Chemo-radioresistance of Small Cell Lung Cancer Cell Lines Derived from Untreated Primary Tumors Obtained by Diagnostic Bronchofiberscopy

New cell lines of small cell lung cancer (SCLC) were established from specimens of untreated primary tumors biopsied by diagnostic bronchofiberscopy. The advantage of this method was ease of obtaining specimens from lung tumors. Establishment of cell lines was successful with 4 of 13 specimens (30%). Clinical responses of the tumors showed considerable variation, but were well correlated with the in vitro sensitivity of the respective cell lines to chemotherapeutic drugs and irradiation. One of the cell lines was resistant to all drugs tested and irradiation, while another was sensitive to all of them. Although the acquired resistance of SCLC is the biggest problem in treatment, the natural resistance to therapy is another significant problem. Either acquired or natural, resistance mechanisms of SCLC may be elucidated by the use of such cell lines derived from untreated tumors. This method and these SCLC cell lines are expected to be useful for the serial study of biologic and genetic changes of untreated and pre-treated tumors, or primary and secondary tumors.     

非小细胞肺癌化疗敏感性与其临床生物学行为

〔目的〕研究非小细胞肺癌对化疗药物原发敏感情况及肺部临床生物学行为对药敏的影响。〔方法〕采用MTT比色法测定31例非小细胞肺癌标本对9种化疗药物的敏感性，每种药物设3个浓度等级，根据每种药物的抑制率进行单因素方差分析。（结果）31例肺癌标本对9种化疗药物的敏感程度依次为；异长春花碱83.87％、长春新碱77.42％、丝裂霉素74.19％、阿霉素69.72％、卡铂69、72％、顺铂61．29％、足叶乙甙58．06%、氨甲喋呤22.58％、5氟脲嘧啶19．35％；随着9种化疗药物浓度的增加，其药物抑制率亦明显增加；足叶动式和阿霉素对鳞癌抑制率明显高于腺癌；足叶乙甙和顺铂对低分化肺癌抑制单明显高于中高分化肺癌。〔结论〕非小细胞肺癌作外药敏性受多个试验因素影响，并与非小细胞肺癌的病理类型和分化程度相关。     

Hospitalization During Chemotherapy for Small Cell Lung Cancer

Ninety patients with small cell lung cancer, who received combination chemotherapy, were studied with regard to hospitalization during the treatment period. Chemotherapy was discontinued in case of tumour progression, or, if progression did not occur, after 18 months. The mean hospitalization time was 18 days per patient which constituted 6.7% of the total tretment time in all 90 patients. The hospitalization rate significantly decreased during the first 10 weeks of treatment, and then remained constantly low, with an average hospital time of 3.7 days per patient during maintenance chemotherapy, accounting for 2% of the total maintenance treatment time. Tumour-associated disability was a major purpose for hospital admissions, accounting for 69% of the hospital time during treatment. Except for the first treatment course, which was routinely given in hospital, chemotherapy was administered on an out-patient basis, and only four patients were admitted to hospital to receive maintenance treatment. In these patients, comorbidity and long-distance living may have contributed to the need for hospitalization. Sixteen patients were admitted to hospital at different times of treatment because of treatment complications, mainly severe infections and haemorrhages. It is concluded, that hospitalization rate is a useful and easily understood treatment outcome measure, which, in our study, implied that patients who responded to chemotherapy also gained an improved social mobility in terms of days outside the hospital, although this should not be interpreted as a comprehensive quality of life measure.     

Current Strategies for Extensive Stage Small Cell Lung Cancer Beyond First-line Therapy

Extensive stage small cell lung cancer carries extremely poor prognosis and adding immune checkpoint inhibitor to platinum etoposide combination in first line only improved outcomes modestly. Once disease recurs, treatment response is only transient in nature. Various strategies that are being explored include dual checkpoint blockade, BiTE and CAR-T cell approaches. Immune checkpoint inhibitors are being combined with PARP inhibitors. Other approaches currently being investigated include liposomal irinotecan and combining known active agents for SCLC in relapsed setting such as newly approved lurbinectedin with doxorubicin, paclitaxel, irinotecan or topotecan with ATR inhibitor (Berzosertib). Temozolomide has also been tested in combination with a Parp inhibitor. New antibody or small molecule drug conjugates are being actively investigated, so is a biomarker based approach. Better understanding of small cell lung cancer disease biology via high through-put genomic, proteomic and methylation profiling offer glimpse of hope in our efforts to contain this deadly disease. A table of representative molecular targets under investigation is provided in the end.     

小细胞肺癌的手术治疗

1962到1983年22年间共手术治疗小细胞肺癌50例,其中27例切除(包括4例姑息切除),1例手术死亡。手术切除后4例5年以上健在(其中3例10年健在)。剖胸探查者无5年健在病例。Ⅰ期患者的5年生存率为17.6％,10年生存率为11.8％;Ⅱ期无2年以上生存者;Ⅲ期仅1例10年以上健在。无淋巴结转移的预后优于有转移者。症状期超过半年者切除率甚低。凡术前病理已证实为小细胞未分化癌,尤其是中心型。不适于手术治疗。作者认为辅助放疗和化疗,确能延长患者的生存期,故根治术后皆应辅助放疗和化疗,以期提高疗效。     

DLL3表达与晚期小细胞肺癌含铂化疗疗效及预后的相关性CSCD

目的探讨Delta-like protein 3(DLL3)与晚期小细胞肺癌(SCLC)顺铂/依托泊苷(EP)方案化疗敏感度及预后的关系。方法选取64例明确诊断为Ⅲ/Ⅳ期的SCLC患者,采用免疫组织化学法检测DLL3在SCLC石蜡包埋组织中的表达情况;χ~2检验分析DLL3表达与化疗疗效的关系,Kaplan-Meier和Cox多因素分析DLL3表达及其他因素对晚期SCLC患者无进展生存期(PFS)和总生存期(OS)的影响。结果在84.1%(54/64)的SCLC组织中可检测到DLL3表达,其表达与患者性别、年龄、吸烟史、分期无相关性(P>0.05)。DLL3高表达组的EP方案化疗有效率及疾病控制率均低于DLL3低表达组(P<0.05);DLL3低表达组的无进展生存期长于DLL3高表达组,差异有统计学意义(P<0.05)。Cox多因素分析结果显示DLL3表达、肿瘤分期、肿瘤直径是晚期SCLC患者PFS的独立预后因素,肿瘤分期是OS的独立预后因素。结论DLL3表达与晚期SCLC EP方案化疗反应率及PFS相关,可能成为预测化疗敏感度的生物标志物。DLL3表达对于晚期SCLC患者的远期预后无预测价值。     

Development and Elongation of Neurite–like Outgrowth on Small Cell Lung Cancer Cell Lines

One (Lu–134A) of nine human small cell lung cancer cell lines which grow as floating cell aggregates changed its morphology dramatically when cells were cultured on a coverslip coated with poly–ethylenimine or extracellular matrix of human lung adenocarcinoma cell line PC–9 cells. The Lu–134A cells adhered to the substrate and developed elongated cytoplasmic processes which gradually grew into long neuronal–like processes. These processes developed to a length of more than 10 times the cell body length after 20 days of culture. Addition of dibutyryl cyclic adenosine 3', 5 –monophosplmte to the cells on these substrates remarkably promoted the development and elongation of the processes, which grew into a netlike arrangement. The characteristics of these elongated neuronal–like processes were studied using immunocytochemical and electron microscopical methods. The processes reacted intensely with monoclonal antibodies against β –tubulin and microtubule–associated protein–2. The swelling portions of the distal tips of these processes reacted strongly with polyclonal antibody against synaptophysin. Neurosecretory granules and bundles of microtuhules were observed within processes. These findings suggested that this human small cell lung cancer cell line (Lu–134A) differentiated into neuronal cells, and indicated that attachment of cells to a substrate is the key to the development of long neurite–like outgrowths.     

小细胞肺癌与TNM分期

小细胞肺癌的临床侵袭性强,易于转移,因而长期以来认为手术疗效较差,治疗方法主要是放化疗,因此分期手段也以美国退伍军人肺癌协会的局限期和广泛期为主。随着肺癌分期手段的进步,分期的准确性进一步提高。大量回顾性的资料表明,早期小细胞肺癌的手术疗效不亚于非小细胞肺癌。而对拟手术的小细胞肺癌的分期也应采用现代更精确的TNM分期。     

ATP生物荧光肿瘤体外药物敏感性检测在乳腺癌中的应用

 目的　评价ATP生物荧光肿瘤体外药物敏感性检测结果是否能真实反映肿瘤的药敏情况以及该方法指导制定化疗方案的可行性。方法　应用ATP生物荧光肿瘤体外药物敏感性检测法 ,检测 4 2例乳腺癌标本对 12种常用药物的敏感性。结果　标本的可评价率为 95 % ,乳腺癌对PTX最敏感 ,体外有效率为 93% ,其次为ADM(6 7% )和 5 Fu(6 4 % ) ,体外有效病例中强敏感病例比例最高的为PTX ,达到6 9 % ,其次为ADM(6 1% )和 5 Fu(5 6 % ) ,检测结果与临床疗效相符。ER/PR、PCNA、p5 3、c erbB 2、绝经与否、淋巴结转移与否与药物是否有效无关。结论　ATP生物荧光肿瘤体外药物敏感性检测法敏感性高、稳定性好、简便、快速 ,检测结果真实可信 ,可用于临床制定个体化的化疗方案。     

Relation between Nucleolar Size and Growth Characteristics in Small Cell Lung Cancer Cell Lines

Relationships among cytological features, doubling time, S-phase percentage, expression of myc- family oncogenes, DNA ploidy and biochemical properties were studied in thirteen small cell lung cancer cell lines. Six cell lines that grew slowly (average doubling time 99 h) and had lower S-phase percentages (average 32%) showed inconspicuous nncleoli (average area of 1.5 μm²), and the remaining seven cell lines that grew quickly (average doubling time 45 h) and had higher S-phase percentages (average 44%) showed large and prominent nncleoli (average area of 6.1 μm²). DNA index value obtained from flow cytometric DNA histograms showed that all cell lines except for H-69 cell line displayed aneuploidy. Ribbon-like cell arrangements were observed in the 7 cell lines that grew quickly, and in 1 cell line that grew slowly. Biochemically, six slow-growing cell lines and four fast-growing cell lines showed high levels of aromatic L-amino acid decarboxylase activity, while in the remaining three fast-growing cell lines its level was low. A high level of c-myc or N- myc oncogene expression was observed in all 7 cell lines that grew quickly, but not in any of the 6 cell lines that grew slowly. It appears that small cell lung cancer cell lines that grow quickly can be expected to have large nucleoli and ribbon-like cell arrangements and to express high levels of myc family oncogenes, and that nucleolar size is a good indicator for growth characteristics.     

Changes in Cell Characteristics Due to Culture Conditions in Cell Lines From Human Small Cell Lung Cancer

Eight cultured cell lines were established from human smallcell lung cancers. Every cell line showed the morphologicaland biochemical characteristics of small cell cancer. Changesin cell characteristics were observed in many of these celllines when culture conditions were changed: "oat cell type"changed to "intermediate cell type" and vice versa when serum-freemedium was changed to serum-supplemented medium; a deficiencyof vitamin A in the medium caused a change to squamous cellsand vice versa; and a tumor promoter (teleocidin B) enhancedthe adherence of these cells to the surface of plastic culturedishes. These findings provide evidence that many small celllung cancer cell lines can change their morphology with changesin the environment of the cells.     

Establishment of a Human Small Cell Lung Cancer Cell Line Producing a Large Amount of Anti-diuretic Hormone

A new cancer cell line (Lu-165) producing a large amount of anti-diuretic hormone (ADH, 2.8 μg/g protein) was established from a 50-year-old small cell lung cancer patient presenting with a syndrome of inappropriate anti-diuretic hormone secretion. These cells grew well in serum-supplemented medium and during more than 100 passages they continued producing a large amount of this hormone. This cell line will be a useful tool for studies of the biochemistry and pathology of ADH-producing cancer.     

Concurrent Cisplatin-etoposide Chemotherapy plus Thoracic Radiotherapy for Limited-stage Small Cell Lung Cancer

A recent approach in the treatment of limited-stage small celllung cancer (LDSCLC) has involved a combined modality of chemotherapyand chest irradiation. In using the modality, the study of schedulingmethods for combining chemotherapy and radiotherapy should leadto other trials of combined modalities against LDSCLC sinceit is the most basic issue to be evaluated. We have thus conducteda multicenter phase II trial of concurrent cisplatin-etoposide(PVP) chemotherapy and radiotherapy for LDSCLC to determinethe effects of the concurrent administration of a PVP regimenand chest irradiation on response rate, relapse, survival andtreatment toxicity. The chemotherapy regimen consisted of afour-week cycle: cisplatin (80 mg/m², given intravenously onday 1) and etoposide (100 mg/m2, given intravenously on days1–3). This cycle was given four to six times within sixmonths. Chest irradiation to the primary tumors at both thehili and the mediastinum was administered in standard fractionson days 2–12 in the first cycle of chemotherapy and ondays 29–47 in the second cycle, with a total dose of 40–50Gy. Prophylactic cranial irradiation was performed among completeremission (CR) or good partial remission (PR) patients aftercompletion of the concurrent therapy. A total of 66 patientswere entered into the trial and 59 were evaluated. The concurrenttherapy induced an overall response rate of 94.9% in 59 patients:24 patients, 40.7% CR, 32 patients, 54.2% PR. The median responseduration was 8.7 months, and the median survival time for alleligible patients was 14.8 months. The percentage of patientswith two-year survival periods was 20. A local relapse withinthe irradiated area was seen in only 22% of relapsed patients.Brain metastases occurred in 24% of patients. Four of 32 patientstreated with prophylactic cranial irradiation had brain metastases.Toxic effects, chiefly grades 3 and 4 leukopenia, as establishedby the World Health Organization, were detected in all treatedpatients. Other toxicities, including radiation-induced esophagitisand pneumonitis, were deemed almost acceptable. We concludedconcurrent treatment of a PVP regimen with chest irradiationto be a feasible and beneficial therapy with an efficacy compatibleto that of other published reports. The outcome of this protocolwarrants further investigation to determine the optimal typeof schedule for concurrent chemoradiotherapy against LDSCLC.     

小细胞肺癌内科个体化治疗的临床研究

目的 探讨针对小细胞肺癌患者个体化治疗的临床疗效.方法 将小细胞肺癌患者100例随机分为对照组和观察组,每组各50例.对照组采用传统一线化疗方案进行治疗;观察组患者通过PCR检测患者体内各基因表型,针对性选择每个患者潜在的敏感化疗药物进行治疗.统计各组患者客观缓解率、疾病控制率、无进展生存时间、总生存时间和安全性分析.结果 与对照组相比,观察组患者总生存时间明显延长,其复发率较低.与对照组相比,观察组患者KPS评分明显较高.结论 通过检测与肿瘤药物相关的基因,可以指导临床针对性用药,从而避免无效化疗,减少患者痛苦,同时显著提高临床疗效.     

一线化疗方案治疗广泛期小细胞肺癌的网状meta分析

背景与目的顺铂/卡波联合伊立替康/依托泊苷双药化疗方案被推荐为治疗广泛期小细胞肺癌（small cell lung cancer of extensive disease, ED-SCLC）的一线化疗方案。我们在网状meta分析中,通过合成直接证据和间接证据,对推荐的化疗方案的短期疗效进行排序。方法我们在EMBASE、PubMed、CENTARL及clinicaltrial.gov数据库检出了相关疗效比较的随机对照试验。ROB工具被用于评估纳入研究的质量, Stata 13.1被用于统计学合成。结果该研究共纳入10项随机对照研究,共计2,378名患者。与依托泊苷联合卡铂相比,肿瘤的完全缓解率（complete remission rate, CR）在伊立替康联合卡铂组明显提高（OR=3.33,95%CI：1.47-7.54, P<0.05）。伊立替康联合卡铂治疗后CR明显优于依托泊苷联合顺铂（OR=4.09,95%CI：1.18-14.12, P<0.05）。结论本研究结果显示：伊立替康联合卡铂一线治疗ED-SCLC的疗效优于依托泊苷。     

小细胞肺癌驱动基因研究进展

小细胞肺癌是一类具有高度侵袭性的肺恶性肿瘤,预后极差,近30年来,其治疗策略无明显进展。积极研究小细胞肺癌分子生物学特征,并筛选潜在驱动基因,有助于为小细胞肺癌开拓新的治疗途径,改善疾病预后。本文将对小细胞肺癌驱动基因研究相关进展进行综述。     

拓扑替康单药治疗小细胞肺癌临床研究

目的探讨拓扑替康单药治疗小细胞肺癌(SCLC)的疗效及安全性.方法初治和复治(SCLC)40例,可评价疗效35例,可评价不良反应40例.拓扑替康1.2mg·m