local therapy

局部治疗
  • 文章类型: Published Erratum
    [这更正了文章DOI:10.3389/fonc.2024.1368926。].
    [This corrects the article DOI: 10.3389/fonc.2024.1368926.].
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  • 文章类型: Journal Article
    背景:对寡转移前列腺癌(OMPC)的兴趣正在增加,和各种临床研究报道了转移定向放射治疗(MDRT)在OMPC中的益处。然而,对通过的定义的承认,评估方法,放射肿瘤学家的治疗方法多种多样。这项研究旨在评估放射肿瘤学家对OMPC问题的共识水平。
    方法:我们为OMPC生成了15个与定义相关的关键问题(KQs),诊断,局部疗法,和端点。此外,代表同步转移性前列腺癌(mPC)的三种临床方案(病例1),异时性mPC伴内脏转移(病例2),并发展了具有去势抵抗和多转移史的异时mPC(病例3)。根据每个场景对15个KQ进行了调整,并转换为23个问题,每个场景6-9个。调查已分发给大韩民国各地的80名放射肿瘤学家。答案选项为0.0-29.9%,30-49.9%,50-69.9%,70-79.9%,80-89.9%,90-100%的协议被认为是否定的,最小,弱,中度,坚强,和近乎完美的协议,分别。
    结果:45名候选人自愿参加了这项研究。在23个问题中,接近完美(n=4),强(n=3),或中等(n=2)协议显示在9个。对于承认为OMPC且协议为93%的案例(案例1),在对整个转移性病变应用确定性放射治疗(RT)方面达成了近乎完美的协议。虽然尚未达成关于转移定向RT(MDRT)最佳剂量分级的≥70%协议,立体定向体RT(SBRT)受到临床容量较高的临床医生的青睐。
    结论:对于公认为OMPC的案例,对于整个转移性病变的最终RT应用,达成了近乎完美的协议。SBRT作为MDRT更受临床量较高的临床医生的青睐。
    BACKGROUND: Interest in the oligometastatic prostate cancer (OMPC) is increasing, and various clinical studies have reported the benefits of metastasis-directed radiation therapy (MDRT) in OMPC. However, the recognition regarding the adopted definitions, methodologies of assessment, and therapeutic approaches is diverse among radiation oncologists. This study aims to evaluate the level of agreement for issues in OMPC among radiation oncologists.
    METHODS: We generated 15 key questions (KQs) for OMPC relevant to definition, diagnosis, local therapies, and endpoints. Additionally, three clinical scenarios representing synchronous metastatic prostate cancer (mPC) (case 1), metachronous mPC with visceral metastasis (case 2), and metachronous mPC with castration-resistance and history of polymetastasis (case 3) were developed. The 15 KQs were adapted according to each scenario and transformed into 23 questions with 6-9 per scenario. The survey was distributed to 80 radiation oncologists throughout the Republic of Korea. Answer options with 0.0-29.9%, 30-49.9%, 50-69.9%, 70-79.9%, 80-89.9%, and 90-100% agreements were considered as no, minimal, weak, moderate, strong, and near perfect agreement, respectively.
    RESULTS: Forty-five candidates voluntarily participated in this study. Among 23 questions, near perfect (n = 4), strong (n = 3), or moderate (n = 2) agreements were shown in nine. For the case recognized as OMPC with agreements of 93% (case 1), near perfect agreements on the application of definitive radiation therapy (RT) for whole metastatic lesions were achieved. While ≥70% agreements regarding optimal dose-fractionation for metastasis-directed RT (MDRT) has not been achieved, stereotactic body RT (SBRT) is favored by clinicians with higher clinical volume.
    CONCLUSIONS: For the case recognized as OMPC, near perfect agreement for the application of definitive RT for whole metastatic lesions was reached. SBRT was more favored as a MDRT by clinicians with a higher clinical volume.
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  • 文章类型: Case Reports
    乳腺癌发病率高,易发生转移,而孤立的肝转移是罕见的。越来越多的证据支持抗人表皮生长因子受体2(HER2)疗法联合化疗治疗乳腺癌的有效性。然而,对其对转移性肝病的影响知之甚少。在管理乳腺癌肝转移方面也缺乏共识,并且尚未进行关于治疗后肝转移消失的管理的研究。
    2021年5月,一名51岁的HER2阳性乳腺癌伴孤立性肝转移的女性患者进行了雌激素受体(ER)(-)的免疫组织化学检查,孕激素受体(PR)(-),和HER2(3+)对她的原发病灶和肝转移。经过17个周期的抗HER2治疗和化疗,病人表达了手术的愿望。然后进行了术前检查,显示了原发性乳腺病变和肝转移的消失。紧接着,做了左乳房切除术,术后病理显示乳腺肿瘤完全缓解。至于肝脏,转移病灶消失的地方,没有相关研究报告如何处理这种情况。最后,经过全院的讨论,患者接受曲妥珠单抗维持治疗.直到现在,在定期随访期间未观察到明显的复发或转移迹象。
    该病例表明,对于肝转移通过药物治疗消失的乳腺癌患者,维持治疗可能是最佳选择。此外,可以推断,在HER2阳性转移性乳腺癌(MBC)中,孤立性肝转移患者可能更有可能获得治愈样结局.然而,需要更多的案例和后续信息来支持这些观点。
    UNASSIGNED: Breast cancer has a high incidence and is prone to metastasis, while isolated liver metastasis is rare. A growing body of evidence supports the effectiveness of treating breast cancer with anti-human epidermal growth factor receptor-2 (HER2) therapy in combination with chemotherapy. However, little is known about its impact on metastatic liver disease. There is also a lack of consensus on managing liver metastases from breast cancer, and no studies have been conducted on managing the disappearance of liver metastases after treatment.
    UNASSIGNED: In May 2021, a 51-year-old female patient with HER2-positive breast cancer with isolated liver metastases had immunohistochemistry of estrogen receptor (ER) (-), progesterone receptor (PR) (-), and HER2 (3+) for both her primary lesion and liver metastases. After undergoing 17 cycles of anti-HER2 therapy and chemotherapy, the patient expressed a desire for surgery. Then a preoperative examination was performed, which revealed the disappearance of both the primary breast lesion and the liver metastases. Immediately afterwards, a left mastectomy was performed, and postoperative pathology showed a complete response to the breast tumor. As for the liver, where the metastatic lesions disappeared, no relevant study has reported how to deal with this situation. Finally, after a hospital-wide discussion, the patient was given trastuzumab maintenance therapy. Until now, no obvious signs of recurrence or metastasis have been observed during regular follow-ups.
    UNASSIGNED: This case suggests that maintenance therapy may be the best option for patients with breast cancer whose liver metastases disappear by medication. Also, it can be inferred that in HER2-positive metastatic breast cancer (MBC), patients with isolated liver metastases may be more likely to achieve a cure-like outcome. Nevertheless, more cases and follow-up information are needed to support these views.
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  • 文章类型: Journal Article
    背景:目前尚不清楚原发性局部肿瘤的治疗程度。如根治性前列腺切除术(RP)和放射治疗(RT),改善低体积转移性激素敏感型前列腺癌(mHSPC)患者的总生存率.然而,数据表明,这些疗法在预防局部肿瘤进展继发的局部事件方面有益处.
    目的:为了评估在全身治疗中增加局部治疗(RP或RT)的疗效,包括雄激素剥夺治疗,多西他赛,和/或雄激素受体轴靶向药物,在预防mHSPC患者的局部事件方面,与单独的全身治疗相比(即,没有前列腺或RP的RT)。
    方法:在2023年11月查询了三个数据库和会议摘要,用于分析接受局部治疗的mHSPC患者的研究。感兴趣的主要结果是预防整体局部事件(尿路感染,尿路梗阻,和肉眼血尿)由于局部疾病进展。根据局部治疗(RP或RT)的类型,进行亚组分析以评估差异结果。
    结果:总体而言,六项研究,包括两项随机对照试验,纳入系统评价和荟萃分析。局部治疗加全身治疗组的局部事件总发生率显著低于仅全身治疗组(相对危险度[RR]:0.50,95%可信区间[CI]:0.28-0.88,p=0.016)。RP显着降低了整体局部事件的发生率(RR:0.24,95%CI:0.11-0.52)和需要手术干预的局部事件的发生率(RR:0.08,95%CI:0.03-0.25)。尽管在整体局部事件方面,RT加全身治疗组和仅全身治疗组之间没有统计学上的显着差异,需要手术干预的局部事件发生率在RT+全身治疗组显著较低(RR:0.70,95%CI:0.49~0.99);需要上尿路手术干预的局部事件发生率在局部治疗组显著较低(RR:0.60,95%CI:0.37~0.98,p=0.04).然而,一项亚组分析显示,RP和RT均不显著影响需要上尿路手术干预的局部事件的预防.
    结论:在一些mHSPC患者中,原发性肿瘤的RP或RT似乎降低了局部进展和需要手术干预的事件的发生率。确定哪些患者最有可能从局部治疗中受益,以及在什么时间点(例如,转移反应后),将有必要建立一项评估风险的研究,好处,以及在mHSPC环境中原发性肿瘤治疗的替代方案。
    结果:我们的研究表明,前列腺的局部治疗,如前列腺癌根治术或放疗,在转移性激素敏感型前列腺癌患者中可以预防局部事件,如尿路梗阻和肉眼血尿。
    BACKGROUND: It remains unclear to what extent the therapy of the primary local tumor, such as radical prostatectomy (RP) and radiation therapy (RT), improves overall survival in patients with low-volume metastatic hormone-sensitive prostate cancer (mHSPC). However, data suggest a benefit of these therapies in preventing local events secondary to local tumor progression.
    OBJECTIVE: To evaluate the efficacy of adding local therapy (RP or RT) to systemic therapies, including androgen deprivation therapy, docetaxel, and/or androgen receptor axis-targeted agents, in preventing local events in mHSPC patients compared with systemic therapy alone (ie, without RT of the prostate or RP).
    METHODS: Three databases and meeting abstracts were queried in November 2023 for studies analyzing mHSPC patients treated with local therapy. The primary outcome of interest was the prevention of overall local events (urinary tract infection, urinary tract obstruction, and gross hematuria) due to local disease progression. Subgroup analyses were conducted to assess the differential outcomes according to the type of local therapy (RP or RT).
    RESULTS: Overall, six studies, comprising two randomized controlled trials, were included for a systematic review and meta-analysis. The overall incidence of local events was significantly lower in the local treatment plus systemic therapy group than in the systemic therapy only groups (relative risk [RR]: 0.50, 95% confidence interval [CI]: 0.28-0.88, p = 0.016). RP significantly reduced the incidence of overall local events (RR: 0.24, 95% CI: 0.11-0.52) and that of local events requiring surgical intervention (RR: 0.08, 95% CI: 0.03-0.25). Although there was no statistically significant difference between the RT plus systemic therapy and systemic therapy only groups in terms of overall local events, the incidence of local events requiring surgical intervention was significantly lower in the RT plus systemic therapy group (RR: 0.70, 95% CI: 0.49-0.99); local events requiring surgical intervention of the upper urinary tract was significantly lower in local treatment groups (RR: 0.60, 95% CI: 0.37-0.98, p = 0.04). However, a subgroup analysis revealed that neither RP nor RT significantly impacted the prevention of local events requiring surgical intervention of the upper urinary tract.
    CONCLUSIONS: In some patients with mHSPC, RP or RT of primary tumor seems to reduce the incidence of local progression and events requiring surgical intervention. Identifying which patients are most likely to benefit from local therapy, and at what time point (eg, after response of metastases), will be necessary to set up a study assessing the risk, benefits, and alternatives to therapy of the primary tumor in the mHSPC setting.
    RESULTS: Our study suggests that local therapy of the prostate, such as radical prostatectomy or radiotherapy, in patients with metastatic hormone-sensitive prostate cancer can prevent local events, such as urinary obstruction and gross hematuria.
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  • 文章类型: Journal Article
    慢性伤口对于那些受影响的人和对于医疗保健系统来说仍然是一个重大的临床挑战。治疗通常是复杂的。所有患者都应接受伤口护理,该护理应纳入涉及本地管理的整体方法,以解决潜在的病因,并提供金标准疗法以支持愈合。避免并发症,更具成本效益。在过去的几十年中,医学取得了重大进展。用于伤口局部治疗的新技术和疗法的发展也在不断增加。为了帮助规范众多伤口产品的临床实践,M.O.I.S.T.概念是由一个多学科专家组开发的。M代表水分平衡,O用于氧气平衡,我支持感染控制,S支持战略,和T用于组织管理。由于M.O.I.S.T.的概念,起源于德语国家,现在旨在为医疗保健专业人员提供一种适用于临床实践的仪器,一组跨学科专家最近对这一概念进行了更新,以使其与国际标准保持一致。M.O.I.S.T.概念现在可以在国际上用作教育工具,也可以用于慢性伤口患者的现代当地治疗概念的实际实施,也可以用于常规临床实践。
    Chronic wounds remain a significant clinical challenge both for those affected and for healthcare systems. The treatment is often comprised and complex. All patients should receive wound care that is integrated into a holistic approach involving local management that addresses the underlying etiology and provides for gold standard therapy to support healing, avoid complications and be more cost effective. There have been significant advances in medicine over the last few decades. The development of new technologies and therapeutics for the local treatment of wounds is also constantly increasing. To help standardize clinical practice with regard to the multitude of wound products, the M.O.I.S.T. concept was developed by a multidisciplinary expert group. The M stands for moisture balance, O for oxygen balance, I for infection control, S for supporting strategies, and T for tissue management. Since the M.O.I.S.T. concept, which originated in the German-speaking countries, is now intended to provide healthcare professionals with an adapted instrument to be used in clinical practice, and a recent update to the concept has been undertaken by a group of interdisciplinary experts to align it with international standards. The M.O.I.S.T. concept can now be used internationally both as an educational tool and for the practical implementation of modern local treatment concepts for patients with chronic wounds and can also be used in routine clinical practice.
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  • 文章类型: Journal Article
    日本乳腺癌学会乳腺癌临床实践指南,2022年版于2022年6月发布。该指南是在尽可能符合“2020年指南发展思想手册”的同时编写的。3.0.“由日本优质医疗保健委员会的思想手册发展委员会于2021年编辑。此外,2021年2月19日至3月4日,对日本乳腺癌协会成员进行了一项关于2018年版指南的调查.根据600多名成员的回应,进行了创新,以使指南更加用户友好。该指南的2018年版旨在为医生和患者提供使用共享决策的支持工具。2022年指南包括两卷:(1)“流行病学和诊断”部分,涵盖“筛查和诊断”,“放射学诊断”,和“病理诊断”,和(2)涵盖“手术治疗”的“治疗”部分,“放射治疗”,和“全身疗法”。我们相信,这份指南的简明摘要将对日本和海外的医生和研究人员有用。
    The Japanese Breast Cancer Society Clinical Practice Guidelines for Breast Cancer, 2022 Edition was published in June 2022. The guidelines were prepared while conforming as much as possible to the \"Minds Manual for Guideline Development 2020 ver. 3.0.\" edited by the Minds Manual Development Committee of the Japan Council for Quality Health Care in 2021. In addition, a survey of Japanese Breast Cancer Society members on the 2018 edition of the guidelines was conducted from February 19 to March 4, 2021. Based on the responses from over 600 members, original innovations were made to make the guidelines more user-friendly. The 2018 edition of the guidelines was developed to provide support tools for physicians and patients to utilize shared decision-making. The 2022 guidelines consist of two volumes: (1) an \"Epidemiology and Diagnosis\" section covering \"Screening and Diagnosis\", \"Radiological diagnosis\", and \"Pathological diagnosis\", and (2) a \"Treatment\" section covering \"Surgical therapy\", \"Radiation therapy\", and \"Systemic therapy\". We believe that this concise summary of the guidelines will be useful to physicians and researchers in Japan and overseas.
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  • 文章类型: Journal Article
    我们比较了根治性前列腺切除术(RP)和放疗(RT)作为原发性肿瘤的局部治疗,并检查了它们与寡转移性前列腺癌(omPC)患者的生存结局和尿路并发症的关系。
    我们评估了2008年1月至2018年12月期间接受原发性肿瘤局部治疗的85例确诊为omPC患者的数据。85名患者中,31例行前列腺RT,而54人接受了RP。轻度转移疾病被定义为存在少于五个无内脏转移的转移性病变。尿路并发症,无进展生存期(PFS),癌症特异性生存率(CSS),使用Kaplan-Meier方法和Cox回归分析评估总生存期(OS).
    接受RT治疗的患者显示出更高的前列腺特异性抗原水平。5年PFS没有显着差异(52.5%与37.9%,p=0.351),CSS(67.6%与84.7%,p=0.473),或操作系统(63.6%与73.8%,RT和RP组之间的p=0.897)。在多变量分析中,局部治疗的类型与PFS无关(风险比[HR]=1.334,p=0.356),CSS(HR=0.744,p=0.475),或OS(HR=0.953,p=0.897)。
    因此,RP似乎是omPC患者的一种可能的治疗选择,表现出与RT相当的肿瘤学结果。
    UNASSIGNED: We compared radical prostatectomy (RP) and radiotherapy (RT) as local therapies for primary tumors and examined their associations with survival outcomes and urinary tract complications in patients with oligometastatic prostate cancer (omPC).
    UNASSIGNED: We evaluated the data of 85 patients diagnosed with omPC who underwent local therapy for primary tumors between January 2008 and December 2018. Of the 85 patients, 31 underwent prostate RT, while 54 underwent RP. Oligometastatic disease was defined as the presence of fewer than five metastatic lesions without visceral metastasis. Urinary tract complications, progression-free survival (PFS), cancer-specific survival (CSS), and overall survival (OS) were evaluated using the Kaplan-Meier method and Cox regression analyses.
    UNASSIGNED: Patients treated with RT showed higher prostate-specific antigen levels. There was no significant difference in the 5-year PFS (52.5% vs. 37.9%, p=0.351), CSS (67.6% vs. 84.7%, p=0.473), or OS (63.6% vs. 73.8%, p=0.897) between the RT and RP groups. In the multivariate analyses, the type of local therapy was not associated with PFS (hazard ratio [HR]=1.334, p=0.356), CSS (HR=0.744, p=0.475), or OS (HR=0.953, p=0.897).
    UNASSIGNED: Therefore, RP seems to be a possible treatment option for patients with omPC, exhibiting oncologic outcomes comparable to those with RT.
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  • 文章类型: Journal Article
    胶质母细胞瘤是一种影响中枢神经系统(CNS)的高度侵袭性和侵袭性肿瘤。五年生存率仅为6.9%,中位生存时间为八个月,在中枢神经系统肿瘤中存活率最低。其治疗包括手术切除,随后的分割放疗和伴随和辅助化疗替莫唑胺。尽管实施了临床干预措施,复发是常见的情况,治疗后几个月,超过80%的病例出现在切除腔的边缘。胶质母细胞瘤的高复发率和位置表明需要更好地了解瘤周脑区(PBZ)。在这次审查中,我们首先描述了主要的放射学,细胞,PBZ的分子和生物力学组织特征;随后,我们讨论它目前的临床管理,潜在的当地治疗方法和未来前景。
    Glioblastoma is a highly aggressive and invasive tumor that affects the central nervous system (CNS). With a five-year survival rate of only 6.9% and a median survival time of eight months, it has the lowest survival rate among CNS tumors. Its treatment consists of surgical resection, subsequent fractionated radiotherapy and concomitant and adjuvant chemotherapy with temozolomide. Despite the implementation of clinical interventions, recurrence is a common occurrence, with over 80% of cases arising at the edge of the resection cavity a few months after treatment. The high recurrence rate and location of glioblastoma indicate the need for a better understanding of the peritumor brain zone (PBZ). In this review, we first describe the main radiological, cellular, molecular and biomechanical tissue features of PBZ; and subsequently, we discuss its current clinical management, potential local therapeutic approaches and future prospects.
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  • 文章类型: Journal Article
    肢端和粘膜黑色素瘤是黑色素瘤的罕见变体。肢端黑色素瘤的年龄调整发病率约为每年每百万个体1.8例,约占所有黑色素瘤病例的2%~3%。另一方面,粘膜黑色素瘤,发病率为每年2.2例,约占所有黑色素瘤病例的1.3%。这些黑色素瘤,除了在生物学和临床上与皮肤黑色素瘤不同,具有一定的临床和病理特征。这些包括更具侵略性的性质和较差的预后。此外,它们表现出不同的突变模式,KIT突变在肢端和粘膜黑素瘤中更为普遍。突变模式的这种差异可能部分解释了相对较差的预后,特别是免疫检查点抑制剂。这篇综述探讨了肢端和粘膜黑色素瘤的各个方面,包括他们的临床表现,病理特征,突变谱,目前的治疗方法,与系统治疗相关的结果,以及解决对现有治疗方法的耐药性的潜在策略。
    Acral and mucosal melanoma are uncommon variants of melanoma. Acral melanoma has an age-adjusted incidence of approximately 1.8 cases per million individuals per year, accounting for about 2% to 3% of all melanoma cases. On the other hand, mucosal melanoma, with an incidence of 2.2 cases per million per year, makes up around 1.3% of all melanoma cases. These melanomas, in addition to being biologically and clinically distinct from cutaneous melanoma, share certain clinical and pathologic characteristics. These include a more aggressive nature and a less favorable prognosis. Furthermore, they exhibit a different mutational pattern, with KIT mutations being more prevalent in acral and mucosal melanomas. This divergence in mutational patterns may partially account for the relatively poorer prognosis, particularly to immune checkpoint inhibitors. This review explores various aspects of acral and mucosal melanoma, including their clinical presentation, pathologic features, mutational profiles, current therapeutic approaches, outcomes associated with systemic therapy, and potential strategies to address resistance to existing treatments.
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  • 文章类型: Journal Article
    局部结合全身治疗可能是晚期不可切除肝细胞癌(uHCC)患者的一种选择。这项研究检查了经动脉栓塞(TAE)和肝动脉灌注化疗(HAIC)联合阿特珠单抗(Atezo)和贝伐单抗(Bev)在直径大于8cm的uHCC患者中的临床益处和不良事件(AE)。
    这项回顾性研究包括直径大于8厘米的uHCC患者,他们在2019年9月30日至2022年9月30日在中山大学附属第一医院接受一线Atezo-Bev和TAE+HAIC治疗。无进展生存期(PFS),总生存期(OS),根据mRECIST的肿瘤反应,并对AE进行了分析。进行多变量Cox分析以检查与PFS相关的因素。
    纳入30例患者。客观缓解率(ORR)为74.4%(95%置信区间[CI],59.3%-89.5%),疾病控制率(DCR)为93.3%(95%CI,85.4%-98.6%)。中位随访时间为11.4(四分位数间距[IQR],5.5-17.9)个月。中位PFS为6.8个月(95%CI,2.6-11.1)。3、6-,9-,12个月生存率为86.2%,82.5%,68.6%,60%,分别。未估计中位OS。肝外转移与PFS独立相关(风险比[HR]=3.468,95%CI,1.001-12.023)。最常见的不良事件是发热(46.7%)。4级AE发生1次为吐血,但未观察到5次AE。
    Atezo-Bev联合TAE和HAIC可能会使直径大于8厘米的uHCC患者受益,具有可管理的AE。
    UNASSIGNED: Local in combination with systemic therapy might be an option for patients with advanced unresectable hepatocellular carcinoma (uHCC). This study examined the clinical benefits and adverse events (AEs) of first-line transarterial embolization (TAE) and hepatic arterial infusion chemotherapy (HAIC) combined with atezolizumab (Atezo) and bevacizumab (Bev) in patients with uHCC of a diameter larger than 8 cm.
    UNASSIGNED: This retrospective study included patients with uHCC of a diameter larger than 8 cm who were treated with first-line Atezo-Bev and TAE+HAIC at the First Affiliated Hospital of Sun Yat-Sen University between September 30, 2019, and September 30, 2022. Progression-free survival (PFS), overall survival (OS), tumor response according to mRECIST, and AEs were analyzed. Multivariable Cox analyses were performed to examine the factors associated with PFS.
    UNASSIGNED: Thirty patients were included. The objective response rate (ORR) was 74.4% (95% confidence interval [CI], 59.3%-89.5%), and the disease control rate (DCR) was 93.3% (95% CI, 85.4%-98.6%). The median follow-up was 11.4 (inter-quartile range [IQR], 5.5-17.9) months. The median PFS was 6.8 (95% CI, 2.6-11.1) months. The 3-, 6-, 9-, and 12-month survival rates were 86.2%, 82.5%, 68.6%, and 60%, respectively. The median OS was not estimated. Extrahepatic metastasis was independently associated with PFS (hazard ratio [HR]=3.468, 95% CI, 1.001-12.023). The most common AEs were fever (46.7%). Grade 4 AEs occurred one time as hematemesis but no 5 AEs were observed.
    UNASSIGNED: Atezo-Bev combined with TAE and HAIC might benefit patients with uHCC of a diameter larger than 8 cm, with manageable AEs.
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