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柴莹

乌镇互联网医院

主任医师/教授 浙江大学医学院附属第二医院-胸外科

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胸骨柄切除,自体肋骨移植重建

Guofei Zhang, MD, Chengxiao Liang, MM, Gang Shen, MD, Wenshan Li, MD, Lijian Huang, MD, Saibo Pan, MD, and Ying Chai, MD Objective: Sternal reconstruction after resection is essential for restoring the rigidity of the chest cavity. How- ever, no consensus has been reached regarding the most physiologic or efficacious material for this procedure. We present our clinical experience with autogenous rib grafts for reconstruction of the manubrium after resec- tion and discuss the refinements in this procedure. Methods: Twelve consecutive patients with a confirmed diagnosis of a primary neoplasm in the manubrium be- tween March 2003 and August 2013 were analyzed retrospectively. All patients underwent manubrium resection and immediate reconstruction with autogenous rib grafts. Results: No cases of perioperative mortality were noted. The median operation time was 129 minutes. One pa- tient experienced mild paradoxical movement; the other patients recovered well without any complications. The median follow-up period after surgery was 69 months. Two patients died. One patient with chondrosarcoma died as a result of cardiac disease 26 months after surgery and another patient with non-Hodgkin lymphoma died as a result of local recurrence 6 months after surgery. Computed tomographic scans for the other 10 patients have shown neither dislocation nor abnormality of the transplanted ribs; moreover, no absorption of the grafts or recurrence was noted. None of the patients required prescription analgesics for the pain at the donor site at the 3-month follow-up visit. Conclusions: This case series demonstrates the successful use of autogenous rib grafts in the reconstruction of the manubrium after resection. We consider that the reconstruction technique is a safe and effective alternative to a complex problem. (J Thorac Cardiovasc Surg 2014;148:2667-72) Primary and secondary sternal tumors are uncommon. In addition, benign lesions in the sternum are very rare; most sternal tumors are malignant, and usually include sarcomas that originate from either the bone or the soft tissues of the sternum.1,2 Although the role of surgical treatment in such cases remains controversial, it should be considered the best option in most patients with primary and secondary malignant tumors involving the sternum, and it can achieve a definitive or palliative cure.3 However, resection of the entire sternum or part of the sternum without any reconstruction may result in paradoxical movement of the thorax and impaired ventilation. Moreover, reconstruction of bony and soft tissue defects of the sternum after resection can also restore chest wall rigidity, which helps to protect the underlying mediastinal structures. The material used for reconstruction of the sternum has evolved considerably over the last several decades.4,5 From the Department of Thoracic Surgery, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China. Disclosures: Authors have nothing to disclose with regard to commercial support. Guofei Zhang and Chengxiao Liang are co-first authors. Received for publication Jan 10, 2014; revisions received April 25, 2014; accepted for publication July 9, 2014; available ahead of print Sept 5, 2014. Address for reprints: Ying Chai, MD, Department of Thoracic Surgery, the Second Affiliated Hospital, College of Medicine, Zhejiang University, No. 88 Jiefang Rd, Hangzhou, 310009 China (E-mail: zetszju@yahoo.com). 0022-5223/$36.00 Copyright ! 2014 by The American Association for Thoracic Surgery http://dx.doi.org/10.1016/j.jtcvs.2014.07.093 Generally, the requirements of an ideal material for use in the reconstruction of the sternum include availability, durability, nonreactivity, and resistance to infection. Although different materials have been described for sternal reconstruction, including autograft, allograft, nondegradable and biodegradable synthetic materials, and tissue engineering products, there is no statistical evidence, either from retrospective comparative series or from prospective randomized trials, to show a significant difference in outcome.4,6,7 The manubrium is a flat bone; it is slightly convex ante- riorly and concave posteriorly. The upper border of this area includes the jugular notch and the upper lateral bor- ders include the clavicular notches, which join with the clavicles and receive the attachments of the sternocleido- mastoid muscles.8 Because of the anatomical characteris- tics of the manubrium, its resection and reconstruction present special difficulties. In our initial report on the use of autogenous rib grafts for the reconstruction of a middle segment defect of the sternum, we proposed that autogenous rib grafts offered important advantages over other materials.9 We have subsequently used this technique in the resection and reconstruction of the manubrium. In the present study, we aimed to retrospectively review our experience of autogenous rib grafts for reconstruction of the manubrium after resections in 12 patients during a 10-year period. CT 1?4 computed tomography MRI 1?4 magnetic resonance imaging PTFE 1?4 polytetrafluoroethylene MATERIALS AND METHODS Study Population Before the study, the Research Review Board at our institution exam- ined and approved our research protocol, which was in accordance with the Declaration of Helsinki. All patients provided written informed consent before surgery. Between March 2003 and August 2013, 12 consecutive patients with a confirmed diagnosis of a primary neoplasm in the manubrium underwent resection and reconstruction using autogenous rib grafts. All patients were evaluated preoperatively using chest radiography, computed tomogra- phy (CT), magnetic resonance imaging (MRI), or a combination of these (Figure 1). The precise location of the tumor, the extent of sternal involve- ment and any infiltration into the adjacent structures were assessed to deter- mine whether it was possible to perform an en bloc radical resection. Of the 12 patients included in the study, 5 were men and 7 were women; the mean (` standard deviation) age was 47.7 ` 12.4 years (range, 23-68 years). The chief complaints before surgery were the presence of a palpable sternal mass in 7 patients, pain in 3, and a mass with pain in 2. Four patients underwent preoperative fine-needle aspiration of the lesion and the result clearly indicated the presence of a primary malignant sternal tumor. Three patients underwent positron emission tomography-CT scanning to confirm that the disease was localized to the sternum with no distant metastases. The patients’ clinical characteristics are presented in Table 1. Operative Technique The patient is intubated using a double-lumen tube under general anes- thesia and is then placed in the supine position. The surgical procedure comprises 3 steps as described in the following. Manubriumresection. Thefirststepinvolvedskinexcision.When the skin and overlying soft tissues are not involved, a vertical elliptical inci- sion is made, encompassing the aspiration site. The skin excision must be large in cases of ulceration, or if the tumor involves subcutaneous tissues. The extent of sternal resection depends on the nature of the tumor and the extent of sternum involvement. First, we determine whether the sternocla- vicular joint or the sternal extremity of the clavicle is involved. If these are not involved, we resect the manubrium along the surface of the sternocla- vicular joint. However, if the sternoclavicular joint or the sternal extremity of the clavicle is involved, the sternoclavicular joint is divided with a Gigli saw at the normal part of the clavicle, after dissection of the surrounding ligament tissue. It is important to avoid injuring the subclavian vessels and nerve during dissection. The tumors are generally resected 3 cm beyond the margin of the lesions, and may include any costal cartilages involved. In all cases, the resection margins are simultaneously examined by the frozen section procedure. The sternum is usually divided with a Gigli saw (Figure 2). We avoid entering the pleural space; however, if the tumor extends into the chest cavity, the extent of the tumor in the upper or lower mediastinum is then assessed. In these cases, the lung and mediastinal structures involved need to be excised en bloc. After sternal resection, a chest tube is placed in the pleural cavity if the pleural space has been entered. Rib harvesting technique. A left or right anterior lateral incision is made parallel to the underlying rib that is to be harvested. The incision depth is increased through the subcutaneous tissue, and passes through muscular tissue and fascia. The muscle is separated in the direction of its fibers. Rib grafts are harvested from the subperiosteum, leaving the perios- teum and pleural portions intact (Figure 3). The ribs are removed using a Gigli saw and infiltrated into a saline solution. When possible, the remain- ing rib periosteum is closed to a tubular form by a separate layer using a 2- 0 absorbable suture. The skin is then closed in layers. Sternal reconstruction. The reconstruction must afford sufficient stability and adequate airtight closure. The ribs are carved into 2 or 3 clips using a Gigli saw as needed. The ends of the 2 rib clips, clavicle, and the edge of the sternum are perforated using an electric drill. The rib clips are placed on the edge of the sternum and clavicle using rib nails, and then fixed using stainless steel wire. The rib grafts are placed to form a T, V, or D shape between the edges of the residual sternum, costal cartilage, and clavicle (Figure 4). For patients with an intact sternoclavicular joint and a small defect after resection, the V position is chosen; however, for patients in whom the sternoclavicular joint and/or partial clavicle are involved and resected, the T or D position is used. The main aim is to restore the stability of the clavicle, and hence, the T position is used for a small defect and the D position is used for a large defect. Thereafter, a drainage tube is placed below the transplanted ribs to drain the effusion af- ter the grafting procedure. Parts of the pectoralis major muscles are then mobilized to cover the grafts. The skin is closed then in layers. Follow-up and Data Collection The patients were followed up at 4 weeks, 3 months, 6 months, and 1 year postoperatively. Follow-up data were obtained from subsequent clinic visits and examinations and telephone interviews with patients and fam- ilies. All patients were evaluated for pain at the donor sites. Routine chest CT scans were obtained at every follow-up visit to exclude dislocation or abnormality of the transplanted ribs, absorption of the grafts, and recurrence. The continuous variables are presented as the mean ` standard devia- tion. All statistical analyses were performed using SPSS for Windows, version 16 (SPSS, Inc, Chicago, Ill). RESULTS All patients underwent a radical en bloc resection of the tumor and involved structures and reconstruction with autogenous rib grafts. Five patients underwent total resec- tion of the manubrium, 2 underwent resection of the manu- brium and partial resection of the sternal body, 3 underwent simultaneous partial costal cartilage resection, and 2 under- went simultaneous partial lung resection. The median oper- ation time was 129 minutes (range, 90-170 minutes) and the median blood loss was 140 mL. Only 1 patient required a blood transfusion. No cases of perioperative mortality were noted. All the patients were extubated within 24 hours of the operation. One patient experienced mild paradoxical movement after this reconstruction; this was because only rib nails were used without fixing with stainless steel wire, which resulted in slippage of the rib grafts. The other patients recovered well without any respiratory complica- tions, wound infection or dehiscence, or instability of the sternum. For all patients, the mean postoperative hospital stay was 7.4 days (range, 5-11 days). On microscopic examination, all margins were tumor free in all patients. The most common malignant histologic type was chondrosarcomas (5 cases); the other primary tu- mors included 1 desmoid tumor, 1 non-Hodgkin lymphoma, 1 plasmacytoma, and 1 malignant fibrous histiocytoma. Three patients had benign tumors, which included FIGURE 1. manubrium. Computed tomographic scan showing massive invasion in the adjuvant chemotherapy; this patient died 6 months after sur- gery. Annual follow-up for the other 10 patients is ongoing. CT scans of the reconstructed chest have shown neither dislocation nor abnormality of the transplanted ribs, and there has been no absorption of the grafts or recurrence. None of the patients required prescription analgesics for the pain at the manubrium graft site at their 3-month follow-up visit. DISCUSSION Surgical treatment should be considered the best option in most patients with primary and secondary malignant tu- mors involving the sternum, and it can achieve a definitive or palliative cure.3,10 However, sternal reconstruction after resection is essential to prevent flap movement and consequent paradoxical respiration, and to restore chest wall rigidity to protect the underlying mediastinal structures.4,11,12 The material used for sternal reconstructions has evolved considerably over the last several decades.4,5 However, there is no statistical evidence, either from retrospective comparative series or from prospective randomized trials, to show a significant difference in outcome. In this case series, we retrospectively reviewed our experience of using autogenous rib grafts for the reconstruction of the manubrium after resection in 12 patients. We believe that this technique is a safe and efficient approach with good results. The primary aim of resection for a sternal malignant tu- mor is to achieve complete (R0) resection. Most benign tu- mors can be adequately detected on plain films; however, CT or MRI is necessary to precisely define the anatomical location of lesions and plan the extent of resection. For ma- lignant sternal tumors, previous studies recommended en bloc resection, covering an area extending at least 3 cm beyond the margin of the tumor, and including structures such as the lungs, thymus, and pericardial tissues that may be invaded by the tumor.6 chondroma, chronic suppurative osteomyelitis, and fibrous dysplasia. Postoperative adjuvant chemotherapy and radiotherapy were administered after sternectomy in 2 patients (1with non-Hodgkin lymphoma and 1 with plasmacytoma). The patients were observed until September 2013. The median follow-up period after surgery was 69 months (mean, 64.2 ` 38.9 months), and 2 patients died during this period. One patient with chondrosarcoma died of car- diac disease 26 months after surgery. In the other patient who had been diagnosed with non-Hodgkin lymphoma, local recurrence was observed, despite postoperative TABLE 1. Clinical characteristics of the 12 patients who underwent manubrium resection and reconstruction Case Symptoms Tumor size (cm) Histologic type Age (y)/sex P 837 M 635 P 434 M,P 334 M 435 M,P 434 M,P 535.5 M 535 M,P 837 41/M M 3.5 3 4 63/M Postoperative treatment — — — — — — — CT ? RT — — — CT ? RT Survival (mo) 68/D 116/A 111/A 104/A 102/A 71/A 70/A 15/D 49/A 4/A 32/A 28/A 42/F 52/F 23/M 39/F 55/M 68/F 53/F 38/M 55/F Chondrosarcoma Fibrous dysplasia Chondroma Malignant fibrous histiocytoma Chronic suppurative osteomyelitis Chondrosarcoma Chondrosarcoma 1 2 3 4 5 6 7 8 9 10 11 12 43/F F, Female; M, male; M, mass; P, pain; CT, chemotherapy; RT, radiation therapy; D, dead; A, alive. M 434 M 434 Non-Hodgkin lymphoma Chondrosarcoma Chondrosarcoma Desmoid tumor Plasmacytoma FIGURE 2. Chondrosarcoma of the manubrium after resection. In general, prosthetic materials for reconstruction should achieve the objective function without inducing a foreign body response, facilitate smooth wound healing, and resist infection.13 However, no consensus has been reached regarding the most physiologic or efficacious material to be used in such procedures. Therefore, the choice of pros- thesis, including synthetic materials and autogenous tissues, is based mainly on the surgeon’s preference. At present, the synthetic materials used in sternal reconstruction include polypropylene/high-density polyethylene mesh, polytetra- fluoroethylene (PTFE), polypropylene/PTFE mesh, vicryl nets, polytetrafluoroethylene patch, methylmethacrylate, stainless steel mesh, resin plate, or metal plate.4,6,7,14 Although these synthetic materials are commercially available, with guaranteed source and quality, diversity, durability, and internal inertness, these reconstruction materials are not completely devoid of complications and are generally removed if wound infection, symptoms of mediastinitis, sepsis, pyothorax, or intolerance to medical treatment develop in the acute or chronic phase. The use of autogenous tissues for sternal reconstruction has been proposed. Because of its rapid incorporation, decreased immune response, more robust vascularization, and accelerated osteointegration, the iliac crest is a popular site for obtaining autologous bone grafts.15,16 However, a few studies have reported on cases of donor site morbidity with the use of the iliac crest graft. Silber and colleagues17 reported the results of a retrospective questionnaire involving 134 patients who received an iliac crest autograft and underwent an average follow-up of 4 years. The acute postoperative complications included difficulty with ambu- lation (51%), extended antibiotic usage (7.5%), and persis- tent drainage (3.7%). The chronic symptoms included pain at the donor site in 26.1% of patients, rated at a mean visual analog scale score of 3.8 out of 10. Therefore, autogenous FIGURE3. Ribgraftsharvestedfromthesubperiosteum,leavingtheperi- osteum and pleural portions intact. rib grafting, which has been proved suitable for reconstruc- tion in maxillofacial surgery, seems to be a good option.18-20 In our initial report on autogenous rib grafts for reconstruction of the middle segment defect of the sternum, we maintained that our rib grafts offered important advantages over other materials, such as rigidity to eliminate the possibility of paradoxical chest movement, inertness to reduce the risk of infection associated with prosthetic materials, and radiolucency to facilitate radiographic inspection. Moreover, they offered good incorporation into the tissues and could easily be fixed under tension to the edges of the sternal defect. In addition, rib grafts are easy to obtain and have a lower financial cost for patients compared with prosthetic materials. Certain details of our technique should be highlighted. We always choose the seventh to ninth rib for reconstruc- tion, as these ribs can be obtained easily through relatively short incisions. After the ribs are identified, they are care- fully dissected to leave their periosteum and pleural por- tions intact. Because the muscle fibers and the periosteum are left intact, patients experience little postoperative pain. Moreover, because of their different characteristics, we excise the rib and retain the costal cartilage. To achieve the best possible connection at the interface between the rib grafts and the sternum, we use a Gigli saw to transect the ribs, clavicle, and manubrium. Drainage tubes can be placed around the transplanted ribs to drain the effusion. The prerequisites for ensuring the successful use of autogenous rib grafts for reconstruction of the sternum include (1) good condition of the recipient site (ie, a good blood supply to the skin and subcutaneous tissue and fresh margins without abnormal bony tissue or infected tissue); FIGURE4. Reconstructionwithautogenousribgrafts.TheribgraftswereplacedintheformofaT(A),V(B),orD(C)betweentheedgesoftheresidual sternum, costal cartilage, and clavicle, where they were fixed using stainless steel wire. (2) sufficient stability of the contact surface of the bones; and (3) the shortest possible exposure of the grafts in vitro (because the surviving osteoblasts on the surface of the bone grafts can produce new bony tissue). When rib graft harvests are considered, most surgeons typically have concerns about chest complications.21,22 Skouteris and colleagues23 reported a retrospective study evaluating 28 patients in whom a total of 31 rib resections had been performed. They noted a pleural tear in 1 patient during the harvesting of a costochondral rib graft, which was repaired without any resultant pneumothorax. No inci- dence of pneumothorax, postoperative pulmonary compli- cations, or wound infection or breakdown was reported. Long-term follow-up showed that none of the patients expe- rienced any chronic donor site discomfort, and all patients accepted the appearance of their scars. In our retrospective case series, the technique has been found to be safe and effi- cient. There were no cases of perioperative mortality. One patient experienced mild paradoxical movement with this reconstruction, as only rib nails were used without fixation with stainless steel wire; the other patients recovered well without any complications. Thus far, none of the patients have reported pain at the donor site from the time of hospital discharge to follow-up. Apart from 1 case with non- Hodgkin lymphoma, no radiological artifact or scattering was observed during the oncological follow-up with both CT and MRI. Limitations There are several limitations to our study. First, compared with procedures involving other synthetic materials, our procedures require an additional incision for rib harvesting; however, no complications at the rib resection site were observed during the follow-up. Second, this study was retrospective and lacked a control group; therefore, the re- sults of our approach for reconstruction could not be compared with those of other prosthetic materials. A pro- spective randomized study is needed to compare our approach more precisely with other approaches. Third, in our case series, only 4 patients underwent preoperative fine-needle aspiration of the lesion. We recommend that all patients with a sternal tumor should undergo a preoper- ative biopsy or fine-needle aspiration of the lesion to clarify the pathology and thus avoid unnecessary surgery. Although some details of the reconstruction were described, the size of the cohort was relatively small. Therefore, further studies with larger patient populations will be needed to verify the favorable outcomes of manubrium reconstruction using this technique. CONCLUSIONS In our series of patients, autogenous rib grafts were suc- cessfully used for reconstruction of the manubrium after resection. We consider that the reconstruction technique us- ing autogenous rib grafts is safe and effective, and offers a simple and satisfactory solution to a complex problem. References 1. Chapelier A. Resection and reconstruction for primary sternal tumors. Thorac Surg Clin. 2010;20:529-34. 2. IncarboneM,NavaM,LequaglieC,RavasiG,PastorinoU.Sternalresectionfor primary or secondary tumors. J Thorac Cardiovasc Surg. 1997;114:93-9.

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体检查出肺部小结节怎么办?(采访节录)

体检时如果查出肺结节,不少人的反应是紧张。他们最担心的是,肺结节是不是肺癌,或发展下去,会不会变成肺癌? 绝大多数肺结节是良性的。自从肺部CT扫描成为常规体检项目后,很多人在体检时查出肺结节或者磨玻璃结节。 “很多患者查出肺结节后,整体提心吊胆,生怕结节是恶性的。实际上,结节以良性居多。”浙二医院范军强副主任医师说,临床上将肺部结节定义为单一的、边界清楚的、影像不透明的、直径小于3厘米、周围完全由含气肺组织所包绕的病变。一般多见于炎症、结核和肿瘤。 也就是说,肺部结节可能是肺炎、肺结核、良性肿瘤,也可能是以前肺结核留下的疤,而真正是肺癌的比例很小。还有些结节比较小,不需要做任何治疗,定期随访就可以了。 如果结节发生改变,一定要注意 虽然大部分肺结节是良性的,但所有的肺癌几乎都是由肺结节演变而来。 因此,鉴别其中的早期肺癌是关键。 肺结节的良、恶性病变,多数在病灶形态、密度、边缘、边界等特征上存在差异。 有些结节不需要随访,临床医生就会判断为恶性肿瘤,而有些结节就需要随访来了解变化趋势。 要判断肺结节的良恶性,不能光看单次的检查结果,而是要结合之前的随访检查结果一起看。如果发现肺结节的大小、密度、形态等没有发生改变,一般是良性结节居多。如果发现大小有变化,比如有增大的趋势,或者形态发生了某些改变,那么就要引起注意了。 范军强建议,查出肺部结节,要根据不同的情况,听从专业医生的建议,3个月、6个月、一年进行定期随访。如果结节发生了变化,则需要结合专业医生的意见进行处理。 45岁以上无论男女可以考虑定期做低剂量螺旋CT检查 在所有的恶性肿瘤中,肺癌排在第一位。据统计,我国每年新增的肺癌患者人数约100万。 范军强副主任说,临床中发现,肺癌患者逐年递增,可能与现在肺癌检出率高有关,当然也不排除发病率的增加,而且有两个新趋势—— 1.腺癌比例逐渐升高。 肺癌主要分为小细胞肺癌和非小细胞肺癌,而非小细胞肺癌中,主要包括鳞癌和腺癌。通俗来说,以往认为鳞癌的发生和吸烟有密切关系,而腺癌大部分与基因突变、环境影响等外界因素有密切联系,但腺癌与吸烟也有密切关系。 十多年前,腺癌在肺癌中的比例在30%左右,但近年来,腺癌的比例逐年上升,目前比例在40%-50%,已经赶超鳞癌的比例了。从日常门诊来看,肺癌患者中,明确有吸烟史的肺癌患者有所下降,没有明确症状的肺癌患者呈上升趋势。 2.女性患者越来越多。 以往认为,肺癌最大的诱因与吸烟有关,患肺癌的人群也是以男性为主。但近年来,门诊中发现女性、不吸烟的肺癌患者越来越多,在数量上并不比男性少。 女性患肺癌的比例为什么会逐年增加?业内专家说得最多的,是和二手烟、厨房油烟、基因突变、环境影响等多种因素有关,但最终原因目前仍不明确。 国外的指南推荐,一般建议对55岁以上的吸烟高危人群做低剂量高分辨CT筛查。但日常体检方面,除了建议45岁以上有吸烟史、家族史的高危人群每年做一次低剂量螺旋CT检查外,也建议45岁以上的女性最好也能定期做一次低剂量螺旋CT检查。 浙医二院胸外科团队竭诚提供诊疗服务 柴?教授作为我省重要的治疗肺癌的专业团队的首席专家说:浙医二院胸外科年手术量近3000例次,其中大部分以肺癌为主,以规范、精准、微创(尤其对浸润性肺癌的系统性淋巴结清扫)为特点,追求肺癌病人的长期生存,尽量减轻病人的创伤和经济负担为目标。 目前科室有医师26位,其中高级职称10位,博士生导师两位(占浙江大学胸外科2/3)。 学科带头人、胸外科主任、肺癌诊疗中心主任、博士生导师 柴?教授特别提醒,目前我国对肺内小结节的过度诊断与过度治疗的现状堪忧。众所周知,胸部CT初筛发现的肺部小结节不一定就是恶性肿瘤,很有可能已经在肺内存在多年,只是病人首次做CT才发现而已。希望医生一定要慎重行事。要让接受肺切除手术的早期肺癌患者影像病理符合率大于90%。这也是浙江大学医学院附属二院胸外科的重要质控指标之一。

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【ESMO2017】晚期非小细胞肺癌一代表皮生长因子受

百字文摘:2017ESMO大会上,柴莹教授团队展示了题目为‘晚期非小细胞肺癌一代表皮生长因子受体酪氨酸激酶抑制剂获得性耐药后加用阿帕替尼治疗的有效性及安全性分析’的研究,该研究在一代EGFR-TKIs获得性耐药后加用阿帕替尼,从而延长了一代EGFR-TKIs的 治疗时间,研究者认为一代EGFR-TKIs治疗时间的延长可延长晚期非小细胞肺癌患者总生存期。就此研究肿瘤资讯采访了柴教授,下面是具体内容。背景 表皮生长因子受体(EGFR) 酪氨酸激酶抑制剂(TKI)对EGFR突变的非小细胞肺癌(NSCLC)患者疗效显著。但是大部分患者在一段时间后会发生耐药,导致疗效减退。抗EGFR药物及抗血管内皮生长因子(VEGF)药物联合用药是目前治疗晚期NSCLC的有效方法之一。本研究的目的是评价NSCLC一代EGFR-TKIs治疗获得性耐药后,加用小剂量阿帕替尼(口服VEGF受体酪氨酸酶抑制剂)的有效性及安全性。 方法 回顾性评估一代EGFR-TKIs治疗有效后疾病缓慢进展的NSCLC患者。患者需继续原第一代EGFR-TKI药物同时加用阿帕替尼250 mg po qd治疗,直至疾病再次进展或出现不可耐受的毒性反应。 结果 共有33例患者纳入研究,男性15例(45.5%),非吸烟患者 20例 (60.6%)(表1)。中位观察时间5.9月(1.5 至 8.9月)。疾病控制率(DCR)90.9%,总体反应率(ORR)51.5%,其中17例为部分缓解(PR),13例为疾病稳定(SD)(表2,图1)。在经历了联合治疗有效后有4次疾病进展。研究中共观察到21件不良反应事件。共观察到1例严重不良反应,该患者因此停药。不良反应发生率由高到低依次为高血压,皮疹、蛋白尿、手足综合征、胃肠道反应、乏力、中性粒细胞减少伴发热、出血、粘膜炎症、谷丙转氨酶升高,卵巢功能不全(表3)。 结论 在埃克替尼或吉非替尼耐药后加用阿帕替尼可以有效延长一代EGFR-TKIs的有效时间,患者得以继续使用第一代EGFR-TKIs,从而潜在延长EGFR-TKIs获得性耐药患者总生存期(OS)。另外该方案在安全性上也可能具有一定的优势。希望在其他的后续治疗方案使用前,我们这一方案可以为EGFR-TKIs获得性耐药患者提供一种新选择。柴莹教授:靶向药物是近十几年的临床热点,大家都热衷于应用靶向药物治疗晚期肺癌。我们知道第一代的靶向药物有一大特点,即其具有一定的自限性,用到若干个月之后可能会产生耐药。出现耐药患者的后续治疗现在成为了一个迫切的问题,目前临床上常用的包括有针对耐药基因的第三代的靶向药物;针对没有突变患者的化疗等。对肿瘤病人最重要的关注点是提高总生存率OS,而目前靶向药物绝大多数研究的主要终点是PFS,甚至DFS,而OS总生存期延长才是患者用药的真正获益。假定第一代靶向药物应用1年疾病进展,如果通过某种方法,能使第一代靶向药物在耐药后还能够继续运用一段时间,再往后用其他后续方案,患者总生存期就因第一代靶向药物应用时间的延长而延长。据此设计本研究方案:当患者使用第一代TKI的靶向药物,主要是易瑞沙和埃克替尼,出现缓慢进展之后,加用阿帕替尼这一新型口服小分子抗血管生成靶向药物,并且是每天一片的最小剂量介入,希望能够延长第一代靶向药物的使用时间。而最终观察结果显示,观察中已经发现多数患者一线TKI靶向药物肺癌进展后再次得到控制,药物使用时间有所延长,而且不少人延长五个月以上。这是相当令人鼓舞的结果,说明了靶向治疗加用阿帕替尼延长了第一代TKI靶向药物的使用时间。希望我们的治疗方案能为以后第一代靶向药物出现耐药的患者提供一种新选择。 当然联合用药,不良反应是另一观察重点。关于安全性的研究结果显示,阿帕替尼每天一片的最小剂量介入,既使得副作用比较小,还能足不出户在家中用药。患者对联合治疗的耐受性和依从性也比较好。肿瘤资讯:请您谈一下刚才讲到的关于EGFR突变患者一线缓慢进展的耐药患者的获益,基于中国现在的诊疗规范下,这一研究的现实意义是什么?柴莹教授:现实意义就是使得这部分患者的总生存期大大的延长。现在有一种情况,患者一有进展大家就去检测,检测了之后,T790突变了,马上进入第三代靶向药物治疗。本研究即使T790突变,仍然使用第一代靶向药物,第一代靶向药物加用阿帕替尼患者还是能够获益的,直到患者再次再进展之后才考虑应用第三代靶向药物,这样患者总生存期得以延长,而这就是临床治疗最主要的目的。肿瘤资讯:谢谢柴教授。最后请您分享一下在今年的ESMO上有哪些重要的收获,或者您关注哪几个重要的研究?柴莹教授:国外欧美人的研究跟国内的研究还是有所差别,为什么呢?因为国内患者的基因突变、生活习惯、人种特征等跟他们有很大的差别,不能把他们的研究直接照搬过来,譬如一代靶向药物马上接三代靶向药物的方案。本研究采用的治疗方案是中国自己的方案,阿帕替尼是中国原研的,治疗方案也是我们自己创造的,并且取得了较好的效果。虽然只是一个开端,继续研究下去一定会取得一定的成果。 国内医生在吸取国际上先进的治疗理念、技术之后,要走出符合国人特征的自己的路。我非常欣赏国内的企业自主研发新药,像阿帕替尼这一新型口服小分子抗血管生成靶向药物的研发。本研究还有很多新的发现,譬如大家都认为只能用在后线治疗的药物,我们将其提到一线来用,也取得了很好的效果,延长了第一代靶向药物的使用寿命。还有一些发现目前在这里不便公开,以后会陆续公布。

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【ESMO2017】晚期非小细胞肺癌一代表皮生长因子受

百字文摘:2017ESMO大会上,柴莹教授团队展示了题目为‘晚期非小细胞肺癌一代表皮生长因子受体酪氨酸激酶抑制剂获得性耐药后加用阿帕替尼治疗的有效性及安全性分析’的研究,该研究在一代EGFR-TKIs获得性耐药后加用阿帕替尼,从而延长了一代EGFR-TKIs的治疗时间,研究者认为一代EGFR-TKIs治疗时间的延长可延长晚期非小细胞肺癌患者总生存期。就此研究肿瘤资讯采访了柴教授,下面是具体内容。背景表皮生长因子受体(EGFR)酪氨酸激酶抑制剂(TKI)对EGFR突变的非小细胞肺癌(NSCLC)患者疗效显著。但是大部分患者在一段时间后会发生耐药,导致疗效减退。抗EGFR药物及抗血管内皮生长因子(VEGF)药物联合用药是目前治疗晚期NSCLC的有效方法之一。本研究的目的是评价NSCLC一代EGFR-TKIs治疗获得性耐药后,加用小剂量阿帕替尼(口服VEGF受体酪氨酸酶抑制剂)的有效性及安全性。 方法回顾性评估一代EGFR-TKIs治疗有效后疾病缓慢进展的NSCLC患者。患者需继续原第一代EGFR-TKI药物同时加用阿帕替尼250mgpoqd治疗,直至疾病再次进展或出现不可耐受的毒性反应。 结果共有33例患者纳入研究,男性15例(45.5%),非吸烟患者20例(60.6%)(表1)。中位观察时间5.9月(1.5至8.9月)。疾病控制率(DCR)90.9%,总体反应率(ORR)51.5%,其中17例为部分缓解(PR),13例为疾病稳定(SD)(表2,图1)。在经历了联合治疗有效后有4次疾病进展。研究中共观察到21件不良反应事件。共观察到1例严重不良反应,该患者因此停药。不良反应发生率由高到低依次为高血压,皮疹、蛋白尿、手足综合征、胃肠道反应、乏力、中性粒细胞减少伴发热、出血、粘膜炎症、谷丙转氨酶升高,卵巢功能不全(表3)。 结论在埃克替尼或吉非替尼耐药后加用阿帕替尼可以有效延长一代EGFR-TKIs的有效时间,患者得以继续使用第一代EGFR-TKIs,从而潜在延长EGFR-TKIs获得性耐药患者总生存期(OS)。另外该方案在安全性上也可能具有一定的优势。希望在其他的后续治疗方案使用前,我们这一方案可以为EGFR-TKIs获得性耐药患者提供一种新选择。 柴莹教授:靶向药物是近十几年的临床热点,大家都热衷于应用靶向药物治疗晚期肺癌。我们知道第一代的靶向药物有一大特点,即其具有一定的自限性,用到若干个月之后可能会产生耐药。出现耐药患者的后续治疗现在成为了一个迫切的问题,目前临床上常用的包括有针对耐药基因的第三代的靶向药物;针对没有突变患者的化疗等。对肿瘤病人最重要的关注点是提高总生存率OS,而目前靶向药物绝大多数研究的主要终点是PFS,甚至DFS,而OS总生存期延长才是患者用药的真正获益。假定第一代靶向药物应用1年疾病进展,如果通过某种方法,能使第一代靶向药物在耐药后还能够继续运用一段时间,再往后用其他后续方案,患者总生存期就因第一代靶向药物应用时间的延长而延长。据此设计本研究方案:当患者使用第一代TKI的靶向药物,主要是易瑞沙和埃克替尼,出现缓慢进展之后,加用阿帕替尼这一新型口服小分子抗血管生成靶向药物,并且是每天一片的最小剂量介入,希望能够延长第一代靶向药物的使用时间。而最终观察结果显示,观察中已经发现多数患者一线TKI靶向药物肺癌进展后再次得到控制,药物使用时间有所延长,而且不少人延长五个月以上。这是相当令人鼓舞的结果,说明了靶向治疗加用阿帕替尼延长了第一代TKI靶向药物的使用时间。希望我们的治疗方案能为以后第一代靶向药物出现耐药的患者提供一种新选择。 当然联合用药,不良反应是另一观察重点。关于安全性的研究结果显示,阿帕替尼每天一片的最小剂量介入,既使得副作用比较小,还能足不出户在家中用药。患者对联合治疗的耐受性和依从性也比较好。 肿瘤资讯:请您谈一下刚才讲到的关于EGFR突变患者一线缓慢进展的耐药患者的获益,基于中国现在的诊疗规范下,这一研究的现实意义是什么? 柴莹教授:现实意义就是使得这部分患者的总生存期大大的延长。现在有一种情况,患者一有进展大家就去检测,检测了之后,T790突变了,马上进入第三代靶向药物治疗。本研究即使T790突变,仍然使用第一代靶向药物,第一代靶向药物加用阿帕替尼患者还是能够获益的,直到患者再次再进展之后才考虑应用第三代靶向药物,这样患者总生存期得以延长,而这就是临床治疗最主要的目的。 肿瘤资讯:谢谢柴教授。最后请您分享一下在今年的ESMO上有哪些重要的收获,或者您关注哪几个重要的研究? 柴莹教授:国外欧美人的研究跟国内的研究还是有所差别,为什么呢?因为国内患者的基因突变、生活习惯、人种特征等跟他们有很大的差别,不能把他们的研究直接照搬过来,譬如一代靶向药物马上接三代靶向药物的方案。本研究采用的治疗方案是中国自己的方案,阿帕替尼是中国原研的,治疗方案也是我们自己创造的,并且取得了较好的效果。虽然只是一个开端,继续研究下去一定会取得一定的成果。 国内医生在吸取国际上先进的治疗理念、技术之后,要走出符合国人特征的自己的路。我非常欣赏国内的企业自主研发新药,像阿帕替尼这一新型口服小分子抗血管生成靶向药物的研发。本研究还有很多新的发现,譬如大家都认为只能用在后线治疗的药物,我们将其提到一线来用,也取得了很好的效果,延长了第一代靶向药物的使用寿命。还有一些发现目前在这里不便公开,以后会陆续公布。

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体检查出肺部小结节怎么办?(采访节录)

体检时如果查出肺结节,不少人的反应是紧张。他们最担心的是,肺结节是不是肺癌,或发展下去,会不会变成肺癌?绝大多数肺结节是良性的。自从肺部CT扫描成为常规体检项目后,很多人在体检时查出肺结节或者磨玻璃结节。“很多患者查出肺结节后,整体提心吊胆,生怕结节是恶性的。实际上,结节以良性居多。”浙二医院范军强副主任医师说,临床上将肺部结节定义为单一的、边界清楚的、影像不透明的、直径小于3厘米、周围完全由含气肺组织所包绕的病变。一般多见于炎症、结核和肿瘤。也就是说,肺部结节可能是肺炎、肺结核、良性肿瘤,也可能是以前肺结核留下的疤,而真正是肺癌的比例很小。还有些结节比较小,不需要做任何治疗,定期随访就可以了。如果结节发生改变,一定要注意虽然大部分肺结节是良性的,但所有的肺癌几乎都是由肺结节演变而来。因此,鉴别其中的早期肺癌是关键。肺结节的良、恶性病变,多数在病灶形态、密度、边缘、边界等特征上存在差异。有些结节不需要随访,临床医生就会判断为恶性肿瘤,而有些结节就需要随访来了解变化趋势。要判断肺结节的良恶性,不能光看单次的检查结果,而是要结合之前的随访检查结果一起看。如果发现肺结节的大小、密度、形态等没有发生改变,一般是良性结节居多。如果发现大小有变化,比如有增大的趋势,或者形态发生了某些改变,那么就要引起注意了。范军强建议,查出肺部结节,要根据不同的情况,听从专业医生的建议,3个月、6个月、一年进行定期随访。如果结节发生了变化,则需要结合专业医生的意见进行处理。45岁以上无论男女可以考虑定期做低剂量螺旋CT检查在所有的恶性肿瘤中,肺癌排在第一位。据统计,我国每年新增的肺癌患者人数约100万。范军强副主任说,临床中发现,肺癌患者逐年递增,可能与现在肺癌检出率高有关,当然也不排除发病率的增加,而且有两个新趋势——1.腺癌比例逐渐升高。肺癌主要分为小细胞肺癌和非小细胞肺癌,而非小细胞肺癌中,主要包括鳞癌和腺癌。通俗来说,以往认为鳞癌的发生和吸烟有密切关系,而腺癌大部分与基因突变、环境影响等外界因素有密切联系,但腺癌与吸烟也有密切关系。十多年前,腺癌在肺癌中的比例在30%左右,但近年来,腺癌的比例逐年上升,目前比例在40%-50%,已经赶超鳞癌的比例了。从日常门诊来看,肺癌患者中,明确有吸烟史的肺癌患者有所下降,没有明确症状的肺癌患者呈上升趋势。2.女性患者越来越多。以往认为,肺癌最大的诱因与吸烟有关,患肺癌的人群也是以男性为主。但近年来,门诊中发现女性、不吸烟的肺癌患者越来越多,在数量上并不比男性少。女性患肺癌的比例为什么会逐年增加?业内专家说得最多的,是和二手烟、厨房油烟、基因突变、环境影响等多种因素有关,但最终原因目前仍不明确。国外的指南推荐,一般建议对55岁以上的吸烟高危人群做低剂量高分辨CT筛查。但日常体检方面,除了建议45岁以上有吸烟史、家族史的高危人群每年做一次低剂量螺旋CT检查外,也建议45岁以上的女性最好也能定期做一次低剂量螺旋CT检查。浙医二院胸外科团队竭诚提供诊疗服务柴教授作为我省重要的治疗肺癌的专业团队的首席专家说:浙医二院胸外科年手术量近3000例次,其中大部分以肺癌为主,以规范、精准、微创(尤其对浸润性肺癌的系统性淋巴结清扫)为特点,追求肺癌病人的长期生存,尽量减轻病人的创伤和经济负担为目标。目前科室有医师26位,其中高级职称10位,博士生导师两位(占浙江大学胸外科2/3)。学科带头人、胸外科主任、肺癌诊疗中心主任、博士生导师柴?教授特别提醒,目前我国对肺内小结节的过度诊断与过度治疗的现状堪忧。众所周知,胸部CT初筛发现的肺部小结节不一定就是恶性肿瘤,很有可能已经在肺内存在多年,只是病人首次做CT才发现而已。希望医生一定要慎重行事。要让接受肺切除手术的早期肺癌患者影像病理符合率大于90%。这也是浙江大学医学院附属二院胸外科的重要质控指标之一。

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