Sun exposure and risk of lymphoid neoplasms in Singapore.

BACKGROUND: Epidemiologic studies have reported an inverse association between sun exposure and non-Hodgkin lymphoma (NHL), but these have been almost exclusively conducted in Western populations residing in temperate locations. We evaluated the association between personal outdoor sun exposure and risk of malignant lymphomas in Singapore. METHODS: A hospital-based case-control study of 541 incident cases of lymphoid neoplasms and 830 controls were recruited during 2004-2008. Participants were interviewed regarding recreational or occupational outdoor activities during childhood and in adulthood. Basic demographics and potential confounders were also collected. Odds ratios (OR) and 95 % confidence intervals (CI) were calculated using unconditional logistic regression analysis. RESULTS: Compared with individuals who did not have regular sun exposure, a lower risk of NHL was observed for those who reported regular exposure on non-school days during childhood [OR, 0.62; 95 % CI, 0.46-0.83] and non-working days in adulthood [OR, 0.70; 95 % CI, 0.51-0.97]. The protective effect was more evident among women. CONCLUSION: Our findings support an inverse relationship between intermittent sun exposure and the risk of NHL. These findings are consistent with the growing evidence from various countries, but further studies, especially prospective studies, are needed in Asian populations.

High incidence of nasopharyngeal cancer: similarity for 60% of mitochondrial DNA signatures between the Bidayuhs of Borneo and the Bai-yue of Southern China.

Populations in Southern China (Bai-yue) and Borneo (Bidayuh) with high incidence of nasopharyngeal cancer(NPC) share similar mitochondrial DNA signatures, supporting the hypothesis that these two populations may share the same genetic predisposition for NPC, which may have first appeared in a common ancestral reference population before the sea levels rose after the last ice age.

Is nasopharyngeal cancer really a "Cantonese cancer"?

Nasopharyngeal cancer (NPC) is endemic in Southern China, with Guandong province and Hong Kong reporting some of the highest incidences in the world. The journal Science has called it a "Cantonese cancer". We propose that in fact NPC is a cancer that originated in the Bai Yue ("proto Tai Kadai" or "proto Austronesian" or "proto Zhuang") peoples and was transmitted to the Han Chinese in southern China through intermarriage. However, the work by John Ho raised the profile of NPC, and because of the high incidence of NPC in Hong Kong and Guangzhou, NPC became known as a Cantonese cancer. We searched historical articles, articles cited in PubMed, Google, monographs, books and Internet articles relating to genetics of the peoples with high populations of NPC. The migration history of these various peoples was extensively researched, and where possible, their genetic fingerprint identified to corroborate with historical accounts. Genetic and anthropological evidence suggest there are a lot of similarities between the Bai Yue and the aboriginal peoples of Borneo and Northeast India; between Inuit of Greenland, Austronesian Mayalo Polynesians of Southeast Asia and Polynesians of Oceania, suggesting some common ancestry. Genetic studies also suggest the present Cantonese, Minnans and Hakkas are probably an admixture of northern Han and southern Bai Yue. All these populations have a high incidence of NPC. Very early contact between southern Chinese and peoples of East Africa and Arabia can also account for the intermediate incidence of NPC in these regions.

Presence of a high-grade component in gastric mucosa-associated lymphoid tissue (MALT) lymphoma is not associated with an adverse prognosis.

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.

Increased but error-prone nonhomologous end joining in immortalized lymphoblastoid cell extracts from adult cancer patients with late radionecrosis.

PURPOSE: To study nonhomologous end joining in extracts of two lymphoblastoid cell lines derived from patients with late radionecrosis after radiotherapy. Both cell lines were previously shown to exhibit impaired rejoining of DNA double-strand breaks in a pulse-field gel electrophoresis assay. METHODS AND MATERIALS: We used a cell-free system and quantitative real-time polymerase chain reaction, as well as sequencing analysis of end joining products. RESULTS: Paradoxically, extracts of the two cell lines display increased rates of in vitro end joining of noncohesive termini compared with normal cell extracts. This increase was seen in the absence of added deoxyribonucleoside triphosphates and was sensitive to inhibition by wortmannin. Sequencing of the joined products revealed that, despite increased rates of end joining, the process was error prone with a greater frequency of deletions compared with that observed in normal controls. CONCLUSION: These findings are consistent with the suggestion that a promiscuous, deletion-prone abnormality of nonhomologous end joining might underpin the predisposition of certain radiotherapy patients to late radionecrosis. We hypothesize that some individuals might harbor subclinical defects in nonhomologous end joining that clinically manifest on challenge with high-dose radiation. Because both quantitative and qualitative aspects of end joining have demonstrably been influenced, we recommend that the study of patient samples should involve a combination of quantitative methods (e.g., quantitative real-time polymerase chain reaction), sequencing analysis, and a comparison of multiple join types.

A novel approach to brachytherapy in hepatocellular carcinoma using a phosphorous32 (32P) brachytherapy delivery device--a first-in-man study.

PURPOSE: While potentially very useful, percutaneously delivered brachytherapy of inoperable intra-abdominal solid tumors faces significant technical challenges. This first-in-man study is designed to determine the safety profile and therapeutic efficacy of a novel phosphorous (32P) brachytherapy device (BrachySil) in patients with unresectable hepatocellular carcinoma. METHODS AND MATERIALS: Patients received single percutaneous and transperitoneal implantations of BrachySil under local anesthesia directly into liver tumors under ultrasound or computed tomographic guidance, at an activity level of 4 MBq/cc of tumor. Toxicity was assessed by the nature, incidence, and severity of adverse events (Common Toxicity Criteria scores) and by hematology and clinical chemistry parameters. Target tumor response was assessed with computed tomographic scans at 12 and 24 weeks postimplantation using World Health Organization criteria. RESULTS: Implantations were successfully carried out in 8 patients (13-74 MBq, mean 40 MBq per tumor) awake and under local anesthesia. Six of the 8 patients reported 19 adverse events, but no serious events were attributable to the study device. Changes in hematology and clinical chemistry were similarly minimal and reflected progressive underlying hepatic disease. All targeted tumors were responding at 12 weeks, with complete response (100% regression) in three lesions. At the end of the study, there were two complete responses, two partial responses, three stable diseases, and one progressive disease. CONCLUSION: Percutaneous implantation of this novel 32P brachytherapy device into hepatocellular carcinoma is safe and well tolerated. A significant degree of antitumor efficacy was demonstrated at this low dose that warrants further investigation.

Randomized trial of radiotherapy versus concurrent chemoradiotherapy followed by adjuvant chemotherapy in patients with American Joint Committee on Cancer/International Union against cancer stage III and IV nasopharyngeal cancer of the endemic variety.

PURPOSE: The Intergroup 00-99 Trial for nasopharyngeal cancer (NPC) showed a benefit of adding chemotherapy to radiotherapy. However, there were controversies regarding the applicability of the results to patients in endemic regions. This study aims to confirm the findings of the 00-99 Trial and its applicability to patients with endemic NPC. PATIENTS AND METHODS: Between September 1997 and May 2003, 221 patients were randomly assigned to receive radiotherapy (RT) alone (n = 110) or chemoradiotherapy (CRT; n = 111). Patients in both arms received 70 Gy in 7 weeks using standard RT portals and techniques. Patients on CRT received concurrent cisplatin (25 mg/m2 on days 1 to 4) on weeks 1, 4, and 7 of RT and adjuvant cisplatin (20 mg/m2 on days 1 to 4) and fluorouracil (1,000 mg/m2 on days 1 to 4) every 4 weeks (weeks 11, 15, and 19) for three cycles after completion of RT. All patients were analyzed by intent-to-treat analysis. The median follow-up time was 3.2 years. RESULTS: Distant metastasis occurred in 38 patients on RT alone and 18 patients on CRT. The difference in 2-year cumulative incidence was 17% (95% CI, 14% to 20%; P = .0029). The hazard ratio (HR) for disease-free survival was 0.57 (95% CI, 0.38 to 0.87; P = .0093). The 2- and 3-year overall survival (OS) rates were 78% and 85% and 65% and 80% for RT alone and CRT, respectively. The HR for OS was 0.51 (95% CI, 0.31 to 0.81; P = .0061). CONCLUSION: This report confirms the findings of the Intergroup 00-99 Trial and demonstrates its applicability to endemic NPC. This study also confirms that chemotherapy improves the distant metastasis control rate in NPC.

Complete tumor response following intratumoral 32P BioSilicon on human hepatocellular and pancreatic carcinoma xenografts in nude mice.

PURPOSE: 32P BioSilicon is a new, implantable, radiological medical device that comprises particles of highly pure silicon encapsulating 32phosphorus (32P) for the treatment of unresectable solid tumors. Prior to administration, the device particles are suspended in a formulant which provides an even suspension of the intended dose for implantation. The primary objective of this animal trial study was to investigate the effects of intratumoral injection of 32)P BioSilicon on human hepatocellular (HepG2) and pancreatic carcinoma (2119) xenografts implanted in nude mice (BALB/c). A secondary objective was the histopathologic examination of the tumor foci and surrounding tissue during the study. METHODS: Cultured human carcinoma cells (HepG2 and 2119) were injected s.c. into the gluteal region of nude mice. When the implanted tumors were approximately 1 cm in diameter, 32P BioSilicon (0.5, 1.0, and 2.0 MBq) or formulant was injected into the tumors. Implanted tumor size was measured once a week for 10 weeks. At study termination, the tumor and surrounding normal tissue were collected and fixed in 10% formalin and processed for histopathologic analysis. RESULTS: 32P BioSilicon produced a reduction in HepG2 tumor volume when compared with formulant control, and complete response was observed among tumors in the 1.0 and 2.0 MBq treatment groups after week 8. There was also significant reduction in 2119 tumor volume in all treated groups, with the complete response rate of 67% in the 2.0 MBq group. CONCLUSION: 32P BioSilicon suppressed the growth of both human hepatocellular and pancreatic carcinoma xenografts implanted in nude mice and complete responses were also observed in tumors at higher radiation doses.

Reduced DNA-dependent protein kinase activity in two cell lines derived from adult cancer patients with late radionecrosis.

Epstein-Barr virus-immortalized lymphoblastoid cell lines were derived from five patients with late radionecrosis. Two of these cell lines exhibited postradiation viability levels intermediate between normal cell lines and that from an individual with ataxia telangiectasia. Compared with controls, these two cell lines exhibited impaired ability to rejoin DNA double-strand breaks on pulsed-field gel electrophoresis and 6-10-fold reduced DNA-dependent protein kinase (DNA-PK) activity in vitro in cell-free extracts. Immunoblotting showed normal levels of Ku70, Ku80 and XRCC4 and the presence of DNA-PKcs in both cell lines. These findings suggest that DNA-PK might be an important factor affecting the predisposition of radiotherapy patients to late radionecrosis.

Normal Sequence and Activity but Reduced Levels of DNA-Pkcs in Human Lymphoblastic Cells Implicate Impaired Protein Stability with Radiosensitive Phenotype.

BACKGROUND: Non-homologous end joining (NHEJ) is the main repair pathway for DNA double strand breaks (DSBs) induced by ionizing radiation in mammalian cells. Subsets of cancer patients are hypersensitive to radiotherapy after standard doses. We sought to determine the radiosensitivity of human lymphoblastic cells (LB0005) for the abnormality in NHEJ components. METHODS: Lymphoblastic (LB0005) cells are derived from an adult cancer patient with late radionecrosis. A low magnesium in vitro DNA-end joining assay was performed to examine for any defect in NHEJ activity. Single-nucleotide polymorphism (SNP) and sequence analysis were performed to examine for abnormality if any, in the genetic sequence of known NHEJ components. RESULTS: LB0005 cells showed a gain of functional abnormality in the NHEJ pathway. While genetic sequence analysis showed no apparent mutational variations in the known classical NHEJ components, DNA-PKcs (DNA-dependent protein kinase catalytic subunit) protein is reduced in quantity compared to normal control, in spite of higher transcript levels. CONCLUSIONS: Taken together cells derived from a radiosensitive patient showed an abnormality in NHEJ activity. Proteins other than the classical NHEJ factors may regulate the NHEJ activity. Furthermore, the defect in theses regulatory proteins may have an impact on the stability of DNA-PKcs.

Janus kinase 3-activating mutations identified in natural killer/T-cell lymphoma.

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.

Weak expression of cyclooxygenase-2 is associated with poorer outcome in endemic nasopharyngeal carcinoma: analysis of data from randomized trial between radiation alone versus concurrent chemo-radiation (SQNP-01).

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.

An Epstein-Barr virus positive natural killer lymphoma xenograft derived for drug testing.

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.

The relationship of hepatitis B virus infection and non-Hodgkin's lymphoma and its impact on clinical characteristics and prognosis.

AIM OF THE STUDY: This study aims to evaluate the association between hepatitis B virus (HBV) and lymphoma and to characterize HBV-related lymphomas. The efficacy of prophylactic lamivudine on HBV reactivation was also evaluated. METHODS: We compared the prevalence rate of HBV infection in 556 patients with lymphoma seen over a 4-yr period with that in a group of 4698 Singapore residents aged 18-69 who participated in the National Health Survey. Next, we compared the clinic-pathologic characteristics of HBV-positive and HBV-negative lymphoma cases. RESULTS: The prevalence rate of HBV infection in our study was 10.3% (57/556), higher than the prevalence rate of 4.1% (192/4698) in the general population (P < or = 0.001). The higher prevalence was observed in both sexes and across different age groups. An association was observed for non-Hodgkin's lymphoma (NHL) but not Hodgkin's lymphoma. The characteristics of HBV-infected patients with lymphoma were similar to those who were HBV-uninfected in terms of age, ECOG, extra-nodal involvement, LDH level, stage, complete remission rate and overall survival. Use of prophylactic lamivudine significantly decreased the incidence of HBV reactivation (13% vs. 38%, P = 0.02) and disruption to chemotherapy (43% vs. 4%, P = 0.02), with a trend towards improved overall survival. CONCLUSIONS: Our findings suggest that an association exists between HBV infection and NHL. However, HBV infection does not appear to have a significant impact on the clinical characteristics and prognosis of NHL. Prophylactic lamivudine should be considered in all HBV-infected patients receiving antracycline and/or steroid containing chemotherapy.

Outcome of patients with nasal natural killer (NK)/T-cell lymphoma treated with radiotherapy, with or without chemotherapy.

BACKGROUND: This study reviews the outcome of patients with nasal natural killer (NK)/T-cell lymphoma treated at the Therapeutic Radiology Department, National Cancer Centre, Singapore, from 1997 to 2003. METHODS: Twenty-one consecutive patients treated with radiotherapy, with or without chemotherapy, were retrospectively reviewed. RESULTS: The median age was 44 years (range, 27-86 years). Thirteen patients had stage I disease, five had stage II disease, and three had stage IV disease. Immunophenotyping was CD 56+ in 18 patients. Median follow-up for patients still alive was 23.4 months (range, 8.9-78.5 months). A median dose of 50 Gy (range, 35-56 Gy) was delivered. Sixteen patients also received chemotherapy. Two-year overall survival was 52.8%. Five patients had rapidly progressive disease, with a median survival of 89 days from diagnosis. The other 16 patients had complete remission, after which four relapsed. There were two local relapses. CONCLUSIONS: This disease often carries a poor prognosis, despite multimodality treatment. Radiotherapy may contribute to local control in some patients.

Primary nasal lymphoma, NK/T-cell type: report of two cases with similar presentation but different outcome.

Two cases of natural killer (NK)/T-cell primary nasal lymphoma with similar clinical presentations are reported, for comparison and contrast, to highlight the clinical issues and challenges posed by this unusual disease, its aggressiveness being matched only by its rarity. Presenting as a lesion in the nasal cavity with histological features of malignant lymphoma, primary nasal lymphoma is an uncommon extranodal lymphoma, which poses problems in both diagnosis and management. In people of oriental descent, the common cell subtype is NK/T-cell. Although it is generally thought that combination treatment with chemotherapy and radiation is the best management for early stage non-Hodgkin's lymphoma (NHL), there is still debate as to whether combined therapy is optimal treatment for this particular subtype of NHL, given that it responds less well to conventional chemotherapy. Herein we report two patients to illustrate these controversies.

Nasal-type extranodal natural killer/T-cell lymphomas: a clinicopathologic and genotypic study of 42 cases in Singapore.

We studied the clinicopathologic features of 42 cases of nasal-type extranodal natural killer (NK)/T-cell lymphoma in Singapore and compared our findings with other series reported in the Asian and Western populations. A panel of immunohistochemical stains, which included CD2, CD3, CD4, CD8, CD56, T-cell intracellular Antigen-1 and granzyme B, and in situ hybridization for Epstein-Barr virus encoded RNA (EBER) were performed. Polymerase chain reaction for T-cell receptor-gamma gene rearrangement using both gel and capillary electrophoresis were evaluated to determine the proportion of tumors which are of true T-cell lineage. We also studied the functional status of the overexpressed p53 protein in these lymphomas by correlating p53 expression with its downstream target protein, p21. In all, 31 out of 42 cases presented in the upper aerodigestive tract. The other sites of involvement included gastrointestinal tract, skin, soft tissue, testis, liver, spleen, bone marrow and brain. The tumors displayed characteristic morphologic features. In situ hybridization for EBER was detected in 41 out of 42 cases (97.6%). The only significant adverse prognostic factor identified was an International Prognostic Index of two or more. A significantly higher proportion of the tumors (27%), compared to previous studies, demonstrated monoclonal T-cell receptor-gamma gene rearrangement. There was, however, no difference in survival or clinicopathologic features between the true NK-cell tumors and their T-cell counterparts. Overexpression of p53 was present in 40% of the cases, but no significant difference in survival rate was detected in patients with p53 overexpression and there was no association between p53 overexpression with large cell morphology, and advanced stage of disease. These findings suggest that molecular aberrations other than those of the p53 pathway may be operative in the pathogenesis of this malignancy.