宫颈癌 肺转移 努力学习中 请版主指点

在人乳头状瘤病毒（HPV）相关的转移或复发的宫颈癌患者中，伊匹单抗（Ipilimumab）的安全性和抗肿瘤活性如何？来自加拿大和美国的研究人员对此展开了研究。<br><br>&nbsp;<br><br>研究人员发现，与HPV相关的转移或复发宫颈癌患者可以耐受伊匹单抗，但伊匹单抗单用并未显示出明显活性。<br><br>&nbsp;<br><br>他们还发现，虽然抗CTLA-4疗法可诱发免疫改变，但是与临床活性无关。这些标志物的改变或许能指导进一步的治疗策略。<br><br>&nbsp;<br><br>根据HPV诱导免疫逃逸的证据，免疫治疗或许是宫颈癌具有吸引力的一种治疗策略。此项多中心临床试验纳入的受试者为，病兆可测量且至少经1线铂类化疗后出现进展的转移性宫颈癌患者。安全队列有6例患者构成，应用的伊匹单抗剂量为3mg/kg，每21天1个周期，共4个周期；随后为II期队列，伊匹单抗剂量10mg/kg，每21天为1个周期，共4个周期；对于经放射学资料观察显示缓解或稳定的患者，随后再进行12周为一个周期，共4个周期的维持治疗。采用登记前或治疗2周期后第7天获取的新鲜肿瘤及档案组织（archival tissue），对治疗前后的外周血实施免疫相关性研究。研究开展时间为2012年12月3日至2014年9月15日。2016年4月至2016年6月及2017年7月，研究人员对数据进行了分析。<br><br><br>研究共入组42例患者【中位年龄：49岁（23-78岁）；29例为宫颈鳞状细胞癌，13例为腺癌；37/40例可获取组织学进行分析的患者被证实HPV阳性；2例患者没有档案组织。3级毒性反应包括4例腹泻，其中3例为结肠炎。<br><br>&nbsp;<br><br>在34例被评估为最佳缓解（RECST 1.1版）的患者中，1例患者出现部分缓解，10例病变稳定。中位无进展生存期和总生存期分别为2.5个月和8.5个月。治疗前，肿瘤内的CD3、CD4、CD8、Foxp3、吲哚胺2，3-双加氧酶和PD-L1表达，并不能预测获益，且在治疗期间未出现显著改变。<br><br>&nbsp;<br><br>多色流式细胞仪检测外周血淋巴细胞显示，治疗初期可诱导性T细胞共刺激分子、PD-1等出现了升高，且呈现出“治疗依赖性”特征，在维持阶段又恢复到了基线水平。<br><br><br>研究链接：<br><br>https://jamanetwork.com/journals/jamaoncology/article-abstract/2663280

又一个哑火的，唉，，，IO疗法对CC这么差，问题出在哪里呢 ？

宫颈癌是由HPV病毒感染引起，由病毒感染到组织增生，再到癌变经历的时间非常漫长，免疫系统早已耐受。

哇,版主进来了,呱唧呱唧欢迎欢迎。
2016年12月时我与国外某HPV科学家发邮件沟通过关于耐受的问题，但后来也没有正面回答是否耐受。

我的問題如下：
1、對於日常監控腫瘤復發，我的想法是：目前的臨床檢驗辦法，比如腫瘤指標、TCT檢查、影像學檢查，均不能在早期預警；那麼以E6E7的檢測是否能解決這個“早期預警”的問題？是否可以從外周血檢測E6E7？并以E6E7的計數結果作為判斷腫瘤復發的依據 ？或者您的實驗室已經開發出了更好的監控方案？
2、關於免疫耐受、免疫逃逸、免疫抑制：從PD1報出的數據來看，ORR12.5%並不算好；我的理解是：因E6E7在癌變過程中持續表達，耐受的概率大於抑制和逃逸，因此，PD1不適用於大多數CC病人。
3、對於暫時CR的病人，哪些醫療方案可以降低復發的概率？是否可以勞煩您給我一些建議？

早期预警看看循环肿瘤DNA是否有异常增加。
CR的宫颈癌病人，目前没太多办法降低复发的概率。

早期预警看看循环肿瘤DNA是否有异常增加。
CR的宫颈癌病人，目前没太多办法降低复发的概率。

我拿着教授发给我的论文，论文里有具体的基因甚至连碱基都明确标注了，然后找了国内N多的检测机构，没人愿意给测，理由是：这个属于定制的pannel，暂时做不了。
所以，我退而求其次，想用elisa测测外周血看看，结果也得不到实验室的支持。
但是从文献来看，无论是elisa还是NGS，检测e6e7是已经证实了的可以提前预警的方法之一。

。

Abstract
For locally advanced cervical cancer (LACC), hypoxia is a characteristic property. This study aimed to investigate whether baseline lactic dehydrogenase (LDH) level, which is a marker of hypoxia, had clinical value in determining neoadjuvant chemotherapy (NACT) response and prognosis for LACC patients. The study cohort included 418 patients with a median follow‐up of 37.5 months. Cox proportional hazards models were used to assess the prognostic value of baseline LDH levels. Multivariate logistic regression analysis was performed to identify independent predictors of complete response after NACT. Backward stepwise selection with the Akaike information criterion was used to identify factors that could be entered into the multivariate regression model. Compared with patients with LDH levels <252.0 μ/L, patients with LDH levels ≥252.0 μ/L were more likely to have an elevated level of squamous cell carcinoma antigen, lymphatic vascular space involvement, lymph node metastasis, and positive parametrium and achieved lower complete remission rates. Baseline LDH levels ≥252.0 μ/L was an independent prognosticator for recurrence‐free survival (adjusted hazard ratio [HR], 3.56; 95% confidence interval [CI] 2.22–5.69; P < 0.0001) and cancer‐specific survival (adjusted HR, 3.08; 95% CI, 1.89–5.01; P < 0.0001). The predictive value of baseline LDH value remained significant in the subgroup analysis. LDH level ≥252.0 μ/L was identified as an independent predictor of complete remission after NACT (adjusted odds ratio [OR], 0.29; 95% CI, 0.15–0.58; P < 0.0001). Baseline LDH ≥252.0 μ/L is an independent prognostic predictor for patients receiving neoadjuvant chemotherapy for LACC. It helps distinguish patients with different prognosis and select patients who are more likely to benefit from NACT.

Discussion
An inverse relationship between LDH levels and length of survival has also been identified in many tumor types, including melanoma 15, breast cancer 16, myeloma 17, hepatocellular carcinoma 18, seminoma 19, nasopharyngeal cancer 20, lung cancer 21, colorectal cancer 10, renal cancer 22, oral cancer 23, and pancreatic cancer 24. For gynecologic malignancies, a strong association between the elevated expression of LDH and an aggressive phenotype has been noted in patients with ovarian and uterine carcinoma 25, 26. In consistent with these findings, our study demonstrated that LACC patients with elevated LDH levels were more likely to have positive SCCA, LVSI, lymph node metastasis, and parametrium invasion. Furthermore, compared with patients with baseline LDH less than 252.0 μ/L, patients with LDH ≥252.0 μ/L had a statistically significant 3.6‐fold risk of cancer recurrence and 3.1‐fold risk of cancer‐specific death, and this association was independent of other potential prognostic factor. The prognostic influence of elevated LDH levels was consistent across all the LACC patient subgroups. Additionally, we found pretreatment LDH levels <252.0 μ/L was an independent predictor of CR after NACT.

又是林仲秋教授的论文，看来林教授要火

418个样本量, 2A及2A之前的分期，新辅助化疗后，LDH取治疗前的基线值252：
LDH>252：淋巴受浸、淋巴转移、宫旁阳性等   概率大大增加
LDH<252:  浸润、受累、转移的概率明显减少

5年复发率统计：
LDH<252:   10.6% ； 1年复发率：0%   3年复发率：10.6   5年复发率：10.6%
LDH>252:   47.9%  ;   1年复发率：12.5%   3年复发率：44.8%    5年复发率：47.9%

Highlights
&#8226;Elevated CYFRA 21-1 shows more meaningful correlation with FIGO stage than SCC-Ag.
&#8226retreatment CYFRA 21–1 levels may be a useful prognostic indicator in patients with Non-SCC with reference to SCC-Ag.
Abstract
Objective
To determine whether pretreatment CYFRA 21-1 levels can be a useful prognostic indicator in cervical cancer with reference to squamous cell carcinoma-antigen (SCC-Ag).

Methods
We retrospectively analyzed data on 506 consecutive cervical cancer patients who were treated by radical hysterectomy or primary concurrent chemoradiation therapy. The pretreatment serum SCC-Ag and serum CYFRA 21-1 levels were measured in these patients. A multivariate analysis using Cox's proportional hazard model was performed to evaluate the prognostic significance of pretreatment variables.

Results
In patients who underwent radical hysterectomy, there was a significant correlation between pretreatment serum SCC-Ag/CYFRA 21-1 levels and patient age, advanced FIGO stage, large tumor size, lymph node metastasis, and deep stromal invasion. In the stepwise Cox regression analysis, large tumor size >4&#8197;cm was an independent prognostic factor for disease-free survival (OR, 3.110; [95% CI, 1.588–6.093], P&#8197;=&#8197;0.001) and overall survival (OR, 8.497; [95% CI, 1.797–40.184], P&#8197;=&#8197;0.007) in patients with squamous cell carcinoma, while pretreatment CYFRA 21-1 (P&#8197;=&#8197;0.010) serum levels had a significant independent effect on overall survival. Likewise, pretreatment CYFRA 21-1 (P&#8197;<&#8197;0.001 and P&#8197;=&#8197;0.006) serum levels were the only independent prognostic factor for disease-free survival and overall survival in patients with non-squamous cell carcinoma.

Conclusion
Pretreatment CYFRA 21-1 levels may be considered as a useful prognostic indicator in cervical cancer with reference to SCC-Ag.

我在前期纠正过自己的观点——只注重SCC。还好，后期改了过来——SCC+CYFRA211. 上文就是我纠正自己观点的证据。

最近帖子阅读量较大，部分看客应该是宫颈癌QQ群的群主或者管理员，很好，欢迎你们来看贴。
希望你们在群里也纠正一下  只看SCC  的观点，只看SCC会误导很多人的。

Phase II study of temsirolimus (CCI-779) in women with recurrent, unresectable, locally advanced or metastatic carcinoma of the cervix. A trial of the NCIC Clinical Trials Group (NCIC CTG IND 199).

Tinker AV1, Ellard S, Welch S, Moens F, Allo G, Tsao MS, Squire J, Tu D, Eisenhauer EA, MacKay H.
Author information
1
BC Cancer Agency, Vancouver Clinic, Vancouver, BC, Canada. atinker@bccancer.bc.ca
Abstract
OBJECTIVE:
HPV infection has been associated with deregulation of the PI3K-Akt-mTOR pathway in invasive cervical carcinomas. This 2-stage phase II study assessed the activity of the mTOR inhibitor, temsirolimus, in patients with measurable metastatic and/or locally advanced, recurrent carcinoma of the cervix.
METHODS:
Temsirolimus 25mg i.v. was administered weekly in 4 week cycles. One response among the first 18 patients was required to proceed to the second stage of accrual. Correlative molecular studies were performed on archival tumor tissue.
RESULTS:
Thirty-eight patients were enrolled. Thirty-seven patients were evaluable for toxicity and 33 for response. One patient experienced a partial response (3.0%). Nineteen patients had stable disease (57.6%) [median duration 6.5 months (range 2.4-12.0mo)]. The 6-month progression free survival rate was 28% (95% CI: 14-43%). The median progression free survival was 3.52 months [95% CI (1.81-4.70)]. Adverse effects were mild-moderate in most cases and similar to other temsirolimus studies. No toxicity>grade 3 was observed. Assessment of PTEN and PIK3CA by IHC, copy number analyses and PTEN promoter methylation status did not reveal subsets associated with disease stability.
CONCLUSION:
Single agent temsirolimus has modest activity in cervical carcinoma with about two-thirds of patients exhibiting stable disease. Molecular markers for treatment benefit remain to be identified.

mTOR的单药维持。替西罗莫斯。
37个样本量，1例PR，19例SD。