improvement of PFS (hazard ratio [HR] 8.27, 95% confidence interval [CI] 2.23-30.74, p = 0.002) and OS (HR 4.20, 95% CI 1.05-16.8, p = 0.04). Nineteen patients had positron emission tomography/computed tomography (PET/CT) evaluation after six cycles of R-CHOP (metabolic complete response 13, partial metabolic response five, and metabolic progression one). All five patients with a metabolic partial response received RT instead of intensive salvage chemotherapy; four remained progression-free. In patients with PMBCL, R-CHOP in combination with involved field radiotherapy portended a 3-year OS rate of 87%, which is comparable to historical survival rates with more intensive chemotherapy regimens.

Efficient and stoichiometric expression of genes concatenated by bi- or multi-cistronic vectors has become an invaluable tool not only in basic biology to track and visualize proteins in vivo, but also for vaccine development and in the clinics for gene therapy. To adequately compare, in vivo, the effectiveness of two of the currently popular co-expression strategies - the internal ribosome entry site (IRES) derived from the picornavirus and the 2A peptide from the foot-and-mouth disease virus (FDMV) (F2A), we analyzed two locus-specific knock-in mouse lines co-expressing SRY-box containing gene 9 (Sox9) and enhanced green fluorescent protein (EGFP) linked by the IRES (Sox9(IRES-EGFP)) or the F2A (Sox9(F2A-EGFP)) sequence. Both the constructs expressed Sox9 and EGFP proteins in the appropriate Sox9 expression domains, with the IRES construct expressing reduced levels of EGFP compared to that of the F2A. The latter, on the other hand, produced about 42.2% Sox9-EGFP fusion protein, reflecting an inefficient ribosome 'skipping' mechanism. To investigate if the discrepancy in the 'skipping' process was locus-dependent, we further analyzed the FLAG(3)-Bapx1(F2A-EGFP) mouse line and found similar levels of fusion protein being produced. To assess if EGFP was hindering the 'skipping' mechanism, we examined another mouse line co-expressing Bagpipe homeobox gene 1 homolog (Bapx1), Cre recombinase and EGFP (Bapx1(F2A-Cre-F2A-EGFP)). While the 'skipping' was highly efficient between Bapx1 and Cre, the 'skipping' between Cre and EGFP was highly inefficient. We have thus demonstrated in our comparison study that the efficient and close to equivalent expression of genes linked by F2A is achievable in stable mouse lines, but the EGFP reporter may cause undesirable inhibition of the 'skipping' at the F2A sequence. Hence, the use of other reporter genes should be explored when utilizing F2A peptides., (© 2011 Chan et al.)

Objective: It is our standard of care to include pelvic lymph node dissection (PLND) in the staging of endometrial cancer, followed by adjuvant vaginal vault brachytherapy. We report our experience and outcome of patients with stage 1C grade 3 endometrial cancer from KK Hospital Singapore., Methods: Records of patients with a diagnosis of stage 1C grade 3 endometrial cancer (based on the 1988 FIGO [International Federation of Gynecology and Obstetrics] staging system) from 1995 to 2008 were retrospectively reviewed. Details of surgery, chemotherapy, and radiotherapy were recorded, as were prognostic factors such as histological subtype and number of lymph nodes removed. Dates and sites of relapses were noted., Results: A total of 31 cases were reviewed; 29 had sufficient records to be analyzed, of which one was excluded as she had a second primary cancer (breast). Median follow-up was 50.1 months (15.5-154 months). All cases underwent total hysterectomy and bilateral salpingo-oophorectomy; the majority (22 [76%]) had PLND as well. Those who did not undergo PLND received external beam radiotherapy instead. All but 1 case received postoperative vaginal vault brachytherapy. Eight of 10 patients with nonendometrioid adenocarcinoma (eg, clear cell) histology also received adjuvant chemotherapy. There were 5 systemic relapses (17.9%) and 1 pelvic recurrence (3.6%). The 5-year disease-free survival is 78.6%. No serious (grade 3 or 4) adverse effects were recorded., Conclusion: Pelvic lymph node dissection and vaginal vault brachytherapy seem to be effective in preventing locoregional recurrences, with few associated adverse effects. However, the rate of systemic relapse is relatively high. Adjuvant chemotherapy should also be considered for cases with poor prognostic factors.

The long-standing traditional method of delivering embryonic stem (ES) cells adjacent to the inner cell mass (ICM) of blastocysts to generate chimeras improved with the advent of laser- or Piezo assisted 8-cell embryo microinjection. Building on this technology but omitting either the laser or the Piezo to penetrate the zona pellucida and making use of earlier embryonic stages (2-cell and 4-cell), we were able to significantly speed up and economize our ES cell microinjection and chimera production throughput. We demonstrate here that embryonic (ES) and induced pluripotent stem (iPS) cells can stay fully pluripotent when delivered into 2-cell- and 4-cell-stage embryos, long before they would naturally be incorporated into the ICM of a blastocyst (E3.5) and give rise to high percentage and germline transmitting chimeras., (2010 Wiley-Liss, Inc.)

Background: This is a retrospective study evaluating the survival outcomes, patterns of failure, and prognostic factors of chemoradiotherapy incorporating high-dose rate brachytherapy in the treatment of locally advanced cervical cancer., Methods: A review of 120 consecutive patients with Federation Internationale de Gynecologie et d'Obstetrique (FIGO) stages IB2 to IVA cervical cancer treated with concurrent cisplatin-based chemoradiotherapy between April 1999 and January 2005. Overall (OS) and disease-free survival (DFS) were analyzed using the Kaplan-Meier method., Results: The 5-year OS and DFS rates were, respectively, 65.0% (35.0% IB2, 65.7% IIA-B, 71.0% IIIA-B, and 40.0% IVA) and 57.3% (30.0% IB2, 58.2% IIA-B, 64.0% IIIA-B, and 40.0% IVA). Most patients had squamous cell carcinoma (89.2%) and belonged to FIGO stages IIB (40.8%) and IIIB (30.8%). All but 4 patients completed the planned radiotherapy regimen. There were 48 documented recurrences, of which 13 were locoregional only, 26 were distant only, and 9 were both sites. Five patients (4.2%) experienced late grade 3 to 4 gastrointestinal toxicity. On multivariate analysis, a preradiotherapy hemoglobin level of less than 10 g/dL and tumor size of 4 cm or greater or bulky on computed tomography were independently significant variables for OS, whereas a nadir hemoglobin level of less than 10 g/dL and presence of radiologically enlarged pelvic or paraaortic lymph nodes were independently significant variables for DFS., Conclusions: We conclude that this regimen is efficacious and feasible, but the safety profile about concurrent administration of high-dose rate brachytherapy and chemotherapy should be studied further. Finally, for cervical cancer patients selected for nonsurgical treatment, radiological assessment of tumor size and lymph node status can provide valuable prognostic information over and above FIGO staging alone.

This is phase II study evaluating a non-platinum-containing regimen, used in conjunction with radiotherapy, in patients with locally advanced non-small cell lung cancer (NSCLC). Patients with non-resectable stage III NSCLC were treated with two cycles of induction gemcitabine (1000mg/m(2)) and vinorelbine (25mg/m(2)) given on D(1,8) every 21 days, followed by thoracic radiotherapy (60-66Gy) with concurrent weekly vinorelbine (15mg/m(2)). The primary objective was to assess response rate and secondary objectives to assess tolerability and to determine the progression-free survival (PFS) and overall survival (OS). Of the 42 patients enrolled on the study, 15 (36%) achieved a partial response (PR) after induction chemotherapy. After chemo-radiotherapy, five patients had complete response (CR) and 19 patients had PR, giving an overall response rate of 52%. The median PFS was 8 months and median OS was 17 months. The regimen was tolerable, with a 21% grade 3/4 neutropenia rate and 38% grade 2/3 esophagitis rate.

We present a case of a patient with metastatic nasopharyngeal carcinoma who failed two lines of palliative combination chemotherapy and was treated with allogeneic nonmyeloablative stem cell transplantation (NST). This patient achieved a durable tumor response, dramatic relief of his symptoms, and elimination of tumor in his bone marrow-an effect likely achieved via a graft-versus-tumor response. Although NST has been explored previously in solid tumors, such as renal cell carcinoma and breast cancer, it has not been widely explored in nasopharyngeal carcinoma. We also present data from a flow cytometric immune analysis and cytokine enzyme-linked immunosorbent assay analysis in the pre- and post-NST period.

Gastric mucosa-associated lymphoid tissue (MALT) lymphoma and diffuse large B cell lymphoma (DLBCL) show a spectrum of disease characterized by varying proportions of low-grade and high-grade components. While the natural history and optimum treatment for low-grade gastric MALT lymphoma and DLBCL is well established, the prognosis and optimal treatment of patients with both low- and high-grade components is not well established. The purpose of our study was to evaluate the clinical characteristics, survival outcomes, and prognostic factors of patients with gastric MALT lymphoma and gastric DLBCL. A retrospective review of patients with gastric MALT lymphoma, gastric DLBCL, or MALT lymphoma with a high-grade component treated at our centers from 1994 to 2006 was performed. Patients were divided into three categories: "pure MALT lymphoma," "MALT lymphoma with high-grade component" (mixed), and "pure DLBCL." Seventy-six patients were included in our study-26 with pure MALT, 22 with MALT with high-grade component ("mixed"), and 28 with pure DLBCL. Pure MALT lymphoma and mixed lymphoma patients had similar clinical characteristics, whereas pure DLBCL patients had less favorable disease characteristics with significantly poorer performance status, higher number of extranodal sites of disease, higher stage, and larger proportion of bone marrow involvement and international prognostic index (IPI) scores compared with mixed lymphoma. The majority of mixed lymphoma (72.7%) and DLBCL patients (71.4%) were treated with chemotherapy. Of patients receiving chemotherapy, a higher proportion of mixed lymphoma and DLBCL patients received anthracycline-based combination chemotherapy regimens compared with MALT lymphoma (73% vs 71% vs 8%) whereas the proportion of mixed lymphoma and DLBCL patients was similar (p = 0.919). At a median follow-up of 37 months, the 5-year overall survival was 66.9%. The 5-year overall survival was 78% for MALT lymphoma, 84% for mixed lymphoma, and 45% for DLBCL. On univariate analysis, DLBCL histology, age, performance status, serum albumin, lactate dehydrogenase, bone marrow, number of extranodal sites, stage, and IPI score were prognostic for inferior survival. On multivariate analysis, DLBCL histology remained significantly prognostic for inferior survival, independent of chemotherapy regimen (hazard ratio (HR) 6.66, 95% confidence interval (CI) 2.01-21.41, p = 0.001). Mixed histology was not prognostic for inferior survival (HR 1.13, 95% CI 0.28-4.54, p = 0.868). Other factors prognostic for inferior survival were serum albumin <37 g/L (HR 3.22, 95% CI 1.11-13.22, p = 0.034) and treatment with non-cyclophosphamide, doxorubicin, vincristine, and prednisolone chemotherapy (HR 4.89, 95% CI 1.67-14.36, p = 0.004). In conclusion, the clinical characteristics of mixed histology MALT lymphoma are similar to low-grade MALT lymphoma and significantly different from pure DLBCL. The prognosis of mixed histology MALT lymphoma is significantly better than pure DLBCL, independent of IPI and chemotherapy regimen, and pure DLBCL histology is independently prognostic of inferior survival outcome.

Background: Retropharyngeal lymph node (RLN) staging in nasopharyngeal carcinoma (NPC) can be controversial., Methods: We retrospectively reviewed all patients with T(2-4), N(0-1) NPC treated between 1992 and 1994 to examine if RLN metastasis resulted in an increased incidence of distant metastases., Results: Of the 667 patients with NPC, 395 had T(2-4), N(0-1) disease, 140 had N(0), and 255 had N(1). All had staging CT scans and were treated with radiotherapy. Median follow-up was 8.3 years. Seventy-four percent showed undifferentiated histology. In this cohort, 187 (47%) had RLN metastases. Multivariate analysis showed that RLN conferred a higher hazard for distant metastasis (p = .04). Using the Kaplan-Meier method, patients with N(0) disease and RLN had a similar hazard for distant metastases as patients with N(1) disease when compared with patients with N(0) disease and without RLN., Conclusion: Patients with N(0) disease and RLN appear to share a similar prognosis to patients with N(1) disease.

Natural killer (NK) lymphomas occurring more frequently in the Far East and South America respond poorly to anthracycline-based regimens. Here we report an in vivo NK lymphoma xenograft (NK-S1) derived from the testicular metastasis of a patient with an extranodal NK lymphoma (nasal type). The NK-S1 xenograft, established in severe combined immune deficient (SCID) mice retained the same imunophenotypic features as the original tumor. NK-S1 disseminated intra-abdominally to the testis, intestine and liver. Although doxorubicin, rapamycin, bevacizumab, rapamycin-doxorubicin, and bevacizumab-doxorubicin had no effects on the growth of subcutaneous NK-S1 xenografts, intraperitoneal (IP) delivery of cyclophosphamide caused complete tumor regression; this tumor regression was associated with apoptosis, upregulation of activated caspase-3, and cleaved Poly(ADP-ribose) polymerase (PARP). In an IP model of NK lymphoma, cyclophosphamide also prolonged the survival of mice and potently inhibited tumor dissemination and ascites formation. Our data suggest that the NK-S1 xenograft is a useful tool for screening preclinical drugs, and cyclophosphamide may be a useful drug for the treatment of this disease.

Introduction: It has been established that combined chemoradiotherapy treatment benefits selected patients with stage III Non Small Cell Lung Cancer (NSCLC). However, locoregional recurrence still poses a problem. The addition of surgery as the third modality may provide a possible solution. We report our experience of using the triple-modality approach in this group of patients., Materials and Methods: This is a retrospective review of 33 patients with stage III NSCLC treated between 1997 and 2005. Patients have good performance status and no significant weight loss. There were 26 males (79 %) with median age of 63 years (range, 43 to 74) and median follow-up of 49 months. Seventy-six percent had Stage IIIA disease. Chemotherapy consisted of paclitaxel at 175 mg/m2 over 3 hours followed by carboplatin at AUC of 5 over 1 hour. Thoracic radiotherapy was given concurrently with the second and third cycles of chemotherapy. All patients received 50 Gray in 25 fractions over 5 weeks., Results: The main toxicities were grade 3/4 neutropenia (30%), grade 3 infection (15 %) and grade 3 oesophagitis (9%). Twenty-five patients (76%) underwent surgery. Of the 8 who did not undergo surgery, 1 was deemed medically unfit after induction chemoradiotherapy and 4 had progressive disease; 3 declined surgery. Nineteen patients (58 %) had lobectomy and 6 had pneumonectomy. The median overall survival was 29.9 months and 12 patients are still in remission., Conclusion: The use of the triplemodality approach is feasible, with an acceptable tolerability and resectability rate in this group of patients.

This study attempted to evaluate the usefulness of the International Prognostic Index (IPI) as a prognostic model in patients treated with R-CHOP (rituximab, cyclophosphamide, vincristine, adriamycin and prednisolone) chemotherapy. We compared 279 patients with DLBCL. Among them, 183 received CHOP while 96 received R-CHOP. Results showed that there were no statistically significant differences between the two groups of patients in terms of both the patient and the lymphoma characteristics. The estimated 2-year survival was significantly higher among patients treated with R-CHOP compared to CHOP alone (85.6% vs. 64.7%, P = 0.004). Both the IPI and age-adjusted IPI were less useful as prognostic models in patients receiving R-CHOP compared to CHOP. In the multivariate analysis, age >or= 60, elevated serum LDH, low serum albumin and advanced stages of disease were each independently associated with decreased survival in patients treated with CHOP. In contrast, among those treated with R-CHOP, only male sex and advanced stage of disease were each independently associated with decreased survival. Using these two factors, patients treated with R-CHOP could be separated into three prognostic groups with 5-year estimated survival ranging from 47% to 100% (P < 0.0001). In summary, we can conclude that with the significant improvement in survival following the use of rituximab, the relevance of previously recognized prognostic factors has to be reassessed and re-evaluated.

Aim: We aimed to compare the frequencies, clinical characteristics, and prognostic factors of peripheral T-cell lymphoma (PTCL) vs. extra-nodal natural killer (NK)/T-cell lymphoma and to characterize the subtypes of extra-nodal NK/T-cell lymphoma., Methods: We reviewed 97 consecutive patients with PTCL and extra-nodal NKT lymphoma from 2000 to 2006. During this period, a total of 780 patients with malignant lymphomas were treated in our center. The diagnostic criteria used were based on the WHO classification system of malignant lymphomas., Results: Extra-nodal-NK/T-cell lymphoma and PTCL comprised 5.0% (39/780) and 7.4% (58/780) of all cases. Of the PTCL cases, histology was PTCL-NOS in 25, anaplastic large cell in 11, angioimmunoblastic T cell in 18 and other subtypes in four patients. Compared with PTCL, extra-nodal NK/T-cell lymphoma was associated with a significantly inferior rates of complete remission (33% vs. 53%, P = 0.05) and 3 yr overall survival (29.5% vs. 47.5%, P = 0.003). On multivariate analysis, extra-nodal NK/T-cell histology was independently associated with decreased survival. Further analysis into this subtype showed the nasal variant (n = 25) differed significantly from extra-nasal variant (n = 14) in terms of stage at presentation (stages III/IV, 36% vs. 79%), international prognostic index scores (high intermediate or high IPI scores, 24% vs. 64%), complete remission rates (48% vs. 7%), and median survival (10 months vs. 1 month, P < 0.0001)., Conclusions: Extra-nodal NK/T-cell lymphoma was associated with a poorer prognosis compared with PTCL and is likely to comprise two distinct variants with different clinical behavior and prognosis.