Second cancers in hematologic malignancies (epidemiologic observations from a 20-year period)

INTRODUCTION: The incidence of malignant tumours have increased steadily worldwide. Prior reports indicate that patients with some hematologic malignancies (for example chronic lymphocytic leukemia, non-Hodgkin's lymphoma) may be at increased risk of second neoplasms. AIM: The aim of the authors was to explore the possible association between hematologic malignancies and subsequent solid tumours. PATIENTS, METHODS: Between January 1, 1983 and December 31, 2002, in the county of Szabolcs-Szatmár-Bereg 151 cases with both malignant hematologic diseases and cancers were registered by the authors. In their 60 patients (50 with lymphoid and 10 with myeloid malignancies) the first tumour was the hematologic malignancy. Among these cases the number of second cancers was 64. RESULTS: The most common kind of second tumours was lung cancer. There was a significant connection between lymphoid malignancies and second cancers as compared to myeloid malignancies and subsequent cancers (p < 0.05). CONCLUSIONS: Analysing the epidemiologic data the authors established the following conclusions: the association of second cancers with hematologic malignancies in most of the cases is not accidental. The age of patients with second cancers seemed to be not too important, but it was of crucial importance in patients with Hodgkin's disease and non-Hodgkin's lymphoma. The role of immunodeficiency in the development of second cancers may be important in patients with Hodgkin's disease, non-Hodgkin's lymphoma and chronic lymphocytic leukemia (the number of second cancers in their patients with multiple myeloma and hairy cell leukemia was too small do draw a conclusion).     

Oncolytic myxoma virus: The path to clinic

Many common neoplasms are still noncurative with current standards of cancer therapy. More therapeutic modalities need to be developed to significantly prolong the lives of patients and eventually cure a wider spectrum of cancers. Oncolytic virotherapy is one of the promising new additions to clinical cancer therapeutics. Successful oncolytic virotherapy in the clinic will be those strategies that best combine tumor cell oncolysis with enhanced immune responses against tumor antigens. The current candidate oncolytic viruses all share the common property that they are relatively nonpathogenic to humans, yet they have the ability to replicate selectively in human cancer cells and induce cancer regression by direct oncolysis and/or induction of improved anti-tumor immune responses. Many candidate oncolytic viruses are in various stages of clinical and preclinical development. One such preclinical candidate is myxoma virus (MYXV), a member of the Poxviridae family that, in its natural setting, exhibits a very restricted host range and is only pathogenic to European rabbits. Despite its narrow host range in nature, MYXV has been shown to productively infect various classes of human cancer cells. Several preclinical in vivo modeling studies have demonstrated that MYXV is an attractive and safe candidate oncolytic virus, and hence, MYXV is currently being developed as a potential therapeutic for several cancers, such as pancreatic cancer, glioblastoma, ovarian cancer, melanoma, and hematologic malignancies. This review highlights the preclinical cancer models that have shown the most promise for translation of MYXV into human clinical trials.     

Carcinogenesis--a synopsis of human experience with external exposure in medicine

Studies in the 1980s of medically irradiated populations have increased our knowledge of radiation carcinogenesis. (1) Investigations of prenatal x-ray exposures, especially in twins, provide evidence that very low doses of ionizing radiation may cause cancer in humans. (2) Fractionated doses appear as effective as single exposures of the same total dose in causing breast cancer, but seem less effective for lung cancer. (3) Excess breast cancers can occur among women exposed under age 10, indicating that the immature breast is susceptible to the carcinogenic action of radiation. (4) Moderate doses on the order of 1 Gy to the brains of children can cause tumors later in life; moderately high doses to the skin can cause cancer when followed by frequent exposure to ultraviolet light. (5) Radiotherapy for cervical cancer can increase the rate of subsequent leukemia with the best fitting dose-response functions including a negative exponential term to account for cell-killing. (6) Low-dose exposures of about 10 cGy may increase the risk of thyroid cancer. (7) Second cancers following radiotherapy for a variety of cancers occur primarily among long-term survivors. (8) Radiotherapy may not significantly increase the risk of leukemia following childhood cancer, whereas chemotherapy with alkylating agents is a major risk factor. (9) Bone cancer occurs after high-dose radiotherapy for childhood cancer, but children with retinoblastoma are not more susceptible to radiation-induced disease than children with other malignancies. (10) High-dose external beam therapy can cause thyroid cancer, whereas high-dose radioactive 131I may not. (11) Studies of cervical cancer patients indicate that the risk of radiation-induced second malignancies follows a time-response model consistent with a constant multiplication of the underlying background incidence, i.e. a relative risk model seems to hold for projecting risks forward in time.     

蛋白质乙酰化与精子DNA稳定性和精子活力

表观遗传学参与调节精子发生和精子形成,其中组蛋白及非组蛋白乙酰化对生精细胞染色质结构重建以及精子活力起关键作用。环磷酸腺苷（cAMP）反应元件连接蛋白（CREB）的结合蛋白（CREB-binding protein,CBP）和p300是两个乙酰化酶,能使核心组蛋白发生乙酰化,其乙酰化作用能被乙酰化酶抑制剂（INHAT）所抑制。睾丸特异的布罗莫结构域（BRDT）蛋白为保守的核蛋白,能够识别乙酰化和非乙酰化的组蛋白。在精子发生早期,BRDT调节基因转录;在精子形成阶段,BRDT识别高度乙酰化组蛋白,接着组蛋白被鱼精蛋白替代,从而使精子形成致密的染色质。非组蛋白α微管蛋白（α-Tubulin）去乙酰化则降低精子活力,在少弱精患者精子中乙酰化α微管蛋白（acetylated α-tubulin,Ac-α-Tu）明显下降。     

Epidemiologic studies of cancer in agricultural workers

The incidence of cancer in agricultural workers is generally low, in part due to the low prevalence of cigarette smoking in this group. However, agricultural workers have elevated risks for several specific cancer types including leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, and cancers of the lip, stomach, prostate, brain, and connective tissue. Two major groups of risk factors have been proposed as causes of hematologic malignancies in agricultural workers. The first group includes various agricultural chemicals. In particular, several studies have found increased risks of malignant lymphoma and soft tissue sarcoma in persons exposed to phenoxy herbicides. However, the evidence is inconsistent and there is a wide variation in relative risk estimates. The second group of risk factors includes various animal viruses. There is currently little evidence concerning the zoonotic nature or human carcinogenicity of these viruses. However, leads have been suggested by recent evidence of increased risks of hematologic malignancies in abattoir workers, veterinarians, and meat inspectors. A third hypothesis, for which little evidence is currently available, is that agricultural work may involve prolonged antigenic stimulus leading to lymphoproliferation. The factors responsible for the increased risks for cancers other than hematologic malignancies are not well understood but may also involve exposure to chemicals or viruses.     

Menin蛋白表观遗传调控特性研究

厦门大学医学院基础医学部高淑彬等的研究论文“SuppressionofLungAdenocarcinomaThroughMeninandPolycombGene-MediatedRepressionofGrowthFactorPleiotrophin”,2009年9月14日于肿瘤学研究权威杂志《癌基因））（Oncogene）在线发表。     

Targeted agents in ovarian cancer

Despite recent advances in the treatment of ovarian cancer, a large majority of women with this diagnosis will die from recurrence of their disease. Targeted therapies, in the form of monoclonal antibodies and small molecule tyrosine kinase inhibitors have significantly altered the management of many solid tumors and hematologic malignancies. No such agents have been approved by the US FDA for use in ovarian cancer, although Phase II data suggests excellent single-agent activity of some of these drugs. Antiangiogenic agents in combination with chemotherapy are being evaluated in Phase III clinical trials, both in the adjuvant setting and in recurrent platinum-sensitive disease. Poly-ADP-ribose polymerase inhibitors are promising agents in BRCA1/2-mutated breast and ovarian cancers. Ongoing clinical trials are exploring the anti-tumor effect of poly-ADP-ribose polymerase inhibitors administered as single agents and in combination with chemotherapy. Many other new drugs are in earlier grades of development. In this article, we review the state of the art in targeted therapies for ovarian cancer and identify future directions for their development in the management of this often devastating disease.     

Personalized cancer vaccines: Targeting the cancer mutanome

The development of next generation sequencing technologies has revolutionized our understanding of how specific genetic events contribute to cancer initiation and progression. Dramatic improvements in instrument design and efficiency, combined with significant cost reductions has permitted a systematic analysis of the mutational landscape in a variety of cancer types. At the same time, a detailed map of the cancer mutanome in individual cancers offers a unique opportunity to develop personalized cancer vaccine strategies targeting neoantigens. Recent studies in both preclinical models and human cancer patients demonstrate that neoantigens (1) are important targets following checkpoint inhibition therapy, (2) have been identified as the target of adoptive T cell therapies, and (3) can be successfully targeted with personalized vaccines. Taken together, these observations provide strong rationale for the clinical translation of personalized cancer vaccines.     

宫颈癌治疗性疫苗的临床研究现状

人乳头瘤状病毒(human papillomavirus,HPV)是宫颈癌的主要致病因子,也是研制宫颈癌防治性疫苗的理想靶点。虽然现在针对HPV感染的宫颈癌预防性疫苗已成功上市,但是对于急需的治疗型疫苗的研发还在进行中。目前有多种类型的治疗性疫苗已用于临床前期及临床试验,并显示出很好的治疗效果。本文从活载体疫苗、多肽/蛋白疫苗、DNA疫苗和DC疫苗几个方面综述了目前国内外宫颈癌治疗性疫苗的研究现状及进展,特别是进入临床阶段的疫苗,从而为治疗性疫苗的研究提供参考。     

肺癌表遗传学研究进展

表遗传学机制在肺癌的形成中占据重要地位,包括DNA的甲基化和组蛋白修饰,肺癌中与癌形成有关基因的失活多与异常甲基化有关,并且组蛋白修饰和甲基化紧密联系着。表遗传学改变多发生在肺癌早期,使得它成为肺癌化学预防的优良指标,了解肺癌表遗传现象的机制及其与传统遗传学的相互作用关系将有利于发现安全、高效的化学预防药物。     

Modern radiotherapy after breast-conserving surgery

In the last four decades breast-conserving surgery followed by whole breast irradiation has become the standard of care for the treatment of early-stage (0-I-II) breast carcinoma. With the advent of breast-screening, incidence of breast carcinomas with more favorable prognostic characteristics has increased significantly. This change in the prognostic profile of newly diagnosed breast cancers opened a new horizon for clinical research seeking for individual risk-adapted protocols of breast cancer radiotherapy. Several groups have been tested the efficacy of accelerated (partial or whole) breast irradiation, which has become the new treatment paradigm in the radiotherapy of early-stage breast cancers. Furthermore, others have attempted to identify subgroups of patients for whom radiotherapy after breast-conserving surgery could be safely omitted. Recently molecular gene expression assays have emerged as promising prognostic and predictive markers for local recurrence. This article reviews the results of these studies focusing on individual risk-adapted radiotherapy after breast-conserving surgery for patients with early-stage breast carcinoma.     

Pandemic whole-virion,Vero-cell-derived,adjuvant-free influenza A H1N1 vaccine in patients with solid tumors and hematologic malignancies receiving concurrent anticancer treatment: Immunogenicity,tolerability, and acceptability during the pandemic situation

Patients with malignancies are considered to be at increased risk of acquiring influenza. Because of higher complication and case fatality rates, preventive measures such as vaccination are of great interest. The objective of this study was to assess the acceptability, tolerability and immunogenicity of an adjuvant-free whole-virion pandemic influenza A (H1N1) vaccine in cancer patients with ongoing anticancer treatment during a ‘pandemic situation’. Adult patients with hematologic malignancies or solid tumors and concurrent cytotoxic, targeted, and/or hormone therapy were recruited during the influenza A (H1N1) pandemic in 2009/2010 and were offered free vaccine. Antibody titers were measured using virus-specific hemagglutination inhibition assay and ELISA. Among 285 patients with solid tumors who were offered vaccination during their therapy, 260 (91.2%) declined and 25 (8.8%) accepted. Seventeen patients with hematologic malignancies were also vaccinated during therapy; 23 healthy individuals served as a control group. When measured using hemagglutination-inhibition assays, rates of seroprotection, seroconversion, and geometric mean titer ratios after the second vaccination were 96%, 70%, and 4.1 respectively among the healthy individuals, 90%, 52%, and 4.3 among patients with solid tumors, and 67%, 13%, and 1.5 among patients with hematologic malignancies during therapy (P < 0.05). When measured using ELISA, seropositivity differed significantly among the three groups after the second vaccination: healthy individuals 74%, patients with solid tumors 57%, those with hematologic malignancies 13% (P < 0.001). The vaccine was well tolerated. Our results demonstrate a low uptake of the well tolerated adjuvant-free influenza A (H1N1) vaccine by cancer patients receiving anticancer treatment during the pandemic of 2009/2010. Among the vaccinated patients, the immune response was weaker than that in healthy individuals. The immune response in patients with hematological malignancies was low. Two doses of vaccine are needed in these immunosuppressed patients.     

组蛋白去乙酰化酶抑制剂联合放疗对宫颈癌细胞的作用

目的:探讨组蛋白去乙酰化酶抑制剂SAHA联合放疗对宫颈癌SiHa细胞的影响。方法:MTT法检测不同浓度SAHA作用SiHa细胞48 h的抑制率并计算IC50。选择抑制率为20%IC50的SAHA与放疗联合。实验分为正常组、单独放疗组、单独SAHA组、SAHA联合放疗组。流式细胞仪法测定各组细胞周期,实时荧光定量PCR法测定各组Bax、p21和Ku70基因的表达。结果:MTT结果显示SAHA对SiHa细胞的毒性作用呈浓度依赖性。细胞周期结果显示SAHA联合放疗组较单独放疗组G0/G1期上调,G2/M期和S期下调。PCR结果显示SAHA联合放疗组p21和Bax的表达较单独放疗组增高,Ku70的表达较单独放疗组降低。结论:SAHA联合放疗对宫颈癌SiHa细胞有良好的放射增敏作用。     

Combined radiotherapy and local external hyperthermia in advanced cancer--animal experiment and clinical study

The response of a mouse's foot to heat was studied. Transplanted syngeneic tumor, C3H mouse mammary carcinoma, was treated with irradiation and hyperthermia in a waterbath. The tumor did not disappear in any of the mice treated with radiotherapy with a dose of 20 Gy alone, but disappearance of the tumor was observed in 11 of 15 and 6 of 8 of the mice treated with combined therapy of irradiation and hyperthermia. There was a significant difference between these two groups. Synergistic effect was confirmed (P less than 0.001, P less than 0.005). Hyperthermia using Thermotron RF-8 was performed on 19 patients (5 bladder cancers, 3 uterine cancers, 3 rectal cancers, 4 soft tissue tumors, 2 oral cancers, 1 biliary tract cancer, 1 renal cancer) between April, 1986 and December, 1986. They were irradiated with a daily dose of 1.5-2.0 Gy, 5 times a week and hyperthermia was performed within 30 minutes after each irradiation once or twice a week. Intratumoral temperature was kept at 43 degrees C-45 degrees C. Temperature over 41 degrees C was maintained in most patients. Clinical response was assessed by tumor regression rates. Partial response a (PRa), defined as 80% or more regression in tumor volume, was obtained in 1 bladder cancer patient and PRb, defined as 50% to less than 80% regression, was obtained in another 5 patients. Side effects were observed in all patients including mild skin burn, nausea and diarrhea. Rectovaginal fistula developed in 1 patient. Combined radiotherapy and hyperthermia seems to be useful in advanced cancer patients.     

Radiation-induced reduction of osteoblast differentiation in C2C12 cells

Therapeutic radiation causes bone damage and may increase fracture risks in treatment for head-and-neck cancer and in pelvic irradiation. These properties can also be used for prevention of heterotopic ossification in hip arthroplasty. To evaluate the effects of ionizing radiation on osteoblast differentiation, C2C12 cells were directed into an osteogenic lineage by treatment with a combination of bone morphogenic protein 2 (BMP-2) (100 ng/ml) and heparin (30 mug/ml) 6 h after irradiation (2 and 4 Gy). Osteoblast differentiation was evaluated based on alkali phosphatase (ALP) activity and expression of mRNA encoding ALP and collagen type I. Ionizing radiation suppressed the growth of C2C12 cells and decreased expression of ALP and collagen type I mRNAs with concomitant reduction of the ALP activity. Although further studies are needed to elucidate the molecular mechanism, our findings suggest that ionizing radiation at therapeutic doses interferes with bone formation by reducing ALP activity and expression of mRNA encoding ALP and collagen type I.     

The occurrence of malignancies in a Hungarian lupus population

INTRODUCTION: Chronic organ damages and complications have become one of the major problems concerning morbidity and mortality in systemic lupus erythematosus. AIMS: Present study was to examine the frequencies and types of malignancies in a lupus population followed regularly in our department, and to find correlation between cancer-associated mortality and the use of immune suppressants. METHODS AND RESULTS: Authors analysed data 860 lupus patients from 1965 till the end of 2004. During study period 164 patients died, 18 of whom from cancer. The frequency of cancer-associated mortality was 11% that was 2% of the total lupus population. Mortality has increased within 10-year periods reaching the maximum between 2001-2004 (8/24, 33%). Age of the 37 patients affected by malignancy was 47.7 (20-73) years. Cancers appeared 13.4 (1-45) years after the diagnosis of lupus. Breast cancer occurred most frequently (n=11) followed by gastro-intestinal malignancies (n=9), then cervix cancer and different hematologic malignancies (5-5 cases), bronchial cancer (n=4) and skin, ovarian and vesical cancers (1-1-1 cases). Relative risk of non-Hodgkin lymphoma and cervix cancer increased significantly as compared to those of the Hungarian general female population. Before the cancer developed 62.2% of patients received azathioprine and/or cyclophosphamide. CONCLUSION: Present results describe and analyse for the first time the association between lupus and malignant disorders in a Hungarian population calling the attention for the increased risk for the development of cancers and the importance of regular screening and extended examinations in SLE patients.