肾癌的靶向治疗

 目前转移性肾癌是最难治的恶性肿瘤之一。基于肾癌发生的分子机制的阐明，从而导致发展有希望治疗靶点的新药。在临床研究中，舒尼替尼和索拉芬尼是治疗晚期或转移性肾癌有明显的效果和可处理的毒性，它属于口服的多靶点酪氨酸激酶抑制剂，抑制血管内皮生长因子受体与血小板衍生的生长因子受体和C-KIT受体酪氨酸激酶。这两种药很快批准作为第二线药物治疗肾癌，并将用作第一线治疗。舒尼替尼或索拉芬尼作为单剂治疗与联合方案治疗肾癌值得进一步研究     

A Systematic Review of Published Clinical Trials in the Systemic Treatment of Adrenocortical Carcinoma: An Initiative Led on Behalf of the Global Society of Rare Genitourinary Tumors

Adrenocortical carcinoma (ACC) is a very rare endocrine cancer and is associated with a poor prognosis. There is a paucity of randomized clinical trials for this rare disease. We aimed to perform a systematic review of the literature on systemic therapy options in different stages of ACC. A systematic review was performed using Pubmed and Embase databases according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. A total of 24 trials of systemic therapy in the treatment of ACC were identified and included in this review. Only one clinical trial in the adjuvant setting was identified, the negative phase III trial ADIUVO, which tested mitotane in low to intermediate-risk ACC patients. In the treatment of advanced ACC, cisplatin-based chemotherapy was evaluated in small and non-randomized phase II trials, and response rates ranged from 21% to 53.5%. The phase III trial FIRM-ACT compared etoposide, doxorubicin, cisplatin, and mitotane versus treatment with streptozotocin and mitotane and showed no difference in OS, but higher RR and PFS were reported with the multi-drug regimen. Six clinical trials of immunotherapy and seven studies of targeted therapy in advanced ACC were included, with modest activity and no phase 3 trials were identified. Treatment recommendations of ACC are based on retrospective and small studies with limited systemic therapy options. International and multi-center collaboration is essential to expand clinical research and improve outcomes.     

Fatigue in renal cell carcinoma: the hidden burden of current targeted therapies

Fatigue is one of the most common symptoms associated with cancer. Persistent fatigue can impair multiple aspects of daily functioning and quality of life, and patients report that treatment-related fatigue has a greater impact than other symptoms, including pain, nausea, and depression. Thus, management of fatigue is recognized as an important component of care for patients with cancer. Treatment of advanced and metastatic renal cell carcinoma (RCC) was, until recently, limited to cytokine-based therapies, which are associated with modest response rates and significant toxicity, including high rates of treatment-related fatigue. The paradigm for RCC treatment has shifted dramatically in the last 5 years with the advent of efficacious targeted therapies. These agents provide the promise of better tolerability because of their more selective mechanisms of action. However, there is considerable variation in the selectivity of targeted agents for RCC, and a review of randomized clinical trials in patients with advanced and/or metastatic disease reveals that there is considerable variation in the tolerability of these agents. Fatigue remains a prominent toxicity with current targeted therapies. Future agents that show better selectivity and potency than current targeted therapies should help to provide better efficacy and tolerability.     

Current management of stage IV nasopharyngeal carcinoma without distant metastasis

Up to one in four patients with nasopharyngeal carcinoma present with non-metastatic stage IV disease (i.e. T4 or N3). Distinct failure patterns exist, despite the routine adoption of contemporary treatment modalities such as intensity modulated radiotherapy and systemic chemotherapy. Concurrent chemoradiotherapy (CCRT) followed by adjuvant chemotherapy or induction chemotherapy followed by CCRT are commonly employed in this setting, with the latter emerging as the preferred option. Additionally, emerging radiation technologies like proton therapy has become available offering new opportunities for prevention of radiation-induced side effects. This article reviews not only the current treatment strategies, but also discusses novel ways to tackle this challenging disease with respect to the patterns of failure.     

Management of renal collecting duct carcinoma: a systematic review and the McMaster experience

Introduction

Collecting duct carcinoma (cdc) is a rare, aggressive form of renal carcinoma that presents at an advanced stage and has a poor prognosis. Little is known concerning the optimal management of cdc. We present the results of a systematic review addressing the management of cdc and the McMaster University cdc series.

Methods

The medline, Cochrane Library, and embase databases and conference proceedings were searched to identify studies relating to the management of cdc. Included studies reported on a minimum of 10 subjects receiving a single intervention. Series in which an evaluation of therapeutic effectiveness was not possible were excluded. The McMaster University (Hamilton, Ontario) series of 6 cases of cdc were retrospectively reviewed.

Results

We identified 3 studies relevant to the management of cdc that included a total of 72 patients. A gemcitabine–cisplatin or –carboplatin regimen resulted in a 26% objective response rate in 23 patients with metastatic cdc. Two additional studies indicated that 49 patients treated with immunotherapy achieved no response. In the McMaster series, cytoreductive nephrectomy was performed in 4 of 6 patients. In 2 patients, mvac therapy (methotrexate–vinblastine–doxorubicin–cisplatin) achieved no response. No significant therapeutic complications occurred, but survival was poor (median: 11 months; range: 10–33 months).

Conclusions

Our review and clinical experience suggest that the current standard of care for metastatic cdc is a gemcitabine–cisplatin regimen.     

肾癌相关长链非编码RNA研究进展

长链非编码RNA(long non-coding RNA,lncRNA)是一类由RNA聚合酶Ⅱ转录及可变剪接而来、长度大于200个核苷酸、无蛋白编码功能的RNA分子。众多研究表明其在表观遗传学、转录等水平发挥重要的调控作用,且其异常表达与肾癌(renal cell carcinoma,RCC)的发生、发展、转移和预后等明显相关。旨在总结RCC相关lncRNA最新研究进展,浅析lncRNA在RCC发生、发展中的潜在分子机制,为RCC的预防、早期诊治及预后评估提供一种新的理论依据。     

Development of novel agents and combinations for renal carcinoma

Based on a better understanding of the pathogenesis of renal carcinoma, the last 5 years has witnessed a rapid transition of novel agents from the bench to the bedside. Multiple new drugs have already been approved for standard use including sunitinib, sorafenib, and temsirolimus with additional agents including everolimus, bevacizumab, and pazopanib under review by the regulatory agencies. This review will highlight the clinical data, which support the use of these novel agents and highlight current approaches exploring combination therapy.     

Current management and future perspectives of penile cancer: An updated review

Penile cancer (PeCa) is a rare disease worldwide, accounting for less than one percent of all malignancies in men. It usually presents as a painless ulcer or lump on the head of the penis. Squamous cell carcinoma represents the most common histological subtype of PeCa, with pathogenesis intimately linked to chronic Human Papilloma Virus (HPV) infection. Surgery is the cornerstone for the treatment of primary PeCa with potential mutilating outcome depending on the nodal extension of the disease. However, in case of extensive lymph node involvement, multidisciplinary treatment including perioperative chemotherapy and inclusion in clinical trial should be considered. To date, advanced or metastatic disease still have poor prognosis and are a therapeutic challenge with limited options, highlighting the need of new treatments and further investigations. Growing efforts to identify molecular alterations, understand the role of HPV and characterize immune contexture have expanded over the past years, providing further perspectives in prognostication, predictive biomarkers and therapeutic intervention.In this review, we provide an updated overview of current management of PeCa focusing on perioperative strategy. We discuss about new insights of the biology of PeCa and comment future directions in the field.     

Hepatocellular carcinoma: systemic therapies and future perspectives

Hepatocellular carcinoma is (HCC) the most common primary malignancy of the liver in adults. It is also the fifth most common solid cancer worldwide and the third leading cause of cancer-related deaths. Treatment options for HCC include liver transplantation, surgical resection, locoregional therapies and chemotherapy. The median survival time of patients following the diagnosis of unresectable disease is approximately 6–20 months, whereas the 5-year survival is less than 5%. Given the projected increase in incidence of HCC due to hepatitis C virus infection and obesity related cirrhosis, there is an urgent need for more intensive research in this cancer. In this article, we review the systemic options available for patients with HCC, its molecular pathogenesis and future therapeutic directions with special emphasis on immune-based and molecularly-targeted therapy.     

Treatments,Outcomes, and Validity of Prognostic Scores in Patients With Sarcomatoid Renal Cell Carcinoma: A 20-Year Single-Institution Experience

Introduction

Metastatic renal cell carcinoma (RCC) with a sarcomatoid component is a rare disease associated with a poor prognosis. We report the outcomes of 47 patients with metastatic sarcomatoid RCC (SRCC) treated with different modalities including chemotherapy, tyrosine kinase inhibitors, or immunotherapy over 2 decades in a French cancer center. Furthermore, we assessed the validity of prognostic scores in this subset of RCC.

Temisorlimus in the treatment of advanced renal cell carcinoma

Temsirolimus is a novel inhibitor of mammalian target of rapamycin (mTOR), which is a central regulator of the response of tumour cells to growth and survival signals. When heavily pretreated patients with advanced solid tumours received intravenous (IV) temsirolimus over a broad dose range, antitumour activity was observed in various tumour types, including advanced renal cell carcinoma (RCC). A study of single-agent temsiroliums in patients with cytokine-refractory metastatic RCC subsequently demonstrated antitumour activity and encouraging progression-free survival and overall survival. Temsirolimus was generally well tolerated over the 3 dose levels tested (25 mg, 75 mg or 250 mg weekly as a 30-minute IV infusion). The most frequent grade 3 or 4 treatment-related adverse events reported (n=110) were hyperglycemia (17%), hypophosphatemia (13%), anemia (9%), and hypertriglyceridemia (6%). Results from a randomized phase III study that enrolled previously untreated patients with advanced RCC and poor-prognostic features have recently demonstrated a significant increase in overall survival (p=0.0089) for patients who received temsirolimus 25 mg IV, 30-minute infusion once weekly compared with those who received interferon-alpha up to 18 million units subcutaneously thrice weekly. On the basis of improved survival, temsirolimus can be considered a first-line treatment for patients with advanced RCC.     

Statins and survival outcomes in patients with metastatic renal cell carcinoma

BackgroundA growing body of evidence has demonstrated the anti-neoplastic activity of statins. The objective of this study was to investigate the effect of statin use on survival in patients with metastatic renal cell carcinoma (mRCC) treated in the modern therapy era.Patients and methodsWe conducted a pooled analysis of mRCC patients treated on phase II and III clinical trials. Statistical analyses were performed using Cox regression and the Kaplan–Meier method.ResultsWe identified 4736 patients treated with sunitinib (n = 1059), sorafenib (n = 772), axitinib (n = 896), temsirolimus (n = 457), temsirolimus + interferon (IFN)-α (n = 208), bevacizumab + temsirolimus (n = 393), bevacizumab + IFN-α (n = 391) or IFN-α (n = 560), of whom 511 were statin users. Overall, statin users demonstrated an improved overall survival (OS) compared to non-users (25.6 versus 18.9 months, adjusted hazard ratio [aHR] 0.801, 95% confidence interval [CI] 0.659–0.972, p = 0.025). When stratified by therapy type, a benefit in OS was demonstrated in statin users compared to non-users in individuals receiving therapy targeting vascular endothelial growth factor (28.4 versus 22.2 months, aHR 0.749, 95% CI 0.584–0.961, p = 0.023) or mammalian target of rapamycin (18.6 versus 14.0 months, aHR 0.657, 95% CI 0.445–0.972, p = 0.035) but not in those receiving IFN-α (15.6 versus 14.8 months, aHR 1.292, 95% CI 0.703–2.275, p = 0.410). Adverse events were similar between users and non-users.ConclusionsWe demonstrate that statin use may be associated with improved survival in patients with mRCC treated in the targeted therapy era. Statins could represent an adjunct therapy for patients with mRCC; however, this is hypothesis generating and requires prospective evaluation.     

Predictors,utilization patterns,and overall survival of patients undergoing metastasectomy for metastatic renal cell carcinoma in the era of targeted therapy

Introduction

Metastasectomy (MSX) is considered a treatment option in patients with metastatic renal cell carcinoma (mRCC) at diagnosis, but its role in the targeted therapy era is unclear. We sought to describe the utilization trends of MSX and survival outcomes in a large US cohort.

Systemic therapy for disseminated basal cell carcinoma: an uncommon manifestation of a common cancer

While basal cell carcinoma (BCC) is the most common human malignancy, distant metastases from this are rare. Current therapy for disseminated BCC is based on anecdotal reports in the absence of clinical trials to guide management. For many years, platinum based cytotoxic chemotherapy was the mainstay of treatment. Advances in the understanding of the biology of BCC have led to the development of targeted therapies (e.g. inhibitors of the hedgehog and the epidermal growth factor receptor pathways) that are currently being investigated in this disease. This review summarizes the available data on the epidemiology and management of disseminated BCC.     

Personalized medicine in CLL: Current status and future perspectives

Chronic lymphocytic leukemia (CLL) is the most common hematologic malignancy in the Western Hemisphere. Despite advances in research and the development of effective treatment regimens, CLL is still largely an incurable disease. Although several prognostic factors have been identified in recent years, most of the new prognostic factors are not utilized, and treatment decisions are still based on clinical staging and limited use of cytogenetic analysis. Patients with advanced disease are treated at diagnosis, whereas others, regardless of their prognostic indicators, are offered treatment only at disease progression. Furthermore, treatment guidelines for elderly or “unfit” patients are unavailable because most CLL trials have included mostly younger, healthier patients. Given theheterogeneity of the clinical manifestations and prognosis of CLL, patients are likely to benefit from a personalized therapeutic approach. Recent advances in CLL pathobiology research, the use of high-throughput technologies, and most importantly, the introduction of novel targeted therapies with high efficacy and low toxicity are currently transforming the treatment of CLL. A personalized approach that includes early intervention in selected patients with CLL is likely to bring physicians closer to the goal of attaining cures in most patients with CLL.