一个多发性内分泌腺瘤病2A型家系新的RET原癌基因突变方式

目的 探讨一个多发性内分泌腺瘤病2A型(MEN2A)家系的临床表现和RET原癌基因突变方式.方法 对一个MEN2A家系成员进行临床调查,提取其中3例具有典型临床表现的患者及15个家庭成员的外周血淋巴细胞DNA,对RET原癌基因的第8、10、11、13～16外显子进行DNA测序分析,并对发现突变的PCR产物进行亚克隆测序.结果 该家系先证者系30岁起先后确诊为嗜铬细胞瘤和甲状腺髓样癌的男性,其一姐患有嗜铬细胞瘤、一弟患有甲状腺髓样癌.在这3例患者及另外2例未发病的家庭成员中,发现了RET原癌基因第11号外显子存在相同的杂合突变,即1893-1895delCGA,系一种新的突变类型.结论 RET原癌基因第11号外显子1893-1895delCGA杂合突变,是一种新突变,可能为该MEN2A家系的致病基因.     

多发性内分泌腺瘤2A 型家系的临床筛查及预防性甲状腺全切除术

目的：探讨多发性内分泌腺瘤2A型（multiple endocrine neoplasia type 2A,MEN 2A）家系筛查的临床意义和进行预防性甲状腺全切除的可行性和有效性。方法对一个MEN 2A家系行家系调查,提取外周血行RET原癌基因和降钙素检测,并对无症状的基因突变携带者行预防性甲状腺全切除术。结果基因检测该家系为RET原癌基因第11外显子第634位点TGC→CGC杂合错义突变,即p．C634R突变,与MEN 2A患者临床表型-甲状腺髓样癌（ medullary thyroid carcinoma ,MTC）或MTC伴肾上腺嗜铬细胞瘤（ pheochromocytom ,PHEO）完全共分离。6例MEN 2A中,男4例,女2例;首次诊断平均年龄33.5（19～65）岁;MTC平均直径2.3（0.7～5.2）cm。其中3例以颈部占位或伴腹泻就诊,接受了不规范的甲状腺切除术或＋双侧Ⅵ区淋巴结清扫或＋侧颈部淋巴结清扫;T2N1bM02例,T3N1bM01例。3例无症状者中2例行预防性甲状腺切除＋双侧Ⅵ区淋巴结清扫,另1例行双侧甲状腺全切除＋双侧Ⅵ区淋巴结清扫＋右侧颈淋巴结清扫术;T1N0M02例,T1N1bM01例。仅见1例无症状者伴发左侧PHEO（1/6）并优先于MTC接受了左侧PHEO切除。6例术后4例降钙素仍升高,其中有症状中的1例（ T3N1bM0）先后接受了4次颈部手术,仍于首次术后130个月出现多处骨转移伴骨痛（T3N1bM1）,服用范得他尼2个月后骨痛消失,至今带瘤生存32个月;另外有症状和无症状者各1例（T2N1bM0和T1N1bM0）,分别在首次术后6、7个月接受了再次手术,包括另1例未再次手术的有症状者（T2N1bM0）,3例至今分别已22、22和20个月,降钙素仍升高。其余2例无症状患者（T1N0M0）术后已随访20个月,降钙素均＜2.0 ng/L。结论对MEN 2A家系进行临床筛查,有利于早期诊断和治疗,改善预后;术前整合RET基因和降钙素检测,对无症状基因突变携带者进行预防性全甲状腺切除是可行、有效的。     

Targeted therapy for NSCLC with driver mutations

Introduction: Activating mutations of the epidermal growth factor receptor (EGFR) gene and rearrangement of anaplastic lymphoma kinase (ALK) gene best illustrate the therapeutic relevance of molecular characterization in non-small cell lung cancer (NSCLC) patients. Several genetic aberrations with a potential prognostic or predictive role have been identified, mainly in adenocarcinoma subtype, including ROS1, RET, MET, HER2, BRAF and KRAS. More recently oncogenic drivers, such as DDR2, FGFR1 and PI3KCA, have been characterized in squamous cell lung carcinoma (SCC) and target agents are currently under evaluation. The aim of this review is to summarize the growing scenario of new targetable oncogenes in NSCLC.

Areas covered: For this review article all published data on NSCLC genomic alterations, including the techniques employed for oncogenic drivers identification, the prevalence of each one in lung cancer subtypes, the preclinical data corroborating their role in tumorigenesis and the potential biological tailored agents tested and under evaluation were collected and analyzed using PubMed.

Expert opinion: Oncogenic products represent reliable targets for drug therapy and the expanding knowledge of molecular pathways involved in lung tumorigenesis is resulting in a dramatic change of treatment strategies leading to an improvement in disease and symptom control, extending life duration and improving quality of life.     

RET,a targetable driver of pancreatic adenocarcinoma

Pancreatic ductal adenocarcinoma (PDA) remains a deadly disease, affecting about 40,000 individuals in the United States annually. We aimed to characterize the role of RET as a co-driver of pancreas tumorigenesis. To assess the role of RET as a co-driver of PDA, we generated a novel triple mutant transgenic mouse based on the cre-activated p53^R172H gene and a constitutively active RET ^M919T mutant (PRC). Survival analysis was performed using Kaplan–Meier analysis. Study of human PDA specimens and Pdx-1-Cre/Kras^G12D /p53^R172H (KPC) mice revealed that RET is upregulated during pancreas tumorigenesis, from inception through precursor lesions, to invasive cancer. We demonstrated that activation of RET is capable of inducing invasive pancreatic carcinomas in the background of the P53 inactivation mutation. Compared to KPC mice, PRC animals had distinct phenotypes, including longer latency to tumor progression, longer survival, and the presence of multiple macrometastases. Enhanced activation of the MAPK pathway was observed as early as the PanIN 2 stage. Sequencing of the exonic regions of KRAS in PRC-derived PDA cells revealed no evidence of KRAS mutations. RET can be an essential co-driver of pancreatic tumorigenesis in conjugation with KRAS activity. These data suggest that RET may be a potential target in the treatment of PDA.     

罕见RET 原癌基因Y606C 突变所致家族性甲状腺髓样癌家系临床特点分析*

目的：分析讨论RET 原癌基因Y 606C 这一罕见突变所致家族性甲状腺髓样癌（familial medullary thyroid carcinoma ,FMTC）的临床生物学特点。方法：对先期确诊的1 个携带RET 原癌基因Y 606C 种系突变的FMTC 家系成员进行RET 基因种系突变筛查,同时行血清降钙素、甲状旁腺素、颈腹部超声等相关临床检查,对患病成员和携带者给予临床干预,并总结分析上述病例临床生物学特点。结果：包括先证者在内,该家系中10例参与基因筛查,发现6 例携带RET 基因第10外显子Y 606C 突变。其中3 例确诊为FMTC 患者（含先证者）,均为女性,平均发病年龄50.0（47～53）岁。发病成员临床均表现为甲状腺肿物伴降钙素升高,未发现甲状旁腺和肾上腺病变。2 例行全甲状腺切除术,1 例行患侧腺叶切除术。术后病理均确诊为甲状腺髓样癌,其中2 例病理分期均属早期,术后随访期间均达生化治愈。家系中另有3 例为突变携带者,平均年龄33.0（15～55）岁。其中2 例颈部超声均提示甲状腺肿物（考虑良性）,另1 例颈部超声未见异常。除1 例拒绝降钙素检测外,其余2 例血清降钙素均正常范围,建议定期复查。结论：RET 原癌基因Y 606C 突变可以导致FMTC 发病,家系成员发病平均年龄较大,肿瘤分期较早,生化治愈率高,预后较好;家系成员基因检测结合颈部超声和降钙素检查有利于甲状腺髓样癌的早期诊断;对于无症状Y 606C 突变携带者,应根据其降钙素水平及颈部超声检查情况实施个体化临床处置。     

A novel susceptibility locus for Hirschsprung's disease maps to 4q31.3-q32.3

We report on a multigenerational family with isolated Hirschsprung's disease (HSCR). Five patients were affected by either short segment or long segment HSCR. The family consists of two main branches: one with four patients (three siblings and one maternal uncle) and one with one patient. Analysis of the RET gene, the major gene involved in HSCR susceptibility, revealed neither linkage nor mutations. A genome wide linkage analysis was performed, revealing suggestive linkage to a region on 4q31-q32 with a maximum parametric multipoint LOD score of 2.7. Furthermore, non-parametric linkage (NPL) analysis of the genome wide scan data revealed a NPL score of 2.54 (p = 0.003) for the same region on chromosome 4q (D4S413-D4S3351). The minimum linkage interval spans a region of 11.7 cM (12.2 Mb). No genes within this chromosomal interval have previously been implicated in HSCR. Considering the low penetrance of disease in this family, the 4q locus may be necessary but not sufficient to cause HSCR in the absence of modifying loci elsewhere in the genome. Our results suggest the existence of a new susceptibility locus for HSCR at 4q31.3-q32.3.     

Cognitive style and counselor credibility: Effects on client endorsement of Rational Emotive Therapy

This study investigated the effects of cognitive style, as assessed by the Thinking/Feeling scale of the Myers-Briggs Type Indicator, and counselor credibility on attitudes toward a Rational-Emotive Therapy (RET) session. Eighty-eight undergraduates, classified as either Thinking or Feeling types, heard an audiotape segment of an RET counseling session with a counselor introduced as either high or low credibility. Given the emphasis placed on cognitive processing in RET, it was predicted that Thinking subjects would have more favorable attitudes toward the counselor and the counseling approach than would Feeling types. It also was hypothesized that this effect would be enhanced when the counselor was introduced as highly credible and minimized with a low credibility introduction. Results supported these predictions.     

Video-assisted thyroidectomy: indications and results

Background and aims Minimally invasive video-assisted thyroidectomy (MIVAT) was set up and introduced in our department in 1998. Its results, after an acceptable relapse, can now be evaluated, also speculating on new possible indications. Patients and methods The procedure is based on a unique incision in the central neck, 2 cm above the sternal notch, using small conventional retractors and needlescopic (2 mm) reusable instruments. Haemostasis is achieved by a harmonic scalpel. Patients, 833, underwent MIVAT since June 1998. There were 715 females and 118 males (ratio 4:1). Lobectomy was carried out in 323 (38.7%) patients, total thyroidectomy in 510 (61.2%) patients. Results Mean operative time of lobectomy was 36.2 min (range: 20–120); for total thyroidectomy, 46.1 min (30–130). Conversion to standard cervicotomy was required in 16 cases (1.9%); Operative complications were represented by transient monolateral recurrent nerve palsy in eight cases (0.9%), definitive monolateral recurrent nerve palsy in seven cases (0.8%). Twenty patients exhibited a hypoparathyroidism, which corresponds to 3.9% of total thyroidectomies performed, but only two showed permanent hypoparathyroidism (0.3%). Conclusion MIVAT can be considered a safe operation offering significant cosmetic advantages with possible new promising indications such as prophylactic thyroidectomy in rearranged during transfection (RET) gene mutation carriers. It is still limited to a minority of patients, in particular, in endemic goitre countries. Electronic Supplementary Materials Supplementary material is available for this article at Presented at the International Symposium, Modern Technologies in Thyroid Surgery”, 10–11 February 2006, Halle/Saale, Germany.