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.     

“Hard” and “soft” lesions underlying the HLA class I alterations in cancer cells: Implications for immunotherapy

The ability of cancer cells to escape from the natural or immunotherapy‐induced antitumor immune response is often associated with alterations in the tumor cell surface expression of Major Histocompatibility Complex (MHC) Class I antigens. Considerable knowledge has been gained on the prevalence of various patterns of MHC Class I defects and the underlying molecular mechanisms in different types of cancer. In contrast, few data are available on the changes in MHC Class I expression happening during the course of cancer immunotherapy. We have recently proposed that the progression or regression of a tumor lesion in cancer patients undergoing immunotherapy could be predetermined by the molecular mechanism responsible for the MHC Class I alteration and not by the type of immunotherapy used, i.e., interleukin‐2 (IL‐2), Bacillus Calmette‐Guèrin (BCG), interferon‐alpha (IFN‐α), peptides alone, dendritic cells loaded with peptides, protein‐bound polysaccharide etc. If the molecular alteration responsible for the changes in MHC Class I expression is reversible by cytokines (“soft” lesion), the MHC Class I expression will be upregulated, the specific T cell–mediated response will increase and the lesion will regress. However, if the molecular defect is structural (“hard” lesion), the MHC Class I expression will remain low, the escape mechanism will prevail and the primary tumor or the metastatic lesion will progress. According to this idea, the nature of the preexisting MHC Class I lesion in the cancer cell has a crucial impact determining the final outcome of cancer immunotherapy. In this article, we discuss the importance of these two types of molecular mechanisms of MHC Class I–altered expression.     

Detection of Minimal Residual Disease Using ctDNA in Lung Cancer: Current Evidence and Future Directions

Advances in DNA sequencing methods have significantly expanded the potential clinical applications of analyzing circulating tumor DNA (ctDNA). This genetic information can identify the presence of targetable mutations and has been explored for cancer screening purposes. ctDNA can be obtained without the risks inherent to biopsy, allowing for serial assessments over time. Several studies have additionally suggested that ctDNA can be used to detect the presence of minimal residual disease (MRD) after surgical resection in several cancer types, including lung cancer. The ability to detect MRD would allow clinicians to tailor adjuvant therapies, which carry risks of significant toxicities and may benefit only select groups of patients. Here, we review the current state of ctDNA profiling methods and evaluate the evidence supporting the use of ctDNA analysis to assess for MRD. We discuss how MRD detection could help identify patients at increased risk of disease recurrence and thus guide treatment decisions for resectable lung cancer. Finally, we propose future steps to validate such approaches and expand the utility of these rapidly progressing technologies.     

Current Trends in Cancer Vaccines - a Bioinformatics Perspective

Cancer vaccine development is in the process of becoming reality in future, due to successful phase II/IIIclinical trials. However, there are still problems due to the specificity of tumor antigens and weakness of tumorassociated antigens in eliciting an effective immune response. Computational models to assess the vaccine efficacyhave helped to improve and understand what is necessary for personalized treatment. Further research is neededto elucidate the mechanisms of activation of antigen specific cytotoxic T lymphocytes, decreased TREG numberfunctionality and antigen cascade, so that overall improvement in vaccine efficacy and disease free survival canbe attained. T cell epitomic based in sillico approaches might be very effective for the design and developmentof novel cancer vaccines.     

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.     

The Future of ctDNA-Defined Minimal Residual Disease: Personalizing Adjuvant Therapy in Colorectal Cancer

Our understanding of the diagnostic and prognostic use of circulating tumor DNA (ctDNA) in colorectal cancer (CRC) has broadly expanded over the past few years. The utilization of ctDNA to detect minimal residual disease is currently being employed across the continuum of cancer care. The lead-time of ctDNA positivity to radiographic recurrence in stage I to III CRC is up to 9 months on average, which provides a therapeutic window for a group of high-risk patients who will ultimately recur. There are several ongoing prospective clinical trials that investigate whether ctDNA can be used as an integral biomarker to risk stratify CRC patients and guide adjuvant treatment decisions. In this review, we summarize the evidence supporting the promise of ctDNA-defined MRD in CRC and highlight the current ctDNA guided adjuvant prospective clinical trials.     

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     

Minimal Residual Disease in Multiple Myeloma: Potential for Blood-Based Methods to Monitor Disease

In recent years, the life expectancy of Multiple Myeloma (MM) patients has substantially improved, but this cancer remains incurable with increasing incidence in the developed world. Most MM patients will eventually relapse due to residual drug-resistant cancerous cells that survive treatment, commonly referred to as minimal residual disease (MRD). Methods to improve MRD detection in MM patients are generating considerable interest as a means of monitoring patients' response to treatment. In clinical laboratories, these methods currently require bone marrow aspirates which are invasive and frequently miss detection of localised disease due to the spatial heterogeneity of disease infiltration. By simplifying serial sampling and allowing for the detection of extramedullary disease, a blood-based method could significantly impact treatment duration and intensity and minimise chemotherapy-induced toxicity. This review will describe the current blood-based techniques available to detect MRD in MM and compare their potential to evaluate patient prognosis and drive therapeutic decisions.     

Cervical Cancer: Etiology,Pathogenesis, Treatment,and Future Vaccines

Cervical cancer is a sexually transmitted disease caused by the human papillomavirus (HPV), especially HPV-16 ‍and -18. Of the half million new cases of cervical cancer reported yearly, 20% occur in India. Mass cancer screening ‍programs to detect and treat cervical cancer and its precursor lesions are not available in India and most other ‍developing countries because of the lack of resources. Curative and palliative treatments are not the same for all ‍patients with cervical cancer because the result depends on the immunological response of the patient. This article ‍describes the natural history of cervical carcinogenesis and the rational behind various modalities of prevention and ‍treatment for the practising gynecological oncologist. Prophylactic vaccines against HPV-16 and -18 and therapeutic ‍vaccines against cervical cancers should be able to overcome the logistical problems that now exist to screen, diagnose ‍and treat cervical cancer and its precursor lesions. ‍     

Minimal Residual Disease in Adult Acute Lymphoblastic Leukemia: Egyptian Experience

Background: Acute lymphoblastic leukemia (ALL) is a clonal disease that affects early lymphoid progenitors in the bone marrow. Minimal residual disease (MRD) is assessed by different methods to monitor disease kinetics after treatment. Aim: to Assess MRD post-induction, at 6 and 12 months after intensive chemotherapy in adult patients with ALL. Patients and Methods:  Seventy adult newly diagnosed acute lymphoblastic leukaemia patients were enrolled between July 2018 and July 2019 at the Clinical Hematology Unit, Ain Shams University hospitals, Egypt. MRD was assessed on the bone marrow samples using multi-parameter four color flow cytometry with 0.01% cut-off; below which cases are deemed MRD negative. Results: After the end of induction period, 13 out of 46 patients (28%) had positive MRD. However, MRD positivity is demonstrable in 14/32(43.8%), and 10/28(35.7%) patients at 6 and 12 months; respectively. MRD positivity was significantly associated with older age group (more than 39 years) and high NCCN risk stratum with p-values <0.05. Moreover, most of MRD positive patients at 12 months of therapy were of T-ALL immunophenotype (P value 0.002).  Patients with complete remission and negative MRD exhibited significantly higher overall survival when compared to patients having MRD positivity (P value 0.027). Conclusion: MRD is a powerful predictor of outcome in ALL and its positivity at different time points is associated with poor prognostic factors as well as survival outcomes.     

Experimental strategies for modification of histocompatibility antigens in tumor cells

Cancer may be thought of as an immunological disorder that arises because certain transformed cells, endowed with the propensity to divide, have learned to evade detection by the immune system. The prospect of intervention by immunotherapy depends very much on our ability to either [1] render cancer cells more recognizable to the immune system, or [2] potentiate the immune system towards a more effective recognition of cancer cells. There is now direct evidence that suppression of the major histocompatibility complex class I antigens, a family of cell-surface glycoproteins required for the presentation of cancer cells to the immune system, is directly responsible for the ability of tumor cells to escape immune surveillance. It has been shown that cancer cells can be made immunogenic either by the expression of an exogenous class I gene introduced by DNA-mediated gene transfer, or by the derepression of endogenous class I genes with interferon; these cells are efficiently rejected by the immune system. Even more interesting is the finding that the immune system can be potentiated to reject tumors by immunization with homologous tumor cells that have been manipulated to express normal levels of class I antigens. Since increasing numbers of human tumors have been found to have greatly reduced levels of class I antigens, these findings suggest a direct route to immunotherapy that involves debulking of the tumor mass, raising the level of class I antigens in a small number of explanted tumor cells, and re-immunizing the host.     

Cancer testis antigens expression in mesothelioma: role of DNA methylation and bioimmunotherapeutic implications

Recent evidences suggest that malignant mesothelioma may be sensitive to immunotherapy; however, little is known about malignant mesothelioma-associated tumour antigens. Focusing on cancer/testis antigens, the expression of well-characterised immunogenic tumour-associated antigens was investigated in malignant mesothelioma cells. At variance with MAGE-4 and NY-ESO-1, malignant mesothelioma cells frequently expressed MAGE-1, -2 and -3, GAGE 1-2, GAGE 1-6, SSX-2 and SSX 1-5, and distinct malignant mesothelioma cells concomitantly expressed at least four cancer/testis antigens. Additionally, the tumour-associated antigens RAGE-1 was expressed at high levels in both benign and malignant mesothelial cells. Lastly, treatment with the DNA hypomethylating agent 5-aza-2'-deoxycytidine induced and up-regulated the expression of the cancer/testis antigen examined in malignant mesothelioma cells. Overall, these findings strongly suggest that cancer/testis antigens-based immunotherapy may represent a suitable therapeutic approach to malignant mesothelioma, and foresee the clinical use of 5-aza-2'-deoxycytidine to design new chemo-immunotherapeutic strategies in malignant mesothelioma patients.     

Potential Therapeutic Efficacy of Curcumin in Liver Cancer

Purpose: Liver cancer, one of the most common cancers in China, is reported to feature relatively highmorbidity and mortality. Curcumin (Cum) is considered as a drug possessing anti-angiogenic, anti-inflammationand anti-oxidation effect. Previous research has demonstrated antitumor effects in a series of cancers. Materialsand Methods: In this study the in vitro cytotoxicity of Cum was measured by MTT assay and pro-apoptotic effectswere assessed by DAPI staining and measurement of caspase-3 activity. In vivo anti-hepatoma efficacy of Cumwas assessed with HepG2 xenografts. Results: It is found that Cum dose-dependently inhibited cell growth inHepG2 cells with activation of apoptosis. Moreover, Cum delayed the growth of liver cancer in a dose-dependentmanner in nude mice. Conclusions: Cum might be a promising phytomedicine in cancer therapy and furtherefforts are needed to explore this therapeutic strategy.     

Treatment Strategies for Residual Disease following Neoadjuvant Chemotherapy in Patients with Early-Stage Breast Cancer

Breast cancer continues to be the most diagnosed cancer among women worldwide. Neoadjuvant chemotherapy is the standard of care for breast cancer patients with locally advanced disease and patients with poor pathological features, such as triple-negative (TN) or human epidermal growth factor receptor-2 (HER2)-positive subtypes. Neoadjuvant therapy offers several advantages, including better surgical outcomes, early systemic treatment for micro-metastases, and accurate tumor biology and chemosensitivity assessment. Multiple studies have shown that achieving pathological complete response (pCR) following neoadjuvant chemotherapy is associated with better prognosis and better treatment outcomes; almost half of such patients may fail to achieve pCR. Tumor proliferative index, hormone receptor (HR) status, and HER2 expression are the major predictors of pCR. Strategies to improve pCR have been dependent on augmenting neoadjuvant chemotherapy with the addition of taxanes and dual anti-HER2 targeted therapy in patients with HER2-positive tumor, and more recently, immunotherapy for patients with TN disease. The clinical management of patients with residual disease following neoadjuvant chemotherapy varies and depends mostly on the level of HR expression and HER2 status. Recent data have suggested that switching trastuzumab to trastuzumab-emtansine (T-DM1) in patients with HER2-positive disease and the addition of capecitabine for patients with HER2-negative and HR-negative subtype is associated with a better outcome; both strategies are incorporated into current clinical practice guidelines. This paper reviews available and ongoing studies addressing strategies to better manage patients who continue to have residual disease following neoadjuvant chemotherapy.     

外源性TGFBI抑制乳腺癌细胞生长的体内外实验

目的 研究转化生长因子β诱导基因 (transforming growth factor-β induced gene, TGFBI) 是否能抑制人乳腺癌细胞株(MDA-MB-231)的体内外增生。方法 将外源性TGFBI稳定转染到人乳腺癌细胞株(MDA-MB-231)中,测定细胞增殖率、细胞周期、软琼脂克隆形成率及P21、P53蛋白表达变化,检测乳腺癌细胞的致瘤性。结果 外源性TGFBI在人乳腺癌细胞株(MDA-MB-231)中能够稳定地高表达;外源性TGFBI可以明显地抑制乳腺癌细胞因血清生长因子刺激的增生;与转染空质粒的对照组细胞V23101比较,外源性TGFBI相对软琼脂克隆形成数减少了90.89%; TGFBI可以使人乳腺癌细胞阻滞在G1期,延缓其进入S期的时间。外源性TGFBI可以延长裸鼠肿瘤发生的潜伏期,并降低肿瘤发生率。结论 TGFBI能够抑制人乳腺癌细胞株(MDA-MB-231)的体内外增生。     

Molecular Minimal Residual Disease Testing in Acute Myeloid Leukemia: A Review for the Practicing Clinician

Minimal residual disease (MRD) testing in acute myeloid leukemia is increasingly being used to assess treatment response and stratify the risk of relapse for individual patients. Molecular methods for MRD testing began with PCR-based assays for individual recurrent mutations. To date, there is robust evidence for testing NPM1, CBFB-MYH11, and RUNX1/RUNXT1 mutations using this approach, though the best timing and threshold level for each mutation varies. More recent approaches have been with PCR-based multigene panels, occasionally combined with flow cytometric techniques, and next-generation sequencing techniques. This review outlines the various techniques used in molecular approaches to MRD, the evidence behind individual mutation testing, and the novel approaches for evaluating multigene MRD so that clinicians can understand and incorporate these evaluations into their practice.