Lung cancer: New biological insights and recent therapeutic advances

Approximately 1.6 million new cases of lung cancer are diagnosed each year throughout the world. In many countries, the mortality related to lung cancer continues to rise. The outcomes for patients with all stages of lung cancer have improved in recent years. The use of systemic therapy in conjunction with local therapy has led to improved cure rates in both resectable and unresectable patient groups. For patients with advanced stage disease, modest but real improvements in overall survival and quality of life have been achieved with systemic chemotherapy. A major focus of research has been the development of molecularly targeted agents and the identification of biomarkers for patient selection. Patients with non-small cell lung cancer with mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase domain achieve response rates of greater than 70% and superior progression-free survival when treated with an EGFR tyrosine kinase inhibitor compared with standard chemotherapy. This has now emerged as the preferred therapeutic approach for the subset of patients with a mutation in exons 19 or 21 of the EGFR. Another promising targeted approach involves the use of an anaplastic lymphoma kinase (ALK) inhibitor in patients with a translocation involving the echinoderm microtubule-associated protein-like 4 (EML4) and -ALK genes. Finally, a paradigm shift in favor of maintenance therapy for patients with advanced stage disease has gained strength from recent data. All of these advances have been made possible by developing a greater understanding of the biology, the discovery of novel anticancer agents, and improved supportive care measures. This article reviews the major strides made in the treatment of lung cancer in the recent past.     

New approaches in metastatic melanoma: biological and molecular targeted therapies

Classical metastatic melanoma therapy is disappointing but important progress has been made in the understanding of melanoma biology. Genetic lesions and several intracellular signaling pathways that could serve as targets for novel therapy have been identified and a number of new agents are under evaluation. Promising tumor cell targets were identified in the cell membrane, cytoplasm and nucleus. New therapeutic approaches, besides monoclonal antibodies and vaccination, include an increasing number of small molecules that have been shown to interfere restrictively with intracellular signaling pathways in melanoma and decrease proliferation, survival, migration or invasion. Other agents can interfere with stromal components of melanoma, such as angiogenesis and components of the immune system.     

New approaches in metastatic melanoma: biological and molecular targeted therapies

Classical metastatic melanoma therapy is disappointing but important progress has been made in the understanding of melanoma biology. Genetic lesions and several intracellular signaling pathways that could serve as targets for novel therapy have been identified and a number of new agents are under evaluation. Promising tumor cell targets were identified in the cell membrane, cytoplasm and nucleus. New therapeutic approaches, besides monoclonal antibodies and vaccination, include an increasing number of small molecules that have been shown to interfere restrictively with intracellular signaling pathways in melanoma and decrease proliferation, survival, migration or invasion. Other agents can interfere with stromal components of melanoma, such as angiogenesis and components of the immune system.     

DNA methylation profiling in acute myeloid leukemia: from recent technological advances to biological and clinical insights

Acute myeloid leukemia represents a heterogeneous malignant hematological disease with a complex underlying biology suggesting multiple patterns of genetic and epigenetic alterations. Recent evidence suggests that epigenetic mechanisms, especially deregulation of DNA methylation, play an important pathogenic role in leukemogenesis and the first epigenetic drugs have entered the clinic. Therefore, an improved understanding of the impact of altered epigenetic patterns on leukemogenesis represents a pre-requisite for improved patient management and outcome. Here, we provide an overview of current advances in deciphering the leukemic epigenome and its clinical relevance. Recent high-throughput analyses and genome-wide studies provide an optimal starting point for future epigenetic and integrative analyses that will further the development and use of predictive and prognostic epigenetic markers in acute myeloid leukemia.     

Array-based cytogenetic approaches in acute myeloid leukemia: clinical impact and biological insights

Conventional cytogenetic studies have shown that the clinical and biological diversity of acute myeloid leukemia (AML) can be attributed, in part, to distinct chromosome aberrations, several of which are now routinely used for diagnosis, risk stratification, and outcome prediction. Although chromosome banding analysis has recently been complemented by the identification of point mutations in a growing number of hematopoiesis-associated genes, current genetic categories do not fully reflect the heterogeneity of AML. To close the gap between standard karyotyping and molecular analyses at the single-base-pair level and gain additional insight into the genetics underlying myeloid leukemogenesis, AML is increasingly being studied using genome-wide, microarray-based cytogenetic methods. These investigations have revealed that AML genomes commonly harbor acquired submicroscopic copy number alterations, even though the prevalence of most of these cryptic lesions appears to be low, as well as regions of uniparental disomy that are often associated with homozygosity of functionally relevant gene mutations. Current efforts are focusing on the application of this expanded knowledge to improve the classification of AML, develop new tools for prognostication and prediction of response to therapy, and accelerate the discovery of genes that are likely to contribute to AML pathogenesis.     

Dermatofibrosarcoma protuberans: from translocation to targeted therapy

Dermatofibrosarcoma protuberans (DFSP), the most common dermal sarcoma, is a low-grade, slow growing fibroblastic malignant neoplasm that most frequently affects middle aged adults and is characterized by a high local recurrence rate and a low propensity for metastasis. Wide surgical resection or Mohs micrographic surgery (MMS) are the preferred approaches for localized disease, while radiation therapy is warranted for inoperable disease or for cases with positive margins where re-excision is not possible. DFSP is generally regarded as refractory to conventional chemotherapy. Treatment options for systemic disease were limited until the discovery of a unique translocation, t(17;22)(q22;q13) (COL1A1;PDGFB) found in a majority of cases. In recent years, imatinib, a PDGFβR, ABL and KIT inhibitor, has revolutionized systemic therapy in DFSP. In this review, we summarize the epidemiological, clinical, histological and genetic characteristics of DFSP and update the readers on its current management.KEYWORDS : Dermatofibrosarcoma protuberans (DFSP), imatinib, Mohs micrographic surgery (MMS), translocation, targeted therapy     

Pancreatic cancer: from molecular pathogenesis to targeted therapy

Pancreatic cancer is a deadly malignancy with still high mortality and poor survival despite the significant advances in understanding, diagnosis, and access to conventional and novel treatments. Though cytotoxic chemotherapy based on the purine analogue gemcitabine remains the standard approach in adjuvant and palliative setting the need for novel agents aiming at the main pathophysiological abnormalities and molecular pathways involved remains soaring. So far, evidence of clinical benefit, though small, exists only from the addition of the targeted agent erlotinib on the standard gemcitabine chemotherapy. Apart from the popular monoclonal antibodies and small molecules tyrosine kinase inhibitors, other novel compounds being tested in preclinical and clinical studies target mTOR, NF-kappaB, proteasome and histone deacetylase. These new drugs along with gene therapy and immunotherapy, which are also under clinical evaluation, may alter the unfavorable natural course of this disease. In this review we present the main pathophysiological alterations met in pancreatic cancer and the results of the florid preclinical and clinical research with regards to the targeted therapy associated to these abnormalities.     

椎间盘退变生物治疗进展

临床上椎间盘退行性疾病在保守治疗基础上,大多数需要通过外科干预达到长期缓解局部疼痛的目的.但由于椎间盘生物力学上的特殊地位,使得如何在保持椎间盘完整性的基础上,促进椎间盘细胞外基质再生的生物治疗方法成为椎间盘退变预防和治疗的研究热点.椎间盘髓核基质数量和成分的改变被认为是椎间盘退变的一个重要原因,目前许多学者试图通过引入各种外源性生长因子、种子细胞、基因以及基因转染的细胞,以期增加髓核细胞外基质含量,恢复II型胶原和蛋白多糖比例,逆转或延缓椎间盘退变的发展进程.     

Hairy cell leukaemia: biological and clinical overview from immunogenetic insights

Hairy cell Leukaemia (HCL) is a rare neoplasm of peripheral B cells which represents a paradox in oncology. Despite its largely unknown origin and behaviour, HCL is one of the few example of dramatic success in the treatment of a malignancy. The recent steps forward to understanding the biology of HCL from immunogenetic and genomic studies have recently provided new insight into diagnosis and prognosis. Several data from immunoglobulin gene (IG) analysis have provided hints regarding the cell of origin and the ongoing selective interactions of the tumour BCR with environmental stimuli. It has also recently emerged that an unmutated status of the HCL IG can be associated with failure to respond to cladribine, genetic abnormalities indicative of poor outcome and aggressive disease. These observations suggest a central role of the tumour B-cell receptor in defining the outcome of HCL and that that IG gene analysis may have biological and prognostic relevance. Hopefully, IG analysis will help tailor treatment strategies for the most aggressive cases.     

New clinical and biological insights from the international TARGIT-A randomised trial of targeted intraoperative radiotherapy during lumpectomy for breast cancer

Background The TARGIT-A trial reported risk-adapted targeted intraoperative radiotherapy (TARGIT-IORT) during lumpectomy for breast cancer to be as effective as whole-breast external beam radiotherapy (EBRT). Here, we present further detailed analyses.Methods In total, 2298 women (≥45 years, invasive ductal carcinoma ≤3.5 cm, cN0–N1) were randomised. We investigated the impact of tumour size, grade, ER, PgR, HER2 and lymph node status on local recurrence-free survival, and of local recurrence on distant relapse and mortality. We analysed the predictive factors for recommending supplemental EBRT after TARGIT-IORT as part of the risk-adapted approach, using regression modelling. Non-breast cancer mortality was compared between TARGIT-IORT plus EBRT vs. EBRT.Results Local recurrence-free survival was no different between TARGIT-IORT and EBRT, in every tumour subgroup. Unlike in the EBRT arm, local recurrence in the TARGIT-IORT arm was not a predictor of a higher risk of distant relapse or death. Our new predictive tool for recommending supplemental EBRT after TARGIT-IORT is at https://targit.org.uk/addrt. Non-breast cancer mortality was significantly lower in the TARGIT-IORT arm, even when patients received supplemental EBRT, HR 0.38 (95% CI 0.17–0.88) P = 0.0091.Conclusion TARGIT-IORT is as effective as EBRT in all subgroups. Local recurrence after TARGIT-IORT, unlike after EBRT, has a good prognosis. TARGIT-IORT might have a beneficial abscopal effect.Trial registration ISRCTN34086741 (21/7/2004), {"type":"clinical-trial","attrs":{"text":"NCT00983684","term_id":"NCT00983684"}}NCT00983684 (24/9/2009).Subject terms: Breast cancer, Radiotherapy, Surgical oncology     

腺泡状软组织肉瘤生物学特征及靶向治疗的研究进展

腺泡状软组织肉瘤(ASPS)是一种罕见的软组织肉瘤,具有高度侵袭性、易转移,患者预后差。ASPS对传统的化疗药物不敏感,虽然早期诊断和手术切除能有效改善患者预后,但是对发生转移的晚期患者,探索新型的治疗手段很有必要。分子靶向治疗在临床治疗中的作用越来越重要。ASPS的恶性表现主要是高度的血管生成效应,这是由血管生成因子过表达和过度活化造成。了解ASPS的生物学特征,包括其发生的分子事件,对于筛选新的分子靶向治疗方案很重要。本文就ASPS的生物学特征及靶向治疗的进展进行综述。     

Nitrosoureas from chemist to physician: Classification and recent approaches to drug design

Molecular design of chemotherapeutic nitrosoureas is reviewed in the light of a chemical classification of N-(2-chloroethyl)-N-nitrosoureas (CNUs), particularly those recently introduced and earlier compounds tested in the clinic. Of the six categories, three are rather arbitrarily based on physicochemical properties: the original, lipid-soluble drugs, water-soluble sugar derivatives, and amides of intermediate character. Others deal with more complex drug designs incorporating antimetabolites (5-fluorouracil), steroids, redox delivery systems, or hypoxia-selective 2-nitroimidazoles. Current attempts to modify the standard 2-chloroethyl group, with implications for interstrand cross-linking of DNA, are considered.Two unfortunate factors influencing the choice of drugs for clinical trial have been prejudice from the physician and commercial interests. The latter requires no further comment, but a strong plea is made for recognition of the CNU group as one of comparatively few valuable tools for rational drug design requiring appropriate pharmacokinetic evaluation, rather than as a somewhat boring hallmark of repetitive chemists.     

Advanced NSCLC: from cytotoxic systemic chemotherapy to molecularly targeted therapy

Approximately a third of non-small cell lung cancer patients present with disseminated disease at the time of diagnosis. For these patients, as well as those with recurrent disease, chemotherapy remains the mainstay of treatment. For several decades, researchers have attempted different combinations of drugs in search for the ‘best’ chemotherapy regimen. Despite the emergence of newer, ‘third-generation’ cytotoxic agents, success is still modest at best. Fortunately, new insights in tumor biology, leading to the design of molecularly targeted drugs, are opening a new era in cancer treatment. These novel agents target molecular pathways specifically found in cancer cells, thus maximizing the antitumor effect while minimizing toxicities on normal cells.     

Advanced NSCLC: from cytotoxic systemic chemotherapy to molecularly targeted therapy

Approximately a third of non-small cell lung cancer patients present with disseminated disease at the time of diagnosis. For these patients, as well as those with recurrent disease, chemotherapy remains the mainstay of treatment. For several decades, researchers have attempted different combinations of drugs in search for the 'best' chemotherapy regimen. Despite the emergence of newer, 'third-generation' cytotoxic agents, success is still modest at best. Fortunately, new insights in tumor biology, leading to the design of molecularly targeted drugs, are opening a new era in cancer treatment. These novel agents target molecular pathways specifically found in cancer cells, thus maximizing the antitumor effect while minimizing toxicities on normal cells.     

Preoperative therapy: recent findings

Preoperative systemic therapy (PST) is the standard treatment for locally advanced breast cancer and a standard option for primary operable breast cancer. PST for breast cancer is as effective as postoperative adjuvant therapy, which permits more lumpectomies and can be used to study breast cancer biology. For locally advanced breast cancer patients, the primary aim of PST is to improve surgical option. For operable breast cancer patients, the primary aim of PST is to obtain freedom from disease. Because of recent advances in treatment and our understanding of the disease, we summarized the current consensus on the adoption and benefits of PST, especially for operable breast cancer patients.