Evolving therapeutic landscape of diffuse large B-cell lymphoma: challenges and aspirations.

Diffuse large B-cell lymphoma (DLBCL) represents the commonest subtype of non-Hodgkin lymphoma and encompasses a group of diverse disease entities, each harboring unique molecular and clinico-pathological features. The understanding of the molecular landscape of DLBCL has improved significantly over the past decade, highlighting unique genomic subtypes with implications on targeted therapy. At the same time, several new treatment modalities have been recently approved both in the frontline and relapsed settings, ending a dearth of negative clinical trials that plagued the past decade. Despite that, in the real-world setting, issues like drug accessibility, reimbursement policies, physician and patient preference, as well as questions regarding optimal sequencing of treatment options present difficulties and challenges in day-to-day oncology practice. Here, we review the recent advances in the therapeutic armamentarium of DLBCL and discuss implications on the practice landscape, with a particular emphasis on the context of the healthcare system in Singapore.

Application of Advanced Mass Spectrometry-Based Proteomics to Study Hypoxia Driven Cancer Progression.

Cancer is one of the largest contributors to the burden of chronic disease in the world and is the second leading cause of death globally. It is associated with episodes of low-oxygen stress (hypoxia or ischemia/reperfusion) that promotes cancer progression and therapeutic resistance. Efforts have been made in the past using traditional proteomic approaches to decipher oxygen deprivation stress-related mechanisms of the disease initiation and progression and to identify key proteins as a therapeutic target for the treatment and prevention. Despite the potential benefits of proteomic in translational research for the discovery of new drugs, the therapeutic outcome with this approach has not met expectations in clinical trials. This is mainly due to the disease complexity which possess a multifaceted molecular pathology. Therefore, novel strategies to identify and characterize clinically important sets of modulators and molecular events for multi-target drug discovery are needed. Here, we review important past and current studies on proteomics in cancer with an emphasis on recent pioneered labeling approaches in mass spectrometry (MS)-based systematic quantitative analysis to improve clinical success. We also discuss the results of the selected innovative publications that integrate advanced proteomic technologies (e.g. MALDI-MSI, pSILAC/SILAC/iTRAQ/TMT-LC-MS/MS, MRM-MS) for comprehensive analysis of proteome dynamics in different biosystems, including cell type, cell species, and subcellular proteome (i.e. secretome and chromatome). Finally, we discuss the future direction and challenges in the application of these technological advancements in mass spectrometry within the context of cancer and hypoxia.

Adolescent with facial swelling.

BackgroundA previously well 15-year-old girl presented with a 2-month history of facial swelling that progressively worsened to involve the neck. There was associated dyspnoea, orthopnoea, headache and throat discomfort. Two weeks before presentation, the patient had an episode of fever for 5 days. On examination, vital signs were within normal limits. Swelling, plethora and venous distension of the face and neck were apparent (figure 1).

Microenvironmental Hypoxia Induces Dynamic Changes in Lung Cancer Synthesis and Secretion of Extracellular Vesicles.

Extracellular vesicles (EVs) mediate critical intercellular communication within healthy tissues, but are also exploited by tumour cells to promote angiogenesis, metastasis, and host immunosuppression under hypoxic stress. We hypothesize that hypoxic tumours synthesize hypoxia-sensitive proteins for packing into EVs to modulate their microenvironment for cancer progression. In the current report, we employed a heavy isotope pulse/trace quantitative proteomic approach to study hypoxia sensitive proteins in tumour-derived EVs protein. The results revealed that hypoxia stimulated cells to synthesize EVs proteins involved in enhancing tumour cell proliferation (NRSN2, WISP2, SPRX1, LCK), metastasis (GOLM1, STC1, MGAT5B), stemness (STC1, TMEM59), angiogenesis (ANGPTL4), and suppressing host immunity (CD70). In addition, functional clustering analyses revealed that tumour hypoxia was strongly associated with rapid synthesis and EV loading of lysosome-related hydrolases and membrane-trafficking proteins to enhance EVs secretion. Moreover, lung cancer-derived EVs were also enriched in signalling molecules capable of inducing epithelial-mesenchymal transition in recipient cancer cells to promote their migration and invasion. Together, these data indicate that lung-cancer-derived EVs can act as paracrine/autocrine mediators of tumorigenesis and metastasis in hypoxic microenvironments. Tumour EVs may, therefore, offer novel opportunities for useful biomarkers discovery and therapeutic targeting of different cancer types and at different stages according to microenvironmental conditions.

Vinorelbine Augments Radiotherapy in Hepatocellular Carcinoma.

There is a need to improve the effectiveness of radiotherapy (RT) in hepatocellular carcinoma (HCC). Therefore, the purpose of this study was to explore the efficacy and toxicity of the anti-microtubule agent Vinorelbine as a radiosensitizer in HCC. The radio sensitivity of 16 HCC patient-derived xenograft (PDX) models was determined by quantifying the survival fraction following irradiation in vitro, and Vinorelbine radio sensitization was determined by clonogenic assay. Ectopic HCC xenografts were treated with a single dose of 8 Gy irradiation and twice-weekly 3 mg/kg Vinorelbine. Tumor growth and changes in the proteins involved in DNA repair, angiogenesis, tumor cell proliferation, and survival were assessed, and the 3/16 (18.75%), 7/16 (43.75%), and 6/16 (37.5%) HCC lines were classified as sensitive, moderately sensitive, and resistant, respectively. The combination of RT and Vinorelbine significantly inhibited tumor growth, DNA repair proteins, angiogenesis, and cell proliferation, and promoted more apoptosis compared with RT or Vinorelbine treatment alone. Vinorelbine improved HCC tumor response to standard irradiation with no increase in toxicity. HCC is prevalent in less developed parts of the world and is mostly unresectable on presentation. Vinorelbine and conventional radiotherapy are cost-effective, well-established modalities of cancer treatment that are readily available. Therefore, this strategy can potentially address an unmet clinical need, warranting further investigation in early-phase clinical trials.

18F-FDG PET/CT in Metastatic Extramammary Paget's Disease.

Extramammary Paget's disease (EMPD) is a rare disease with an estimated prevalence of 0.1 to 2.4 per 1,000,000 person-years. Metastatic EMPD has a poor prognosis with a 5-year survival of approximately 7%. Local therapy is the only curative option with surgery being recommended for resectable disease. It is therefore crucial to be able to stage such patients appropriately. The utility of F-FDG PET/CT for this disease is not well established. We share a case on how F-FDG PET/CT was used to stage metastatic EMPD.

Hypoxia-induced tumor exosomes promote M2-like macrophage polarization of infiltrating myeloid cells and microRNA-mediated metabolic shift.

Developing tumors rapidly outgrow their oxygen supply and are subject to hypoxia, which stimulates hypersecretion of tumor-derived exosomes that promote angiogenesis, metastasis, and immunosuppression, but the molecular mediators of these pathological effects remain poorly defined. Using quantitative proteomics, we identified that exosomes produced by hypoxic tumor cells are highly enriched in immunomodulatory proteins and chemokines including CSF-1, CCL2, FTH, FTL, and TGFß. Modeling exosome effects on tumor-infiltrating immune cells, we observed a potent ability of these hypoxia-induced vesicles to influence macrophage recruitment and promote M2-like polarization both in vitro and in vivo. In addition, hypoxic, but not normoxic, tumor exosomes enhanced oxidative phosphorylation in bone marrow-derived macrophages via transfer of let-7a miRNA, resulting in suppression of the insulin-Akt-mTOR signaling pathway. Together, these data demonstrate that hypoxia promotes tumor secretion of biomolecule-loaded exosomes that can modify the immunometabolic profile of infiltrating monocyte-macrophages to better evade host immunity and enhance tumor progression.

Irradiation of Epithelial Carcinoma Cells Upregulates Calcium-Binding Proteins That Promote Survival under Hypoxic Conditions.

Hypoxia is thought to promote tumor radio-resistance via effects on gene expression in cancer cells that modulate their metabolism, proliferation, and DNA repair pathways to enhance survival. Here we demonstrate for the first time that under hypoxic condition A431 epithelial carcinoma cells exhibit increased viability when exposed to low-dose γ-irradiation, indicating that radiotherapy can promote tumor cell survival when oxygen supply is limited. When assessed using iTRAQ quantitative proteomics and Western blotting, irradiated tumor cells were observed to significantly up-regulate the expression of calcium-binding proteins CALM1, CALU, and RCN1, suggesting important roles for these mediators in promoting tumor cell survival during hypoxia. Accordingly, shRNA-knockdown of CALM1, CALU, and RCN1 expression reduced hypoxic tumor cell resistance to low-dose radiation and increased apoptosis. These data indicate that γ-irradiation of hypoxic tumor cells induces up-regulation of calcium-binding proteins that promote cancer cell survival and may limit the efficacy of radiotherapy in the clinic.

Re-examination of Opisthorchis viverrini Infection in Northeast Thailand.

BACKGROUND: Liver fluke infection caused by the parasite Opisthorchis viverrini (O. viverrini), a human carcinogen, is endemic in north-eastern Thailand and remains a major health problem. OBJECTIVES: The objectives of the study were to (1) resurvey the prevalence of O. viverrini infection in a field site from the Khon Kaen Cohort Study (in newly recruited subjects as well as previous cohort subjects surveyed in 1992); (2) investigate how subjects' lifestyle habits and their exposure to health promotion initiatives influence changes in prevalence of O. viverrini infection. MATERIALS AND METHODS: The prevalence of O. viverrini infection in the cohort subjects (as well as new subjects) was investigated using faecal egg counts. Information on demographic factors, lifestyle and awareness of health promotion initiatives were obtained through questionnaires. RESULTS: O. viverrini infection rates in the same individuals of the cohort were lower in 2006 than in 1992. Also, by studying the period effect, the current 35-44 year olds had a 12.4% (95% CI 3.9% to 20.9%) lower prevalence of O. viverrini infection than the 35-44 year olds in 1992 (24.2% versus 11.8%). Lifestyle choices showed that smoking and alcohol consumption were associated with an increased chance of acquiring O. viverrini infection with adjusted odds ratios of 10.1 (95%CI 2.4-41.6) and 5.3 (95%CI 1.2-23.0), respectively. CONCLUSIONS: Our study has demonstrated that although the prevalence of O. viverrini infection over a 14-year period has decreased, unhealthy lifestyle was common with smoking and alcohol consumption being associated with increased chances of infection, emphasising the double burden of disease which developing countries are facing.

The effect of test kit provision, and individual and family education on the uptake rates of fecal occult blood test in an Asian population: a randomized controlled trial.

PURPOSE: The purpose of the study was to investigate whether fecal occult blood test (FOBT) home-delivery and individual education or combined with family education increases FOBT uptake rates in Singapore. METHODS: This is a randomized controlled intervention study of Singaporean residents aged 50 years and above, conducted in May 2012 till May 2013. Eligible individuals in randomly selected households were screened, and one member was randomly selected and allocated to one of the four arms: Group A (individual and family education, FOBT kits provided), Group B (individual education only, FOBT kits provided), Group C (no education, FOBT kits provided) and Group D (no education or FOBT kits provided). RESULTS: Overall response rate was 74.7 %. The FOBT return rates for groups A, B, C and D were 24.5 % [CI 16.2-34.4 %], 25.3 % [CI 16.4-36.0 %], 10.7 % [CI 4.7-19.9 %] and 2.2 % [CI 0.3-7.7 %], respectively. Respondents who were provided education and home-delivered FOBT kits were 15 times more likely to return FOBT kits [Group A: OR 15.0 (3.4-66.2); Group B: OR 15.5 (3.5-68.8)] and those provided with home-delivered FOBT without education were five times more likely to return FOBT kits [Group C: OR 5.8 (1.2-28.3)] than those without education and FOBT kits (Group D). There was no significant difference in return of FOBT kits whether education was provided to subject with or without a family member. CONCLUSION: Home delivery of FOBT kits increased FOBT return rates and individual education combined with home-delivered FOBT increased FOBT return rates even further. However, additional combination with family education did not increase FOBT rates further.

Biological response of cancer cells to radiation treatment.

Cancer is a class of diseases characterized by uncontrolled cell growth and has the ability to spread or metastasize throughout the body. In recent years, remarkable progress has been made toward the understanding of proposed hallmarks of cancer development, care, and treatment modalities. Radiation therapy or radiotherapy is an important and integral component of cancer management, mostly conferring a survival benefit. Radiation therapy destroys cancer by depositing high-energy radiation on the cancer tissues. Over the years, radiation therapy has been driven by constant technological advances and approximately 50% of all patients with localized malignant tumors are treated with radiation at some point in the course of their disease. In radiation oncology, research and development in the last three decades has led to considerable improvement in our understanding of the differential responses of normal and cancer cells. The biological effectiveness of radiation depends on the linear energy transfer (LET), total dose, number of fractions and radiosensitivity of the targeted cells or tissues. Radiation can either directly or indirectly (by producing free radicals) damages the genome of the cell. This has been challenged in recent years by a newly identified phenomenon known as radiation induced bystander effect (RIBE). In RIBE, the non-irradiated cells adjacent to or located far from the irradiated cells/tissues demonstrate similar responses to that of the directly irradiated cells. Understanding the cancer cell responses during the fractions or after the course of irradiation will lead to improvements in therapeutic efficacy and potentially, benefitting a significant proportion of cancer patients. In this review, the clinical implications of radiation induced direct and bystander effects on the cancer cell are discussed.

Are we ready for positron emission tomography/computed tomography-based target volume definition in lymphoma radiation therapy?

Fluorine-18 fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) has become indispensable for the clinical management of lymphomas. With consistent evidence that it is more accurate than anatomic imaging in the staging and response assessment of many lymphoma subtypes, its utility continues to increase. There have therefore been efforts to incorporate PET/CT data into radiation therapy decision making and in the planning process. Further, there have also been studies investigating target volume definition for radiation therapy using PET/CT data. This article will critically review the literature and ongoing studies on the above topics, examining the value and methods of adding PET/CT data to the radiation therapy treatment algorithm. We will also discuss the various challenges and the areas where more evidence is required.

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.

Cancer and radiation therapy: current advances and future directions.

In recent years remarkable progress has been made towards the understanding of proposed hallmarks of cancer development and treatment. However with its increasing incidence, the clinical management of cancer continues to be a challenge for the 21st century. Treatment modalities comprise of radiation therapy, surgery, chemotherapy, immunotherapy and hormonal therapy. Radiation therapy remains an important component of cancer treatment with approximately 50% of all cancer patients receiving radiation therapy during their course of illness; it contributes towards 40% of curative treatment for cancer. The main goal of radiation therapy is to deprive cancer cells of their multiplication (cell division) potential. Celebrating a century of advances since Marie Curie won her second Nobel Prize for her research into radium, 2011 has been designated the Year of Radiation therapy in the UK. Over the last 100 years, ongoing advances in the techniques of radiation treatment and progress made in understanding the biology of cancer cell responses to radiation will endeavor to increase the survival and reduce treatment side effects for cancer patients. In this review, principles, application and advances in radiation therapy with their biological end points are discussed.

Role of Radiotherapy in Modern Treatment of Hodgkin's Lymphoma.

Hodgkin's Lymphoma was incurable until the advent of effective therapeutic radiation around the first half of the 20th century. As survival rates improved, the long-term toxicities from radiotherapy began to emerge. This together with the availability of effective chemotherapy has encouraged a combined modality approach for early-staged disease and the omission of radiotherapy in advanced-staged disease. The differing toxicities of radiotherapy and chemotherapy has promoted ongoing research to identify the utility of each of these modalities in the modern management of Hodgkin's Lymphoma. This article will provide a critical review of the developments and indications for modern radiotherapy, in context with advances in chemotherapy, for the treatment of Hodgkin's Lymphoma.