Studies of Rare Cancers

原发性肝癌由肝细胞癌（HCC）和肝内胆管癌（ICC）两种主要组织学类型组成，是世界上第六大最常见的癌症，也是第二大最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，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。我们的研究一直集中在确定与发病率增加有关的因素。虽然过量饮酒和丙型肝炎病毒感染是主要的危险因素，但我们的研究发现，糖尿病和肥胖导致的风险大于其他因素导致的风险。为了进一步研究这些发现，我们在两项基于美国的研究中检查了这些因素的贡献。我们还在研究发达国家的抗糖尿病药物、非甾体抗炎药和他汀类药物是否会影响肝癌的风险。虽然HPV与超过90%的肛门癌有关，但目前尚不清楚HPV诱发的肛门癌的自然历史是否与子宫颈癌相似。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方式的情况下，临床医生经常求助于高分辨率肛门镜检查，一种类似于阴道镜检查的诊断程序，以及定向活检。肛门癌在一般人群中很少见，但在人类免疫缺陷病毒（HIV）阳性的男男性行为者（MSM）中却要常见100倍。HIV在肛门HPV自然史中的作用尚不清楚，也不清楚HIV阳性男男性行为者的筛查方法是否需要修改。更好地了解艾滋病毒阳性个体中hpv相关肛门肿瘤疾病的自然史对于做出肛门癌二级预防的明智决策至关重要。与Kaiser Permanente Northern California合作，我们进行了肛门癌筛查研究（ACSS），对363名hiv阳性男男性行为者进行了横断面评估，以描述HPV的自然史，并评估各种筛查方法在肛门癌前检测中的临床应用。我们评估了该人群中肛门HPV感染和肛门癌前病变的危险因素，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的，质量与宫颈细胞学相当，进行了建模练习，以评估肛门癌前病变与个体HPV基因型的关系，并估计肛门癌前病变中HPV疫苗可预防的部分。并证明了先前在宫颈癌筛查中评估的几种生物标志物的准确性和临床实用性，包括HPV DNA检测与基因分型，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.