Studies of Rare Cancers

原发性肝癌包括肝细胞癌和肝内胆管细胞癌两种主要的组织学类型，是世界上第六大常见癌症，也是第二大常见的癌症死亡原因。虽然80%以上的肝癌发生在亚洲和撒哈拉以南非洲地区，但几十年来，美国和欧洲等低发病率地区的发病率一直在上升。我们的研究一直专注于确定与这种发病率增加相关的因素。虽然过量饮酒和丙型肝炎病毒感染是主要的风险因素，但我们的研究发现，糖尿病和肥胖症的风险比其他因素的风险更大。为了跟进这些发现，我们在两项以美国为基础的研究中检验了这些因素的贡献。我们还在研究抗糖尿病药物、非类固醇消炎药和他汀类药物是否会影响发达国家患肝癌的风险。尽管90%以上的肛门癌与HPV有关，但尚不清楚HPV诱导的肛门癌的自然病史是否与宫颈癌相似。目前还没有公认的肛门癌筛查方法；在缺乏标准和有效的筛查模式的情况下，临床医生通常求助于高分辨率肛门镜，这是一种类似于阴道镜的诊断程序，并进行定向活检。肛门癌在普通人群中很少见，但在人类免疫缺陷病毒(HIV)阳性的男男性行为者(MSM)中，肛门癌的发病率是普通人的100倍。艾滋病毒在肛门HPV自然病史中的作用尚不清楚，也不清楚艾滋病毒阳性男男性行为者的筛查方法是否需要修改。在HIV阳性个体中更好地了解HPV相关的肛门肿瘤疾病的自然病史是至关重要的，以便做出关于肛门癌二级预防的明智决定。我们与Kaiser Permanente North California合作，进行了肛门癌筛查研究(ACSS)，这是一项对363名HIV阳性MSM的横断面评估，以描述HPV的自然历史，并评估各种筛查方法在肛门癌前病变检测中的临床应用。我们评估了这一人群中肛门HPV感染和肛门癌前病变的风险因素，研究了肛门样本的最佳采样策略，表明肛门细胞学是可重复性的，质量可与宫颈细胞学相媲美，我们进行了建模练习以评估肛门癌前病变与单个HPV基因型的关系，并估计了HPV疫苗可预防的肛门癌前病变的比例，并证明了几种以前在宫颈癌筛查中被评估的生物标志物的准确性和临床实用性，包括HPV DNA检测结合基因分型、HPV mRNA检测和p16/ki-67细胞学。

Primary liver cancer, composed of two major histologic types, hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), is the sixth most frequently occurring cancer in the world and the second most common cause of cancer mortality. While over 80% of liver cancers occur in Asia and sub-Saharan Africa, incidence has been increasing in low-rate areas, such as the U.S. and Europe, for several decades. Our research has been focusing on identifying factors associated with this increase in incidence. While excessive alcohol consumption and hepatitis C virus infection are major risk factors, our research has found that the risk attributable to diabetes and obesity is greater than the risk attributable to other factors. To follow-up on these findings, we are examining the contributions of these factors in 2 U.S. based research studies. We are also examining whether medications such as anti-diabetic drugs, non-steroidal anti-inflammatory drugs and statins affect the risk of liver cancer in developed countries.Although HPV is implicated in over 90% of anal cancers, it is unknown if the natural history of HPV-induced anal cancer is similar to that of the cervix. There is currently no accepted method for anal cancer screening; in the absence of a standard and effective screening modality, clinicians often resort to high-resolution anoscopy, a diagnostic procedure akin to colposcopy, and directed biopsies. Anal cancer is rare in the general population but is 100 times commoner among human immunodeficiency virus (HIV)-positive men who have sex with men (MSM). The role of HIV in anal HPV natural history is not well understood and it is not clear whether the screening approaches for HIV-positive MSM need to be modified. It is crucial to better understand natural history of HPV-related anal neoplastic disease among HIV-positive individuals to make informed decisions about secondary prevention of anal cancer. In collaboration with Kaiser Permanente Northern California, we have conducted the Anal Cancer Screening Study (ACSS), a cross-sectional assessment on 363 HIV-positive MSM to describe the natural history of HPV and evaluate the clinical utility of various screening approaches for anal precancer detection. We have evaluated risk factors for anal HPV infection and anal precancer in this population, studied optimal sampling strategies for anal samples, showed that anal cytology is reproducible and the quality is comparable to cervical cytology, conducted modeling exercises to evaluate attribution of anal precancer to individual HPV genotypes and estimate the HPV vaccine-preventable fraction of anal precancer, and have demonstrated the accuracy and clinical utility of several biomarkers that were previously evaluated in cervical cancer screening, including HPV DNA testing with genotyping, HPV mRNA testing, and p16/Ki-67 cytology.