颈段,胸上段食管癌颈部及双锁骨上区域预防放疗的疗效分析

目的 分析颈段、耻段食管癌颈部及双锁骨上区域预防放疗的疗效。方法 ６０例颈段、胸上段食管癌患者,采用颈部及双锁骨上区域放疗,ＤＴ４５￣５０Ｇｙ／４．４－６周,与同期病人对照结果 预防组淋巴结转移率１．７％,明显低于对照组１８．３％,Ｐ〈０．０１。两组生存率比较,２、３年生存率预防组有明显提高,结论 颈段、胸上段食管癌颈部及双锁骨上区域预防放疗有肯定的效果。     

100例食管癌后程加速放疗的研究

评价后程加速放疗对食管癌病人的疗效。材料与方法自１９９１年１０月至１９９３年５月对１００例食管癌病人进行了研究，随机分为两组：常规组（５０例），后超组（５０例）。两组包括颈段４例，胸上段３５例，脾中段５６例及胸下段５例。全部病人均为鳞癌。常规照射：１８０－２００ｃＧｙ／次，５次／周，总量６０００ｃＧｙ／６周；后程加速照射：前３周同常规组，共３０００ｃＧｙ／３周，第４周起，１５０ｃＧｙ／次，日２次，间隔６小时，照射量为３０００ｃＧｙ／２周，总照射量６０００ｃＧｙ／５周。结果局控率后超组９８％（４９／５０），常规组９４％（４７／５０），１，２，３年生存率分别为８４％（４２／５０）、５６％（２８／５０）、４８％（２４／５０）及６２％（３１／５０）。３４％（１７／５０）２２％（１１／５０），后超组明显好于常规组（Ｐ＜０．０１）。两组放疗副反应无差别，其主要死因是局部复发、次为出血、穿孔及远处转移，后超组死于出血、穿孔者并不多于常规组。结论后程加速照射能明显提高食管癌病人１，２，３年生存率，不增加放疗副反应及并发症。     

小于3cm的食管癌放射治疗的疗效分析

目的分析３ｃｍ以下食管癌病人的预后及与照射量之间的关系。材料与方法自１９７７年１月到１９８８年１２月共收治３ｃｍ以下的食管癌１９３例，男１１８例，女７５例。全部有病理证实，均为鳞癌。其中包括颈段癌３例，胸上段癌７８例，胸中段癌１０５例，胸下段癌７例。照射方法采用６０Ｃｏ外照射，常规３野，２００ｃＧｙ／次，５次／周，照射量４０８８～７３４５ｃＧｙ。结果１，３，５和８年生存率分别为７１．５％、４０．４％、３０．１％和１６．５％。以５０００～７０００ｃＧｙ组生存率最高，＞７０００ｃＧｙ组最差，且＜５０００ｃＧｙ组１和３年生存率明显高于＞７０００ｃＧｙ组，５和８年生存率无差别。结论食管癌病人的病变越短，生存率越高；病变部位与生存率的关系不大；最佳的照射量应为６０００ｃＧｙ左右／５周，对于３ｃｍ以下较早期的食管癌病人，放射治疗中不宜追求高剂量。     

胸上中段食管癌放疗与术疗远期疗效对比分析报告

目的 探讨食管癌胸上中段的道选治疗方法。方法 对〈５ｃｍ的胸上中段食管癌４３３例中单纯放疗２４４例与单纯手术１８９例远期疗效进行回顾性分析。结果 食管癌胸上段１、３、５年生存率放疗组分别为７１．４％、４４．３％、２５．７％,手术组为６６．７％、３８．１％、９．５％。胸中段１、３、５年生存率放疗组分别为６４．５％、２０．１％、１３．２％,手术组为７０．８％、３４．４％、２１．４％。结论 胸上段食管癌     

180例可手术食管癌单纯放疗的疗效分析

１８０例经组织学证实为食管癌并经外科医生确认食管病变可进行手术，但因各种原因而未能手术者。病变长度２～９ｃｍ。作者采用常规等中心三野照射或先前后野对穿后改为等中心照射，总量５～７周为５０～７０Ｇｙ。全组病人１、３、５年生存率分别为６４．４％、３４．４％、２３．３％。３、５年生存率上段好于中下段（Ｐ＜０．０５）。能手术的食管癌单纯放疗的疗效与手术治疗相似。上段癌单纯放疗的疗效稍好于手术或放射加手术综合治疗，中段癌放疗的疗效稍差于手术，下段癌放疗疗效比手术明显差。     

颈段、胸上段食管癌颈部及双锁骨上区域预防放疗的疗效分析

目的　分析颈段、胸上段食管癌颈部及双锁骨上区域预防放疗的疗效。方法　 60例颈段、胸上段食管癌患者 ,采用颈部及双锁骨上区域预防放疗 ,DT 45～ 5 0Gy/4 .4～ 6周 ,与同期病人对照。结果　预防组淋巴结转移率 1 7% ,明显低于对照组 18 3 % ,P <0 0 1。两组生存率比较 ,2、3年生存率预防组有明显提高。结论　颈段、胸上段食管癌颈部及双锁骨上区域预防放疗有肯定的效果。     

晚期食管癌术前加速放疗与术前常规放疗随机分组临床研究：附1…

对１７７例晚期食管癌进行了术前加速放疗（８７例）和术前常规放疗（９０例）。照射方法：两组均在模拟机下定位，上界锁骨上缘，下界下横膈。加速组前一后二野轮照，每天照射２次，每次２Ｇｙ，两次照射间隔６￣８小时，前野照射剂量２０Ｇｙ，后背两斜野各１０Ｇｙ，总量４０Ｇｙ，疗程１２￣１４天；常规组前后二野对穿轮照，每天照射１次２Ｇｙ，总量４０Ｇｙ，疗程２６￣２８天。两组放疗后３￣４周行食管癌根治术。结果：加速     

小细胞肺癌术后化疗后预防性脑照射是否必要

目的小细胞肺癌根治术后巩固化疗后预防性脑照射是否能减低脑转移率,提高生存率。方法１９７８年３月～１９９４年７月收治了小细胞肺癌术后化疗后脑预防照射２５例。男１８例,女７例。术后病理分期Ⅰ,Ⅱ,ⅢＡ分别为８,８和９例。化疗方案：ＣＯＭＥ（Ｃ：环磷酰胺;Ｏ：长春新硷;Ｍ：甲氨蝶呤;Ｅ：依托泊甙）,ＣＯＭＣ（Ｃ：环磷酰胺;Ｏ：长春新硷;Ｍ：甲氨蝶呤;Ｃ：卡铂）,ＣＡＥ（Ｃ：环磷酰胺;Ａ：阿霉素;Ｅ：依托泊甙）,ＣＥＣＡＰ（Ｃ：卡铂;Ｅ：依托泊甙;Ｃ：环磷酰胺;Ａ：阿霉素;Ｐ：顺铂）。２４Ｇｙ照射３例,３０Ｇｙ照射２２例。同期根治术后化疗后未作脑预防照射４５例作对照。结果脑转移率：预防组８％（２／２５）,对照组２０％（９／４５）。预防组１,３,５年生存率分别为８８．０％,６０．０％和４７．４％。对照组分别为７３．３％,４２．２％和３４．２％。预防组Ⅰ,Ⅱ,ⅢＡ期５年生存率分别为６０．０％,５７．０％和２８．６％,对照组的分别为５７．０％,３０．８％和９．０％。结论小细胞肺癌预防性脑照射有可能减低脑转移率,提高生存率,但因病例数少不能下结论。     

食管癌放疗后存活5年以上患者的生活质量观察

目的：了解管癌放疗后生存５年以上患者的生活质量。方法：自１９７３年到１９８８年我们共收治了１４４４例食管癌患者，生存５年以上有１００例，作者对１００例患者作随访调查喏止段１３例，中段８５例；下段２例。鳞癌９７例；腺癌３例。根据Ｘ线片食管病灶长度分成早期〈３ｃｍ的５例，中期３￣５ｃｍ的３３例；晚期〉５ｃｍ的６２例＾６０Ｃｏ体外照射，前１后２野常规照线次１．８￣２Ｇｙ，５次／周，照射总量５５－８５Ｇｖ     

晚期食管癌术前加速放疗与术前常规放疗随机分组临床研究（附117例疗效分析）

对１７７例晚期食管癌进行了术前加速放疗（８７例）和术前常规放疗（９０例）。照射方法：两组均在模拟机下定位，上界锁骨上缘，下界平横膈。加速组前一后二野轮照，每天照射２次，每次２Ｇｙ，两次照射间隔６～８小时，前野照射剂量２０Ｇｙ，后背两斜野各１０Ｇｙ，总量４０Ｇｙ，疗程１２～１４天；常规组前后二野对穿轮照，每天照射１次２Ｇｙ，总量４０Ｇｙ，疗程２６～２８天。两组放疗后３～４周行食管癌根治术。结果：加速组与常规组１年生存率分别为８９％和８８％、２年为８５％和６５％、３年为６９％和４８％、４年为６０％和４１％；轻度放疗反应分别为９％和３４％、中度为４１％和３９％、重度为５０％和２７％；淋巴结转移分别为１３％和２４％；根治性手术切除率分别为９５％和９０％。结果表明，术前加速放疗联合外科手术是综合治疗晚期食管中段癌的较好方法，不仅疗程缩短，而且生存率也有一定提高，值得进一步研究。     

采用肺校正对329例食管癌放疗后生存率的再分析

目的：探讨食管癌放疗最佳剂量。材料与方法：1973－19764年间60CO外照射329例食管癌的5年、8年、10年、13年生存率分析，对组织剂量6400cGy组7400cGy组分别行肺校正后靶区剂量分别是7000cGy、8250cGy。结果：肺校正后7000cGy组5年、8年、10年、13年生存率分别为13％（15／114）、9．6％（11／114）、7％（8／114）、1．8％（2／114）。8250cGy组5年8年、10年、13年生存率分别为8．3％（17／204）、2．4％（5／204）、1．5％（3／204）、0（0/204）。两组对此肺校正后7000cGy组明显高于8250cGy组P＜0．005。结论：食管癌放疗行肺校正是必要的，肺校正后靶区剂量7000cGy~7700cGy我们认为是根治性放疗的最佳剂量。     

陀螺刀治疗脑转移瘤的疗效观察

目的观察陀螺刀治疗脑转移瘤的近期疗效和不良反应。方法采用国产陀螺刀治疗脑转移瘤118例,用50%～60%等剂量曲线包裹靶区,全组周边处方剂量3 800～4 200 cGy,中位处方剂量4 000 cGy,350 cGy/次,5次/周,评价其近期疗效及不良反应。结果 118例患者完全缓解26例(22.03%),部分缓解74例(62.71%),稳定16例(13.56%),进展2例(1.69%),总有效率为84.74%,临床获益率98.31%。1年局部控制率为32.20%,1年总生存率为43.13%。结论陀螺刀治疗脑转移瘤的近期疗效较好,不良反应发生率较低,是1种有效的局部治疗方法,其远期疗效有待进一步观察。     

Recombinant murine GM-CSF increases resistance of some factor dependent hematopoietic progenitor cells to low-dose-rate gamma irradiation

The effects of murine recombinant IL-3 (multi-CSF) and murine recombinant GM-CSF (granulocyte-macrophage colony stimulating factor) on the radiation biology of clonal hematopoietic progenitor cell lines were evaluated. Four clonal cell lines with growth response to either IL-3 or GM-CSF (FDCP-1JL26, and bg/bg d64) or exclusively dependent on IL-3 (32D cl 3 and B6SUtA), were pre-incubated in IL-3, or GM-CSF, for 7 days prior to gamma irradiation, then washed and irradiated at 5 cGy/min, or 116 cGy/min, and transferred to semisolid medium supplemented with either IL-3, or GM-CSF, for assay of 7 day greater than or equal to 50 cell colonies. The cell lines demonstrated similar radiosensitivity and lack of a detectable dose-rate effect when grown in IL-3 (FDCP-1JL26: D0 154, n 1.05 at 5 cGy/min, and D0 138, n 1.16 at 116 cGy/min; bg/bg d64: D0 95.7, n 1.16 at 5 cGy/min, and D0 97.7 n .993 at 116 cGy/min; B6SUtA: D0 101, n 1.29 at 5 cGy/min, D0 100, n 1.27 at 116 cGy/min; and cell line 32D cl 3: D0 123, n 1.65 at 5 cGy/min, and D0 126, n 1.17 at 116 cGy/min). In contrast, FDCP-1JL26 cells demonstrated a significant relative radioresistance at low-dose-rate when grown in recombinant GM-CSF, (D0 217, n 1.27 at 5 cGy/min, D0 138, n 1.34 at 116 cGy/min, p less than .005). The increase in radioresistance of FDCP-1 cells at low-dose-rate was induced either by preincubation in GM-CSF with transfer to IL-3, or by preincubation in IL-3 and transfer to recombinant GM-CSF. Growth factor independent malignant subclones of lines B6SUtA and FDCP-1JL26 demonstrated a significant increase in radioresistance at low-dose-rate (B6SUtA EL4JL: D0 187, n 1.39 at 5 cGy/min, and D0 133, n 1.73 at 116 cGy/min (p. less than .05); and FDCP-1JL26 F7 cl 2: D0 191, n 1.17 at 5 cGy/min, and D0 150, n 1.31 at 116 cGy/min [p less than .05]). Thus, some hematopoietic progenitor cell lines are induced by GM-CSF to grow after irradiation at low-dose-rate similar to the growth of clonal malignant cell lines. The data may have implications for the radiation biology of normal hematopoietic progenitor cells in two circumstances: (a) selective survival of GM-CSF responsive cells after total body irradiation, and (b) selective survival of some hematopoietic progenitors in vivo during clinical recombinant GM-CSF infusion.     

50例鼻咽癌调强放疗中内耳受量评价

目的：分析鼻咽癌调强放疗对双侧内耳受量的影响。方法：选择2015年5月至12月就诊于成都军区总医院50例经病理确诊为鼻咽癌的患者,所有患者均接受30次调强放疗。再由一名主治医师在原始的CT图像上勾画出双侧的耳蜗、前庭及内耳道,并在计划的优化过程中对上述结构进行条件一致的剂量限定,最后通过DVH图对上述结构进行剂量分析,包括最大剂量点（Dmax ）、最小剂量点（Dmin ）及平均剂量（Dmean ）。结果：左侧耳蜗的最大剂量点、最小剂量点及平均剂量的均值分别为5366．3cGy、3981．2cGy、4550．1cGy;左侧前庭分别为4323．2cGy、3310．8cGy、3821．1cGy;左侧内耳道分别为5290．8cGy、3828．7cGy、4453．6cGy;右侧耳蜗的最大剂量点、最小剂量点及平均剂量的均值分别为5344．5cGy、3954．2cGy、4550．1cGy;右侧前庭分别为4368．3cGy、3262．9cGy、3796．0cGy;右侧内耳道分别为5165．0cGy、3765．2cGy、4375．2cGy。结论：在鼻咽癌的调强放疗计划设计过程中对内耳结构进行剂量限定,能在不减少靶区受量的同时有效的降低内耳结构的受照射剂量。     

骨转移癌不同放疗分割方法的止痛作用探讨

目的 探讨关于局部野放射治疗骨转移癌的不同分割方法的止痛效果。方法 97例患者,40例采用常规分割照射,Dr 200 cGy/次,每周5次,Dr 3600-5000 cGy;57例采用低分割照射,DT300-500 cGy/次,每周3-5次,Dr 2000-3000 cGy。结果 放疗起到了明显的止痛作用,常规分割放疗组与低分割放疗组止痛效果大致相似,差异无显著性(P>0.05)。结论 骨转移癌的放射治疗应根据病情来决定。对一般情况好,预计生存期长的患者应积极给予全剂量的分割治疗,而对于病情相对较重、行动又不方便、预计生存期短的患者,应采取低分割照射,同样可以起到止痛作用。     

Hyperfractionated total body irradiation for T-depleted HLA identical bone marrow transplants

Twenty patients suffering from malignant hemopathies (mean age 31.7 years) were given hyperfractionated total body irradiation (TBI) (120 cGy/3 fractions per day: total dose = 1440 cGy/4 days) as conditioning for T-depleted HLA identical allogeneic bone marrow transplantation. At an average of 12 months (range of 4.5-22 months) follow-up there were two cases of early death and two cases (11%) of rejection. There were no cases of acute or chronic graft versus host disease (GVHD) nor cases of interstitial pneumonitis. The average time for durable engraftment was 22 days. Disease-free survival at 12 months was 65%. To improve the results and further reduce the percent of rejection, the authors propose intensifying the immunosuppressive conditioning by increasing the cyclophosphamide dose and that of TBI so that a total dose of 1560 cGy is reached.     

Defining the appropriate radiation dose for pretreatment PSA < or = 10 ng/mL prostate cancer

PURPOSE: To investigate whether a dose response exists for biochemical no evidence of disease (bNED) control in prostate cancer patients with pretreatment prostate-specific antigen (PSA) < or = 10 ng/mL and to identify the patient subgroups affected. METHODS AND MATERIALS: Between 5/89 and 10/97, 488 T1-T3 NX-0 M0 prostate cancer patients with PSA < or = 10 ng/mL were treated with three-dimensional conformal radiation therapy (3D-CRT) alone. Median and mean pretreatment PSA values were 6.3 and 6.2, respectively. Gleason scores of 2-6 and 7-10 were noted in 386 and 102 men, respectively. AJCC 1992 palpation T1-T2AB tumors were noted in 415 patients. Perineural invasion (PNI) was noted in 60 men. Mean and median age was 67 and 68 years, respectively. Dose to the center of the prostate ranged from 6260 cGy to 8409 cGy with a mean and median of 7423 cGy and 7278 cGy, respectively. Patients were stratified into three groups according to dose: <7250 cGy, 7250-7599 cGy, and > or =7600 cGy. Median dose in these three groups was 7067 cGy, 7278 cGy, and 7734 cGy, respectively. Univariate analysis was performed to determine differences in bNED control (American Society for Therapeutic Radiology and Oncology [ASTRO] Consensus Guidelines definition of failure) by dose group for the entire cohort, for 310 good prognosis patients (T1-T2A, Gleason score 2-6, absence of PNI), and for 178 poor prognosis patients (T2B-T3 or Gleason score 7-10 or presence of PNI) (1). Multivariate analysis (MVA) was performed to determine if dose was an independent predictor of bNED control. Median follow-up was 36 months. RESULTS: A dose response was not demonstrated for the entire group of patients with pretreatment PSA < or =10 ng/mL. Doses of <7250 cGy, 7250-7599 cGy, and > or =7600 cGy were associated with 5-year bNED control rates of 73%, 86%, and 89%, respectively (p = 0.12). MVA demonstrated prognosis group (p = 0. 038) to be the only independent predictor of bNED control. Good prognosis patients had a 5-year bNED of 85% and no dose response was seen. The subgroup of poor prognosis patients demonstrated a 5-year bNED control rate of 81% and a dose response was seen for those receiving > or =7600 cGy, compared to the two lower dose groups (94% vs. 75% vs. 70%; p = 0.0062). MVA for the poor prognosis subset demonstrated dose (p = 0.01) to be the only independent predictor for improved bNED control. CONCLUSIONS: The poor prognosis subset of PSA < or =10 ng/mL prostate cancer patients benefit from dose escalation. A dose response is not demonstrated for prostate cancer patients with pretreatment PSA < or =10 ng/mL and other favorable features.     

4D模板辅助125I粒子治疗晚期恶性肿瘤的剂量学研究

目的 探讨4D模板在¹²⁵I粒子治疗晚期恶性肿瘤中的安全性及剂量研究。方法 选取陕西省肿瘤医院胸外科自2018-2019年晚期恶性肿瘤患者98例,采用4D模板导航放射性¹²⁵I粒子植入治疗。术前放疗计划、术中优化、术毕即刻剂量验证,术后评定植入剂量。观察治疗结果。结果 98例肿瘤患者全部顺利完成粒子植入术,植入部位行外照射和未行外照射的大体肿瘤体积植入剂量分别为(12489±414)cGy和(15036±514)cGy,V100%分别为84.7%~94.1%和88.2%~93.7%;临床靶体积植入剂量分别为(7450±621)cGy和(9080±761)cGy。剂量植入质量评估优91%(89/98)、良7%(7/98)、中2%(2/98)、差0。疼痛患者症状缓解率为92%(36/39)。行外照射和未行外照射1、2年局控率分别为61%、36%和82%、54%(P=0.02)。48例肺部植入者气胸发生率为19%(9例),咯血发生率为10%(5例),其他部位植入者均未出现相应并发症。结论 4D模板辅助¹²⁵I粒子治疗恶性肿瘤安全有效,术中实时针道角度调节和剂量优化使植入剂量得到精准控制。     

Radiation exposure during head repositioning with the automatic positioning system for gamma knife radiosurgery

PURPOSE: To measure radiation exposure to a patient during head repositioning with the automatic positioning system (APS) for Gamma Knife radiosurgery. METHODS AND MATERIALS: A 16-cm diameter spherical solid phantom, provided by the manufacturer, was mounted to the APS unit using a custom-made holder. A small-volume ionization chamber (0.07-cm(3) volume) was placed at the center of the phantom. We recorded the temporal variation of ionization current during the entire treatment. Measurements were made for 3 test cases and 7 clinical cases. RESULTS: The average transit time between successive shots, during which the APS unit was moving the phantom for repositioning the shot coordinates, was 20.5 s for 9 cases. The average dose rate, which was measured at the center of the phantom and at a point outside the shot location, was 0.36 +/- 0.09 cGy/min when the beam output was approximately 3.03 Gy/min for the 18-mm collimator helmet. Hence, the additional intracranial radiation dose during the APS-driven head repositioning between two successive shots (or APS transit dose) was 0.12 +/- 0.050 cGy. The APS transit dose was independent of the helmet size and the position of shots within the phantom relative to the measurement point. CONCLUSION: The head repositioning with the APS system adds a small but not negligible dose to the dose expected for the manual repositioning method.     

A phase I/II trial of three-dimensionally planned concurrent boost radiotherapy and protracted venous infusion of 5-FU chemotherapy for locally advanced rectal carcinoma

BACKGROUND: Improving the response to preoperative therapy may increase the likelihood of successful resection of locally advanced rectal cancers. Historically, the pathologic complete response (pCR) rate has been < approximately 10% with preoperative radiation therapy alone and < approximately 20% with concurrent chemotherapy and radiation therapy. METHODS AND MATERIALS: Thirty-seven patients were enrolled on a prospective Phase I/II protocol conducted jointly at Washington University, St. Louis and the Catholic University of the Sacred Heart, Rome evaluating a three-dimensionally (3D) planned boost as part of the preoperative treatment of patients with unresectable or recurrent rectal cancer. Preoperative treatment consisted of 4500 cGy in 25 fractions over 5 weeks to the pelvis, with a 3D planned 90 cGy per fraction boost delivered once or twice a week concurrently (no time delay) with the pelvic radiation. Thus, on days when the boost was treated, the tumor received a dose of 270 cGy in one fraction while the remainder of the pelvis received 180 cGy. When indicated, nonaxial beams were used for the boost. The boost treatment was twice a week (total boost dose 900 cGy) if small bowel could be excluded from the boost volume, otherwise the boost was delivered once a week (total boost dose 450 cGy). Patients also received continuous infusion of 5-fluorouracil (1500 mg/m(2)-week) concurrently with the radiation as well as postoperative 5-FU/leucovorin. RESULTS: All 37 patients completed preoperative radiotherapy as planned within 32--39 elapsed days. Twenty-seven underwent proctectomy; reasons for unresectability included persistent locally advanced disease (6 cases) and progressive distant metastatic disease with stable or smaller local disease (4 cases). Actuarial 3-year survival was 82% for the group as a whole. Among resected cases the 3-year local control and freedom from disease relapse were 86% and 69%, respectively.Twenty-four of the lesions (65%) achieved an objective clinical response by size criteria, including 9 (24%) with pCR at the primary site (documented T0 at surgery). The most important factor for pCR was tumor volume: small lesions with planning target volume (PTV) < 200 cc showed a 50% pCR rate (p = 0.02).There were no treatment associated fatalities. Nine of the 37 patients (24%) experienced Grade 3 or 4 toxicities (usually proctitis) during preoperative treatment. There were an additional 7 perioperative and 2 late toxicities. The most important factors for small bowel toxicity (acute or late) were small bowel volume (> or = 150 cc at doses exceeding 4000 cGy) and large tumor (PTV > or = 800 cc). For rectal toxicity the threshold is PTV > or = 500 cc. CONCLUSION: 3D planned boost therapy is feasible. In addition to permitting the use of nonaxial beams for improved dose distributions, 3D planning provides tumor and normal tissue dose-volume information that is important in interpreting outcome. Every effort should be made to limit the treated small bowel to less than 150 cc. Tumor size is the most important predictor of response, with small lesions of PTV < 200 cc most likely to develop complete responses.