增强扫描对基于4DCT胸段食管癌GTV勾画及IGTV构建的影响

目的 探讨增强扫描与否对基于4DCT勾画的胸段食管癌原发肿瘤各时相GTV差异及对IGTV构建的影响。方法 25例胸段食管癌患者,胸上段8例、胸中段9例、胸下段8例,自由呼吸状态下序贯完成普通4DCT与增强4DCT扫描,同一勾画者按照同一标准先在平扫4DCT各图像上勾画GTV并构建相应IGTV。1个月后同一勾画者再在增强4DCT图像上勾画GTV并构建相应IGTV。结果 基于增强扫描图像勾画的靶区变异系数小于平扫图像勾画的(P=0.000),但胸上、下段食管癌患者二者的GTVz轴长度、GTV、IGTV均相近(P=0.529、0.110;P=0.158、0.416;P=0.147、0.615),而对胸中段食管癌患者二者的GTVz轴长度、GTV、IGTV不同(P=0.005、0.035、0.021)。结论 对胸中段食管癌患者,增强4DCT扫描可减小靶区勾画误差并可构建相对精确的IGTV,而对胸上、下段食管癌患者靶区勾画及IGTV构建无显著影响。     

部分乳腺外照射自主呼吸控制不同呼吸状态靶区体积重合度的研究

目的 探讨保乳术后部分乳腺外照射(EB-PBI)自主呼吸控制(ABC)不同呼吸状态体积重合度及其差异,从靶区体积重合的角度,表述ABC辅助呼吸运动对EB-PBI分次内靶区位移的影响.方法 对术腔放置银夹拟行EB-PBI的患者行乳腺托架固定ABC辅助CT模拟定位,同时采集适度深吸气呼吸控制(mDIBH)状态、自由呼吸(FB)状态、深吸气呼吸控制(DEBH)状态各2套CT图像.应用Pinnacle3治疗计划系统,进行2套mDIBH图像间、2套FB图像间、2套DEBH图像间及mDIBH与DEBH图像间自动融合,计算融合图像.选定进行融合的2套图像的大体肿瘤体积(GTV)、临床靶区体积(CTV)、计划靶区体积(PTV)的重合度,比较同一配准中3种靶区各自重合度间及不同配准中同一种靶区重合度间的差异.结果 mDIBH/mDIBH配准中,GTV/GTV、CTV/CTV和PTV/PTV重合度分别为(83.54±11.41)%、(93.00±6.49)%和(95.26±4.90)%,GTV/GTV与CTV/CTV、GTV/GTV与PTV/PTV重合度间差异均有统计学意义(P＜0.05),而CTV/CTV与PTV/PTV重合度间差异无统计学意义(P＞0.05).FB/FB配准中,GTV/GTV、CTV/CTV、PTV/PTV重合度分别为(72.55±29.10)%、(89.36±9.53)%和(92.47±7.25)%,GTV/GTV与CTV/CTV、CTV/CTV与PTV/PTV重合度间差异均无统计学意义(均P＞0.05),而GTV/GTV与PTV/PTV重合度间差异有统计学意义(P＜0.05).DEBH/DEBH配准中,GTV/GTV、CTV/CTV、PTV/PTV重合度分别为(79.48±22.31)%、(92.83±6.77)%和(95.05±4.81)%,3组靶区两两间重合度差异均有统计学意义(均P＜0.05).mDIBH/mDIBH与DEBH/DEBH间、mDIBH/mDIBH与FB/FB间、FB/FB与DEBH/DEBH间的GTV、CTV和PTV重合度差异均无统计学意义(均P＞0.05),而mDIBH/mDIBH与mDIBH/DEBH间、FB/FB与mDIBH/DEBH间的GTV、CTV和PTV重合度差异均有统计学意义(均P＜0.05).结论 ABC辅助实施EB-PBI,两次mDIBH间、两次FB间和两次DEBH间各靶区体积重合度差异不明显,且三者的PTV/PTV重合度均达到较高水平.因此,从靶区重合度的角度,若施照前进行在线摆位误差校正,EB-PBI实施进行呼吸控制的必要性值得商榷.     

不同大体肿瘤体积纵轴外扩长度在食管鳞癌根治性放化疗中的疗效比较

目的:比较食管癌选择性淋巴结区域照射（elective node irradiation ,ENI）基础上原发病灶大体靶区纵向外扩不同长度的生存差异,探讨食管鳞癌（esophageal squamous cell cancer,ESCC）临床靶区的优化。方法:回顾性分析2009年5 月至2012年11月厦门大学附属第一医院行放化疗初治的ENI 的ESCC患者。根据大体靶区纵向外扩长度不同分为纵向外扩范围≤ 3 cm组及> 3 cm组,依次命名为临床肿瘤体积1 组（clinical tumor volume of group1,CTV 1）及临床肿瘤体积2 组（clinical tumor volume of group 2,CTV 2）,比较不同纵向外扩长度的临床肿瘤体积（clinical tumor volume ,CTV ）分组的生存率及不良反应差异。结果:142 例患者纳入研究,其中CTV 1 组81例,CTV 2 组61例,两组生存差异及不良反应的发生率差异均无统计学意义。结论:基于ENI 的ESCC原发病灶纵向外扩3 cm形成的CTV 照射后的生存率不低于GTV 纵向外扩> 3 cm的CTV 照射。建议选择性淋巴结区域照射时GTV纵轴外扩≤ 3 cm。      

基于4DCT的食管癌靶区运动的初步研究

目的 探讨4DCT下的平静呼吸状态食管癌靶区运动特征。方法 20例食管癌患者在平静呼吸状态下采用4DCT采集食管肿瘤运动信息,勾画GTV,测量并记录每个GTV等中心点坐标、体积,并计算中心点在不同呼吸时相的移动距离及体积变化情况。结果 同段食管癌靶区中心在头脚方向位移(0.521±0.319) cm,较左右方向的(0.169±0.083) cm、前后方向的(0.167±0.095) cm均大(P均<0.05)(颈段P=0.009;胸上段P=0.016;胸中段P=0.000)。不同段食管癌靶区中心在同一方向最大位移不同(左右P=0.023;前后P=0.212;头脚P=0.007)。各呼吸时相中食管癌运动规律并不完全一致,以T0时相为基准时相,食管癌GTV等中心点在T50时相时各三维方向上的位移最大。呼气末与吸气末食管靶区体积无变化(P=0.313)。结论 同段食管癌靶区在不同方向运动幅度不同,不同段病灶同一方向的运动幅度也不同,行精确放疗时应综合考虑。对于颈段及胸中上段食管癌,依据吸气末和呼气末融合图像获得ITV可行。颈段及胸中上段食管靶区在呼吸周期中形变不明显。     

基于放疗中重复四维CT的食管癌大体肿瘤体积位移变化的比较研究

目的 基于重复四维CT (4DCT)模拟定位增强扫描探讨放疗中胸段食管癌原发肿瘤分次放疗内靶区位移变化。方法 29例胸段食管癌患者分别于放疗前及放疗10、20、30次时行4DCT模拟定位增强扫描,获得各时相原发肿瘤大体肿瘤体积(GTV)及内大体肿瘤体积(IGTV)。比较同次4DCT扫描所得胸上、中、下段食管癌GTV三维方向位移差异,各时段4DCT扫描所得同段食管癌GTV间同一方向位移差异及疗程中IGTV空间位置和体积变化。结果 胸中段患者初次及放疗20次时GTV位移在左右、前后、上下方向均不同(P=0.000~0.016),放疗10次时GTV位移上下与左右、前后方向均不同(P=0.000~0.006);胸下段患者初次及放疗10、20次时GTV位移上下与前后方向也不同(P=0.004~0.013);放疗疗程中不同治疗时段间GTV同一方向位移均相似(P=0.102~0.823)。疗程中IGTV空间位置变化不明显(P=0.689~0.999),而其体积在放疗20次时缩小最明显(P=0.012~0.029)。结论 放疗疗程中不同时段同一部位食管癌同一方向位移变化并不明显,尽管放疗20次时IGTV明显缩小但疗程中其空间位置变化不大。     

三维CT与四维CT确定食管癌原发肿瘤内在大体肿瘤体积比较研究

目的 比较基于三维CT (3DCT)和四维CT (4DCT)4种方法确定的食管癌内在大体肿瘤体积(IGTV)位置、体积及匹配指数(MI)的差异。方法 13例食管癌患者于同次CT模拟定位时序贯完成3DCT和4DCT扫描,并依据国际抗癌联盟或美国癌症研究联合会食管分段标准分为胸上段组(A组)和胸中下段组(B组)。采用4种方式获得IGTV:4DCT 10个呼吸时相的GTV融合得到IGTV₁₀;0%和50%时相融合得到IGTV₂;在最大密度投影(MIP)图像上勾画得到IGTV_MIP;基于3DCT图像上GTV依据4DCT图像测得的靶区运动范围外扩得到IGTV_3D。结果 A组左右、前后、上下方向位移差异无统计学意义(0.11、0.09、0.18 cm,χ²=1.06,P=0.589);B组上下方向位移>左右、前后方向(0.47、0.15、0.12 cm,χ²=12.00,P=0.002)。A组IGTV₁₀与IGTV₂、IGTV_3D靶区中心三维方向位移差异均无统计学意义(t=－2.24~0.00,P=0.089~1.000),MI分别为0.88、0.54。B组IGTV₁₀和IGTV_3D靶区中心左右、前后、头脚位移差异无统计学意义(t=－0.80、－0.82、－1.16,P=0.450、0.438、0.285),MI为0.59;而IGTV₁₀和IGTV₂靶区中心位移在左右方向差异有统计学意义(t=2.97,P=0.021),MI为0.86。IGTV_MIP体积10(t=－2.84,P=0.025),IGTV_MIP和IGTV₁₀靶区中心左右、前后、头脚位移差异无统计学意义(t=－0.25、0.84、－1.22,P=0.809、0.429、0.263),IGTV₁₀对IGTV_MIP的MI为0.78。结论 对胸段食管原发肿瘤,基于4DCT图像进行靶区勾画在保证靶区覆盖率的同时缩小了内靶体积,但IGTV₂ 和IGTV_MIP均不能包含食管原发肿瘤的全部运动信息。     

三维CT与四维CT确定胸段食管癌计划靶体积比较研究

目的 比较基于三维CT (3DCT)和四维CT (4DCT)构建的胸段食管癌原发肿瘤计划靶体积(PTV)的位置及体积差异性。
方法 43例胸段食管癌患者于同次CT模拟定位时序贯完成3DCT和4DCT扫描。通过4DCT获取自由呼吸状态下靶区中心点三维方向最大位移,依据靶区位移不均匀外扩获取PTV 3D ,常规外扩获取PTV conv ,PTV 4D 则通过4DCT的10个时相靶区融合获得。
结果 胸上、中、下段食管癌患者PTV3D和PTVconv与PTV4D中心点位置差异三维方向上中位数均<03cm,PTV4D/PTV3D分别为0.80、0.88、0.71,PTV4D/PTVconv分别为0.67、0.73、0.76(χ2=－3.18、－2.98、－3.06,P=0001、0003、0002)。胸上、中、下段食管癌PTV3D与PTV4D靶区相似度中位数分别为0.87、0.90、0.81,PTVconv与PTV4D的分别为0.80、0.84、0.83(χ2=－3.18、－2.98、－3.06,P=0.001、0.003、0.002)。三组患者PTV3D及PTVconv对PTV4D的包含度差异均<2%。胸上、中段食管癌PTV3D造成正常组织受照体积比PTVconv降低了11.81%、11.86%,胸下段食管癌增加了2.93%。
结论 对胸中上段食管癌3DCT不均匀外扩构建的PTV与4DCT构建的PTV符合度较好,对胸下段食管癌常规外扩构建的PTV与4DCT构建的PTV符合度相对较为理想。     

3D-CT勾画的食管胃结合部癌放疗疗程中靶区体积和位移变化研究

目的 三维适形放疗过程中靶区各方向的位移差异很大,有关食管胃结合部癌适形放射治疗过程中靶区位移的研究较少.本研究基于三维CT(three dimensional computed tomography,3D-CT)探讨食管胃结合部癌三维适形放疗(three dimensional conformal radiotherapy,3D-CRT)疗程中靶区位移和体积变化.方法 选取2014-01-01-2015-12-31山东大学附属山东省肿瘤医院行3D-CRT的20例食管胃结合部癌患者,基于放疗前3D-CT定位图像勾画原发肿瘤大体肿瘤体积(gross tumor volume,GTV)并定义为GTV1,基于GTV1构建相对应的临床靶区体积(clinical target vol-ume,CTV)和计划靶区体积(planning target volume,PTV)并分别定义为CTV1和PTV1;放疗至15～20次时重复定位,基于复位3D-CT扫描图像勾画GTV并定义为GTV2,构建CTV2和PTV2.比较初次和重复定位GTV体积变化和中心位移,计算初次和重复定位靶区间包含度(degree of inclusion,DI)和匹配指数(matching index,MI).结果 GTV靶区中心位移中位数分别为X轴1.7 mm,y轴2.5 mm,Z轴3.0mm,但是3个方向位移差异无统计学意义,P=0.142;GTV1和GTV2间MI1、PTV1和PTV2间MI2分别为51.75％和69.39％;GTV2对GTV1的DI1、PTV2对PTV1的DI2分别为81.49％和84.33％;GTV2较GTV1体积缩小平均15.98 cm3,体积回缩率为25.26％.PTV、GTV的MI和DI与GTV几何中心在X、y、Z轴的位移成负相关,相关性最强的是GTV DI、MI与GTV几何中心在X、Z轴上的位移.GTV靶区中心在X、y、Z轴上的位移,在临床分型之间差异无统计学意义,GTV靶区中心在X轴的位移在3种病理类型之间差异有统计学意义,P=0.027.结论 在放疗过程中,食管胃结合部癌的体积变化和靶区中心位移是明显的,因此有必要重复定位以重新勾画靶区,保证放疗计划的合理性,减少脱靶体积及不必要正常组织照射.     

PET-CT定位图像上医生对肺癌大体肿瘤体积和临床靶体积定义的影响

目的 研究医生在PET-CT图像上对勾画肺癌大体肿瘤体积(GTV)和临床靶体积(CTV)的影响.方法 选取10例2008-2009年间PET-CT定位的肺癌患者,由本科胸组4位主任医生和副主任医生各自独立确定其GTV、CTV.比较每位患者GTV、CTV的平均值、最大值/最小值、变异系数(标准差/平均值);同时比较CTV外轮廓边界位置并计算其系统误差.结果 GTV、CTV最大值与最小值比的平均值分别为1.66、1.65,变异系数分别为0.20、0.17,体积差异较大原因主要为同侧肺门和纵隔淋巴结区域不同.CTV头脚方向与左右、前后方向系统误差分别为0.48 cm与0.37、0.32 cm (F=0.40、0.60、0.15,P=0.755、0.618、0.928).结论 不同放疗科医生在肺癌患者PET-CT定位图像上定义靶区存在差异,GTV、CTV最大值与最小值比的平均值均在1.7以下,差异较大主要原因为位于肺门或纵隔淋巴结区域.CTV头脚方向系统误差较左右和前后方向稍大但均<5 mm.

Abstract：

Objective To study the variation of gross tumor volume (GTV) and clinical target volume (CTV) definition for lung cancer between different doctors.Methods Ten lung cancer patients with PET-CT simulation were selected from January 2008 to December 2009.GTV and CTV of these patients were defined by four professors or associate professors of radiotherapy independently.Results The mean ratios of largest to smallest GTV and CTV were 1.66 and 1.65, respectively.The mean coefficients of variation for GTV and CTV were 0.20 and 0.17, respectively.System errors of CTV definition in three dimension were less than 5 mm, which was the largest in inferior and superior (0.48 cm,0.37 cm,0.32 cm;F=0.40,0.60,0.15,P=0.755,0.618,0.928).Conclusions The variation of GTV and CTV definition for lung cancer between different doctors exist.The mean ratios of largest to smallest GTV and CTV were less than 1.7.The variation was in hilar and mediastinum lymphanode regions.System error of CTV definition was the largest (<5 mm) in cranio-caudal direction.     

胸段食管癌原发灶靶区位移及影响因素分析

目的 基于4DCT扫描探讨胸段食管癌原发肿瘤靶区(GTV)三维方向位移及其影响因素。方法 65例胸段食管癌患者在自由呼吸状态下完成4DCT、3DCT模拟定位,获取呼吸周期中GTV左右(LR)、前后(AP)和上下(SI)方向位移,记录GTV上下缘与主动脉弓及隆突下缘、双侧膈顶距离。依据年龄、性别、肿瘤部位、病理类型、体积和长度分组,分析上述因素对GTV位移的影响及肿瘤上下缘位置差异与位移相关性。结果 GTV在LR、AP、SI方向位移分别为0.15、0.12、0.34 cm,胸下段GTV在LR及AP方向位移明显大于上、中段(P=0.036、0.014),SI方向相似(P=0.123)。性别、年龄及体重指数差异对GTV位移无影响(P_LR=0.46、0.96、0.73,P_AP=0.924、0.594、0.865,P_SI=0.955、0.264、0.139),肿瘤长度差异仅对LR方向位移有影响(P=0.014);GTV位移与淋巴结存在与否无相关性(P=0.502、0.665、0.815),但与其上下缘距离气管隆突距离呈负相关(P=0.000~0.014)。结论 平静呼吸状态下胸段食管癌GTV的SI方向位移最大,而年龄、性别、体重等及纵隔转移淋巴结存在与否并不影响靶区外扩范围,靶区分次内外扩范围应参照肿瘤分段及食管癌与气管隆突的毗邻关系。     

Experience in the treatment of synchronous and metachronous carcinoma of the oesophagus and the head and neck

BACKGROUND AND OBJECTIVES: Treatment of multiple primary squamous cell carcinomas of the head and neck and oesophagus is controversial. The poor prognosis of these 2 types of carcinoma taken individually and their anatomic proximity complicate the therapeutic strategy and limit the treatment choices for each location. METHODS: From 1986 to 1998, 43 patients received curative treatment for multiple synchronous (n = 30) or metachronous (n = 13) primary neoplasms of the oesophagus and head and neck. For synchronous cancers, the therapeutic strategy consisted of first curing the head and neck cancer and then planning oesophagectomy according to the type of head and neck cancer therapy. RESULTS: Ten total oesopharyngolaryngectomies and 33 subtotal oesophagectomies were performed. The postoperative mortality rate was 9.3% (4/43). The rate of anastomotic leakage was 30% (13/43), and all such leaks were cervical. Pulmonary infection occurred in 19% of cases (8/43). A past history of cervical radiation therapy or cervicotomy did not appear to be a significant risk factor for anastomotic leakage or pulmonary complications. Oesophagectomy did not affect the functional results in the 31 patients whose larynx could be preserved. CONCLUSIONS: Oesophagectomy after head and neck cancer treatment is possible with a low mortality rate and acceptable morbidity.     

Clinicopathological study of carcinomas of the lip and the mucosa of the upper and lower lips

BACKGROUND: Lip carcinomas are rare oral tumors, and there have been few reports of lip carcinoma in Japan. METHODS: Of 914 patients with oral carcinomas treated between January 1980 and December 1998, 12 (1.3%) had lip carcinoma and 5 (0.5%) had lip mucosal carcinoma. We investigated the clinicopathological features of these 17 patients. RESULTS: Of the 12 patients with carcinoma of the lip, 10 had squamous cell carcinomas (9, external lower lip; 1 commissures) and 2 had mucoepidermoid carcinomas (external upper lip). Of the 5 patients with lip mucosal carcinoma, 3 had squamous cell carcinomas (2, mucosa of the lower lip; 1, mucosa of the upper lip), 1 had mucoepidermoid carcinoma (mucosa of the lower lip), and 1 had acinic cell carcinoma (mucosa of the lower lip). Of the 12 patients with lip carcinoma, 9 were classified as stage I, 2 as stage II, and 1 as stage III; all 5 of the patients with lip mucosal carcinoma were stage I. Five patients with lip carcinoma were treated by resection, 5 by a combination of resection and reconstruction, and 2 by radiotherapy alone. All patients with lip mucosal carcinoma were treated by resection. After the initial therapy, 3 patients without neck dissection had regional recurrences and received delayed neck dissection, and 2 died with neck regional recurrence after dissection. The 5-year cumulative survival rates of the patients with lip carcinoma and those with lip mucosal carcinoma were 82.5% and 80.0%, respectively. CONCLUSION: We suggest that early-stage carcinomas of the lip and of the mucosa of the upper and lower lips are frequent, and we found that the outcome of these patients was excellent. However, an aggressive therapeutic approach to the lip carcinoma patient with cervical metastasis appears warranted, in an attempt to improve locoregional control and ultimate survival.     

The relation between the aging of the steroid generating system and the geneses of cancers of the stomach, the breast and the uterine cervix

The purpose of the present study is to test the validity of the steroid carcinogenesis hypothesis in humans by investigating the problem whether or not a cancer-specific change of the hormonal milieu emerges at a specified stage of life where the growth rate of cancer risk is at its zenith. A case-control study of 14 urinary steroid excretions was conducted for each of 3 human neoplasias. The identification and the size (in parenthesis) of the population units used in this study were,given as follows: a) the male gastric cancer group (421); b) the male control group (104); c) the female breast cancer group (245); d) the cervical cancer group (345); e) the female control group (127). Two kinds of steroid parameters were employed for the statistical analysis of hormonal data: a) the logarithm of a steroid excretion figure (mu g/day), as expressed by log x; b) the logarithm of a relative weight of a given steroid to tetrahydrocortisol, as expressed by log x/THF. The case-control difference for each parameter was expressed in terms of a t-value of Student's t-test. The steroid deviation profile was prepared for each neoplasia and for each of the log x data set and the log x/THF data set. The results obtained are as follows: a) the 2 steroid parameters (log x and log x/THF) for each of 14 urinary steroids were both subject to change with the progress of host age. The rate of age-dependent change was different for each steroid parameter and for each population unit. b) The above differential age dependency of the steroid parameters gave rise to a continual transition of the steroid deviation profile in the course of aging. c) The hormonal traits of male gastric cancer, female breast cancer and cervical cancer were described each as a complex of androgen depression and glucocorticoid stimulation (male gastric cancer), a sequential emergence of premenopausal progestin depression and postmenopausal predominance of glucocorticoid over androgen (female breast cancer), and a complex of androgen-glucocorticoid depression over progestin (cervical cancer). d) The emergence of the above cancer-specific steroid disorders chronologically coincided with the quasiexponential growth phase of cancer risk (and slow growth phase of cancer risk in postmenopausal breast cancer). e) The usefulness of the log x/THF type deviation profile for the assessment of the hormonal milieu of the host was verified by both theoretical approach to the problem and its application to the real data of a case-control study. f) The age dependent decline of androgens was generally much faster in their progressions than that of glucocorticoids - a finding to suggest the possibility that the production of a cancer-specific steroid deviation profile might have taken the form of the stress shift of Hans Selye, since both phenomena share depletion of gonadal steroids relative to glucocorticoid in common. The etiological relevancy of the 3 cancer-specific steroid changes to the geneses of 3 cancers:was discussed in the light of the experimental pathology studies in our laboratory as well as in other laboratories.     

Degree of manifestation of therapeutic pathomorphosis and the nature of the change in the estrogen and progesterone receptors after the radiation and chemotherapy of breast cancer

Estradiol and progesterone receptor levels were measured in 130 patients with stage III breast tumors before treatment and following preoperative radiation or chemotherapy. The data were evaluated versus the morphologic features of posttreatment pathomorphosis of tumor. Standard fractionated radiation (total dose of 70 Gy) was followed by pronounced postradiation pathomorphosis and a decrease in the level and incidence of steroid receptors in 72.7-87.5%. The essentially unchanged receptor profile of tumor following large-fraction (total dose-20 Gy) irradiation as well as presence of estradiol and progesterone receptors in the originally receptor-negative neoplasms after chemotherapy were matched by a slight degree of pathomorphosis.     

Effect of freezing the helix and the rim or edge of the human and pig ear

We have studied the effect of increasing freeze times on the normal pig's ear and on a variety of lesions of the human ear. The clinical and laboratory data suggest that cartilage necrosis secondary to cryosurgery is a dose-related phenomenon and is uncommon with the freeze times used in clinical practice. Cryosurgery is an effective and cosmetically acceptable treatment for superficial skin lesions of the ear.     

Patient-reported outcomes: Assessment and current perspectives of the guidelines of the Food and Drug Administration and the reflection paper of the European Medicines Agency

AimsPatient-reported outcomes (PROs) have recently gained greater credibility with regulatory bodies aiming to standardise their use and interpretation in RCTs, thereby supporting medicinal product submissions. For this reason, the United States (US) Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) have released guidelines. This review paper provides an overview of the current perspectives and views on these guidelines.MethodTo evaluate the FDA and EMEA PRO guidelines, 47 expert responses to the FDA guidance were qualitatively reviewed. Two reviewers independently extracted data from these letters and checked these responses to warrant consistency and agreement in the evaluation process. A PubMed literature review was systematically examined to obtain supporting evidence or related articles for both the guidance documents.ResultsGenerally, there is agreement between regulatory authorities and the research community on the contents of the FDA and EMEA PRO draft guidance. However, disagreements exist on significant philosophical topics (e.g. the FDA focuses more on conceptual models and symptoms than the EMEA) and design topics (e.g. the FDA is more restrictive on issues of recall bias, blinding of oncology trials and degrees of psychometric validation than researchers and the EMEA). This could influence the approval of PRO claims.ConclusionPRO guidance from the EMEA and FDA has been valuable, and has raised the profile and active debate of PROs in oncology. However, our review of the current opinion shows that there are controversial aspects of the guidance. Consequently, greater latitude should be given to how the guidance is interpreted and applied.     

Urbanization and the incidence of abnormalities of squamous and glandular epithelium of the cervix

BACKGROUND: The large data bases of the Dutch cervical screening program can be exploited to establish the relation between urbanization and the incidence of abnormalities of the squamous and glandular epithelium, including mild or greater changes of the squamous and glandular epithelium of the cervix. METHODS: Six cytology laboratories in the context of the Dutch cervical screening program screened over 190,000 cervical smears. Urbanization (place of residence) data were derived from postal codes. All smears were coded with the Dutch national coding system, the Dutch national classification system KOPAC, in which squamous abnormalities are coded S4-S9, and glandular cell changes are coded G4-G9. From the scores per 1000 screened women, the relative risk (RR) of living in a large city compared with living in rural areas was calculated. To investigate a trend in incidence in relation to urbanization, the Schaafsma method was used. RESULTS: Of the smears with positive cytology, mild squamous dysplasia (S4) had the highest incidence per 1000 screened women (4.32), and the lowest incidence was found for adenocarcinoma (in situ; G7/G9; RR, 0.07). The RR for urban women ranged from 1.73 for moderate squamous dysplasia (S5) to 7.55 for adenocarcinoma (in situ; G7/G9). For smears with positive cytology for both squamous and glandular abnormalities, the Schaafsma method indicated a significant positive trend. CONCLUSIONS: The incidence of squamous and glandular abnormalities are maximal in women who live in a large city, which, in The Netherlands, is where there also is a population at high risk for human papillomavirus and bacterial vaginosis.     

Osteonecrosis of the jaw and the role of macrophages

Nitrogen-containing bisphosphonates have been associated with the development of osteonecrosis of the jaws (ONJ), but the lack of reliable epidemiological data and appropriate animal models has restricted our understanding of ONJ pathophysiology and limited its management. The best available information is from histopathologic findings, which implicate bone necrosis and infection, although it is not clear which is primary. However, there are data suggesting that macrophages could well be the central factor in allowing the infection to develop first, followed by local necrosis, which could also account for the development of ONJ in patients treated with denosumab, a human monoclonal antibody to the receptor activator of nuclear factor-κB ligand. This review examines the evidence that macrophages could play a prominent role in development of ONJ and the proposal that it may be more appropriate to view ONJ as a drug and not only a bisphosphonate-related complication.