Sarcomatoid renal cell carcinoma: Biology and treatment advances

Sarcomatoid transformation in renal cell carcinoma, so called sacromatoid RCC (sRCC), is associated with an aggressive behavior and a poor prognosis. Current therapeutic approaches are largely ineffective. Recent studies looking into the genomic and molecular characterization of sRCCs have provided insights into the biology and pathogenesis of this entity. These advances in molecular signatures may help development of effective treatment strategies. We herein present a review of recent developments in the pathology, biology, and treatment modalities in sRCC.     

今非昔比:放疗在肾癌中的发展现况

肾细胞癌对传统的常规分割放疗不敏感,而立体定向放射治疗(SBRT)能够有效提高肾癌放疗反应率,在局限期和转移期肾癌中的应用愈发广泛。本文通过对SBRT治疗肾癌的基础研究及临床实践资料进行归纳,显示SBRT是局限期不可手术肾癌根治性治疗的替代手段,是转移期肾癌局部治疗的有效手段,与靶向治疗联合安全且可能存在治疗增益,而SBRT的免疫效应以及与免疫治疗的联合将成为未来的探索热点。     

Systemic therapy in the management of localized and locally advanced renal cell carcinoma: Current state and future perspectives

Systemic therapy strategies in the setting of localized and locally advanced renal cell carcinoma have continued to evolve in two directions: (i) as adjuvant therapy (to reduce the risk of recurrence or progression in high‐risk localized groups); or (ii) as neoadjuvant therapy as a strategy to render primary renal tumors amenable to planned surgical resection in settings where radical resection or nephron‐sparing surgery was not thought to be safe or feasible. In the realm of adjuvant therapy, the results of adjuvant therapy phase III randomized clinical trials have been mixed and contradictory; nevertheless, the findings of the landmark Sunitinib Treatment of Renal Adjuvant Cancer study have led to approval of sunitinib as an adjuvant agent in the USA. In the realm of neoadjuvant therapy, presurgical tumor reduction has been shown in a number of phase II studies utilizing targeted molecular agents and in a recently published small randomized double‐blind placebo‐controlled study, and an expanding body of literature suggests benefit in select patients. Thus, large randomized clinical trial data are not present to support this approach, and guidelines for use of presurgical therapy have not been promulgated. The advent of immunomodulation through checkpoint inhibition represents an exciting horizon for adjuvant and neoadjuvant strategies. The present article reviews the current status and future prospects of adjuvant and neoadjuvant therapy in localized and locally advanced renal cell carcinoma.     

Treatment strategies for advanced renal cell carcinoma: A new paradigm for surgical treatment

The induction of targeted drugs for the treatment of metastatic renal cell carcinoma has changed the treatment strategy for systemic therapy. Surgical treatment for metastatic renal cell carcinoma should also be reconsidered in the light of the effect of targeted drugs. The clinical benefit of cytoreductive nephrectomy for cases of metastatic renal cell carcinoma was proved in randomized trials in the cytokine era. However, at present, there has not been level 1 evidence for this in the targeted therapy era. Patients with better performance status and without poor risk factors tend to benefit from cytoreductive nephrectomy. Two ongoing large‐scale randomized studies might shed light on this issue. One of the remarkable differences in the efficacy between cytokines and targeted drugs, particularly tyrosine kinase inhibitors, is the reduction in the size of the primary tumors by tyrosine kinase inhibitors, including sunitinib and axitinib. Initial experiences with targeted therapy suggest that the neoadjuvant setting of tyrosine kinase inhibitors could be a viable option when the primary tumor shows local invasion and/or is unresectable. The present study does not support the routine neoadjuvant use of sunitinib because of the possibility of disease progression during the neoadjuvant therapy, and modest response and benefit. Axitinib, in contrast, shows larger reduction in the size of the primary tumor and might be used in the near future. Another issue is the combination of targeted therapy with metastasectomy. There is a lack of evidence for improved prognosis resulting from the neoadjuvant setting of tyrosine kinase inhibitors followed by metastasectomy. Further studies are warranted to investigate this.     

Sequence of treatment in locally advanced and metastatic renal cell carcinoma

The spectrum of drugs that have shown activity in advanced or metastatic renal cell carcinoma (RCC) has led to a debate on the optimal sequence of treatments. There is agreement on recommending targeted agents as the standard of care in this disease. Uncertainty, however, remains on the best first-line drug choice. Physicians and patients may select sunitinib, bevacizumab in combination with interferon-alpha (IFN-α), pazopanib, or—in poor risk patients—temsirolimus. There are also a variety of therapies with proven efficacy on hand in the second-line setting: sorafenib, pazopanib, axitinib, and everolimus. While most randomized RCC trials assessed progression free survival (PFS) as primary endpoint, some agents were shown to improve median overall survival (OS), and given in sequence they have extended the life expectancy of RCC patients from 13 months in the cytokine era to over 30 months. Despite the progress made, there are sobering aspects to the oncologic success story in RCC, as the new treatments do not obtain an objective response or disease stabilization (SD) in all patients. There are also as yet no predictors to select patients who might benefit and those who are primary resistant to specific drugs, and ultimately almost all patients will experience disease progression. Bearing inevitable treatment failure in mind, availability of further drugs and switching therapy while the patient is in a condition to continue pharmacotherapy is essential. Of note, depending on the setting, only 33-59% of patients receive second-line treatment. In this review we present data on first-, second-, and third-line treatment in RCC, and discuss the difficulties in their interpretation in the context of treatment sequence. We summarize biological aspects and discuss mechanisms of resistance to anti-angiogenic therapy and their implications for treatment selection.     

Emerging immunotherapy in advanced renal cell carcinoma

Immunotherapy has recently catapulted to the forefront of treatments for patients with solid tumors. Given its inherent immunogenic properties, renal cell carcinoma (RCC) has historically responded to immunotherapy and remains primed for further development. Although immunotherapy with high-dose interleukin 2 was a primary treatment for advanced RCC (aRCC), recent discoveries of key molecular and immunological alterations have led to the FDA-approval of nivolumab, an antiprogrammed cell death inhibitor, which has demonstrated an overall survival in patients with previously treated aRCC. However, despite recent therapeutic advances, aRCC remains an incurable disease for most patients. In this review, we assess the current landscape and future developments of immunotherapy in aRCC.     

偶发肾癌和症状肾癌临床诊疗特点比较的Meta分析

目的 比较偶发肾癌和症状肾癌的临床诊疗特点,阐述早期检出肾癌的重要意义.方法 检索Medline、PubMed、Cochrane Library、Web of Science、万方数据库、CNKI中文期刊数据库2000年1月1日至2016年12月31日国内外公开发表的所有关于偶发肾癌和症状肾癌临床研究的文献,按照纳入和排除标准对文献进行筛选,对纳入研究的文献进行数据提取和质量评价,采用Review Manager 5.3软件进行Meta分析.结果 共纳入23篇文献,总计肾癌患者10 065例,其中偶发肾癌患者4 251例,症状肾癌患者5 814例.两组患者在肿瘤直径上平均差(MD)为-1.58(95% CI:-2.05~-1.11),在肿瘤病理分级(G1和G2)、保留肾单位手术例数、临床分期(T1和T2)、淋巴结转移、远处器官转移上比值比(OR)分别为3.01(95% CI:2.62~3.45)、3.47(95% CI:2.72~4.44)、3.95(95% CI:3.24~4.81)、0.20(95% CI:0.11~0.35)和0.24(95% CI:0.17~0.35),差异均有明显统计学意义(P<0.000 1);在手术年龄上MD为0.23(95% CI:-1.64~2.09),差异无统计学意义(P=0.81).结论 与症状肾癌相比,偶发肾癌具有肿瘤体积小、肿瘤病理分级低、临床分期早、淋巴结转移及远处器官转移少等特点,因此早期发现肾癌对提高患者生活质量及生存率十分重要.     

Immune checkpoint inhibitors further aggravate proteinuria in patients with metastatic renal cell carcinoma after long-term targeted therapy

BackgroundIncreasing number of patients with metastatic renal cell carcinoma (mRCC) are receiving subsequent programmed cell death protein-1 (PD-1) inhibitor combination therapy following tyrosine-kinase inhibitor (TKI) resistance. To explore whether PD-1 inhibitor would further deteriorate proteinuria and renal function, we observed their proteinuria’s and renal function’s condition since the administration of PD-1 inhibitor.MethodsTo assess the change in proteinuria and renal function, the data of 141 patients with mRCC treated with TKI were collected, 66 of whom were further prescribed PD-1 inhibitor. Proteinuria and estimated glomerular filtration rate (eGFR) were measured and analyzed. Logistic regression models were established to identify the predictors of proteinuria deterioration and significant eGFR decline (≥15%).ResultsOf the 141 patients, 74 (52%) had an increase in proteinuria level after an average of 22.98 months of TKI treatment. In multivariate analysis, longer duration of TKI (>12 months) and administration of PD-1 inhibitor were independent predictors for proteinuria deterioration. The median eGFR decreased from 81.56 mL/min/1.73 m² to 66.75 mL/min/1.73 m² after TKI treatment. Logistic regression identified older age (>60 years old) and longer duration of TKI (>12 months) as independent predictors for significant eGFR decline. Finally, of the 66 patients who received subsequent PD-1 inhibitor, 34 had sufficient proteinuria and eGFR data at follow-up. The level of proteinuria increased further after the administration of PD-1 inhibitor, although the decrease in eGFR was not statistically significant (P=0.182). Log-rank analysis identified proteinuria deterioration and eGFR decline were both significantly associated with patent’s survival (P<0.001).ConclusionsTargeted therapy was associated with an increase in proteinuria level and a decrease in eGFR in patients with mRCC. The administration of PD-1 inhibitor contributed to exacerbation in proteinuria, but no significant difference in a decrease of eGFR was observed.     

Papillary renal cell carcinoma: clinicopathological characteristics in 40 patients

BACKGROUND: Two different subtypes of papillary renal cell carcinoma (PRCC) have so far been identified, type-1 with small cells and pale cytoplasm and type-2 with large cells and eosinophilic cytoplasm. It has generally been accepted that type-1 tumors have favorable features in comparison with type-2 tumors, suggesting that these subtypes could be different clinicopathological entities, and, as a result, that the subtypes need to be characterized. Forty cases of PRCCs were reviewed, with special attention to the distinct clinicopathological difference and the response to cytokine therapy. METHODS: Thirty-five cases of PRCC diagnosed between January 1997 and August 2007 were reviewed. PRCCs were classified according to the criteria of Delahunt and Eble. RESULTS: Of these 40 patients, 20 and 20 were diagnosed to be type-1 and type-2 PRCCs, respectively. No lymphatic or vascular invasion or distant metastasis were observed in patients with type-1 PRCC. The nuclear grade in all type-1 PRCCs was low grade. The nuclear grade (P 相似文献   

Recent advances in the treatment of advanced renal cell carcinoma: towards multidisciplinary personalized care

What's known on the subject? and What does the study add? With recent improvements in the prognosis for patients with metastatic renal cell carcinoma (mRCC), focus is now shifting towards maximising clinical benefit from targeted therapies. Factors other than efficacy data are increasingly being considered when selecting a treatment strategy, with a view towards optimising clinical outcomes. This review examines the development and efficacy of targeted agents for the management of mRCC and discusses the potential factors, including resistance mechanisms, sequential therapy, prognostic and predictive markers of response, and adverse event management, that may contribute to successful individually tallored treatment of patients with this disease.

• ? Targeted agents have substantially improved outcomes for patients with metastatic renal cell carcinoma (mRCC).
• ? Treatment focus is now shifting towards achieving a continuum of care such that long‐term benefit and extended survival may be achieved through the optimal use of targeted agents.
• ? To achieve this goal, a number of factors which impact on treatment selection and outcomes need to be considered when treating patients with mRCC, such as the optimal sequence of targeted therapies (and the related issue of resistance mechanisms).
• ? Recent advances are also likely to impact on the future treatment of mRCC. Examples include the identification of predictive biomarkers as well as a consideration of patient risk profiles or the safety profile of the selected targeted agent. In addition, attention is focusing on re‐defining the role of surgery for the treatment of RCC in the context of targeted therapies.
• ? This review examines the recent and future advances that offer the potential for personalizing treatment by selecting the most appropriate treatment for each patient with a view towards optimizing clinical outcomes.

     

靶向治疗时代转移性肾癌多学科综合治疗的单中心经验总结

目的总结在靶向药物治疗基础上单中心转移性肾癌的多学科诊疗经验。方法回顾性分析2007年12月至2019年2月中山大学肿瘤防治中心经多学科诊疗团队(multi-disciplinary team,MDT)诊治的168例转移性肾癌(metastatic renal cell,mRCC)患者的临床数据。根据治疗方式将患者分为3组。单纯靶向药物治疗(A组)76例,男55例,女21例;年龄52(17~73)岁;透明细胞癌60例,非透明细胞癌16例;国际转移性肾细胞癌联合数据库(International Metastatic Renal Cell Carcinoma Database consortium,IMDC)预后评分低危11例,中危48例,高危17例;初诊时即有转移44例;行原发灶切除术63例。靶向药物治疗+局部治疗(B组)66例,男55例,女11例;年龄54(21~86)岁;透明细胞癌49例,非透明细胞癌17例;IMDC预后评分低危13例,中危39例,高危14例;初诊时即有转移32例;行原发灶切除术56例。靶向药物治疗+局部治疗+免疫治疗(C组)26例,男19例,女7例;年龄52(23~83)岁;透明细胞癌15例,非透明细胞癌11例;IMDC预后评分低危9例,中危13例,高危4例;初诊时即有转移9例;行原发灶切除术26例。3组患者一般资料比较差异均无统计学意义(P>0.05)。一线靶向治疗药物为舒尼替尼、索拉非尼、阿昔替尼。舒尼替尼50 mg,每日1次,用药4周停2周;索拉非尼400 mg,每日2次;阿昔替尼5 mg,每日2次。接受舒尼替尼、索拉非尼、阿昔替尼一线治疗者分别为103、18、39例。靶向药物治疗时间均>6个月。免疫治疗采用派姆单抗(Pembrolizumab)2 mg/kg静脉应用,每3周1次,或低剂量(20 mg)派姆单抗孵育经体外扩增后的自体外周血树突状细胞细胞因子诱导杀伤细胞(dendritic cells cytokine induced killer,DC.CIK),每周1次,4次后改为每2周1次。18例采用DC.CIK,8例采用派姆单抗。局部治疗方式包括立体定向放疗(stereotactic body radiation therapy,SBRT)和外科治疗(手术切除或能量消融治疗)。根据靶向药物治疗效果,转移灶部位、数量、与周围器官关系,以及患者的意愿,经MDT专家讨论后决定局部治疗方式。92例接受局部治疗,其中单纯外科治疗34例,单纯SBRT 37例,外科治疗+SBRT 21例。比较3组的疗效和不良反应情况,分析不同治疗方法与患者总生存时间(overall survival,OS)的关系。结果168例中位随访23个月(6~117个月)。中位无进展生存时间(progression free-survival,PFS)为18.3个月,中位OS为33.5个月;2年生存率为66%,5年生存率为35%。A、B、C组的中位OS分别为29.8个月、44.6个月和未达,2年生存率分别为58%、67%和89%,5年生存率分别为12%、46%和57%。在靶向药物治疗的基础上接受联合治疗者的预后均优于单纯靶向药物治疗者,5年总OS分别为51%和11%。C组的中高危mRCC患者预后明显优于A、B组。在接受免疫治疗的患者中,靶向药物治疗联合DC.CIK与联合派姆单抗的中位OS分别为49.1个月和53.1个月,差异无统计学意义(P=0.541)。单因素分析结果显示,OS与IMDC评分、原发灶切除、治疗模式相关(P<0.05)。多因素分析结果显示,OS与治疗模式、原发灶切除显著相关(P<0.05),靶向药物治疗+免疫治疗+局部治疗可使mRCC患者死亡风险下降约60%(HR=0.39,95%CI 0.17~0.89,P=0.026)。78例使用靶向药物治疗发生3~4级不良反应,12例因无法耐受一线靶向药物治疗不良反应而停药或换药。16例采用靶向药物联合免疫治疗发生3~4级药物不良反应,主要为疲乏8例次、白细胞降低4例次、血小板降低3例次、转氨酶和胆红素升高3例次。靶向药物治疗联合DC.CIK治疗的严重不良反应发生例数少于联合派姆单抗治疗(6例与12例),特别是显著降低了血液学毒性(2例与5例)和肝毒性(0例与3例),差异均有统计学意义(P<0.05)。外科治疗后出现ClavienⅢ~Ⅳ级并发症16例次,主要为感染和切口延期愈合6例次、不全肠梗阻4例次,围手术期输血15例次。SBRT治疗后6例出现美国放射肿瘤协作组评分(Radiotherapy Oncology Group,RTOG)3级不良反应,其中骨髓抑制4例,皮肤反应和放射性神经炎2例,未观察到≥4级不良反应。结论在靶向药物治疗基础上联合免疫治疗和局部治疗的mRCC患者预后明显优于采用单纯靶向药物治疗的患者。经MDT诊疗的综合治疗可使mRCC患者生存获益。     

Optimal management of metastatic renal cell carcinoma: an algorithm for treatment

The treatment of metastatic renal cell carcinoma (mRCC) has been changed by the introduction of targeted agents. Consideration of individual patient factors, such as previous treatment and prognostic risk, e.g. according to the Memorial Sloan‐Kettering Cancer Center (MSKCC) risk criteria), can assist in ensuring that patients receive appropriate targeted therapies. Available clinical evidence shows sunitinib to be the reference standard of care for the first‐line treatment of mRCC in patients at favourable or intermediate prognostic risk according to MSKCC criteria. Combined treatment with bevacizumab plus interferon‐α can also be considered for the first‐line treatment of mRCC in this setting. For the first‐line treatment of poor‐risk patients, temsirolimus has shown benefit in a phase III study, while sunitinib can also be considered. For second‐line treatment in cytokine‐refractory patients, sorafenib is recommended based on phase III trial results; sunitinib has also shown activity after failure of cytokine therapy or targeted agents. As well as antitumour activity, the tolerability of targeted agents should be evaluated in the context of individual patients, considering factors such as comorbidities and age. As our understanding of the activity of targeted agents for mRCC increases, we should ensure that these agents are used appropriately to provide patients with optimal treatment benefits.     

Integration of surgery and systemic therapy for renal cell carcinoma

Proper integration of surgery and systemic therapy is essential for improving outcomes in renal cell carcinoma (RCC). There is no current role for adjuvant therapy after nephrectomy for clinically localized disease. The potential benefits of neoadjuvant therapy for locally advanced nonmetastatic disease are in need of further study. In metastatic disease, the proper integration of cytoreductive surgery and systemic therapy remains to be elucidated. Presurgical targeted therapy is feasible and may be beneficial. Pending the results of randomized controlled trials, upfront cytoreductive nephrectomy in appropriate patients will likely continue as the paradigm of choice in metastatic RCC.     

Overview and management of toxicities associated with systemic therapies for advanced renal cell carcinoma

The advent of novel targeted agents for metastatic renal cell carcinoma (RCC) has offered clinical benefits over traditional immunotherapy (e.g., interleukin-2 and interferon-α) in both efficacy and safety profiles. The major classes of these targeted therapies for metastatic RCC include the tyrosine-kinase inhibitors, monoclonal antibody against vascular endothelial growth factor, and inhibitors of the mammalian target of rapamycin. Most recently, the success of immune checkpoint inhibitors—notably antibodies directed against programmed death-1 and its ligand—has also been demonstrated in RCC. With such progress in therapy, early detection, and subsequent management of treatment-related adverse events allow for patients to remain on active therapy for as long as possible and also enhance the probability of patients tolerating subsequent second line options. However, despite such impressive gains in efficacy with these new agents, therapeutic progress are primarily palliative in nature—hence, the critical importance of minimizing discomfort and potential harm in this patient population cannot be understated.     

Update on the medical treatment of metastatic renal cell carcinoma

CONTEXT: Metastatic renal cell carcinoma (mRCC) has long been treated only by immunotherapy with good results only in a small population of patients. In recent years, major improvements in treatment possibilities have occurred with the advent of anti-angiogenic drugs. In the past 2 yr, pivotal phase III trials have confirmed this major breakthrough by increasing the progression-free survival rates and/or overall survival rates provided by sunitinib, sorafenib, and bevacizumab, and more recently by the mTOR (mammalian target of rapamycin) inhibitors temsirolimus and everolimus. OBJECTIVE: To update the previous review on smart drugs published in the European Journal in 2006 (Patard JJ, et al. Understanding the importance of smart drugs in renal cell carcinoma. Eur Urol 2006; 49:633-43). EVIDENCE ACQUISITION: Critical review of published literature 2006-2008 (Pubmed website search words: renal cell carcinoma and/or targeted therapy and prospective trials) and more recent meeting abstracts (American Society of Clinical Oncology 2007). Quality assessment included prospective phase I-III trials and critical evaluations with low numbers of patients, retrospective analyses, and slide presentations of meeting abstracts. EVIDENCE SYNTHESIS: This review presents the current situation and provides more recent data on sequential treatment, the association of targeted drugs, and the treatment of non-clear-cell histologies. CONCLUSIONS: Treatment of mRCC with targeted therapy centers on at least two major pathways: angiogenesis and mTOR involving inhibiting drugs that may be used alone, in combination, or sequentially.     

肾肿瘤剜除术治疗肾细胞癌、肾血管平滑肌脂肪瘤

目的探讨肾肿瘤剜除术治疗肾细胞癌及肾血管平滑肌脂肪瘤的疗效。方法回顾分析15例在我院进行肾肿瘤剜除术的肾细胞癌及肾血管平滑肌脂肪瘤患者的临床及病理资料。结果全部肾肿瘤均成功剜除,平均热缺血时间为15min,术中肿瘤剜除面平均出血25ml,术后无继发出血,无急性肾小管坏死、慢性肾功能不全及尿瘘等并发症发生。术后平均随访时间为2．5年,均未见肿瘤复发或转移。依据2003AJCC肾癌分期方法,所有肾癌患者均为Tla期,组织学形态为透明细胞癌。病理分级按Fuhrman标准为G1。结论肾肿瘤剜除术对有假性包膜的Tla肾细胞癌和肾血管平滑肌脂肪瘤是有效和安全的,术后并发症少,可以最大程度地保留肾脏功能。     

基于肿瘤免疫微环境的免疫治疗策略在晚期肾透明细胞癌中的应用进展

近期的临床研究结果显示,仍有大量晚期肾透明细胞癌(ccRCC)患者对免疫检查点抑制剂(ICIs)无反应。提高ccRCC患者免疫治疗反应是当前迫切的临床需求。靶向不同的肿瘤免疫微环境成分成为克服晚期ccRCC免疫治疗耐药性和优化治疗策略的突破点。本文概述晚期ccRCC免疫治疗面临的挑战,并总结基于肿瘤免疫微环境的新型免疫治疗策略,包括靶向其他共抑制分子和共刺激分子、改良细胞因子疗法、小分子免疫调节剂、靶向免疫代谢和癌症疫苗等。     

Radio frequency ablation of renal cell carcinoma: preliminary clinical experience

PURPOSE: We assess the feasibility, safety and efficacy of radio frequency ablation of small peripheral renal cell carcinomas. MATERIALS AND METHODS: Five patients with a histologically proven renal cell carcinoma 30 to 40 mm. in diameter were treated with radio frequency ablation. A triple needle electrode was percutaneously advanced into each tumor under sonographic (4 cases) or computerized tomography (CT) (1) guidance. The radio frequency generator was activated for 15 minutes in each location where the electrode had been placed. Patients were then followed with CT and blood tests every 2 months for 6 months and every 3 months thereafter. RESULTS: Four tumors required 1 radio frequency delivery and 1 required 2 applications during the same session. No complications were encountered except for a subcapsular hematoma in 1 patient, which resolved spontaneously. Two patients experienced transient hematuria. Of the patients 4 were discharged from the hospital after 2 days and 1 after 1 day. After 6 to 18 months (median 9) all patients were tumor-free on CT without suppress additional treatment. CONCLUSIONS: In this small preliminary study radio frequency ablation of small peripheral renal cell carcinomas appears to be a feasible, safe and promising technique.     

Successful treatment with sirolimus for an angiomyolipoma mimicking renal cell carcinoma in a transplanted kidney

Angiomyolipoma (AML) is a benign mesenchymal tumor composed of blood vessels, smooth muscle, and mature adipose tissue. AMLs in the kidney allografts are rare. We report a case of AML that was incidentally found 1 year after transplantation. Abdominal computed tomography showed a 4‐cm renal tumor with contrast enhancement and an early washout pattern, resembling a renal cell carcinoma. Tumor biopsy proved a lipid‐poor AML. Tumor diameter decreased to 2.4 cm after 6 months of treatment with sirolimus. Sirolimus not only reduces tumor size, but also benefits a transplant patient who needs immunosuppression.