Malignant Lymphomas in Patients with HIV Infection

During the last two decades, the occurrence of non-Hodgkin's lymphoma (NHLs) has been increasing both in the general population, in which their incidence doubled, and in people with human immunodeficiency virus (HIV) infection, in whom a 100-fold increase has been observed since the onset of the AIDS epidemic. HIV infected patients are living longer owing to advances in antiretroviral therapy and treatment of prophylaxis against opportunistic infections but because of their immunodeficiency they are at high risk of cancers, especially NHL. The natural history of cancers in patients with HIV infection differs from that of the general population. Unusual aspects of tumor localization, growth behaviour and therapeutical response, distinguish tumors in patients with from those without HIV infection. The pathologic and virological aspects of HIV-related tumors are peculiar and a pathological classification of HIV associated systemic lymphomas based on the morphological features of the two main types, i.e. blastic and anaplastic cell lymphomas has been formulated. The treatment of HIV-related neoplasms is controversial as it is not clear whether conventional therapy and in particular chemotherapy is able to modify the natural history of these malignancies in HIV setting. Moreover the treatment of HIV-related tumors presents several problems, due to the aggressive behaviours of tumors and because of immunosuppressive chemotherapy employed in patients with immunodeficiency.     

Hodgkin's Disease and Non-Hodgkin's Lymphoma in an HIV Positive Patient

The occurrence of HIV associated non-Hodgkin's lymphoma (NHL) is a well recognized event. HIV associated Hodgkin's disease (HD) has also been observed. A unique patient with both entities is described. The patient was a 29 year old homosexual male who developed clinical IIA nodular sclerosis HD in 1985. He was HIV + with CD4/CD8 = 0.2 and his sister had HD 20 years earlier. He received MOPP and had a complete response. In October 1988 he developed weight loss with an abdominal mass and biopsy revealed diffuse small non-cleaved NHL, with bone marrow involvement. This was his first AIDS associated illness. Probes identified clonally rearranged DNA fragments in the J region of IgH chains and clonal rearrangements in the c-myc gene were also observed but EBV sequences could not be demonstrated. He was treated with m-BACOD but died in March 1989. His course was not complicated by opportunistic infection. Possible etiologies for the HD include his HIV status or shared sibling environment. The development of the NHL may have resulted from HIV infection and/or secondary to his treatment for HD. The relationship between the two lymphomas is uncertain and factors other than HIV exposure and its immune dysfunction may have been causal.     

白血病微小残留病的检测及相关治疗中DNA甲基化的研究进展

DNA甲基化异常在恶性肿瘤中是一种最常见的表观遗传学改变,它在基因表达调控、基因组稳定性中起着重要作用,与白血病的发生、发展密切相关。肿瘤相关基因甲基化状态的分析可作为一种生物标志物用于白血病微小残留病的检测及复发风险的评估。因此,诱导抑癌基因去甲基化在抗肿瘤药物研究中具有重要意义。本文就近年来在DNA甲基化与白血病发生的关系及白血病去甲基化相关治疗的研究进展作一综述。     

Minimal Residual Disease in Head and Neck Cancer

Squamous cell carcinoma of the head and neck (HNSCC) is a complex disease. Patients with more advanced stages are treated with curative intent by a combination of surgery and radiotherapy, but still about 50% develop a relapse: locally, regionally and at distant sites. This clinical outcome strongly indicates that small histologically undetectable tumor deposits remain at these sites: minimal residual disease. In this article the different aspects related to minimal residual head and neck cancer will be reviewed shortly. The management of patients with head and neck cancer as well as the clinical problems in diagnosis and treatment will be described. The crucial role of minimal residual disease in head and neck cancer will be defined and diagnostic approaches to address the problem will be reviewed. We argue that the infiltration and dissemination of HNSCC takes place beyond the level of histopathological detection, and further that molecular staging will at least in part fill in the gap between anatomical TNM staging and the clinical outcome. However, it is not only the presence of infiltrated or disseminated tumor cells that will determine the prognosis. Also the biological characteristics of the tumor cells at the various sites are important for the clinical follow-up. Promising therapeutic approaches to deal with minimal residual disease will be discussed shortly. Finally the issues field cancerization and second primary tumors in head and neck cancer are addressed as these are closely linked to local recurrence and distant metastases. Moreover, second primary tumors will gain more importance when the primary disease and the frequency of relapses are better controlled.     

A New Chemotherapy Regimen for Treatment of Hodgkin's Disease Associated with Minimal Genotoxicity

Recently, the combination chemotherapy Novantrone, Oncovin, Velban, Prednisone [NOVP] was developed by The University of Texas M. D. Anderson Cancer Center for treatment of Hodgkin's disease [HD]. Preliminary clinical results show that NOVP is as effective as the traditional Mechlorethamine, Oncovin, Procarbazine, Prednisone [MOPP] regimen in achieving remission, but with fewer side-effects. To determine if NOVP is genotoxic, we studied the induction of chromosome breaks and sister chromatid exchanges [SCEs] in lymphocytes of 42 HD patients both before and during NOVP treatment. Furthermore, in vitro bleomycin treatment was used to unmask potential single-stranded DNA breaks inducted by the therapy. Our results showed that NOVP did not cause elevated levels of chromosome or single-stranded DNA breaks, or SCEs. These results together with previous findings that NOVP caused minimal acute and gonadal toxicities suggest that NOVP is less toxic than MOPP. Therefore, this new regimen shows promise as an effective and minimally toxic regimen for treatment of HD.     

Minimal residual disease detection in lymphoma and multiple myeloma: impact on therapeutic paradigms

Early identification of patients at high risk of relapse is a major goal of current translational research in oncohematology. Minimal residual disease (MRD) detection by polymerase chain reaction-based methods is currently part of the routine clinical management of patients with acute lymphoblastic leukemia. However, the current knowledge indicates that it is also a useful prognostic tool in several mature lymphoproliferative disorders. Its utility is currently well established in follicular lymphoma, mantle cell lymphoma, and multiple myeloma. In some of these entities, clinical trials employing MRD as a decision-making tool are currently ongoing. In the present review, we will discuss the 'state of the art' of MRD evaluation in these three neoplasms with the ultimate aim of providing critical take-home messages for clinicians working in the field. Moreover, we will outline the role of MRD detection in the design of future clinical trials.     

Breast cancer in Hodgkin's disease and non-Hodgkin's lymphoma survivors.

BACKGROUND: Better therapeutic approaches for patients with Hodgkin's disease (HD) and non-Hodgkin's lymphomas (NHL) resulted in high cure rates, at cost of serious late side effects. Second primary tumours are a major concern for long-term survivors, and breast cancer (BC) is the most common solid tumour among women treated for HD. Materials and methods: Fifty-three women treated for primary BC with previous history of malignant lymphoma were identified in our institution, 35 with HD (66%), 18 (34%) with NHL. A comparison group was randomly selected from our database matching for each patient with previous lymphoma, two patients with primary BC (rate 1 : 2) for age, stage (pathological tumour size [pT] status and nodal status), year of diagnosis, and estrogen and progesterone status (positive versus negative). The primary end points were disease-free survival (DFS) and overall survival (OS). RESULTS: The two groups of patients were compared for biological features: histopathological diagnosis, grading, lymphatic invasion, c-erbB2 overexpression, and Ki-67. Considering these variables, no significant differences were observed between the two groups with the exception of Ki-67, which was found higher in those with previous HD or NHL (65% versus 49%, respectively, P = 0.0526, borderline significant). Comparing the two groups for treatment approach, no differences were found for surgical and medical therapy (endocrine therapy and chemotherapy). However, regarding patients with node-positive disease (14 versus 35 patients), five patients in the lymphoma group (36%), compared with 24 (69%) in the matched group received anthracycline-based therapy (P = 0.0345). As expected, radiotherapy was used very differently in the two groups, with 36% of patients in the study group undergoing intraoperative radiotherapy with electrons versus 10% in the control group (P = 0.0001). Five-year DFS was 54.5% for the study cohort compared with 91% for controls (P < 0.0001). Five-year OS percentages were also statistically different (86.6% and 98.6%, respectively, P = 0.031). CONCLUSIONS: Previous history of malignant lymphoma is a negative prognostic factor for women diagnosed subsequently with BC. Some undertreatment of women with the latter might be hypothesised as the reason for the worse outcome. Influence of other variables, like previous exposure to cytotoxics, or some unknown biological features related to the previous disease and treatment, should still be investigated in the attempt to improve the dire outcome of these patients.     

Identification of Changes in Gene Expression Associated with Minimal Residual Disease

Minimal residual disease (MRD), the tumour burden which remains after a course of treatment that has resulted in clinical remission [1], appears to differ in certain characteristics from the primary tumour population. Certainly the cells which comprise MRD have had to escape from the constraints of the primary tumour mass, invade normal tissue and penetrate small vessels in order to enter the circulation in which they then have had to survive. Such activities are the consequence of the expression of specific proteins and these may well be a reflection of alterations in DNA or RNA levels. Identifying the changes in RNA expression levels between related cell groups exhibiting different phenotypes recently has become a great deal easier as a consequence of developments in analytical procedures such as Differential Display (DD) and Serial Analysis of Gene Expression (SAGE). Application of these procedures to MRD cells recovered from blood, bone marrow or lymph node, should identify novel sequences associated with tumour progression and the development of disseminated disease.     

Clinical potential of introducing next-generation sequencing in patients at relapse of acute myeloid leukemia

Relapse of acute myeloid leukemia (AML) remains a major determinant of outcome. A number of molecularly directed treatment options have recently emerged making comprehensive diagnostics an important pillar of clinical decision making at relapse. Acknowledging the high degree of individual genetic variability at AML relapse, next-generation sequencing (NGS) has opened the opportunity for assessing the unique clonal hierarchy of individual AML patients. Knowledge on the genetic makeup of AML is reflected in patient customized treatment strategies thereby providing improved outcomes. For example, the emergence of druggable mutations at relapse enable the use of novel targeted therapies, including FLT3 inhibitors or the recently approved IDH1/2 inhibitors ivosidenib and enasidenib, respectively. Consequently, some patients may undergo novel bridging approaches for reinduction before allogeneic stem cell transplantation, or the identification of an adverse prognostic marker may initiate early donor search. In this review, we summarize the current knowledge of NGS in identifying clonal stability, clonal evolution, and clonal devolution in the context of AML relapse. In light of recent improvements in AML treatment options, NGS-based molecular diagnostics emerges as the basis for molecularly directed treatment decisions in patients at relapse.     

呼吸系统原发性淋巴瘤11例临床分析

目的了解呼吸系统原发性淋巴瘤(PLRS)的临床病理特点及治疗结果。方法分析11例患者的临床表现、影像学改变、病理类型、治疗及生存情况。结果原发于气管2例,原发于肺9例。临床表现主要为咳嗽胸闷、发热、胸片和胸部cT扫描表现为肿块或阴影。病理类型为霍奇金(HD)2例;非霍奇金淋巴瘤(NHL)9例,包括低度恶性7例,其中黏膜相关淋巴瘤5例(55．6％),中度恶性2例。10例行手术治疗,8例术后加化疗,2例术后加放疗。治疗后2例HD患者的无病生存期超过5年,黏膜相关淋巴瘤和其它类型的NHL中位生存期分别为39个月和34个月。结论PLRS的临床和影像学表现为非特异性,病理类型以低度恶性黏膜相关淋巴瘤多见,外科手术为治疗首选,预后良好。     

呼吸系统原发性淋巴瘤11例临床分析(英文)

目的了解呼吸系统原发性淋巴瘤(PLRS)的临床病理特点及治疗结果。方法分析11例患者的临床表现、影像学改变、病理类型、治疗及生存情况。结果原发于气管2例,原发于肺9例。临床表现主要为咳嗽胸闷、发热、胸片和胸部 CT 扫描表现为肿块或阴影。病理类型为霍奇金(HD)2例;非霍奇金淋巴瘤(NHL)9例,包括低度恶性7例,其中黏膜相关淋巴瘤5例(55.6%),中度恶性2例。10例行手术治疗,8例术后加化疗,2例术后加放疗。治疗后2例 HD 患者的无病生存期超过5年,黏膜相关淋巴瘤和其它类型的 NHL 中位生存期分别为39个月和34个月。结论 PLRS 的临床和影像学表现为非特异性,病理类型以低度恶性黏膜相关淋巴瘤多见,外科手术为治疗首选,预后良好。     

Clinical Relevance of Minimal Residual Cancer in Patients with Solid Malignancies

With the advent of new therapeutic modalities, the treatment options for oncologists can vary greatly depending upon the aggressiveness of the patient's cancer. Patients may receive no therapy, adjuvant therapy, aggressive adjuvant therapy (taxane based), monoclonal antibody therapy (e.g. Herceptin) or bone marrow transplantation. It is now mandatory to determine accurate prognostic patient profiles at diagnosis and during therapy to determine who would benefit most from a particular therapeutic regimen or to determine who should be shifted into more aggressive therapy. We now have ultra-sensitive methods of tumor cell detection that can determine the presence of minimal residual cancer (MRC) in marrow, stem cell product (SCP) and lymph node to help create these prognostic profiles. The author has conducted a critical review of the literature regarding the type of testing used to detect MRC, the incidence of MRC in marrow, SCP, and lymph node, and the clinical significance of MRC at diagnosis and during therapy.To date it is now clear that immunohistochemistry is a very useful diagnostic tool with adequate sensitivity to detect MRC. The presence of MRC at diagnosis in marrow and/or lymph node is associated with a poor prognosis for a number of disorders including breast cancer, neuroblastoma, gastrointestinal tumors, and lung cancer. In addition, the presence of MRC during therapy in marrow and/or SCP is associated with a very poor prognosis for patients with breast cancer. The use of testing for MRC in the patient provides prognostic information that may be of use to the oncologist.     

Familial Lymphomas A review of the literature with report of cases in Jerusalem

Non-Hodgkin's lymphoma Although non-Hodgkin's lymphoma (NHL) is a common disorder, there are relatively few reports occurring in family groups. Extensive review of the literature by Ladish et al. in 1978¹ revealed 38 multiple-case families with NHL, most of whom were sibpairs, either sibs alone (6.3%) or sibs plus other relatives (13%), including a pair of monozygotic twins². The mean age of diagnosis in these cases was 23.5 years compared with 42.3 years for the general population with NHL. About half of the familial cases were extranodal (44 cases), primarily involving the gastro-intestinal tract in 26 cases, with the distal small bowel and cecum being most frequently affected. No histologic type was predominant in the affected families³. As described for Hodgkin's disease (HD)^4,5 increased incidence with small family size has been observed for NHL; however, no change in risk has been seen with increasing family size⁶.     

RT—PCR方法对检测乳腺癌干细胞富集血残存肿瘤细胞的价值

目的：旨在用敏感的ＲＴ－ＰＣＲ方法扩增目的基因,用于检测干细胞富集血中残存的肿瘤细胞。方法：应用ＲＴ－ＰＣＲ方法检测样品ＭＵＣ１,Ｋ１９基因的表达情况。结果：乳腺癌细胞系ＭＣＦ－７中ＭＵＣ１,Ｋ１９表达阳性,而在淋巴细胞中则未见有表达。进一步用淋巴细胞稀释乳腺癌细胞来检测该方法的灵敏度。ＭＵＣ１,Ｋ１９检测残存肿瘤细胞的灵敏度均达到１／１０＾５,在此基础上,完成了１５例乳腺癌患者中干细胞富集血检测     

The clinical significance of residual disease in childhood acute lymphoblastic leukemia as detected by polymerase chain reaction amplification of antigen-receptor gene sequences

The polymerase chain reaction (PCR) has been applied to detect occult leukemia cells in children with acute lymphoblastic leukemia who are otherwise considered in complete remission by traditional morphological examination of bone marrow specimens. To determine whether PCR provides unique prognostic information of use for the clinical investigator, we reviewed the 20 clinical studies published to date. From this review, it is evident that discrepancies exist for the detection of residual disease for patients who remain in complete remission and for those who relapse. However, because of the fundamentally different approaches used to apply the PCR method to each of these studies, an entirely different interpretation can be reached when critical technical factors are considered. The combined data from the various studies suggest that a consistent pattern for residual disease disappearance over many months exists for patients who remain in extended complete remission and a pattern of residual disease persistence and reappearance preceding clinical findings exists for the majority of those who ultimately relapse in the bone marrow.     

Fine-Needle Aspiration Cytology and Immunocytochemistry of Abdominal Non-Hodgkin's Lymphomas

The cytomorphology and immunologic characteristics of cells obtained by fine-needle aspiration biopsy of 34 consecutive patients with abdominal lymphomas were analyzed. Nineteen patients had no previous diagnosis, while 15 had previously known or suspected lymphomas. On cytology 21 high-grade and 13 low-intermediate-grade lymphomas were diagnosed. Immunologic characterization of aspirated cells identified one T-cell and 33 B-cell neoplasms. A monoclonal light chain expression was detected in 27 of the B-cell lymphomas. The results were in good agreement with those from histologic (n = 19) and immunohistochemical (n = 5) evaluations. The value and accuracy of fine-needle aspiration cytology in conjunction with immunocytochemistry are detailed.     

Primary Hodgkin's Disease of the Tonsil. Report of a Case and Review of the Literature

A 31 year-old woman with mixed cellularity Hodgkin's disease with isolated tonsilar involvement is reported. Local radiotherapy was given, and the patient remained assymptomatic, without evidence of disease 16 months from the time of diagnosis. After a review of the literature only 17 well-documented cases of Hodgkin's disease arising in the nasopharynx have been found. After reviewing this data, we suggest that systematic examination of the Waldeyer's ring should always be performed in cases of Hodgkin's disease arising in the laterocervical lymph nodes.