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Performance of 3D-T1W-TSE has been proven superior to 3D-MP-GRE at 3 T on brain metastases (BM) contrast-enhanced (CE) MRI. However, its performance at 1.5 T is largely unknown and sparsely reported. This study aims to assess image quality, lesion detectability and conspicuity of 1.5 T 3D-T1W-TSE on planning MRI of frameless BM radiotherapy. 94 BM patients to be treated by frameless brain radiotherapy were scanned using 3D-T1W-TSE with immobilization on multi-vendor 1.5 T MRI-simulators. BMs were jointly diagnosed by 4 reviewers. Enhanced lesion conspicuity was quantitatively assessed by calculating contrast ratio (CR) and contrast-to-noise ratio (CNR). Signal-to-noise ratio (SNR) reduction of white matter due to the use of flexible coil was assessed. Lesion detectability and conspicuity were compared between 1.5 T planning MRI and 3 T diagnostic MRI by an oncologist and a radiologist in 10 patients. 497 BMs were jointly diagnosed. The CR and CNR were 75.2 ± 39.9% and 14.2 ± 8.1, respectively. SNR reduced considerably from 31.7 ± 8.3 to 21.9 ± 5.4 with the longer distance to coils. 3 T diagnostic MRI and 1.5 T planning MRI yielded exactly the same detection of 84 BMs. Qualitatively, lesion conspicuity at 1.5 T was not inferior to that at 3 T. Quantitatively, lower brain SNR and lesion CNR were found at 1.5 T, while lesion CR at 1.5 T was highly comparable to that at 3 T. 1.5 T 3D-T1W-TSE planning MRI of frameless BM radiotherapy was comprehensively assessed. Highly comparable BM detectability and conspicuity were achieved by 1.5 T planning MRI compared to 3 T diagnostic MRI. 1.5 T 3D-T1W-TSE should be valuable for frameless brain radiotherapy planning. more...

Hogstad et al. show that the somatic BRAFV600E mutation in myeloid dendritic cell precursors in Langerhans cell histiocytosis promotes lesion formation through impaired dendritic cell migration and resistance to apoptosis, which can be rescued with targeted MAPK pathway inhibition., Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia characterized by granulomatous lesions containing pathological CD207+ dendritic cells (DCs) with constitutively activated mitogen-activated protein kinase (MAPK) pathway signaling. Approximately 60% of LCH patients harbor somatic BRAFV600E mutations localizing to CD207+ DCs within lesions. However, the mechanisms driving BRAFV600E+ LCH cell accumulation in lesions remain unknown. Here we show that sustained extracellular signal–related kinase activity induced by BRAFV600E inhibits C-C motif chemokine receptor 7 (CCR7)–mediated DC migration, trapping DCs in tissue lesions. Additionally, BRAFV600E increases expression of BCL2-like protein 1 (BCL2L1) in DCs, resulting in resistance to apoptosis. Pharmacological MAPK inhibition restores migration and apoptosis potential in a mouse LCH model, as well as in primary human LCH cells. We also demonstrate that MEK inhibitor-loaded nanoparticles have the capacity to concentrate drug delivery to phagocytic cells, significantly reducing off-target toxicity. Collectively, our results indicate that MAPK tightly suppresses DC migration and augments DC survival, rendering DCs in LCH lesions trapped and resistant to cell death. more...

The mononuclear phagocyte system (MPS) comprises monocytes, macrophages and dendritic cells (DCs). Over the past few decades, classification of the cells of the MPS has generated considerable controversy. Recent studies into the origin, developmental requirements and function of MPS cells are beginning to solve this problem in an objective manner. Using high-resolution genetic analyses and fate-mapping studies, three main mononuclear phagocyte lineages have been defined, namely, macrophage populations established during embryogenesis, monocyte-derived cells that develop during adult life and DCs. These subsets and their diverse subsets have specialized functions that are largely conserved between species, justifying the introduction of a new, universal scheme of nomenclature and providing the framework for therapeutic manipulation of immune responses in the clinic. In this review, we have commented on the implications of this novel MPS classification in solid organ transplantation. more...

Dendritic cells (DCs) are critical for the launching of protective T cell immunity in response to viral infection. Viruses can directly infect DCs, thereby compromising their viability and suppressing their ability to activate immune responses. How DC function is maintained in light of this paradox is not understood. By analyzing the susceptibility of primary human DC subsets to viral infections, we report that CD141 + DCs have an innate resistance to infection by a broad range of enveloped viruses, including HIV and influenza virus. In contrast, CD1c + DCs are susceptible to infection, which enables viral antigen production but impairs their immune functions and survival. The ability of CD141 + DCs to resist infection is conferred by RAB15, a vesicle-trafficking protein constitutively expressed in this DC subset. We show that CD141 + DCs rely on viral antigens produced in bystander cells to launch cross-presentation–driven T cell responses. By dissociating viral infection from antigen presentation, this mechanism protects the functional capacity of DCs to launch adaptive immunity against viral infection. more...

Pregnancy-associated breast cancer is the most common malignancy during pregnancy with an expected rise in incidence. The belief in the need for termination of pregnancy and that chemotherapy is contra-indicated during pregnancy is challenged by recent evidence. Patients can consider breast-conserving surgery and sentinel lymph node biopsy with acceptably low fetal risk from radiation exposure. A range of chemotherapeutics is possible in the second trimester in terms of drug class and frequency. Hormonal therapy and monoclonal antibody therapy are contra-indicated during pregnancy and lactation. Fetal outcome after in-utero exposure to chemotherapy appears similar to that in a non-pregnant population. Future pregnancy, in most situations, does not appear to be contra-indicated but a multidisciplinary and patient-centred approach is recommended. Fertility preservation techniques are also being developed with reported success and consequent pregnancies. more...

CD4+Foxp3+ regulatory T cells (Treg) are critical regulators of immune homeostasis and self-tolerance. Whereas thymic-derived or natural Treg stably express Foxp3, adaptive or induced Treg (iTreg) generated from peripheral CD4 T cells are susceptible to inflammation-induced reversion to pathogenic effector T cells. Building upon our previous observations that T cell–expressed receptors for C3a (C3aR) and C5a (C5aR) drive Th1 maturation, we tested the impact of C3aR/C5aR signaling on induction and stability of alloreactive iTreg. We observed that genetic deficiency or pharmacological blockade of C3aR/C5aR signaling augments murine and human iTreg generation, stabilizes Foxp3 expression, resists iTreg conversion to IFN-γ/TNF-α–producing efffector T cells, and, as a consequence, limits the clinical expression of graft-versus-host disease. Taken together, the findings highlight the expansive role of complement as a crucial modulator of T cell alloimmunity and demonstrate proof-of-concept that targeting C3a/C3aR and C5a/C5aR interactions could facilitate iTreg-mediated tolerance to alloantigens in humans. more...

Blockade of C3aR/C5aR signaling in nT reg cells augments in vitro and in vivo suppression, abrogates autoimmune colitis, and prolongs allogeneic skin graft survival., Thymus-derived (natural) CD4+ FoxP3+ regulatory T cells (nT reg cells) are required for immune homeostasis and self-tolerance, but must be stringently controlled to permit expansion of protective immunity. Previous findings linking signals transmitted through T cell–expressed C5a receptor (C5aR) and C3a receptor (C3aR) to activation, differentiation, and expansion of conventional CD4+CD25− T cells (T conv cells), raised the possibility that C3aR/C5aR signaling on nT reg cells could physiologically modulate nT reg cell function and thereby further impact the induced strength of T cell immune responses. In this study, we demonstrate that nT reg cells express C3aR and C5aR, and that signaling through these receptors inhibits nT reg cell function. Genetic and pharmacological blockade of C3aR/C5aR signal transduction in nT reg cells augments in vitro and in vivo suppression, abrogates autoimmune colitis, and prolongs allogeneic skin graft survival. Mechanisms involve C3a/C5a-induced phosphorylation of AKT and, as a consequence, phosphorylation of the transcription factor Foxo1, which results in lowered nT reg cell Foxp3 expression. The documentation that C3a/C3aR and C5a/C5aR modulate nT reg cell function via controlling Foxp3 expression suggests targeting this pathway could be exploited to manipulate pathogenic or protective T cell responses. more...

Summary Background For women with oestrogen receptor (ER)-positive early breast cancer, treatment with tamoxifen for 5 years substantially reduces the breast cancer mortality rate throughout the first 15 years after diagnosis. We aimed to assess the further effects of continuing tamoxifen to 10 years instead of stopping at 5 years. Methods In the worldwide Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) trial, 12 894 women with early breast cancer who had completed 5 years of treatment with tamoxifen were randomly allocated to continue tamoxifen to 10 years or stop at 5 years (open control). Allocation (1:1) was by central computer, using minimisation. After entry (between 1996 and 2005), yearly follow-up forms recorded any recurrence, second cancer, hospital admission, or death. We report effects on breast cancer outcomes among the 6846 women with ER-positive disease, and side-effects among all women (with positive, negative, or unknown ER status). Long-term follow-up still continues. This study is registered, number ISRCTN19652633. Findings Among women with ER-positive disease, allocation to continue tamoxifen reduced the risk of breast cancer recurrence (617 recurrences in 3428 women allocated to continue vs 711 in 3418 controls, p=0·002), reduced breast cancer mortality (331 deaths vs 397 deaths, p=0·01), and reduced overall mortality (639 deaths vs 722 deaths, p=0·01). The reductions in adverse breast cancer outcomes appeared to be less extreme before than after year 10 (recurrence rate ratio [RR] 0·90 [95% CI 0·79–1·02] during years 5–9 and 0·75 [0·62–0·90] in later years; breast cancer mortality RR 0·97 [0·79–1·18] during years 5–9 and 0·71 [0·58–0·88] in later years). The cumulative risk of recurrence during years 5–14 was 21·4% for women allocated to continue versus 25·1% for controls; breast cancer mortality during years 5–14 was 12·2% for women allocated to continue versus 15·0% for controls (absolute mortality reduction 2·8%). Treatment allocation seemed to have no effect on breast cancer outcome among 1248 women with ER-negative disease, and an intermediate effect among 4800 women with unknown ER status. Among all 12 894 women, mortality without recurrence from causes other than breast cancer was little affected (688 deaths without recurrence in 6454 women allocated to continue versus 679 deaths in 6440 controls; RR 0·99 [0·89–1·10]; p=0·78). For the incidence (hospitalisation or death) rates of specific diseases, RRs were as follows: pulmonary embolus 1·87 (95% CI 1·13–3·07, p=0·01 [including 0·2% mortality in both treatment groups]), stroke 1·06 (0·83–1·36), ischaemic heart disease 0·75 (0·60–0·95, p=0·02), and endometrial cancer 1·74 (1·30–2·34, p=0·0002). The cumulative risk of endometrial cancer during years 5–14 was 3·1% (mortality 0·4%) for women allocated to continue versus 1·6% (mortality 0·2%) for controls (absolute mortality increase 0·2%). Interpretation For women with ER-positive disease, continuing tamoxifen to 10 years rather than stopping at 5 years produces a further reduction in recurrence and mortality, particularly after year 10. These results, taken together with results from previous trials of 5 years of tamoxifen treatment versus none, suggest that 10 years of tamoxifen treatment can approximately halve breast cancer mortality during the second decade after diagnosis. Funding Cancer Research UK, UK Medical Research Council, AstraZeneca UK, US Army, EU-Biomed. more...

Dendritic cells (DCs) are critical for launching of protective T cell immunity in response to viral infection. Viruses can directly infect DCs, thereby compromising their viability and suppressing their ability to activate immune responses. How DC function is maintained in light of this paradox is not understood. By analyzing the susceptibility of primary human DC subsets to viral infections, we report that CD141+ DCs have an innate resistance to infection by a broad range of enveloped viruses, including human immunodeficiency virus (HIV) and influenza virus. In contrast, CD1c+ DCs are susceptible to infection which enables viral antigen production but impairs their immune functions and survival. The ability of CD141+ DCs to resist infection is conferred by RAB15, a vesicle trafficking protein constitutively expressed in this DC subset. We show that CD141+ DCs rely on viral antigens produced in bystander cells to launch cross-presentation driven T cell responses. By dissociating viral infection from antigen presentation, this mechanism protects the functional capacity of DCs to launch adaptive immunity against viral infection. more...

Results of studies published since 2002 reveal that T cells and antigen-presenting cells (APCs) produce complement proteins. The immune cell-derived, alternative pathway complement components activate spontaneously, yielding local, but not systemic, production of C3a and C5a. These anaphylatoxins bind to their respective G-protein-coupled receptors, C3aR and C5aR, expressed on both partners. The resultant complement-induced T cell activation and APC activation drive T cell differentiation, expansion and survival. Complement deficiency or blockade attenuates T cell-mediated autoimmunity and delays allograft rejection in mice. Increasing complement activation, achieved by genetic removal of the complement regulatory protein decay-accelerating factor, enhances murine T cell immunity and accelerates allograft rejection. The findings support the need for design and testing of complement inhibitors in humans. more...

BACKGROUND: Current measures for breast cancer prevention and options for treatment adopted in Hong Kong are mainly based on research data and clinical evidence from overseas. It is essential to establish a cancer-specific registry to monitor the status of breast cancer in Hong Kong. OBJECTIVES: We summarized the current status of breast cancer in Hong Kong based on the data collected from Hong Kong Breast Cancer Registry (HKBCR). METHODS: Prevalent and newly diagnosed breast cancers (including in situ and invasive breast cancers) were registered in the HKBCR. Information on patient demographics, risk factors, medical information, and survival were analyzed and reported in this study. RESULTS: Data of 2,330 breast cancer patients were analyzed. We observed an earlier median age at diagnosis in Hong Kong than those reported in other countries. Distribution of cancer stage was: stage 0 (11.4%), stage I (31.4%), stage II (41%), stage III (12.5%), stage IV (0.8%), and unclassified (2.9%). The percentages of patients who received surgery, chemotherapy, radiation therapy, and endocrine therapy were 98.7, 67.9, 64.8, and 64.1%, respectively. At a median follow-up of 1.2 years, locoregional recurrence was recorded at 2%, distant recurrence at 2.8%, and breast-cancer-related mortality at 0.3%. CONCLUSIONS: The HKBCR serves as a surveillance program to monitor disease and treatment patterns. It is pivotal to support research for more effective breast cancer prevention and treatment strategies in Hong Kong. more...

Although induction of CD8 T-cell responses to transplants requires CD4-cell help, how this help is transmitted remains incompletely characterized. In vitro, cognate interactions between CD4 T cells and dendritic cells (DCs) induce C3a and C5a production. CD8(+) T cells lacking C3a receptor (C3aR) and C5a receptor (C5aR) proliferate weakly to allogeneic DCs despite CD4 help, indicating that CD4-cell help is mediated, in part, through DC-derived C3a/C5a acting on CD8(+) T cell-expressed C3aR/C5aR. In support of this concept, augmenting DC C5a/C3a production bypasses the requirement for CD4- and CD40-dependent help to wild-type CD8(+) T cells. CD4-deficient recipients of allogeneic heart transplants prime weak CD8 responses and do not acutely reject their grafts. In contrast, CD4-deficient chimeric mice possessing decay accelerating factor deficient (Daf1(-/-)) bone marrow, in which DC C3a/C5a production is potentiated, acutely reject transplants through a CD8 cell-dependent mechanism. Furthermore, hearts transplanted into CD40(-/-) mice prime weak CD8-cell responses and survive indefinitely, but hearts transplanted into Daf1(-/-)CD40(-/-) recipients undergo CD8 cell-dependent rejection. Together, the data indicate that heightened production and activation of immune cell-derived complement bypasses the need for CD40/CD154 interactions and implicate antigen-presenting cell-produced C5a and C3a as molecular bridges linking CD4 help to CD8(+) T cells. more...

While activation of serum complement mediates antibody-initiated vascular allograft injury, increasing evidence indicates that complement also functions as a modulator of alloreactive T cells. We tested whether blockade of complement activation at the C5 convertase step affects T cell-mediated cardiac allograft rejection in mice. The anti-C5 mAb BB5.1, which prevents the formation of C5a and C5b, synergized with subtherapeutic doses of CTLA4Ig to significantly prolong the survival of C57BL/6 heart grafts that were transplanted into naive BALB/c recipients. Anti-C5 mAb treatment limited the induction of donor-specific IFNγ-producing T cell alloimmunity without inducing Th2 or Th17 immunity in vivo and inhibited primed T cells from responding to donor antigens in secondary mixed lymphocyte responses. Additional administration of anti-C5 mAb to the donor prior to graft recovery further prolonged graft survival and concomitantly reduced both the in vivo trafficking of primed T cells into the transplanted allograft and decreased expression of T cell chemoattractant chemokines within the graft. Together these results support the novel concept that C5 blockade can inhibit T cell-mediated allograft rejection through multiple mechanisms, and suggest that C5 blockade may constitute a viable strategy to prevent and/or treat T cell-mediated allograft rejection in humans. more...

> Background: The incidence rate of breast cancer is rising rapidly in Hong Kong. Lymphedema is a serious long-term complication of breast cancer surgery and radiation therapy. > Objective: The objectives of this study were to evaluate risk factors associated with the development of lymphedema for patients with breast cancer who have had an axillary lymph node dissection and to explore potential factors associated with moderate to severe lymphedema. > Methods: This was a matched case-control study of 202 women undergoing a unilateral axillary dissection for breast cancer, consisting of 101 cases with lymphedema and 101 controls who matched cases in terms of surgery date, axillary radiotherapy, and cancer stage. Arm circumferences were measured to determine presence and severity of lymphedema. Potential risk factors were collected by using clinical data and a questionnaire. A multiple logistic regression was used to obtain the adjusted odds ratios for potential risk factors for developing lymphedema. Exploratory analysis was also performed to identify factors associated with the development of moderate to severe lymphedema. > Results: Adjusted odds ratios for the development of lymphedema were 3.80 (95% confidence interval [Cl] = 1.84 7.87) for previous inflammation infection and 1.06 (95% Cl = 1.02 1.10) for an increase of 1 year of age at axillary dissection. On exploratory analysis, adjusted odds ratios for moderate to severe degree of lymphedema were 4.53 (95% Cl = 2.16 9.52) for previous inflammation infection, 2.94 (95% Cl = 1.44 6.03) for operation on dominant arm, 1.11 (95% Cl = 1.01 1.22) for an increase of 1 kg/m 2 in body mass index (BMI) at recruitment, and 1.05 (95% Cl = 1.01 1.10) for an increase of 1 year of age at recruitment time. > Discussion: Previous inflammation-infection and advanced age at axillary dissection are risk factors associated with the initiation of lymphedema. Previous inflammation-infection, operation on the side of the dominant hand, obesity, and aging are potential risk factors associated with the aggravation of lymphedema. Greater BMI is still a risk factor for lymphedema progression even in a lower BMI population. more...

Objectives This is a single center, randomized, double-blind placebo-controlled study to evaluate the NK(1)-receptor antagonist, aprepitant, in Chinese breast cancer patients. The primary objective was to compare the efficacy of aprepitant-based antiemetic regimen and standard antiemetic regimen for the prevention of chemotherapy-induced nausea and vomiting (CINV) in patients who received moderately emetogenic chemotherapy. The secondary objective was to compare the patient-reported quality of life in these two groups of patients. Patients and Methods Eligible breast cancer patients were chemotherapy-naive and treated with adjuvant AC chemotherapy (i.e. doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2). Patients were randomly assigned to either an aprepitant-based regimen (day 1, aprepitant 125 mg, ondansetron 8 mg, and dexamethasone 12 mg before chemotherapy and ondansetron 8 mg 8 h later; days 2 through 3, aprepitant 80 qd) or a control arm which consisted of standard regimen (day 1, ondansetron 8 mg and dexamethasone 20 mg before chemotherapy and ondansetron 8 mg 8 h later; days 2 through 3, ondansetron 8 mg bid). Data on nausea, vomiting, and use of rescue medication were collected with a self-report diary, patients quality of life were assessed by self-administered Functional Living Index-Emesis (FLIE). Results Of 127 patients randomized, 124 were assessable. For CINV in Cycle 1 AC, there was no significant difference in the proportion of patients with reported complete response, complete protection, total control, ‘no vomiting’, ‘no significant nausea’ and ‘no nausea’. The requirement of rescue medication appears to be lesser in patients treated with the aprepitant-based regimen compared to those with the standard regimen (11% vs. 20%; P = 0.06). Assessment of FLIE revealed that while there was no difference in the nausea domain and the total score between the two groups; however, patients receiving standard antiemetic regimen had significantly worse quality of life in the vomiting domain (mean score [SD] = 23.99 [30.79]) when compared with those who received the aprepitant-based regimen (mean score [SD] = 3.40 [13.18]) (P = 0.0002). Both treatments were generally well tolerated. Patients treated with the aprepitant-based regimen had a significantly lower incidence of neutropenia (53.2% vs. 35.5%, P = 0.0468), grade ≥ 3 neutropenia (21.0% vs. 45.2, P = 0.0042) and delay in subsequent cycle of chemotherapy (8.1% vs. 27.4%, P = 0.0048). Conclusion The aprepitant regimen appears to reduce the requirement of rescue medication when compared with the control regimen for prevention of CINV in patients receiving both an anthracycline and cyclophosphamide, and is associated with a better quality of life during adjuvant AC chemotherapy. more...

Aims To assess the dosimetric effect of using a split-organ delineation approach during intensity-modulated radiotherapy (IMRT) treatment planning for advanced T-stage nasopharyngeal carcinoma (NPC). Materials and methods Twenty NPC patients with T3–4 tumours were studied. A reference (REF) IMRT plan was generated based on a standard treatment planning protocol, with a set of user-defined dose constraints for optimisation. An investigative (INV) IMRT plan was then generated based on the same protocol, but treating several organs at risk (OARs; parotid glands, temporal lobes, cochlea, auditory nerves and planning organ at risk volume [PRV] of the brainstem) as split organs consisting of target-overlapping and non-target-overlapping sub-segments. These sub-segments were assigned independent dose constraints. The REF and INV plans were compared with respect to target coverage and OAR sparing. Target coverage was evaluated by the D min (minimum dose), V 66 / V 60 (percentage volume of gross target volume [GTV]/planning target volume [PTV] receiving 66Gy/60Gy), target conformity index (CI), and tumour control probability (TCP). The sparing of OARs was evaluated by the commonly used dose end points for the respective OAR, and normal tissue complication probability (NTCP). Results For PTV coverage, the INV plan was superior to the REF plan in terms of D min ( P =0.000), CI ( P =0.005) and TCP ( P =0.002). This is attributed to an increase in dose to the PTV-OAR overlapping sub-segments. Regarding the sparing of OARs, there was a significant reduction in the mean dose of the parotid glands ( P =0.002), and a slight, but non-significant, increase in NTCP of the temporal lobes, cochlea and brainstem. Conclusions Using a split-organ delineation approach in IMRT treatment planning for advanced T-stage NPC, a significant improvement in the target coverage and TCP could be achieved, whereas the mean dose of the parotid was reduced significantly. There was insignificant change in the NTCP of the temporal lobe, parotid gland, cochlea and brainstem, but a significant change in the NTCP of the auditory nerve. The approach provides the planner extra room to manipulate the dose constraints during optimisation, and to obtain the desired result in less attempts. This approach also has the potential to be used in a broader context for IMRT planning for other tumour sites. more...

INTRODUCTION Breast cancer is the leading cause of death of Hong Kong women with increasing incidence. This study aimed to determine any prognostic differences between screen-detected and self-detected cases of breast cancer in a cohort of Hong Kong patients. METHODS This was a case series with internal comparison carried out in a private hospital in Hong Kong. Approximately 3000 cases of Chinese patients diagnosed with ductal carcinoma in situ or invasive breast cancer were reviewed. RESULTS The screen-detected group showed better pathological characteristics than the self-detected group. Number of lymph nodes involved, invasive tumour size, and tumour grade were more favourable in the screen-detected group. There was also a lower proportion of patients with pure invasive ductal carcinoma and mastectomy in the screen-detected group. CONCLUSION This study provides indirect evidence that women in the local population may gain clinical benefit from regular breast cancer screening. The findings need to be validated in a representative population of Hong Kong women. more...

BackgroundThe Oncotype DX Breast Cancer Assay is validated to assess risk of distant recurrence and likelihood of chemotherapy (CT) benefit in estrogen receptor-positive ESBC in various populations. In Hong Kong, > 80% of breast cancers are early stage breast cancer (ESBC) and > 60% of these women receive CT. This prospective study measured changes in CT type and recommendations, as well as physician impression of assay impact in a homogenous Chinese population.MethodsConsecutive patients with estrogen receptor-positive, T1-3 N0-1mi M0 ESBC were offered enrollment. After surgery, physicians discussed treatment options with patients, then ordered the assay, then reassessed treatment recommendation considering assay results. Changes in treatment recommendation, CT utilization, physician confidence, and physician rating of influence on their treatment recommendations were measured.ResultsA total of 146 evaluable patients received pre- and post-testing treatment recommendations. CT recommendations (including changes in intensity of CT) were changed for 34 of 146 patients (23.3%; 95% confidence interval, 16.7%-31.0%); change in intensity occurred in 7 of 146 (4.8%). There were 27 changes in treatment recommendations of adding or removing CT altogether (18.5% change; 95% confidence interval, 12.6%-25.8%). CT recommendations decreased from 52.1% to 37.7%, a net absolute reduction of 14.4% (P < .001; 27.6% net relative reduction). Pre-assay, 96% of physicians agreed/strongly agreed that they were confident in their treatment recommendation; post-assay, 90% of physicians agreed/strongly agreed with the same statement. Thirty percent of physicians agreed/strongly agreed that the test had influenced their recommendation, similar to the proportion of changed recommendations.ConclusionsThe Oncotype DX Assay appears to influence physician ESBC adjuvant treatment recommendations in Hong Kong. more...

To compare the benefit achieved by concurrent chemoradiotherapy (CRT) and/or accelerated fractionation (AF) vs. radiotherapy (RT) alone with conventional fractionation (CF) for patients with T3-4N0-1M0 nasopharyngeal carcinoma (NPC).All patients were irradiated with the same RT technique toor =66 Gy at 2 Gy per fraction, conventional five fractions/week in the CF and CF+C (chemotherapy) arms, and accelerated six fractions/week in the AF and AF+C arms. The CF+C and AF+C patients were given the Intergroup 0099 regimen (concurrent cisplatin plus adjuvant cisplatin and 5-fluorouracil).Between 1999 and April 2004, 189 patients were randomly assigned; the trial was terminated early because of slow accrual. The median follow-up was 2.9 years. When compared with the CF arm, significant improvement in failure-free survival (FFS) was achieved by the AF+C arm (94% vs. 70% at 3 years, p = 0.008), but both the AF arm and the CF+C arm were insignificant (por = 0.38). Multivariate analyses showed that CRT was a significant factor: hazard ratio (HR) = 0.52 (0.28-0.97), AF per se was insignificant: HR = 0.68 (0.37-1.25); the interaction of CRT by AF was strongly significant (p = 0.006). Both CRT arms had significant increase in acute toxicities (p0.005), and the AF+C arm also incurred borderline increase in late toxicities (34% vs. 14% at 3 years, p = 0.05).Preliminary results suggest that concurrent chemoradiotherapy with accelerated fractionation could significantly improve tumor control when compared with conventional RT alone; further confirmation of therapeutic ratio is warranted. more...

Background and purpose To define the dose–response relationship of nasopharyngeal carcinoma (NPC) above the conventional tumoricidal dose level of 66Gy when the basic radiotherapy (RT) course was given by the 2D Ho's technique. Patients and methods Data from all five regional cancer centers in Hong Kong were pooled for this retrospective study. All patients ( n =2426) were treated with curative-intent RT with or without chemotherapy between 1996 and 2000 with the basic RT course using the Ho's technique. The primary endpoint was local control. The prognostic significance of dose-escalation (‘boost') after 66Gy, T-stage, N-stage, use of chemotherapy, sex and age (≤40 years vs >40 years) was studied. Both univariate and multivariate analyses were performed. Results On multivariate analysis, T-stage ( P P =0.01; HR, 0.34) were the only significant factors affecting local failure for the whole study population, and for the population of patients treated by radiotherapy alone, but not for patients who also received chemotherapy. The following were independent determinants of local failure for patient groups with different T-stages treated by radiotherapy alone: use of a boost in T1/T2a disease ( P =0.01; HR, 0.33); use of a boost ( P P =0.01; HR, 1.02) in T3/T4 tumors. Among patients with T2b tumors treated by radiotherapy alone and given a boost, the use of a 20Gy-boost gave a lower local failure rate than a 10Gy-boost. There was no apparent excess mortality attributed to RT complications. Conclusions Within the context of a multi-center retrospective study, dose-escalation above 66Gy significantly improved local control for T1/T2a and T3/4 tumors when the primary RT course was based on the 2D Ho's technique without additional chemotherapy. ‘Boosting' in NPC warrants further investigation. Caution should be taken when boosting is considered because of possible increase in radiation toxicity. more...

GM-CSF and transforming growth factor beta (TGFbeta ) are required for the generation of Langerhans cells (LC), members of the dendritic cell (DC) family. Tumor necrosis factor alpha (TNFalpha) and IL-4 can enhance LC differentiation from human monocytes or CD34(+) progenitors. Here, we show that M-CSF-cultured DC precursors derived from CD34(+) progenitors resemble dermal CD14(+) cells and readily convert to LC-like DC in GM-CSF/TGFbeta. The cells express Langerin, CD1a, and CCR6, migrate in response to CCR6 ligand CCL20, and contain Birbeck granules. TNFalpha and IL-4, added separately or together, have an inhibitory effect on LC differentiation. Cells differentiated in the presence of IL-4 and TNFalpha express low levels of CCR7. This suggests that M-CSF-conditioned DC precursors retain the capacity to efficiently undergo a differentiation program, giving rise to LC-like DC solely through the effect of GM-CSF and TGFbeta. more...

CD14+interstitial cells reside beneath the epidermis of skin and mucosal tissue and may therefore play an important role in viral infections and the shaping of an antiviral immune response. However, in contrast to dendritic cells (DC) or blood monocytes, these antigen-presenting cells (APC) have not been well studied. We have previously described long-lived CD14+cells generated from CD34+hematopoietic progenitors, which may represent model cells for interstitial CD14+APC. Here, we show that these cells carry DC-SIGN and differentiate into immature DC in the presence of granulocyte-macrophage colony-stimulating factor. We have compared the CD14+cells and the DC derived from these cells with respect to dengue virus and human immunodeficiency virus type 1 (HIV-1) infection. Both cell types are permissive to dengue virus infection, but the CD14+cells secrete the anti-inflammatory cytokine interleukin 10 and no tumor necrosis factor alpha. Regarding HIV, the CD14+cells are permissive to HIV-1, release higher p24 levels than the derived DC, and more efficiently activate HIV Pol-specific CD8+memory T cells. The CD14+DC precursors infected with either virus retain their DC differentiation potential. The results suggest that interstitial CD14+APC may contribute to HIV-1 and dengue virus infection and the shaping of an antiviral immune response. more...

This phase III randomized study compared concurrent cisplatin-radiotherapy (CRT) versus radiotherapy (RT) alone in patients with locoregionally advanced nasopharyngeal carcinoma. A total of 350 patients were randomly assigned to receive external RT alone or concurrently with cisplatin at a dosage of 40 mg/m(2) weekly. The primary endpoint was overall survival, and the median follow-up was 5.5 years. The 5-year overall survival was 58.6% (95% confidence interval [CI] = 50.9% to 66.2%) for the RT arm and 70.3% (95% CI = 63.4% to 77.3%) for the CRT arm. In Cox regression analysis adjusted for T stage, age, and overall stage, the difference in overall survival was statistically significantly in favor of concurrent CRT (P = .049, hazard ratio [HR] = 0.71 [95% CI = 0.5 to 1.0]). Subgroup analysis demonstrated that there was no difference between overall survival in the arms for T1/T2 stage (P = .74, HR = 0.93 [95% CI = 0.59 to 1.4]), whereas there was a difference between the arms for T3/T4 stage (P = .013, HR = 0.51 [95% CI = 0.3 to 0.88]), favoring the CRT arm. The regimen of weekly concurrent CRT is a promising standard treatment strategy for locoregionally advanced nasopharyngeal carcinoma patients. more...

In most Western countries, screening mammography and breast-conserving therapy (BCT) are now well-established practices and have been well accepted by women over the last two decades. There are limited data on the acceptability of these strategies by Chinese women in an Oriental society where a population-based screening program has not been established and mastectomy is still commonly practiced. A survey was conducted of 1012 Hong Kong Chinese women, ages 18-69 years, to assess the level of knowledge, perceptions, and attitudes on screening mammography and the surgical management of early breast cancer. Most women (58%) had never heard of mammographic screening, and housewives were more likely to have heard of it than nonhousewives (49% versus 37%; p = 0.0001). The majority (82%) of those who had heard of mammographic screening believe that it can detect early breast cancers and reduce mortality, however, only 58% of these women would participate in yearly screening and clinical breast examination despite acknowledging the potential benefits; a lack of time and the cost were the predominant reasons given. Forty-seven percent of women had the misconception that mastectomy was the only curative treatment; when the alternative was explained, the overall rate for choosing BCT rose from 29% to 49%. There was no correlation between age and the choice of surgery. Most women (75%) felt that breast reconstruction after mastectomy was desirable and acceptable. A lack of knowledge on mammographic screening is prevalent and the concept of preventive health care has a low priority in this Chinese population. Mastectomy is still widely perceived as the only curative treatment; BCT with cosmetic reconstruction is seen as an acceptable alternative. Interventions to improve the accuracy of information and to encourage preventive health care behaviors will have a positive impact on establishing cancer screening programs and providing quality cancer care in the future. more...

To evaluate the efficacy of using intensity-modulated radiotherapy (IMRT) in the primary treatment of nasopharyngeal carcinoma (NPC), including the role of dose escalation above 66 Gy level.Between July 2000 and September 2002, 63 newly diagnosed NPC patients were treated with IMRT. The disease was Stage I in 9 (14%), Stage II in 18 (29%), Stage III in 22 (35%), and Stage IV in 14 (22%). The prescribed dose was 66 Gy to the gross tumor volume (GTV) and positive neck nodes, 60 Gy to the planning target volume (PTV), and 54-60 Gy to the clinically negative neck. All 20 (100%) patients with T1-2a tumors received intracavitary brachytherapy (ICB) boost, and 15/42 (36%) patients with T2b-T4 tumors received conformal boost (8 Gy/4 fractions). Nineteen patients with advanced stage disease also received either neoadjuvant or concurrent chemotherapy. Acute and late normal tissue effects were graded according to the Radiation Therapy Oncology Group (RTOG) radiation morbidity scoring criteria. Local relapse-free survival (LRFS), nodal relapse-free survival (NRFS), distant metastasis-free survival (DMFS), and overall survival (OS) were estimated using the Kaplan-Meier method.With a median follow-up of 29 months (range 8-45 months), 4 patients developed local in-field failure, 1 patient developed regional relapse, and 13 patients developed distant metastases. All 4 patients with local failure had either T3 or T4 disease before primary treatment and did not have ICB or conformal boost. The 3-year actuarial LRFS, NRFS, DMFS, and OS were 92%, 98%, 79%, and 90%, respectively. Multivariate analysis showed that dose escalation above 66 Gy was significantly associated with better PFS and DMFS, whereas GTV size was a significant adverse factor for OS. The worst acute mucositis was Grade 1 or 2 in 36 (59%), and Grade 3 in 25 (41%) patients. Acute dysphagia requiring tube feeding occurred in 5 (8%) patients. The proportion of patients with Grade 2-3 xerostomia was 57% at 3 months, and 23% at 2 years after IMRT. Within the subset of patients with a mean parotid dose of31 Gy, the proportions with Grade 2-3 xerostomia were 30% and 17% at 3 months and 2 years, respectively.Our experience of using IMRT in the primary treatment of NPC showed a very high rate of locoregional control and favorable toxicity profile. Furthermore, we found that dose escalation above 66 Gy of IMRT-based therapy was a significant determinant of progression-free survival and distant metastasis-free survival for advanced T-stage tumors. Distant metastases represent the predominant mode of treatment failure. more...

OBJECTIVE To examine the impact of the 21-gene Oncotype DX Breast Cancer Assay on the adjuvant treatment decision-making process for early-stage breast cancer in Hong Kong. DESIGN Retrospective study. SETTING Private hospital, Hong Kong. PATIENTS Study included cases of early-stage breast cancer (T1-2N0-1M0, oestrogen receptor-positive, human epidermal growth factor receptor 2-negative) that were presented at a multidisciplinary breast meeting at a single site. Cases were selected for Oncotype DX testing with the assistance of Adjuvant! Online. The recommendations for adjuvant therapy before and after obtaining the Oncotype DX Recurrence Score results were analysed. RESULTS A total of 154 cases that met the inclusion criteria were discussed at our multidisciplinary breast meeting. Of these, 64 cases with no clear recommendation by the Meeting Panel were selected for this study and reviewed. The distribution of Recurrence Score results was similar to that reported by others, with a somewhat higher proportion of low Recurrence Scores. Treatment recommendation was changed for 20 (31%) patients after the Oncotype DX result was received. Of the changes in treatment decisions, 16 (80%) were changes to lower-intensity regimens (either equipoise or hormonal therapy). The number of cases receiving an equipoise recommendation decreased by nine (82%), based on the additional information provided by the Oncotype DX test. CONCLUSION The Oncotype DX Recurrence Score information impacts the decision-making process for adjuvant therapy for early-stage breast cancer in the multidisciplinary care setting in Hong Kong. A larger-scale study is required to gain more experience, evaluate its impact more thoroughly, and assess its cost-effectiveness. more...

Purpose: To evaluate the efficacy of high-dose (≥60 Gy) reirradiation using mainly external beams in salvaging local failures of nasopharyngeal carcinoma (NPC) after modern primary radical radiotherapy that delivered radical dose-to-target volumes defined by CT scan. Methods and Materials: Nine hundred and three patients with nondisseminated NPC whose primary radical radiotherapy was administered between 1984 and 1989 inclusive were studied. One hundred and seventy-six had local failures comprising 9 persistences and 167 recurrences. In 10 patients the local failures were preceded or accompanied by (within 2 months) distant metastases, and these were given supportive treatment or palliative radiotherapy in low dose ( more...

We present the magnetic resonance imaging (MRI), computed tomography (CT) and ultrasound appearances of three cases of pediatric head and neck rhabdomyosarcomas, involving the orbit, parameningeal region (nasopharynx and nasal sinus), and trapezius muscle anatomically. The histopathological subtypes included two embryonal and one alveolar. MRI is a superior imaging technique with its high contrast resolution of soft tissue tumors and multiplanar noninvasive capability. The literature on CT and MRI appearances of head and neck rhabdomyosarcomas is reviewed. more...

Purpose : To evaluate the significant prognosticators in nasopharyngeal carcinoma (NPC). Methods and Materials : From 1984 to 1989, 903 treatment-naive nondisseminated (M0) NPC were given primary radical radiotherapy to 60-62.5 Gy in 6 weeks. All patients had computed tomographic (CT) and endoscopic evaluation of the primary tumor. Potentially significant parameters (the patient's age and sex, the anatomical structures infiltrated by the primary lesion, the cervical nodal characteristics, the tumor histological subtypes, and various treatment variables were analyzed hy both monovariate and multivariate methods for each of the five clinical endpoints : actuarial survival, disease-free survival, free from distant metastasis, free from local failure, and free from regional failure. Results : The significant prognosticators predicting for an increased risk of distant metastases and poorer survival included male sex, skull base and cranial nerve(s) involvement, advanced Ho's N level, and presence of fixed or partially fixed nodes or nodes contralateral to the side of the bulk of the nasopharyngeal primary. Advanced patient age led to significantly worse survival and poorer local tumor control. Local and regional failures were both increased by tumor infiltrating the skull base and/or the cranial nerves. In addition, regional failure was increased significantly by advancing Ho's N level. Parapharyngeal tumor involvement was the strongest independent prognosticator that determined distant metastasis and survival rates in the abscence of the overriding prognosticators of skull base infiltration, cranial nerve(s) palsy, and cervical nodal metastasis. Conclusions : The significant prognosticators are delineated after the advent of CT and these should form the foundation of the modern stage classification for NPC. more...

BACKGROUND Distant metastases are common in patients with nasopharyngeal carcinoma (NPC), and their presence is the most important factor in limiting survival. We aimed to study the prognosticators determining survival subsequent to distant metastasis from NPC. METHODS A study by both mono- and multivariate analyses was carried out in 945 patients presenting between 1984 and 1989. Forty-two presented with metastases and 247 developed metastasis after primary radiotherapy. RESULTS Patients who presented with distant metastasis (M1-classification) had a significantly shorter survival than those who developed metastases after primary radiotherapy. The presence of hepatic metastases, short metastasis free interval, and older age at presentation significantly predicted short survival after the diagnosis of distant metastasis. Patients with metastases preceded by, and/or accompanied with, locoregional recurrence had comparable survival to those without, despite their association with a significantly longer metastasis free interval. A history of locoregional recurrence was however not compatible with long term, disease free survival, and, in its presence, advanced T-classification on presentation predicted poor survival subsequent to metastasis. Long term disease free survival (64–117 months) was attained in 4 young patients (age < 40 years) with isolated intrathoracic metastases in the absence of locoregional recurrence after achieving a complete response to aggressive treatment, with chemotherapy, radiotherapy, and/or surgery, usually multimodal. CONCLUSIONS Some of the clinical prognosticators have been identified and an attempt was made to subclassify distant metastases according to possible differences in prognosis. A subset of metastatic NPC was identified which is compatible with long term, disease free survival. Investigations during follow-up should be directed toward the early detection of such potentially salvageable cases. Cancer 1996;77:2423-31. more...

The aims of this retrospective study were to determine the role of intracavitary brachytherapy given shortly after external beam radiotherapy in the primary radical treatment of non-metastatic nasopharyngeal (NPC) cancer patients, and the prognostic factors governing local tumour control. From 1984 to 1989, 903 patients with non-disseminated NPC who had had no previous treatment were managed at the Prince of Wales Hospital, where investigation and treatment methods had been standardized according to a departmental protocol. The external radiotherapy dose of 60.0–62.5 Gy in 6 weeks was given to all patients. Parapharyngeal booster radio-therapy with a single photon beam to 20 Gy in 2 weeks was given to those with parapharyngeal tumour extension. Computed tomography of the nasopharynx and skull base, and pretreatment nasopharyngoscopy and biopsy were performed in all patients. Nasopharyngoscopy was repeated at 4 weeks after the last day of external irradiation. Local persistence in 99 patients was treated additionally by intracavitary brachytherapy to 24 Gy in three fractions over 15 days. Fifty-one patients with early stage primary disease (Ho Stage T 1 and T 2n (nasal)) who responded completely to external radiotherapy were given adjuvant intracavitary brachytherapy to 18 Gy in three fractions over 15 days. Intracavitary therapy was an inadequate salvage treatment for the locally persisting T 3 , T 2o (oropharyngeal) and T 2p (parapharyngeal) disease, but there was a trend towards improved local control after intracavitary brachytherapy for the locally persisting T 1 tumours. Adjuvant brachytherapy did not enhance local tumour control for the early T-stage tumours that completely responded to external radiotherapy. Both forms of intracavitary brachytherapy were safe with few and acceptable complications. In the 903 non-disseminated NPCs, the patient's age and tumour involvement of the skull base and cranial nerves were significant independent prognostic factors governing local tumour control. In the 358 patients with Ho T 3 disease, tumour involvement of the orbits and the laryngopharynx significantly worsened local tumour control. The presence of local persistence at 4 weeks after external radiotherapy, for which therapeutic brachytherapy was given, was marginally significant as a prognostic factor in addition to the presence of cranial nerve palsy. more...

Host macrophages protect against graft-versus-host disease in part by engulfing donor T cells and inhibiting their proliferation., Acute graft-versus-host disease (GVHD) results from the attack of host tissues by donor allogeneic T cells and is the most serious limitation of allogeneic hematopoietic cell transplantation (allo-HCT). Host antigen-presenting cells are thought to control the priming of alloreactive T cells and the induction of acute GVHD after allo-HCT. However, whereas the role of host DC in GVHD has been established, the contribution of host macrophages to GVHD has not been clearly addressed. We show that, in contrast to DC, reducing of the host macrophage pool in recipient mice increased donor T cell expansion and aggravated GVHD mortality after allo-HCT. We also show that host macrophages that persist after allo-HCT engulf donor allogeneic T cells and inhibit their proliferation. Conversely, administration of the cytokine CSF-1 before transplant expanded the host macrophage pool, reduced donor T cell expansion, and improved GVHD morbidity and mortality after allo-HCT. This study establishes the unexpected key role of host macrophages in inhibiting GVHD and identifies CSF-1 as a potential prophylactic therapy to limit acute GVHD after allo-HCT in the clinic. more...

Decay-accelerating factor (DAF) is a cell surface regulator that accelerates the dissociation of C3/C5 convertases and thereby prevents the amplification of complement activation on self cells. In the context of transplantation, DAF has been thought to primarily regulate antibody-mediated allograft injury, which is in part serum complement-dependent. Based on our previously delineated link between DAF and CD4 T cell responses, we evaluated the effects of donor Daf1 (the murine homolog of human DAF) deficiency on CD8 T cell-mediated cardiac allograft rejection. MHC-disparate Daf1−/− allografts were rejected with accelerated kinetics compared with wild-type grafts. The accelerated rejection predominantly tracked with DAF’s absence on bone marrow-derived cells in the graft and required allograft production of C3. Transplantation of Daf1−/− hearts into wild-type allogeneic hosts augmented the strength of the anti-donor (direct pathway) T cell response, in part through complement-dependent proliferative and pro-survival effects on alloreactive CD8 T cells. The accelerated allograft rejection of Daf1−/− hearts occurred in recipients lacking anti-donor Abs. The results reveal that donor DAF expression, by controlling local complement activation on interacting T cell APC partners, regulates the strength of the direct alloreactive CD8+ T cell response. The findings provide new insights into links between innate and adaptive immunity that could be exploited to limit T cell-mediated injury to an allograft following transplantation. more...

Background An important question in dengue pathogenesis is the identity of immune cells involved in the control of dengue virus infection at the site of the mosquito bite. There is evidence that infection of immature myeloid dendritic cells plays a crucial role in dengue pathogenesis and that the interaction of the viral envelope E glycoprotein with CD209/DC-SIGN is a key element for their productive infection. Dermal macrophages express CD209, yet little is known about their role in dengue virus infection. Methods and Findings Here, we showed that dermal macrophages bound recombinant envelope E glycoprotein fused to green fluorescent protein. Because dermal macrophages stain for IL-10 in situ, we generated dermal-type macrophages from monocytes in the presence of IL-10 to study their infection by dengue virus. The macrophages were able to internalize the virus, but progeny virus production was undetectable in the infected cells. In addition, no IFN-α was produced in response to the virus. The inability of dengue virus to grow in the macrophages was attributable to accumulation of internalized virus particles into poorly-acidified phagosomes. Conclusions Aborting infection by viral sequestration in early phagosomes would present a novel means to curb infection of enveloped virus and may constitute a prime defense system to prevent dengue virus spread shortly after the bite of the infected mosquito., Author Summary Mosquito-transmitted pathogens are a major challenge to humans due to ever-increasing distribution of the vector worldwide. Dengue virus causes morbidity and mortality, and no anti-viral treatment or vaccine are currently available. The virus is injected into the skin when an infected mosquito probes for blood. Among the skin immunocytes, dendritic cells and macrophages are equipped with pathogen-sensing receptors. Our work has shown that dermal macrophages bind the dengue virus envelope protein. We demonstrate that monocyte-derived dermal macrophages are resistant to infection and present evidence that this is due to sequestration of the virus into fusion-incompetent intracellular vesicles. This identifies skin macrophages as the first innate immune cell potentially capable of protecting the human host from infection by dengue virus shortly after a mosquito bite. These findings have important implications for better understanding the early infection events of dengue virus and of other skin-penetrating pathogens. more...

The primary tumor regression pattern of 50 patients with nasopharyngeal carcinoma was reported. The tumor regression was monitored either by indirect nasopharyngeal mirror examination and biopsy or fiberoptic endoscope and biopsy. Fiberoptic endoscope and biopsy was found to be more accurate in noting residual tumor. It is recommended that booster radiation dose to the residual primary tumors be withheld unless positive biopsy samples persist at 10 or more weeks after radiotherapy. more...

Purpose This randomized trial compared the rates of delayed xerostomia between two-dimensional radiation therapy (2DRT) and intensity-modulated radiation therapy (IMRT) in the treatment of early-stage nasopharyngeal carcinoma (NPC). Patients and Methods Between November 2001 and December 2003, 60 patients with T1-2bN0-1M0 NPC were randomly assigned to receive either IMRT or 2DRT. Primary end point was incidence of observer-rated severe xerostomia at 1 year after treatment based on Radiotherapy Oncology Group /European Organisation for the Research and Treatment of Cancer late radiation morbidity scoring criteria. Parallel assessment with patient-reported outcome, stimulated parotid flow rate (SPFR), and stimulated whole saliva flow rate (SWSFR) were also made. Results At 1 year after treatment, patients in IMRT arm had lower incidence of observer-rated severe xerostomia than patients in the 2DRT arm (39.3% v 82.1%; P = .001), parallel with a higher fractional SPFR (0.90 v 0.05; P < .0001), and higher fractional SWSFR (0.41 v 0.20; P = .001). As for patient's subjective feeling, although a trend of improvement in patient-reported outcome was observed after IMRT, recovery was incomplete and there was no significant difference in patient-reported outcome between the two arms. Conclusion IMRT is superior to 2DRT in preserving parotid function and results in less severe delayed xerostomia in the treatment of early-stage NPC. Incomplete improvement in patient's subjective xerostomia with parotid-sparing IMRT reflects the need to enhance protection of other salivary glands. more...

Dendritic cells (DC) obtained by culturing myeloid precursors in GM-CSF undergo maturation and induce an efficient T cell response when stimulated with microbial products. DC precursors themselves also recognize microbial products, and it remains unclear how these stimulated DC precursors modulate the immune response. We show here that M-CSF-conditioned human DC precursors responded to LPS, Mycobacteria bovis, and inflammatory cytokines by a rapid and robust production of IL-10, largely superior to that observed with immature DC or monocytes. The endogenous IL-10 restrained the DC precursors from converting into professional APC, as blocking the IL-10 receptor in the presence of LPS resulted in the formation of efficient T cell stimulators. LPS stimulation concomitant with DC differentiation gave rise to immature DC, which were tolerant to a secondary LPS exposure. Furthermore, the LPS-activated DC precursors reduced bystander DC maturation and anti-CD3/CD28-triggered T cell activation. These data suggest that when exposed to inflammatory or microbial signals, M-CSF-conditioned DC precursors can participate in the modulation of inflammation and immune response by rapid release of IL-10. more...

Background & Purpose: It is time consuming to contour numerous structures on CT images during intensity-modulated radiation therapy (IMRT) planning for nasopharyngeal carcinoma (NPC). The present study compares the dosimetry of using ‘interpolated’ contours and ‘real’ contours in advanced-stage NPC. Methods & Materials: Twenty NPC patients with T3-4 tumors were selected and contours of targets and OARs were delineated on consecutive CT images. For each patient, a reference (REF) IMRT plan was generated based on these ‘real’ contours. An investigative (INV) IMRT plan was generated with the same planning protocol but based on ‘interpolated’ contours that were reformed after deleting the contours on alternate slices and replacing the deleted contours by the interpolated contours of the adjacent slices. The dose-endpoints of targets and OARs between two plans were compared. Results: For both the gross tumor volume (GTV) and planning target volume (PTV), all cases in both plans achieved 95% volume receiving the prescribed dose, and less than 1% volume receiving more...

Large B cell lymphomas can comprise numerous CD14+ cells in the tumor stroma, which raises the question of whether monocytes can support B cell survival and proliferation. We show that the coculture of monocytes with B cells from peripheral blood or from diffuse large B cell lymphoma enabled prolonged B cell survival. Under these conditions, diffuse large lymphoma B cells proliferated, and addition of B cell-activating factor of the TNF family (BAFF) and IL-2 enhanced cell division. Monocytes and dendritic cells (DC) had similar antiapoptotic activity on healthy B cells but displayed differences with respect to B cell proliferation. Monocytes and cord blood-derived CD14+ cells promoted B cell proliferation in the presence of an anti-CD40 stimulus, whereas DC supported B cell proliferation when activated through the BCR. DC and CD14+ cells were able to induce plasmocyte differentiation. When B cells were activated via the BCR or CD40, they released the leukocyte attractant CCL5, and this chemokine is one of the main chemokines expressed in diffuse large B cell lymphoma. The data support the notion that large B cell lymphoma recruit monocytes via CCL5 to support B cell survival and proliferation. more...

A 7-year-old boy with Ph+ ALL received an allogeneic BMT in second remission. Conditioning included cyclophosphamide 60 mg/kg for 2 days, TBI 2 Gy twice daily for 3 days (12 Gy) and a single testicular boost of 4 Gy. He remained in hematological remission after BMT but developed isolated testicular relapse at 17 months. He underwent orchiectomy of the affected testis, 24 Gy testicular radiotherapy and systemic chemotherapy. He remains in remission 24 months after the testicular relapse. This is the first report of isolated testicular relapse which received a testicular irradiation boost included in the conditioning. more...

We report on a 37-year-old woman who developed a desmoid tumor over the left chest within the field of previous radiotherapy for carcinoma of the breast. She had a history of bilateral sequential carcinoma of the breasts (a right-breast lesion followed by a left-breast lesion) and underwent bilateral mastectomy and adjuvant radiotherapy, with adjuvant chemotherapy given only to the right-breast cancer. Possible causal factors and treatment options for such tumors are highlighted. This case illustrates the importance of histologic confirmation for clinically suspicious local recurrence in patients with a history of breast cancer. more...

Purpose To evaluate the effect of combining circulating Epstein-Barr viral (EBV) DNA load data with TNM staging data in pretherapy prognostication of nasopharyngeal carcinoma (NPC). Patients and Methods Three hundred seventy-six patients with all stages of NPC were studied. Pretreatment plasma/serum EBV DNA concentrations were quantified by a polymerase chain reaction assay. Determinants of overall survival were assessed by multivariate analysis. Survival probabilities of patient groups, segregated by clinical stage (I, II, III, or IV) alone and also according to EBV DNA load (low or high), were compared. Results Pretherapy circulating EBV DNA load is an independent prognostic factor for overall survival in NPC. Patients with early-stage disease were segregated by EBV DNA levels into a poor-risk subgroup with survival similar to that of stage III disease and a good-risk subgroup with survival similar to stage I disease. Conclusion Pretherapy circulating EBV DNA load is an independent prognostic factor to International Union Against Cancer (UICC) staging in NPC. Combined interpretation of EBV DNA data with UICC staging data leads to alteration of risk definition of patient subsets, with improved risk discrimination in early-stage disease. Validation studies are awaited. more...

Aims The role of adjuvant chemoradiation for gastric cancer after curative R0 gastrectomy was first established by the US Intergroup 0116 study. Although confirmatory studies are in progress, few data are available regarding its application to the Chinese population. We describe our radiotherapy technique and report the treatment results in Hong Kong. Materials and methods This was a single centre retrospective study on 63 Chinese patients who underwent adjuvant chemoradiation for gastric adenocarcinoma between June 2000 and December 2004. The treatment protocol was based on that of the Intergroup study. Computed tomography planned anteroposterior opposing field arrangement and treatment under breath hold at deep inspiration position were adopted. Results In total, 63 patients, mean age 50 years, with gastric cancer stage IB to limited metastatic IV disease were analysed. The median follow-up time was 27.2 months. The relapse-free survival and overall survival at 3 years were 50 and 54%, respectively. The recurrence pattern was dominated by distant failure and only one patient developed isolated locoregional recurrence. Of the 10 patients who had positive microscopic surgical margins after surgery, seven had recurred and died. On multivariate analysis, margin status was the only significant prognosticator for survival. Thirty per cent of patients experienced grade 3 or above acute toxicity (24% haematological, 14% gastrointestinal) and one patient died of neutropenic sepsis. There was one case of grade 3 late toxicity. Conclusions The outcome after adjuvant chemoradiation for gastric cancer seemed to be favourable, with manageable toxicities, in the Chinese population. Locoregional failure was uncommon. Patients with microscopic surgical margin involvement had a very high failure rate despite adjuvant chemoradiation. more...

It is of clinical importance to distinguish a primary malignancy from a metastatic malignancy in the breast, since the management of each type is different. Rhabdomyosarcoma is a common extramammory primary malignancy that may metastasize to the breast in the pediatric age group. Such breast metastases usually occur in adolescent girls (older than the median age for rhabdomyosarcoma), with primary tumors located at the extremities and an alveolar histologic pattern. We present a case of a 14 year old girl in whom gray-scale and color Doppler imaging clearly showed the features of alveolar rhabdomyosarcoma mestastatic to the breasts. more...

Purpose To assess the efficacy of neoadjuvant paclitaxel and carboplatin (TC) followed by concurrent cisplatin and radiotherapy (RT) in patients with locoregionally advanced nasopharyngeal carcinoma (NPC) and to monitor treatment response with plasma Epstein-Barr virus (EBV) DNA. Patients and Methods Thirty-one patients with International Union Against Cancer stages III and IV undifferentiated NPC had two cycles of paclitaxel (70 mg/m2 on days 1, 8, and 15) and carboplatin (area under the curve 6 mg/mL/min on day 1) on a 3-weekly cycle, followed by 6 to 8 weeks of cisplatin (40 mg/m2 weekly) and RT at 66 Gy in 2-Gy fractions. Plasma EBV DNA was measured serially using the real-time quantitative polymerase chain reaction method. Results All patients completed planned treatment. Response to neoadjuvant TC was as follows: 12 patients (39%) achieved partial response (PR) and 18 achieved (58%) complete response (CR) in regional nodes; five patients (16%) achieved PR and no patients achieved CR in nasopharynx. At 6 weeks after RT, one patient (3%) achieved PR and 30 patients (97%) achieved CR in regional nodes, and 31 patients (100%) achieved CR in nasopharynx; 29 patients (93%) had EBV DNA level of less than 500 copies/mL. Neoadjuvant TC was well tolerated, and the most common acute toxicity of cisplatin plus RT was grade 3 mucositis (55%). At median follow-up of 33.7 months (range, 7 to 39.3 months), six distant and three locoregional failures occurred. Plasma EBV DNA level increased significantly in eight of nine patients who experienced treatment failure but did not increase in those who did not. The 2-year overall and progression-free survival rates were 91.8% and 78.5%, respectively. Conclusion This strategy was feasible and resulted in excellent local tumor control. Serial plasma EBV DNA provides a noninvasive method of monitoring response in NPC. more...

PurposeTo determine whether therapy with a DNA methyltransferase inhibitor is effective in achieving demethylation and gene re-expression in tumor DNA in patients.MethodsBiopsy specimens were obtained from patients with Epstein-Barr virus-associated tumors, enrolled on a clinical trial of 5-azacitidine, within 72 hours of the conclusion of the last infusion of the first cycle of therapy, and compared to pretreatment specimens. Methylation-specific polymerase chain reaction, bisulfite genomic sequencing, and immunohistochemistry were used to assess demethylation and gene re-expression.ResultsSubstantial degrees of demethylation were detected in all latent and lytic Epstein-Barr virus promoters examined. Immunohistochemistry suggested activation of a previously silent viral antigen expression in one instance.ConclusionPharmacologic reversal of dense CpG methylation in tumor tissue can be achieved in patients. more...

Background and purpose: This pilot study assesses the psychosocial impact of different modalities of breast cancer surgery in Chinese patients and their husbands. Methods: Thirty-six patients who underwent conservative breast therapy (BCT) for breast cancer were compared with 36 women who underwent total mastectomy (TM) on four aspects of psychosocial adjustment. They were matched in pairs in terms of stage of disease, age and time since surgery. Where available, their husbands were also consented for similar assessment. Results: Women who underwent BCT showed a significantly better response to their body and sexual image than those who underwent TM. This difference did not translate into any significant difference in terms of emotional and symptomatic aspects, daily activities, or fear of recurrences. The husbands of patients in the TM group showed significantly more emotional and symptomatic distress and greater change in the perception of their wives' body and sexual images. Conclusion: This is the first of such study conducted in a Chinese population. The lack of differences in certain psychosocial aspects may indicate a generally good adjustment in the TM patients after their surgery. It may also relate to the fact that volunteers for the study were themselves representative only of the patient population who adapted well to the surgery, and those patients who were emotionally distressed tended to decline to participate. Psychosocial disruption in the patients' families is reflected in our study where patients' husbands in the TM group were significantly more disturbed. However, due to the limited number of patients studied, the findings are not yet conclusive and require further studies for confirmation. Copyright © 2003 John Wiley & Sons, Ltd. more...

PURPOSE: Nasopharyngeal carcinoma (NPC) is highly sensitive to both radiotherapy (RT) and chemotherapy. This randomized phase III trial compared concurrent cisplatin-RT (CRT) with RT alone in patients with locoregionally advanced NPC. PATIENTS AND METHODS: Patients with Ho’s N2 or N3 stage or N1 stage with nodal size ≥ 4 cm were randomized to receive cisplatin 40 mg/m2 weekly up to 8 weeks concurrently with radical RT (CRT) or RT alone. The primary end point was progression-free survival (PFS). RESULTS: Three hundred fifty eligible patients were randomized. Baseline patient characteristics were comparable in both arms. There were significantly more toxicities, including mucositis, myelosuppression, and weight loss in the CRT arm. There were no treatment-related deaths in the CRT arm, and one patient died during treatment in the RT-alone arm. At a median follow-up of 2.71 years, the 2-year PFS was 76% in the CRT arm and 69% in the RT-alone arm (P = .10) with a hazards ratio of 1.367 (95% confidence interval [CI], 0.93 to 2.00). The treatment effect had a significant covariate interaction with tumor stage, and a subgroup analysis demonstrated a highly significant difference in favor of the CRT arm in Ho’s stage T3 (P = .0075) with a hazards ratio of 2.328 (95% CI, 1.26 to 4.28). For T3 stage, the time to first distant failure was statistically significantly different in favor of the CRT arm (P = .016). CONCLUSION: Concurrent CRT is well tolerated in patients with advanced NPC in endemic areas. Although PFS was not significantly different between the concurrent CRT arm and the RT-alone arm in the overall comparison, PFS was significantly prolonged in patients with advanced tumor and node stages. more...