BACKGROUND & AIMS: BACKGROUND:Paronychia has been reported in as many as 10% of patients treated with gefitinib. Although conservative management and treatment with topical or systemic antibiotics are beneficial, no effective method exists for intractable cases. Platelet-rich plasma (PRP)consists of a high concentration of platelets that promote wound healing through chemotaxis, cell proliferation,angiogenesis, and tissue remodeling. OBSERVATIONS:We herein report a refractory case of gefitinib-induced paronychia successfully treated with autologous PRP. A 68-year-old woman who had been diagnosed as having lung adenocarcinoma with multiple bone and brain metastases initiated gefitinib therapy at an oral dose of 250 mg/d. After 1 month, multiple paronychia with periungual granulation appeared on the nailfold of the first, second, and third toenails of both feet.Because the paronychia recurred repeatedly despite use of a topical antibiotic, topical corticosteroid, and short term systemic antibiotic, she started PRP treatment. After 3 months, the lesion showed marked improvement with minimal pain or discharge. CONCLUSION:This case highlights the therapeutic challenges of using PRP to promote tissue repair in intractable gefitinib-induced paronychia and merits further investigation.

背景与目标： 背景：据报道，吉非替尼治疗的患者中有多达10％患有甲旁沟炎。尽管保守治疗和局部或全身性抗生素治疗是有益的，但对于顽固性病例，尚无有效方法。富含血小板的血浆（PRP）由高浓度的血小板组成，这些血小板通过趋化性，细胞增殖，血管生成和组织重塑促进伤口愈合。
观察：我们在这里报道了吉非替尼诱导的自体PRP成功治疗的顽固性病例。一名被确诊患有多发性骨和脑转移的肺腺癌的68岁妇女开始以250 mg / d的口服剂量进行吉非替尼治疗。 1个月后，双脚第一，第二和第三趾甲的指甲褶上出现多发性甲状旁腺肉芽肿，尽管使用了局部抗生素，局部皮质类固醇和短期全身性抗生素，但甲状旁腺反复发作，因此开始进行PRP。治疗。 3个月后，病变表现出明显的改善，疼痛或分泌物最少。
结论：该病例突出了在难治性吉非替尼诱导的甲状旁腺中使用PRP促进组织修复的治疗挑战，值得进一步研究。

BACKGROUND & AIMS: :The modest response of patients with head and neck squamous cell carcinoma (HNSCC) and non-small cell lung carcinoma (NSCLC) to epithelial growth factor receptor tyrosine kinase inhibitors such as gefitinib and erlotinib indicates the need for the development of biomarkers to predict response. We determined gefitinib sensitivity in a panel of HNSCC cell lines by a 5-day 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and confirmed these responses with analysis of downstream signaling by immunoblotting and cell cycle arrest. Basal gene expression profiles were then determined by microarray analysis and correlated with gefitinib response. These data were combined with previously reported NSCLC microarray results to generate a broader predictive index. Common markers of resistance between the two tumor types included genes associated with the epithelial to mesenchymal transition. We confirmed that increased protein expression of vimentin combined with the loss of E-cadherin, claudin 4, and claudin 7 by immunoblotting was associated with gefitinib resistance in both HNSCC and NSCLC cell lines. In addition, the loss of the Ca(2+)-independent cell-cell adhesion molecules EpCAM and TROP2 in resistant lines was confirmed by immunofluorescence. Tumor xenografts derived from the gefitinib-sensitive UM-SCC-2 were growth-delayed by gefitinib, whereas the gefitinib-resistant 1483 xenografts were unaffected. These data support a role for epithelial to mesenchymal transition in establishing gefitinib resistance for both HNSCC and NSCLC, and indicate that clinical trials should address whether these biomarkers will be useful for patient selection.

背景与目标： 头颈部鳞状细胞癌（HNSCC）和非小细胞肺癌（NSCLC）对上皮生长因子受体酪氨酸激酶抑制剂（如吉非替尼和厄洛替尼）的反应中等，表明需要开发生物标志物来预测反应。我们通过5天3-（4,5-二甲基噻唑-2-基）-2,5-二苯基四唑溴甲烷测定法确定了一组HNSCC细胞系中的吉非替尼敏感性，并通过免疫印迹和细胞分析下游信号证实了这些反应循环逮捕。然后通过微阵列分析确定基础基因表达谱，并将其与吉非替尼反应相关。这些数据与先前报道的NSCLC芯片结果相结合，以产生更广泛的预测指标。两种肿瘤类型之间共同的抗药性标志包括与上皮向间质转化相关的基因。我们确认，波形蛋白的蛋白质表达增加，以及免疫印迹导致E-钙粘蛋白，claudin 4和claudin 7的损失与吉非替尼耐药在HNSCC和NSCLC细胞系中均相关。另外，通过免疫荧光证实了抗性系中Ca（2）独立的细胞间粘附分子EpCAM和TROP2的损失。来自吉非替尼敏感的UM-SCC-2的肿瘤异种移植物被吉非替尼生长延迟，而耐吉非替尼的1483个异种移植物不受影响。这些数据支持上皮向间充质转变在建立对HNSCC和NSCLC的吉非替尼耐药性中的作用，并表明临床试验应解决这些生物标记物是否对患者选择有用。

BACKGROUND & AIMS: BACKGROUND:EGFR tyrosine kinase inhibitors (TKIs) are widely used for advanced nonsmall cell lung cancer (NSCLC) patients with a sensitizing EGFR mutation and provide a promising treatment strategy. However, acquired resistance to EGFR-TKIs restricts their application. The mechanisms underlying acquired resistance to TKIs have been explored and Phosphoinositide 3- kinase (PI3K)/Akt/mTOR pathway plays a very important role in NSCLC development as well as EGFR-TKI resistance. Polyphyllin II(PP II) is the main steroidal saponin constituent which derives from the root of Paris polychylia. OBJECTIVE:We examined the sensitizing effect of PP II to gefitinib on proliferation, apoptosis, PI3K/Akt/mTOR signaling pathway and tumor growth on gefitinib-resistant NSCLC in vitro and in vivo. METHODS:Gefitinib-resistant PC-9/ZD cells and gefitinib-sensitive PC-9 cells were used. In the absence of PI3K siRNA, MTT assay, Annexin V/PI analyses, Western blot, and Immunohistochemistry analysis by TUNEL assays for xenograft model were carried out. RESULTS:PP II promoted the anti-proliferative effects of gefitinib and gefitinib-induced apoptosis via activation of caspases and cleavage of PARP. PP II elevated sensitization of gefitinib through targeting the PI3K/Akt/mTOR. PP II with gefitinib treatment was more effective in inhibiting tumor growth and PI3K inactivation on gefitinib-resistant xenograft. CONCLUSION:The results indicated that PP II elevated sensitization of drug-resistant PC-9/ZD cells to gefitinib through the inhibition of PI3K/Akt/mTOR signaling pathway. It provides a potential new strategy to overcome gefitinib resistance for EGFR-TKI resistant NSCLC.

背景与目标： 背景：EGFR酪氨酸激酶抑制剂（TKIs）被广泛用于患有致敏性EGFR突变的晚期非小细胞肺癌（NSCLC）患者，并提供了有希望的治疗策略。但是，获得性对EGFR-TKI的耐药性限制了它们的应用。已经探究了获得的对TKIs耐药性的潜在机制，磷酸肌醇3-激酶（PI3K）/ Akt / mTOR途径在NSCLC的发展以及EGFR-TKI耐药性中起着非常重要的作用。 Polyphyllin II（PP II）是类固醇皂苷的主要成分，其来源于巴黎木瓜的根。
目的：我们研究了PP II对吉非替尼在体外和体内对吉非替尼耐药的NSCLC增殖，凋亡，PI3K / Akt / mTOR信号通路和肿瘤生长的敏化作用。
方法：使用耐吉非替尼的PC-9 / ZD细胞和对吉非替尼敏感的PC-9细胞。在没有PI3K siRNA的情况下，进行了MTT测定，膜联蛋白V / PI分析，蛋白质印迹和通过TUNEL测定的免疫组织化学分析，用于异种移植模型。
结果：PP II通过激活半胱氨酸蛋白酶和PARP的裂解，促进了吉非替尼的抗增殖作用和吉非替尼诱导的细胞凋亡。 PP II通过靶向PI3K / Akt / mTOR提高了吉非替尼的敏感性。吉非替尼治疗的PP II在耐吉非替尼的异种移植物中抑制肿瘤生长和PI3K失活更有效。
结论：PP II通过抑制PI3K / Akt / mTOR信号通路提高了耐药PC-9 / ZD细胞对吉非替尼的敏感性。它为克服吉非替尼对EGFR-TKI耐药的NSCLC的耐药性提供了潜在的新策略。

BACKGROUND & AIMS: :Gefitinib, a tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR), has been used to treat numerous cancers; however, evidence has shown that cancer cells can become resistant to gefitinib during therapy. Here, we report a human proto-oncogene, securin, which displays resistance to death in cancer cells. Gefitinib treatment decreases securin levels at the protein level by inducing protein instability but did not affect on the securin gene expression. Treatment with gefitinib induced cytotoxicity in various human cancer cell types, including RKO (colon cancer), A549 (lung cancer), BFTC905 (bladder cancer), MCF7 (breast cancer) and A375 (skin cancer). BFTC905 and A549 cells expressed relatively high levels of the phosphorylated and total EGFR proteins; however, A375, MCF7 and RKO cells did not markedly express these proteins. Moreover, following treatment with gefitinib, the securin-wild type cancer cells were more resistant to apoptotic induction than the securin-null cancer cells. Surprisingly, both the securin-wild type and securin-null cancer cells expressed the EGFR protein at similar levels. Treatment with gefitinib induced mitochondrial dysfunction, cytochrome c release, caspase-3 activation and poly (ADP-ribose) polymerase protein cleavage, indicating that apoptosis occurred in these cancer cells. The transfection of a GPF-securin expression vector increased both the proliferation rates and resistance to gefitinib-induced death in these cancer cells. Taken together, these findings demonstrate that the presence of securin promotes resistance to gefitinib-induced apoptosis via an EGFR-independent pathway in human cancer cells.

背景与目标： ：吉非替尼，一种表皮生长因子受体（EGFR）的酪氨酸激酶抑制剂，已被用于治疗多种癌症；但是，有证据表明，癌细胞可以在治疗过程中对吉非替尼产生抗药性。在这里，我们报道了人类的原癌基因，securin，在癌细胞中显示出对死亡的抵抗力。吉非替尼治疗可通过诱导蛋白质不稳定性来降低蛋白质水平上的安全性蛋白水平，但不影响安全性蛋白基因表达。吉非替尼治疗可引起多种人类癌细胞类型的细胞毒性，包括RKO（结肠癌），A549（肺癌），BFTC905（膀胱癌），MCF7（乳腺癌）和A375（皮肤癌）。 BFTC905和A549细胞表达相对较高水平的磷酸化和总EGFR蛋白。但是，A375，MCF7和RKO细胞没有明显表达这些蛋白质。此外，在用吉非替尼治疗后，与无securin的癌细胞相比，securin野生型的癌细胞对凋亡诱导的耐受性更高。出人意料的是，野生型和非雌激素型癌细胞都以相似的水平表达EGFR蛋白。用吉非替尼治疗可引起线粒体功能障碍，细胞色素c释放，caspase-3激活和聚（ADP-核糖）聚合酶蛋白裂解，表明这些癌细胞发生了凋亡。 GPF-securin表达载体的转染提高了这些癌细胞中的增殖率和对吉非替尼诱导的死亡的抵抗力。综上所述，这些发现表明，securin的存在通过人类癌细胞中的EGFR独立途径增强了对吉非替尼诱导的凋亡的抵抗力。

BACKGROUND & AIMS: :Two patients with non-small cell lung cancer presented with multiple brain metastases. They received gefitinib orally for the treatment of the primary lung lesions. About one month later, the brain metastases unexpectedly disappeared or became smaller. The patients survived without recurrence of brain metastases and growth of lung lesions for 3-4 years. Gefitinib is a selective epidermal growth factor receptor tyrosine kinase inhibitor and is approved for use in the treatment of non-small cell lung cancer. Gefitinib may be very effective for multiple brain metastases in patients with non-small cell lung cancer.

背景与目标： ：两名非小细胞肺癌患者出现多发性脑转移。他们口服吉非替尼治疗原发性肺部病变。大约一个月后，脑转移意外消失或变小。患者存活了3-4年，没有脑转移复发和肺部病变的增长。吉非替尼是一种选择性的表皮生长因子受体酪氨酸激酶抑制剂，被批准用于治疗非小细胞肺癌。吉非替尼对非小细胞肺癌患者的多发性脑转移可能非常有效。

BACKGROUND & AIMS: BACKGROUND:The prognosis of non-small-cell lung cancer (NSCLC) with brain metastases is very poor. Currently, therapeutic methods for this patient population include whole-brain radiation therapy (WBRT), surgery, radiosurgery and systemic treatment. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) could be effective on cerebral metastases of mutated NSCLC. However, which EGFR-TKIs is more appropriate is still unknown. METHODS:We conducted a retrospective analysis of advanced NSCLC patients with brain metastases for EGFR targeted therapy from November 2013 to April 2018 at Dongguan People's Hospital, Southern Medical University, China. A total of 43 patients were recruit in this study. Among them, 21 cases received icotinib (125 mg, thrice a day) and 22 cases received gefitinib (250 mg, once a day) until disease progression or unacceptable toxicity. The primary end point of this study was intracranial PFS (iPFS). The relationships between therapeutic arms and patients characteristics were performed using Pearson's chi-square test or Fisher's exact test. The differences in PFS among the two arms were analyzed using Kaplan-Meier curves and log rank tests. RESULTS:There was no significant difference of intracranial ORR (66.6% versus 59.1%, P = 0.62) and DCR (85.7% versus 81.8%, P = 0.73) between the two arms. The median intracranial PFS (iPFS) for icotinib and gefitinib arms were 8.4 months (95% CI, 5.4 to 11.3 months) and 10.6 months (95% CI, 6.3 to 14.8 months), respectively (P = 0.17). Adverse events of the two study arms were generally mild. None of the patients experienced dose reduction of EGFR-TKIs. CONCLUSIONS:Our study showed that icotinib and gefitinib had similar efficacy for brain metastasis of EGFR mutated NSCLC. Large randomized studies are suggested to further illuminate the effect of these two EGFR-TKIs on cerebral lesions of NSCLC.

背景与目标： 背景：非小细胞肺癌（NSCLC）伴脑转移的预后很差。当前，针对该患者群体的治疗方法包括全脑放射治疗（WBRT），手术，放射外科手术和全身治疗。表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKIs）可能对突变的NSCLC的脑转移有效。但是，哪种EGFR-TKIs更合适仍是未知的。
方法：我们对2013年11月至2018年4月在中​​国南方医科大学附属东莞人民医院进行EGFR靶向治疗的晚期NSCLC脑转移患者进行了回顾性分析。本研究共招募了43名患者。其中21例接受艾替尼（125毫克，每天三次），22例接受吉非替尼（250毫克，每天一次），直到疾病进展或出现不可接受的毒性。这项研究的主要终点是颅内PFS（iPFS）。治疗组与患者特征之间的关系使用皮尔逊卡方检验或费舍尔精确检验进行。使用Kaplan-Meier曲线和对数秩检验分析了两组之间PFS的差异。
结果：两组之间的颅内ORR（66.6％比59.1％，P = 0.62）和DCR（85.7％比81.8％，P = 0.73）无显着差异。 icotinib和gefitinib组的颅内PFS（iPFS）中位数分别为8.4个月（95％CI，5.4至11.3个月）和10.6个月（95％CI，6.3至14.8个月）（P = 0.17）。两个研究组的不良反应一般较轻。没有患者的EGFR-TKIs剂量降低。
结论：我们的研究表明，icotinib和gefitinib在EGFR突变的NSCLC的脑转移中具有相似的疗效。建议进行大规模的随机研究，以进一步阐明这两种EGFR-TKI对NSCLC脑损伤的影响。

BACKGROUND & AIMS: Background:Our previous clinical study has shown that Chinese herbal medicine (CHM) Fuzheng Kang-Ai (FZKA) decoction is effective in treating advanced lung cancer patients through prolonging the drug resistance to Gefitinib (GFTN). Our basic study found that FZKA decoction could enhance the inhibition effect of GFTN in lung cancer by inactivating PI3K/Akt pathway. Moreover, our recent work showed that FZKA induced lung cancer cell apoptosis via STAT3/Bcl-2/Caspase-3 pathway. Thus in this study, we aim to elucidate how FZKA enhances the effect of GFTN in lung cancer from the perspective of cell apoptosis. Methods:Cell proliferation and colony formation assay were performed to detect the cell growth inhibition. Flow cytometry and TUNEL assay were carried out to test the cell apoptosis. Mitochondrial membrane potential (MMP) assay was done to measure the alteration of MMP. Caspase-3/-9 activity assay was used to test the activity of caspase-3/-9. Western blot and qRT-PCR were done to detect the expression of STAT3 and Bcl-2 family as well as Caspase-3/-9 and Cyt-C at protein and mRNA levels, respectively. Transient transfection was performed to silence STAT3 using siSTAT3. Animal model was done to validate the molecular mechanisms in vivo and immunohistochemistry was done to detect the expression of Bax and Caspase-3. Results:Firstly, our results showed that FZKA enhanced the inhibition effect of GFTN in lung cancer both in vitro and in vivo. Secondly, cell apoptosis was enhanced when treating lung cancer cells with both FZKA and GFTN, a process involving the mitochondria and the Bcl-2 family. And Bcl-2 family was involved in this process. Interestingly, STAT3 plays a critical role on mediating the above process. Last but not the least, the enhanced effect of cell apoptosis induction of GFTN by FZKA was validated in animal model. Conclusion:Our findings conclude that Fuzheng Kang-Ai decoction enhances the effect of GFTN-induced cell apoptosis in lung cancer through the mitochondrial pathway, providing a novel molecular mechanism by which FZKA sensitizes to GFTN by delaying drug resistance in treating lung cancer patients.

背景与目标： 背景：我们先前的临床研究表明，中药复方抗癌汤可通过延长对吉非替尼（GFTN）的耐药性来有效治疗晚期肺癌患者。我们的基础研究发现，FZKA汤可通过灭活PI3K / Akt途径来增强GFTN对肺癌的抑制作用。此外，我们最近的工作表明FZKA通过STAT3 / Bcl-2 / Caspase-3途径诱导肺癌细胞凋亡。因此，在这项研究中，我们旨在从细胞凋亡的角度阐明FZKA如何增强GFTN在肺癌中的作用。
方法：通过细胞增殖和集落形成实验检测细胞的生长抑制情况。进行流式细胞术和TUNEL法检测细胞凋亡。进行了线粒体膜电位（MMP）测定以测量MMP的变化。 Caspase-3 / -9活性测定用于测试caspase-3 / -9的活性。进行了蛋白质印迹和qRT-PCR来分别检测STAT3和Bcl-2家族以及Caspase-3 / -9和Cyt-C在蛋白质和mRNA水平上的表达。使用siSTAT3进行瞬时转染以使STAT3沉默。建立动物模型以验证体内分子机制，并进行免疫组织化学以检测Bax和Caspase-3的表达。
结果：首先，我们的结果表明，FZKA在体外和体内均增强了GFTN对肺癌的抑制作用。其次，当用FZKA和GFTN处理肺癌细胞时，细胞凋亡得到增强，这一过程涉及线粒体和Bcl-2家族。 Bcl-2家族参与了这一过程。有趣的是，STAT3在介导上述过程中起着至关重要的作用。最后但并非最不重要的一点是，在动物模型中验证了FZKA增强GFTN诱导细胞凋亡的作用。
结论：我们的研究结论表明，扶正抗癌汤通过线粒体途径增强了GFTN诱导的肺癌细胞凋亡的作用，为FZKA延缓耐药性对肺癌的耐药提供了新的分子机制。

BACKGROUND & AIMS: :Response to gefitinib is strongly associated with the status of the epidermal growth factor receptor gene. Here we report the different treatment responses in a case of lung adenocarcinoma coexpressing mutant-type gene in the primary lung mass and a wild-type gene in the metastatic bone lesions. This case demonstrated that at least two strains of tumor cells were present in a single patient. This may be one of the mechanisms of gefitinib resistance.

背景与目标： 吉非替尼的反应与表皮生长因子受体基因的状态密切相关。在这里，我们报道了在原发性肺部肿块中共表达突变型基因并在转移性骨病变中表达野生型基因的情况下，肺腺癌的不同治疗反应。该病例证明在单个患者中存在至少两种肿瘤细胞株。这可能是吉非替尼耐药的机制之一。

BACKGROUND & AIMS: PURPOSE:Abnormally high levels of epidermal growth factor receptor (EGFR) protein are associated with advanced tumor stage/grade. The objective of this study was to evaluate the effects of the specific EGFR tyrosine kinase inhibitor gefitinib on activation of the Akt and mitogen-activated protein kinase (MAPK) pathways in human urothelial cell carcinoma (UCC) cell lines and to identify potential markers of gefitinib responsiveness in biopsy samples of UCC. EXPERIMENTAL DESIGN:Changes in markers of UCC growth and invasion after exposure to gefitinib were studied in six human UCC cell lines expressing various levels of EGFR. The findings were related to activation of Akt and MAPK. We studied the influence of gefitinib on intraepithelial expansion of the responsive 1207 cell line. EGFR, Akt, and MAPK activation was studied by Western blot analysis of a panel of 57 human UCC. RESULTS:Gefitinib had a growth-inhibitory and anti-invasive effect in two of six UCC cell lines (i.e., 647V and 1207). Gefitinib was also able to block the expansion of 1207 at the expense of normal urothelial cells. These effects did not depend on the level of expression of EGFR but they were associated with the down-regulation of MAPK and Akt activity; in 1207 cells, gefitinib activity was associated with p27 up-regulation and p21 and matrix metalloproteinase-9 down-regulation. Similarly, the Akt and MAPK pathways were found to be strongly phosphorylated in association with EGFR activation in a subset of human UCC specimens. CONCLUSIONS:Activation of EGFR, Akt, and MAPK defines a subset of UCC which might provide information for the identification of gefitinib responders.

背景与目标： 目的：表皮生长因子受体（EGFR）蛋白异常高水平与晚期肿瘤分期/分级有关。这项研究的目的是评估特定的EGFR酪氨酸激酶抑制剂吉非替尼对人尿路上皮细胞癌（UCC）细胞系中Akt和丝裂原激活的蛋白激酶（MAPK）通路活化的影响，并鉴定吉非替尼的潜在标志物UCC活检样本的反应性。
实验设计：在六种表达不同水平EGFR的人UCC细胞系中研究了吉非替尼暴露后UCC生长和侵袭标志物的变化。这些发现与Akt和MAPK的激活有关。我们研究了吉非替尼对响应性1207细胞系上皮内扩增的影响。 EGFR，Akt和MAPK活化是通过对57个人的UCC进行蛋白质印迹分析来研究的。
结果：吉非替尼在六个UCC细胞系中的两个（即647V和1207）具有生长抑制和抗侵袭作用。吉非替尼还能够以正常尿路上皮细胞为代价来阻止1207的扩增。这些作用并不取决于EGFR的表达水平，但与MAPK和Akt活性的下调有关。在1207个细胞中，吉非替尼的活性与p27的上调以及p21和基质金属蛋白酶9的下调有关。同样，在人类UCC标本的一个子集中，发现Akt和MAPK途径与EGFR激活相关地被强烈磷酸化。
结论：EGFR，Akt和MAPK的激活定义了UCC的一个子集，该子集可能为鉴定吉非替尼反应者提供信息。

BACKGROUND & AIMS: PURPOSE:To determine the maximum tolerated doses (MTD), toxicities, efficacy, and pharmacokinetics (PK) of gefitinib combined with irinotecan, 5-fluorouracil (5-FU) and leucovorin (IFL) in patients with previously untreated advanced colorectal cancer. EXPERIMENTAL DESIGN:Starting doses were gefitinib 250 mg/day orally without interruption, irinotecan 100 mg/m(2) as a 90 min intravenous (i.v.) infusion, 5-FU 400 mg/m(2) bolus i.v. and leucovorin 20 mg/m(2) i.v. on days 1 and 8 of a 21-day cycle. Dose escalations involved increasing gefitinib to 500 mg then increasing irinotecan to 125 mg/m(2) and 5-FU to 500 mg/m(2). RESULTS:Twenty-four patients received therapy. The starting doses proved to be the MTD, as attempts to increase the dose of either gefitinib or the chemotherapeutic agents resulted in dose-limiting toxicities. Gastrointestinal effects and bone marrow suppression were the principal toxicities; however, only 1/17 (6%) patients treated with the MTD had severe (grades 3-4) diarrhea and severe neutropenia occurred in only two (12%) patients. Partial responses occurred in 10/17 patients receiving the MTD and another five had stable disease. Median progression-free and overall survivals were 12.2 and 26.6 months, respectively. In ten patients treated with the MTD, the steady-state PK of gefitinib was not affected by IFL nor did gefitinib appear to influence the PK of either irinotecan or 5-FU. CONCLUSIONS:Gefitinib can be safely combined with an intermittent weekly schedule of IFL. Evidence of promising activity should encourage further clinical evaluation of epidermal growth factor receptor tyrosine kinase inhibitors, such as gefitinib, combined with multiagent chemotherapy for metastatic colorectal cancer.

背景与目标： 目的：确定吉非替尼联合伊立替康，5-氟尿嘧啶（5-FU）和亚叶酸（IFL）联合治疗吉非替尼的最大耐受剂量（MTD），毒性，疗效和药代动力学（PK）。
实验设计：起始剂量为吉非替尼250 mg /天，口服不间断，伊立替康100 mg / m（2），静脉内（i.v.）90分钟输注，5-FU 400 mg / m（2）静脉内推注。和亚叶酸钙20 mg / m（2）静脉注射在21天周期的第1天和第8天。剂量增加包括将吉非替尼增加至500 mg，然后将伊立替康增加至125 mg / m（2），将5-FU增加至500 mg / m（2）。
结果：24例患者接受了治疗。事实证明，起始剂量是MTD，因为尝试增加吉非替尼或化学治疗剂的剂量会导致剂量限制的毒性。胃肠道疾病和骨髓抑制是主要的毒性。但是，只有1/17（6％）的MTD患者出现了严重的腹泻（3-4级），而仅2例（12％）的患者出现了严重的中性粒细胞减少。在接受MTD的10/17例患者中出现部分反应，另外5例病情稳定。中位无进展生存期和总生存期分别为12.2和26.6个月。在10例接受MTD治疗的患者中，吉非替尼的稳态PK不受IFL的影响，吉非替尼似乎也没有影响伊立替康或5-FU的PK。
结论：吉非替尼可以与间歇性IFL每周计划安全地合并使用。有希望的活动的证据应鼓励对表皮生长因子受体酪氨酸激酶抑制剂（如吉非替尼）与多药化疗联合治疗转移性结直肠癌进行进一步的临床评价。

BACKGROUND & AIMS: PURPOSE:The purpose of this research was to assess the effects of single agent and combination treatment with trastuzumab and gefitinib on tumor growth and tumor microenvironment in two HER-2/neu overexpressing breast xenograft models, MDA-MB-435/LCC6(HER-2) (LCC6(HER-2); estrogen receptor negative) and MCF-7(HER-2) (estrogen receptor positive). EXPERIMENTAL DESIGN:LCC6(HER-2) and MCF-7(HER-2) cells, both in tissue culture and xenografts grown in SCID-Rag 2M mice, were treated with trastuzumab and gefitinib, alone or in combination. The rate of tumor growth was determined. In addition, tumor HER-2/neu and epidermal growth factor receptor expression, cell viability, cell cycle distribution, and proportion of viable hypoxic cells were determined by flow cytometric analyses of single tumor cell suspensions. RESULTS:Both tumor models were very sensitive to trastuzumab and moderately sensitive to gefitinib in vivo. The combination resulted in therapeutic effects, as judged by inhibition of tumor growth, which was greater (albeit not statistically significant) than that observed with trastuzumab administered as a single agent. Trastuzumab was effective in down-regulating HER-2/neu, and gefitinib mediated a reduction in epidermal growth factor receptor expression on tumor cells. In LCC6(HER-2) tumors, trastuzumab significantly reduced tumor cell viability, which was not improved by the addition of gefitinib. Gefitinib dramatically reduced the proportion of viable hypoxic cells in LCC6(HER-2) and MCF-7(HER-2) tumors. This effect was abrogated by the addition of trastuzumab. CONCLUSIONS:Although in vivo efficacy studies in two HER-2/neu overexpressing breast xenograft models showed that the combination of trastuzumab and gefitinib was effective, analyses of various cellular parameters failed to reveal beneficial effects and argue that this drug combination may not be favorable.

背景与目标： 目的：本研究旨在评估曲妥珠单抗和吉非替尼单药联合治疗对两种HER-2 / neu过表达乳腺癌异种移植模型MDA-MB-435 / LCC6（HER- 2）（LCC6（HER-2）；雌激素受体阴性）和MCF-7（HER-2）（雌激素受体阳性）。
实验设计：在组织培养物中和在SCID-Rag 2M小鼠中生长的异种移植物中，分别用曲妥珠单抗和吉非替尼处理LCC6（HER-2）和MCF-7（HER-2）细胞。确定肿瘤的生长速率。另外，通过对单个肿瘤细胞悬液进行流式细胞术分析来确定肿瘤HER-2 / neu和表皮生长因子受体的表达，细胞生存力，细胞周期分布以及存活的低氧细胞的比例。
结果：两种肿瘤模型在体内对曲妥珠单抗非常敏感，对吉非替尼敏感。通过抑制肿瘤生长来判断，该组合产生的治疗效果比曲妥珠单抗单药给药时观察到的疗效更大（尽管在统计学上不显着）。曲妥珠单抗可有效下调HER-2 / neu，吉非替尼介导肿瘤细胞表皮生长因子受体表达的降低。在LCC6（HER-2）肿瘤中，曲妥珠单抗显着降低了肿瘤细胞的生存能力，但吉非替尼的添加并不能改善其生存能力。吉非替尼显着降低了LCC6（HER-2）和MCF-7（HER-2）肿瘤中低氧存活细胞的比例。通过加入曲妥珠单抗可以消除这种作用。
结论：尽管在两种过表达HER-2 / neu的乳腺异种移植模型中进行了体内疗效研究，结果显示曲妥珠单抗和吉非替尼联合使用是有效的，但对各种细胞参数的分析未能显示出有益的作用，并认为这种药物联合可能不利。

BACKGROUND & AIMS: PURPOSE:An inflammatory-immunological marker, neutrophil-to-lymphocyte ratio (NLR), was evaluated as a surrogate indicator for prognosis of advanced lung adenocarcinoma patients. METHODS:The subjects of this study were 199 never smokers with advanced lung adenocarcinoma, who were enrolled in a prospective randomized phase III study (First-SIGNAL) comparing gefitinib with gemcitabine plus cisplatin as first-line therapy. The values of NLR were assessed at two time points: at baseline (pretreatment) and on day 1 of the second cycle (posttreatment). RESULTS:A higher posttreatment NLR was associated with a worse tumor response (median posttreatment NLR, 1.56 for partial response, 1.64 for stable disease, and 2.70 for progressive disease; P < 0.001). The risk of progression was higher when the posttreatment NLR was higher [hazard ratio (HR) = 1.23, 95 % confidence interval (CI) 1.15-1.31; P < 0.001]. A high posttreatment NLR was associated with an increased risk of death (HR = 1.13, 95 % CI 1.06-1.21; P < 0.001). These associations did not differ according to treatment arms. When total patients were divided into four groups according to the cutoff points of pre- and posttreatment NLRs, those with a high pretreatment NLR that declined substantially after treatment showed improved survival compared with those with a high pretreatment NLR that remained high even after treatment (median overall survival, 22.0 and 15.8 months, respectively; P < 0.001). CONCLUSIONS:A high posttreatment NLR is associated with poor prognosis. An early reduction in the NLR after effective treatment may indicate survival improvement in the patients with poor prognosis.

背景与目标： 目的：炎性免疫标记物，嗜中性粒细胞与淋巴细胞之比（NLR）被评估为晚期肺腺癌患者预后的替代指标。
方法：本研究的受试者为199位从不吸烟的晚期肺腺癌患者，他们参加了一项前瞻性随机III期研究（First-SIGNAL），比较吉非替尼与吉西他滨加顺铂作为一线治疗。在两个时间点评估NLR值：在基线（治疗前）和第二个周期的第1天（治疗后）。
结果：较高的治疗后NLR与较差的肿瘤反应相关（治疗后中位NLR为1.56，部分反应为1.64，稳定疾病为2.70，进行性疾病为2.70; P <0.001）。当治疗后的NLR较高时，进展风险较高[风险比（HR）= 1.23，95％置信区间（CI）1.15-1.31; P <0.001]。较高的治疗后NLR会增加死亡风险（HR = 1.13，95％CI 1.06-1.21; P <0.001）。这些关联根据治疗方式而没有不同。当根据治疗前和治疗后NLR的临界点将患者分为四组时，与治疗前NLR较高但仍在治疗后仍高的患者相比，治疗前NLR较高而在治疗后明显下降的患者的生存期得到了改善。总生存期分别为22.0和15.8个月; P <0.001）。
结论：较高的治疗后NLR与不良预后有关。有效治疗后NLR的早期降低可能表明预后不良患者的生存率得到了改善。

BACKGROUND & AIMS: :Gefitinib resistance in triple negative breast cancer (TNBC) is a growing important concern. Glutathione peroxidase 4 (GPX4) is a main regulator of ferroptosis, which is pivotal for TNBC cell growth. We investigated GPX4-mediated ferroptosis in gefitinib sensitivity in TNBC. Gefitinib resistant TNBC cells MDA-MB-231/Gef and HS578T/Gef were constructed and treated with lentivirus sh-GPX4 and ferroptosis inhibitor ferrostatin-1. GPX4 expression, cell viability and apoptosis were detected. Malondialdehyde (MDA), glutathione (GSH), reactive oxygen species (ROS) levels were evaluated. The levels of ferroptosis-related proteins were detected. Subcutaneous tumor model was established in nude mice, and gefitinib was intraperitoneally injected to evaluate tumor growth, apoptosis, and Ki-67 expression. GPX4 was increased in gefitinib-resistant cells. After silencing GPX4, the inhibition rate of cell viability was increased, the limitation of colony formation ability was reduced, apoptosis rate was increased, and the sensitivity of cells to gefitinib was improved. After silencing GPX4, MDA and ROS production were increased, while GSH was decreased. Silencing GPX4 promoted ferroptosis. Inhibition of GPX4 promoted gefitinib sensitivity by promoting cell ferroptosis. In vivo experiments also revealed that inhibition of GPX4 enhanced the anticancer effect of gefitinib through promoting ferroptosis. Overall, inhibition of GPX4 stimulated ferroptosis and enhanced TNBC cell sensitivity to gefitinib.

背景与目标： ：吉非替尼在三阴性乳腺癌（TNBC）中的耐药性日益受到关注。谷胱甘肽过氧化物酶4（GPX4）是铁质增生的主要调节剂，对TNBC细胞的生长至关重要。我们调查了吉非替尼在TNBC中GPX4介导的肥大症。构建了耐吉非替尼的TNBC细胞MDA-MB-231 / Gef和HS578T / Gef，并用慢病毒sh-GPX4和促肥大抑制剂ferrostatin-1处理。检测GPX4的表达，细胞活力和凋亡。评估了丙二醛（MDA），谷胱甘肽（GSH），活性氧（ROS）的水平。检测到与受精症相关的蛋白质水平。在裸鼠中建立皮下肿瘤模型，并腹膜内注射吉非替尼以评估肿瘤的生长，凋亡和Ki-67表达。吉非替尼耐药细胞中GPX4升高。 GPX4沉默后，细胞活力的抑制率增加，集落形成能力的局限性降低，细胞凋亡率增加，细胞对吉非替尼的敏感性提高。将GPX4沉默后，MDA和ROS产量增加，而GSH降低。沉默GPX4会促进ferroptosis。抑制GPX4通过促进细胞肥大症而促进了吉非替尼敏感性。体内实验还显示，抑制GPX4可通过促进ferroptosis来增强吉非替尼的抗癌作用。总体而言，抑制GPX4可刺激肥大症，并增强TNBC细胞对吉非替尼的敏感性。

BACKGROUND & AIMS: PURPOSE:The epidermal growth factor receptor (EGFR) inhibitor gefitinib (Iressa) has shown antitumor activity in clinical trials against cancers, such as non-small cell lung cancer and head and neck squamous cell carcinoma (HNSCC). Research on non-small cell lung cancer has elucidated factors that may predict response to gefitinib. Less is known about molecular markers that may predict response to gefitinib in HNSCC patients. EXPERIMENTAL DESIGN:We analyzed possible associations of responsiveness to gefitinib with molecular markers of the EGFR/ErbB receptor family signaling pathway using 10 established HNSCC lines in vitro. IC50 of gefitinib sensitivity was determined using clonogenic survival assays. ErbB signaling was assessed by Western and real-time reverse transcription-PCR analyses of EGFR, ErbB2, ErbB3, and ErbB4 expression levels as well as by phosphorylation analysis of pEGFR, pErbB2, pErbB3, pAkt, and pErk. EGFR sequences encoding kinase domain and EGFR gene copy numbers were determined by cDNA sequencing and real-time PCR, respectively. Finally, responsiveness to gefitinib was compared with responsiveness to the anti-EGFR antibody cetuximab (Erbitux). RESULTS:Expression levels of pErbB2 (P = 0.02) and total ErbB3 protein (P = 0.02) associated with resistance to gefitinib. Combining gefitinib with pertuzumab (Omnitarg), an antibody targeting ErbB2 heterodimerization, provided additional growth-inhibitory effect over gefitinib alone on relatively gefitinib-resistant HNSCC cell lines. The same markers did not predict resistance to cetuximab. In contrast, a similar trend suggesting association between EGFR gene copy number and drug sensitivity was observed for both gefitinib (P = 0.0498) and cetuximab (P = 0.053). No activating EGFR mutations were identified. CONCLUSIONS:EGFR amplification may predict sensitivity to gefitinib in HNSCC. However, other EGFR/ErbB receptor family members than EGFR may contribute to resistance to gefitinib. ErbB2 and ErbB3 may have potential as predictive markers and as therapeutic targets for combination therapy in treatment of HNSCC with gefitinib.

背景与目标： 用途：表皮生长因子受体（EGFR）抑制剂吉非替尼（Iressa）在针对癌症的临床试验中显示出抗肿瘤活性，例如非小细胞肺癌和头颈鳞状细胞癌（HNSCC）。对非小细胞肺癌的研究阐明了可能预测对吉非替尼反应的因素。关于可能预测HNSCC患者对吉非替尼反应的分子标志物知之甚少。
实验设计：我们使用10条已建立的HNSCC细胞系，分析了对吉非替尼反应性与EGFR / ErbB受体家族信号传导途径的分子标记物之间的可能联系。吉非替尼敏感性的IC50使用克隆发生生存测定法确定。通过对EGFR，ErbB2，ErbB3和ErbB4表达水平的Western和实时逆转录PCR分析以及对pEGFR，pErbB2，pErbB3，pAkt和pErk的磷酸化分析，评估了ErbB信号传导。分别通过cDNA测序和实时PCR确定编码激酶结构域的EGFR序列和EGFR基因拷贝数。最后，将对吉非替尼的反应性与对抗EGFR抗体西妥昔单抗（Erbitux）的反应性进行了比较。
结果：与吉非替尼耐药相关的pErbB2（P = 0.02）和总ErbB3蛋白（P = 0.02）的表达水平。吉非替尼与靶向ErbB2异二聚化的抗体pertuzumab（Omnitarg）的组合，在相对耐吉非替尼的HNSCC细胞系上提供了比单独吉非替尼更高的生长抑制作用。相同的标记不能预测对西妥昔单抗的耐药性。相反，吉非替尼（P = 0.0498）和西妥昔单抗（P = 0.053）观察到相似的趋势，表明EGFR基因拷贝数与药物敏感性之间存在关联。未鉴定出激活的EGFR突变。
结论：EGFR扩增可能预示了HNSCC对吉非替尼的敏感性。但是，除EGFR外，其他EGFR / ErbB受体家族成员可能会导致对吉非替尼的耐药性。 ErbB2和ErbB3可能具有作为吉非替尼治疗HNSCC的联合治疗的预测标志物和治疗靶标的潜力。

BACKGROUND & AIMS: BACKGROUND:Several studies implicated that lung cancer progression was governed by the interaction between estrogen receptor (ER) and epidermal growth factor receptor (EGFR) signaling pathways. Combined targeting of EGFR and ER may have the synergistic effect in lung cancer treatment. The aim of this study was to explore the potential utility of inhibiting these two pathways with combination of anastrozole and gefitinib in non-small cell lung cancer (NSCLC) cell lines. MATERIALS AND METHODS:The expression levels of ER (ER-α and ER-β) in lung cancer cell lines (A549, H460, SPC-A-1, H1299) and normal bronchus epithelial cell BEAS-2B were detected using real-time PCR and Western blot. Immunocytochemistry was used to locate ER-α and ER-β in cell line with highest ER expression levels. The cells were treated with anastrozole or gefitinib alone or in combination. The cell proliferation inhibition was detected by the CCK8 assay, cell cycle and apoptosis effects were detected by flow cytometry; the expression levels of phosphorylated-EGFR (p-EGFR), ERK, phosphorylated-ERK (p-ERK), AKT and phosphorylated-AKT (p-AKT) were detected by Western blot. RESULTS:Among these cell lines the expression levels of ER in A549 cells were highest. In A549 cell line, ER-α was mainly localized in the cytoplasm, whereas ER-β was mainly localized in the cytoplasm and to a lesser degree in the nucleus. The combination of two drugs increased the proliferation inhibition rates for 24h, 48 h, 72 h to 37.66 ± 1.02%, 63.41 ± 2.02%, 70.50 ± 0.86%, respectively, which was closely associated with elevation of the G0/G1 phase fraction (P<0.05). Apoptosis rates of A549 cells treated with anastrozole, gefitinib alone or in combination were 10.72 ± 1.12%, 17.40±1.28%, 23.02 ± 2.32%, respectively (P<0.05). The synergistic effects of the combination therapy were accompanied by reduction of p-EGFR, p-ERK and p-AKT expression compared with individual treatment. CONCLUSIONS:The results of this study suggest that the combination of anastrozole and gefitinib compared with either drug alone can maximally inhibit cell proliferation, induce apoptosis, and affect downstream signaling pathways. Our study supports functional interaction between the ER and the EGFR pathways in lung cancer and provides a clinically exploitable strategy for non-small cell lung cancer patients.

背景与目标： 背景：多项研究表明，肺癌的进展受雌激素受体（ER）和表皮生长因子受体（EGFR）信号通路之间相互作用的支配。 EGFR和ER的联合靶向可能在肺癌治疗中具有协同作用。这项研究的目的是探讨在非小细胞肺癌（NSCLC）细胞系中使用阿那曲唑和吉非替尼联合抑制这两种途径的潜在效用。
材料与方法：实时检测肺癌细胞系（A549，H460，SPC-A-1，H1299）和正常支气管上皮细胞BEAS-2B中ER（ER-α和ER-β）的表达水平PCR和蛋白质印迹。免疫细胞化学法用于在具有最高ER表达水平的细胞系中定位ER-α和ER-β。单独或联合用阿那曲唑或吉非替尼处理细胞。 CCK8法检测细胞增殖抑制作用，流式细胞术检测细胞周期和凋亡效应。 Western blot检测磷酸化EGFR（p-EGFR），ERK，磷酸化ERK（p-ERK），AKT和磷酸化AKT（p-AKT）的表达水平。
结果：在这些细胞系中，ER在A549细胞中的表达水平最高。在A549细胞系中，ER-α主要位于细胞质中，而ER-β主要位于细胞质中，程度较小。两种药物的组合分别将24h，48h，72h的增殖抑制率分别提高到37.66±1.02％，63.41±2.02％，70.50±0.86％，这与G0 / G1相分数的升高密切相关（ P ＜0.05）。单独或联合使用阿那曲唑，吉非替尼治疗的A549细胞凋亡率分别为10.72±1.12％，17.40±1.28％，23.02±2.32％（P <0.05）。与单独治疗相比，联合治疗的协同作用伴随着p-EGFR，p-ERK和p-AKT表达的降低。
结论：这项研究的结果表明，与单独使用这两种药物相比，阿那曲唑和吉非替尼的组合可以最大程度地抑制细胞增殖，诱导细胞凋亡并影响下游信号通路。我们的研究支持肺癌中ER和EGFR通路之间的功能相互作用，并为非小细胞肺癌患者提供了可临床利用的策略。