Evaluation of the eighth TNM classification on p16-positive oropharyngeal squamous cell carcinomas in the Netherlands and the importance of additional HPV DNA testing

BackgroundOropharyngeal squamous cell carcinomas (OPSCCs) are traditionally caused by smoking and excessive alcohol consumption. However, in the last decades high-risk human papillomavirus (HPV) infections play an increasingly important role in tumorigenesis. HPV-driven OPSCCs are known to have a more favorable prognosis, which has led to important and marked changes in the recently released TNM-8. In this 8th edition, OPSCCs are divided based on p16 immunostaining, with p16 overexpression as surrogate marker for the presence of HPV. The aims of this study are to evaluate TNM-8 on a Dutch consecutive cohort of patients with p16-positive OPSCC and to determine the relevance of additional HPV DNA testing.Patients and methodsAll OPSCC patients without distant metastases at diagnosis and treated with curative intent at VU University Medical Center (2000–2015) and Erasmus Medical Center (2000–2006) were included (N = 1204). HPV status was determined by p16 immunostaining followed by HPV DNA PCR on the p16-immunopositive cases. We compared TNM-7 and TNM-8 using the Harrell’s C index.ResultsIn total, 388 of 1204 (32.2%) patients were p16-immunopositive. In these patients, TNM-8 had a markedly better predictive prognostic power than TNM-7 (Harrell’s C index 0.63 versus 0.53). Of the 388 p16-positive OPSCCs, 48 tumors (12.4%) were HPV DNA-negative. This subgroup had distinct demographic, clinical and morphologic characteristics and showed a significantly worse five-year overall survival compared with the HPV DNA-positive tumors (P < 0.001).ConclusionsTNM-8 has a better predictive prognostic power than TNM-7 in patients with p16-positive OPSCC. However, within p16-positive OPSCCs, there is an HPV DNA-negative subgroup with distinct features and a worse overall survival, indicating the importance to perform additional HPV DNA testing when predicting prognosis and particularly for selecting patients for de-intensified treatment regimens.     

p16, HPV,and Cetuximab: What Is the Evidence?

Squamous cell carcinoma of the head and neck (SCCHN) is the sixth most common cancer worldwide. It has recently been appreciated that human papillomavirus (HPV) status (or p16 status, which is a frequently used surrogate for HPV status) is prognostic for oropharyngeal SCCHN. Here, we review and contextualize existing p16 and HPV data, focusing on the cetuximab registration trials in previously untreated, locoregionally advanced, nonmetastatic SCCHN (LA SCCHN) and in recurrent and/or metastatic SCCHN (R/M SCCHN): the IMCL‐9815 and EXTREME clinical trials, respectively. Taken together, the available data suggest that, while p16 and HPV are prognostic biomarkers in patients with LA SCCHN and R/M SCCHN, it could not be shown that they are predictive for the outcomes of the described cetuximab‐containing trial regimens. Consequently, although HPV status provides prognostic information, it is not shown to predict therapy response, and so is not helpful for assigning first‐line therapy in patients with SCCHN. In addition, we discuss assays currently used to assess p16 and HPV status, as well as the differentiation between these two biomarkers. Ultimately, we believe HPV E6/E7 polymerase chain reaction–based mRNA testing may represent the most informative technique for assessing HPV status in patients with SCCHN. While p16 is a valid surrogate for HPV status in oropharyngeal carcinoma (OPC), there is a higher risk of discordance between p16 and HPV status in non‐OPC SCCHN. Collectively, these discussions hold key implications for the clinical management of SCCHN.

Implications for Practice

Human papillomavirus (HPV) status (or its commonly utilized surrogate p16) is a known prognostic biomarker in oropharyngeal squamous‐cell carcinoma of the head and neck (SCCHN). We evaluated implications of the available evidence, including cetuximab registration trials in previously untreated locoregionally advanced (LA) SCCHN and recurrent and/or metastatic (R/M) SCCHN. We conclude that, although p16 and HPV are prognostic biomarkers for both LA and R/M SCCHN, they have not been shown to be predictive of response to the described cetuximab‐containing regimens for either indication. Thus, current evidence suggests that benefits of cetuximab are observed in both p16‐/HPV‐positive and ‐negative SCCHN.     

The current and future impact of human papillomavirus on treatment of squamous cell carcinoma of the head and neck

BackgroundSquamous cell carcinoma of the head and neck (SCCHN) was traditionally associated with smoking and alcohol use; however, human papillomavirus (HPV) infection has recently been implicated as a novel risk factor for oropharyngeal tumors. Furthermore, HPV-associated oropharyngeal carcinoma (OPC) appears to be a distinct entity with different epidemiology, biology, and clinical outcomes.MethodsHere, we comprehensively review the existing data regarding HPV status and prognostic or predictive outcomes in both the locoregionally advanced (LA) and recurrent/metastatic (RM) disease setting and discuss ongoing trials that may eventually impact the treatment of patients with HPV-positive (HPV+) SCCHN.ResultsA body of retrospective and prospective data established an association between HPV+ OPC and better survival, particularly for LA disease. Current data on RM disease are limited, but they also suggest prognostic significance for HPV.ConclusionsBetter outcomes in HPV+ LA disease may allow for less aggressive treatment in the future, and several trials are evaluating deintensified regimens in patients with HPV+, LA OPC; it should be emphasized that deintensification strategies are appropriate only in a clinical research setting and only for selected subgroups of HPV+ patients. In addition, HPV-targeted strategies, such as vaccines, are currently undergoing clinical evaluation. On the other hand, the prognostic impact of HPV in RM disease requires further validation before any modifications in treatment can be made. Likewise, the predictive significance of HPV status in both disease settings remains to be defined.Clinical Trial NumbersNCT00226239, NCT00301028, NCT00387127, NCT00410826, NCT00503997, NCT00514943, NCT00544414, NCT00768664, NCT00939627, NCT01084083, NCT01302834, NCT01687413, NCT01706939.     

Analysis of prognostic factors in 766 patients with small cell lung cancer (SCLC): the role of sex as a predictor for survival.

The data of 766 patients participating in three German multicentre trials were analysed with regard to the relationship between baseline characteristics and prognosis in small cell lung cancer (SCLC). The central aim of this analysis has been to evaluate the role of gender as an independent prognostic factor in SCLC. The minimum follow-up period for the 652 male and 114 female patients was 36 months. Female patients were shown to have a higher complete remission rate (35% vs 25%), a superior median survival (ms) (12.1 months (mo) vs 9.8 mo), and a favourable 2-year survival rate (2ys) (19% vs 8%) to male ones. Various other prognostic factors have been proved to be significant, such as extent of disease, clinical performance status, and history of smoking, whereas weight loss prior to chemotherapy and age have been less important factors. We have been able to ascertain that women's responses were better than those of male patients independent of any other relevant prognostic variable. Furthermore, results were found to be even more advantageous for female patients with additional favourable prognostic parameters, i.e. for patients with limited disease (ms 15.2 mo vs 12.0 mo; 2ys 29% vs 9%) or with good performance status (ms 13.4 mo vs 10.4 mo; 2ys 24% vs 7%). A most remarkable observation was made in that the favourable prognostic effect of the female gender was restricted to patients aged less than 60 years (ms 13.3 mo vs 10.1 mo; 2ys 26% vs 5%), whereas for older women no advantages over men's results were established (ms 9.3 ml vs 9.1 mo; 2ys 8% vs 7%). A proportion of 32% of female patients with limited disease aged less than 60 years achieved a 3-year survival rate. We conclude (a) that sex constitutes a major prognostic factor in SCLC and is especially useful as a predictor for long-term survival, and (b) that the favourable prognostic value of the female sex is restricted to younger patients.     

Is Minimal Residual Disease Monitoring Clinically Relevant in Adults with Acute Myelogenous Leukemia?

In the past year, there has been increasing attention towards understanding the clinical relevance of minimal residual disease (MRD) assessment. The monitoring of MRD levels at various stages of therapy has considerable potential to impact the guidance of treatment for AML patients and improve outcomes. Thus, efforts have increased to address important concerns regarding MRD measurements. These concerns include: (1) what should be monitored; (2) what methodologies should be used; (3) whether such methodologies are standardized across laboratories; (4) how prognostic levels are defined; (5) when MRD should be monitored; and (6) what treatment options are available for MRD positive patients. In this review, we will discuss the methodologies available for MRD and the studies available to date aiming to address the concerns around the use of MRD measurements for AML patients     

Predictive modelling in hormone-refractory prostate cancer (HRPC)

Because the evidence is not yet solid enough to strongly recommend whether or not to treat hormone-refractory prostate cancer (HRPC) patients at certain stages of the disease, predictive models might help in decision making. The importance of prognostic models lies in their ability to capture clinically relevant and measurable variables for routine use by clinicians to inform patients, and improve palliation and treatment decisions. Basically this allows for the creation of homogeneous prognostic strata for randomised comparative trials of therapeutic agents. In the last few years different models to predict patient outcome in HRPC have been published in the literature. Recently, based on the phase III randomised trial of docetaxel, a multivariate prognostic model incorporating PSA kinetics has been developed to predict survival at 1, 2 and 5 years in metastatic HRPC men treated with chemotherapy. This novel model includes new independent clinical prognostic factors in addition to PSA-DT such as baseline pain, type of progression at baseline (measurable disease or bone scan compared with PSA only), presence of liver metastases and the number of metastatic disease sites. This nomogram will be a helpful tool to stratify patients for further docetaxel-based trials and could also help us to delineate the potential benefits of chemotherapy at certain points during the natural history of HRPC.     

Prognostic factors in breast-cancer and their controversies (review)

The status of the axillary lymph nodes (AX) is widely accepted as the most significant prognostic factor in breast cancer. Nevertheless, there are large differences in the clinical outcomes of patients with the same AX status, which suggest that we should seek further prognostic variables. At present, several biologic factors, such as DNA ploidy, c-erbB-2 expression, EGFR, p53 alteration, and HPA staining, have been proposed. However, their value as prognostic indicators remains undetermined. Whether these factors are independent prognostic factors, or merely related to other variables, such as AX metastasis, is unclear. A clear need for a new biologic markers to serve as more reliable prognostic factors exists.     

Psoriasin expression is associated with survival in patients with human papillomavirus-positive base of tongue squamous cell carcinoma

Patients with human papillomavirus-positive (HPV+) base of tongue squamous cell carcinomas (BOTSCC) have an improved survival compared with patients with HPV-negative BOTSCC and it has been suggested that treatment should be tailored. Before individualized treatment can be introduced, additional prognostic markers are required. A prognostic role of psoriasin has previously been demonstrated outside BOTSCC. Therefore, the present study aimed to examine psoriasin in BOTSCC, with focus on HPV+ BOTSCC, in relation to prognosis. A total of 72 BOTSCC samples were stained for psoriasin by immunohistochemistry, and the association between expression and clinical outcomes was analyzed. Patients with low psoriasin expression exhibited significantly improved overall survival (OS; P=0.001) and disease-free survival (DFS; P=0.007), which also was observed in patients with HPV+ BOTSCC (OS, P<0.001; DFS, P=0.02). Furthermore, psoriasin was a significant prognostic factor in univariable and multivariable analyses. In conclusion, psoriasin could be used as a prognostic marker in HPV+ BOTSCC.     

美国癌症联合委员会甲状腺癌分期系统（第8版）修订对甲状腺乳头状癌分期的影响

背景与目的：2017年美国癌症联合委员会发布了TNM分期系统第8版（TNM-8）,该研究旨在比较TNM-8和第7版（TNM-7）分期规则下甲状腺乳头状癌（papillary thyroid carcinoma,PTC）患者分期的变化。方法：该研究共纳入2013—2015年因甲状腺乳头状癌而在中国医学科学院北京协和医学院北京协和医院行初治手术治疗的患者4 265例,手术范围至少包括患侧腺叶切除及患侧淋巴结清扫。根据年龄、性别、肿瘤大小、侵犯范围、淋巴结转移情况及远处转移情况,分别应用TNM-7及TNM-8分期规则进行分期,并对结果进行比较。结果：4 265例患者中,男性1 069例,女性3 196例。根据TNM-7分期,Ⅰ、Ⅱ、Ⅲ、Ⅳa、Ⅳb和Ⅳc期患者数量分别为3 093例（72.50%）、23例（0.54%）、942例（22.09%）、199例（4.67%）、1例（0.02%）和7例（0.16%）;而根据TNM-8分期,Ⅰ、Ⅱ、Ⅲ和Ⅳb期患者数量则分别为3 996例（93.60%）、259例（6.00%）、9例（0.20%）和1例（0.02%）。共有1 163例（27.3%）患者分期发生了调整,均为降期。降期原因包括年龄的划分升至55岁（781例,67.1%）、TNM分期规则调整（265例,22.8%）和T分期规则调整（117例,10.1%）。在3 059例微小癌患者中,根据TNM-7分期,Ⅰ~Ⅳ期的患者数量分别为2 323例（75.94%）、3例（0.10%）、649例（21.22%）和84例（2.70%）;根据TNM-8分期,Ⅰ~Ⅳ期的患者数量则分别为2 917例（95.30%）、138例（4.50%）、3例（0.10%）和1例（0.03%）。结论：应用TNM-8,与TNM-7相比,Ⅲ~Ⅳ期患者比例大幅减少,对于微小癌患者该特点更加突出,能更好地反映疾病的严重程度。     

Low-grade lymphomas: new entities and treatment concepts

Therapy for patients with low-grade lymphomas has never been standardized. Recently, new entities have been described which are included in the REAL classification, and whether these entities should be regarded as separate diseases is not yet clear. Regardless, three new developments in the management of patients with low-grade lymphomas deserve special attention for treatment programs in the future. First, it appears that patients with stage I, II, and III low-grade lymphomas may enjoy very prolonged disease-free intervals after treatment with combination chemotherapy and radiation therapy programs. Although investigators disagree on prognostic factors, new features, such as β₂-microglobulin appear to predict results better than any other feature, and future studies should address this prognostic factor in assessing their results. Second, for patients with advanced stage disease, administration of interferon as maintenance therapy prolongs the disease-free interval, and use of this drug should be further investigated. Finally, molecular studies using PCR forbcl-2 may be clinically relevant in detecting residual disease in patients with follicular lymphomas, and future studies should focus on the value of eliminating the residual disease from blood and marrow.     

Chapter 5: Viral and host factors in human papillomavirus persistence and progression

Understanding the interdependent roles that host and viral factors play in cervical cancer pathogenesis is important for distinguishing women at the highest risk of human papillomavirus (HPV) persistence and progression to cervical cancer. Ongoing research on viral factors such as viral variants is providing important clues regarding HPV oncogenesis; the comprehensive characterization of the HPV genome and the function of viral genes by HPV type and variant will further this understanding. Although the biologic importance of viral integration and viral load measurements in cervical neoplasia is still being debated, available data are difficult to interpret because of methodologic limitations; to sufficiently address the importance of these events will require further methods validation and subsequent application in epidemiologic studies. Continued and expanded investigation of host immune responses-humoral, cellular, and innate immunity-should specifically address the outcomes of HPV persistence and progression to cervical cancer. Molecularly based assays paired with functional assays will be integral toward the identification and validation of key immune pathways and genes specifically relevant to cervical cancer pathogenesis. Novel technologies such as gene expression microarrays will further allow comprehensive identification of relevant genes that are important at various stages of cervical pathogenesis. The study of viral and host factors will undoubtedly lead to markers that may hold diagnostic and/or prognostic value; the clinical validity and utility of these molecular events will, therefore, need to be carefully assessed before implementation in a population setting.     

滤泡性淋巴瘤预后因素的研究进展

滤泡性淋巴瘤(follicular lymphoma,FL)是一组在生物学特征、临床表现及预后等方面存在高度异质性的血液肿瘤,多种因素影响其预后。既有的FL预后模型,包括滤泡淋巴瘤国际预后指数(follicular lymphoma international prognostic index,FLIPI)、FLI PI-2等主要强调基线临床及实验室检查特点对预后的影响,且价值有限。近年来随着分子影像学、基因测序等现代技术的发展,肿瘤代谢负荷参数、分子生物学特征(如肿瘤微环境特点、表观遗传学改变等)等在FL预后预测方面的价值逐渐被挖掘,尤其与既有临床预后指数结合(如包含7个基因突变情况的临床遗传学风险模型m7-FLIPI)时更是提高了预测的准确性。除基线预后因素外,FL治疗反应的预后价值也是近年来研究的热点。本文根据国内外研究进展,从组织学特点、肿瘤代谢负荷、基于临床特征建立的预后模型、肿瘤微环境、治疗反应、分子遗传学特征等方面对影响FL患者预后的因素进行综述。     

Human Papillomavirus: Changing Paradigms in Oropharyngeal Cancer

The human papillomavirus (HPV) has recently been identified as an important etiologic agent in the development of squamous cell carcinoma of the oropharynx. The HPV- associated cancers appear to have a different biology than the HPV-negative cancers, and affect a population that is more likely to be young, male, Caucasian, and nonsmoking. More importantly, however, is the recognition that patients with an HPV-associated oropharyngeal cancer have a distinctly better survival after treatment than those patients with HPV-negative tumors, although their prognosis is significantly worse if there is a history of tobacco abuse. HPV-associated oropharynx cancer should be recognized as a new biologic entity and studied separately from HPV-negative cancers in future clinical trials. The potential for disease prevention with the use of the current HPV vaccines is discussed.     

人乳头瘤病毒检测阴性子宫颈癌的研究进展

子宫颈癌是妇科最常见的恶性肿瘤，研究证实99.7%的宫颈癌是因感染人乳头瘤病毒（human papillomavirus，HPV）造成的，但几乎所有的研究中都发现有HPV检测阴性的子宫颈癌存在。HPV检测阴性的子宫颈癌可以概括为假阴性和真阴性两种情况，造成假阴性的原因有病变小、取材有限、病毒载量低、非高危人乳头瘤病毒基因型、技术错误或检测灵敏度不足等。现有的筛查方式具有一定局限性，一些具有高灵敏度和特异性的新型分子标记物如微小核糖核酸、FAM19A4基因甲基化等已被证明有望作为子宫颈癌早期检测和诊断的指标。近年来关于HPV阴性子宫颈癌的研究越来越多，但对HPV阴性子宫颈癌患者临床特点的分析存在差异。本文主要对HPV阴性子宫颈癌假阴性的原因、筛查诊断及临床特点方面进行综述。     

Frequency of Human Papillomavirus (HPV) 16 and 18 Detection in Paraffin- Embedded Laryngeal Carcinoma Tissue

Background and Objective: Human papilloma virus (HPV) 16 and HPV18 have been detected in head and neck squamous cell carcinomas (HNSCC) and there is evidence that detection of HPVs would have better prognostic value than patients with HNSCC negative for HPVs. Thus, this study was conducted to evaluate frequency of HPV 16 and HPV 18 genotypes in patients with laryngeal carcinoma. Materials and methods: Fifty formalin-fixed, paraffin-embedded (FFPE) tissue blocks of laryngeal cancers were collected. Sections were prepared at 5 μm and DNA was extracted from each sample and subjected to the polymerase chain reaction (PCR) to detect HPV-16/18 DNA s. Results: All samples were squamous cell carcinomas (SCCs). Overall 14/50 (28%) were positive for HPVs, 8 (18%) with HPV-16 and 6 (12%) with HPV-18. Additionally, 2 (4%) mixed infections of HPV 16 and 18 genotypes were observed among these cases. Conclusions: Overall, 28% of HNSCC samples proved positive for HPV16 and HPV18 genotypes, two high-risk HPV types. It is important to further assess whether such viral infection, could be a risk factor in HNSCC progression.     

Management of extramedullary leukemia as a presentation of acute myeloid leukemia

Extramedullary involvement is considered to be an uncommon presentation of acute myeloid leukemia (AML), although some data suggest it may be present in up to 30% of patients. Extra-medullary involvement by AML can present in a variety of clinical manifestations, most notably in the form of myeloid sarcoma, leukemia cutis, and central nervous system involvement. Each presents a unique clinical scenario in terms of symptoms and management. Extramedullary disease in any form presenting without evidence of bone marrow disease is still considered evidence of systemic disease and is usually treated as such. Most commonly, extramedullary disease presents concurrently with bone marrow disease, and although it may require additional local therapy in the form of intrathecal chemotherapy or radiation, the principles of systemic treatment remain unchanged. The prognostic impact of extramedullary disease is unclear. Specifically, whether hematopoietic stem cell transplantation should be considered in first remission irrespective of other prognostic factors has not been established. Patients who undergo transplantation have similar outcomes as patients without extramedullary disease, although they do have a higher rate of extramedullary relapse. More research is needed to define the molecular basis for extramedullary disease, its prognostic impact, and optimal management.     

Human papillomavirus detection and comorbidity: critical issues in selection of patients with oropharyngeal cancer for treatment De-escalation trials

BackgroundThe presence of human papillomavirus (HPV)-infection in oropharyngeal squamous cell carcinoma (OPSCC) is a major determinant in prognostic risk modeling. However, most risk models are based on clinical trials which only include a selected patient population. The clinical significance of HPV and other prognostic factors in patients with OPSCC remains to be evaluated in a large, unselected cohort, which also includes patients with stage I/II disease and patients with severe comorbidity.Patients and methodsAll patients diagnosed with OPSCC in 2000–2006 in two Dutch university hospitals were included. The presence of an oncogenic HPV infection was determined by p16-immunostaining, followed by a high-risk HPV general primer 5+/6+ DNA PCR on the p16-positive cases. Cox regression analysis was carried out to compare survival rates between HPV-positive and HPV-negative patients and a prognostic model was generated by recursive partitioning.ResultsIn total, 163 of 841 (19.4%) tumors were HPV-positive. Patients with HPV-positive OPSCC had a more favorable overall survival [73.5% versus 40.9% after 5 years; P < 0.001; hazard ratio = 0.34, 95% confidence interval (CI) 0.25–0.48] compared with patients with HPV-negative OPSCC. Patients with p16-positive but HPV DNA-negative tumors showed a significantly less favorable survival than patients with p16-positive and HPV DNA-positive tumors (P < 0.001). A prognostic model was developed in which patients were classified into three risk groups according to HPV status, nodal stage and comorbidity. [Harrell's concordance index of 0.68 (95% CI 0.65–0.71)].ConclusionsTumor HPV status is a strong and independent prognostic factor for survival among patients with OPSCC. A prognostic risk model was proposed, based on our large, unselected cohort of patients with HPV status, comorbidity and nodal stage being the important prognostic factors. In addition, this study emphasizes the importance of performing an HPV DNA-specific test besides p16-immunostaining.     

A Patient‐Centered Approach to Counseling Patients With Head and Neck Cancer Undergoing Human Papillomavirus Testing: A Clinician's Guide

The International Agency for Research on Cancer and the National Cancer Institute have acknowledged human papillomavirus (HPV)‐16 as an independent risk factor for oropharyngeal cancer (OPC). HPV‐positive oropharyngeal cancer (HPVOPC) is a sexually transmitted entity that is on the rise; within the next 10 years, the annual number of HPV‐associated OPC cases is projected to exceed the annual number of cervical cancer cases in the United States. Recognition of HPV status in OPC has broad implications beyond the traditional oncological concerns of timely diagnosis, accurate staging, and appropriate treatment of cancer patients. The National Comprehensive Cancer Network recommends testing the tumor site for HPV‐status during OPC management; it is likely this will become a standard component of care for patients with high‐probability tumors of the oropharynx. As the practice of HPV testing becomes more common, it behooves providers to be able to adequately address the concerns of patients with HPVOPC. Although there are currently few relevant studies focusing on this population, existing literature on HPV‐infected women and patients with cervical cancer strongly supports the concept that patients with HPVOPC need education to optimally address concerns such as self‐blame, guilt, intimacy, and interpersonal relationships. When HPV testing is done, it should be accompanied by evidence‐driven and patient‐centered counseling to best minimize negative psychosocial outcomes and ensure optimum health promotion. Based on the current state of the literature, this article is intended to be a reference for physicians to effectively manage psychosocial outcomes when diagnosing patients with HPV‐associated OPC.     

Management of chronic lymphocytic leukemia

Significant progress has been made in the past two decades in the understanding of immunobiology of CLL and the development of clinical staging systems and identification of other prognostic factors in CLL. A significant advance in the management of CLL has also been made. Now we know when to initiate therapy. We recommend that patients with stage 0 and patients with stages I and II associated with good prognostic features such as absence of disease-related symptoms, long lymphocyte doubling time, nondiffuse bone marrow infiltration, and low tumor load not be treated; they should be followed at 2- to 6-month intervals. We recommend initiation of therapy for patients with stages I and II, associated with poor prognostic features such as presence of disease-related symptoms, short lymphocyte doubling time, diffuse bone marrow infiltration, and high tumor load and for patients with stages III and IV. However, we still do not know what constitutes the optimal therapy for the disease. In one large randomized study, the response rate as well as survival superiority of CHOP (with low-dose Adriamycin) over COP in previously untreated patients with stage C disease was observed. In another large randomized study, only a response rate advantage of CHOP (with standard dose Adriamycin) over chlorambucil and prednisone (in previously untreated patients with stages B and C) was seen. No randomized studies have compared CHOP versus chlorambucil and prednisone in patients with stages III and IV or stage C. At present, our recommendation for the treatment of patients with advanced disease is chlorambucil and prednisone therapy. New drugs under clinical trials for CLL include (1) deoxycoformycin, (2) 2-chlorodeoxyadenosine, and (3) fludarabine monophosphate. Both deoxycoformycin and 2-chlorodeoxyadenosine have been shown to have some activity in previously treated CLL patients with advanced disease. The effectiveness of these agents, however, has not been tested yet in untreated patients with advanced disease. Fludarabine monophosphate, on the other hand, has been shown to be very effective in both previously treated and untreated patients with advanced disease. Allogeneic bone marrow transplantation recently has been found to be of benefit in some patients (37 to 46 years) in a preliminary study; this therapeutic procedure should be tested further in a larger population of younger patients (less than 50 years) with advanced CLL. New agents such as lymphokines (interferons and IL-2) and monoclonal antibodies have been investigated for their efficacy and found to be minimally effective in previously treated patients with advanced disease.(ABSTRACT TRUNCATED AT 400 WORDS)     

CD8+ tumour‐infiltrating lymphocytes in relation to HPV status and clinical outcome in patients with head and neck cancer after postoperative chemoradiotherapy: A multicentre study of the German cancer consortium radiation oncology group (DKTK‐ROG)

We examined the prognostic value of tumour‐infiltrating lymphocytes (TILs) in patients with squamous cell carcinoma of the head and neck (SCCHN) after surgery and postoperative cisplatin‐based chemoradiotherapy. FFPE‐tissue originating from the surgery of 161 patients treated in 8 DKTK partner sites was immunohistochemically stained for CD3 and CD8. Their expression was correlated with clinicopathological characteristics as well as overall survival (OS), local progression‐free survival (LPFS) and distant metastases free‐survival (DMFS), also in the context of the HPV16‐DNA/p16 status. After a median follow‐up of 48 months (range: 4100 months), OS at 4 years was 46.5% for the entire cohort. In multivariate analysis, high CD8 expression was confirmed as an independent prognostic parameter for OS (p = 0.002), LPFS (p = 0.004) and DMFS (p = 0.006), while CD3 expression lacked significance. In multivariate analysis HPV16 DNA positivity was associated with improved OS (p = 0.025) and LPFS (p = 0.013) and p16‐positive patients showed improved DMFS (p = 0.008). Interestingly, high CD8 expression was a prognostic parameter for the clinical outcome in both HPV16 DNA‐positive and HPV16 DNA‐negative patients. Similar findings were observed in the multivariate analysis for the combined HPV16 DNA/p16 status. Altogether, CD8+ TILs constitute an independent prognostic marker in SCCHN patients treated with adjuvant chemoradiotherapy. These data indicate that CD8‐positive TILs have antitumour activity and could be used for treatment stratification. Further validation of the prognostic value of CD8+ TILs as a biomarker and its role in the immune response in SCCHN patients after adjuvant chemoradiotherapy is warranted and will be performed in the prospective DKTK‐ROG study.