PTH免疫缩小转移性副甲状腺肿瘤


  July 23, 2004 - 根据发表在7月号临床内分泌学与代谢期刊(Journal of Clinical Endocrinology and Metabolism)上的一项个案试验显示,副甲状腺荷尔蒙(PTH)免疫可让转移性甲状腺癌患者肿瘤的消退与正常化临床上、荷尔蒙与生化参数正常化。
  
  比利时列日市列日大学Sart Timan中心医院D. Betea医师与他的同事指出,转移性副甲状腺癌,主要问题源自于过多PTH失去控制的作用,且造成发病与死亡的主要原因是高钙血症与骨骼疾病;由于副甲状腺癌大部分对化学或放射线疗法效果不佳,因此较难以治疗或转移疾病的治疗选择是受限的。
  
  为了研究PTH免疫的可能性,研究[人员召募了一位50岁患有难以治疗副甲状腺癌,合并肺部转移的女性病患;这位病患于34个月内使用胎牛与修饰后人类PTH片段,以及完整的人类PTH混合Freund's辅助剂。
  
  第2次免疫后2周,已经确认产生所有PTH片段的抗体;第4次免疫后,已经观察到PTH与血中钙离子浓度持续地降低,第5次免疫后1个月,PTH从191 ng/L下降到84.5 ng/L,而血中总钙离子浓度从12.12 mg/dl下降到正常浓度范围(9.48 mg/dl)。
  
  在这一段时间,病患在气喘、恶心与肌肉无力严重度上表现出戏剧化改善;在接下来3个月的时间里,她的食慾恢复正常,体重也增加10公斤,每日摄取液体2公升且已经停止使用利尿剂furosemide。
  
  24个月后追踪发现,离子的与总钙离子浓度仍然维持正常,随之病患产生轻微低血钙症,那时的PTH浓度是48.8 ng/L。
  
  相较于治疗前,第21个月时计算机断层扫描显示,肺部转移肿瘤大小明显地降低(从39.2%-71.4%,P<.05);肺部病灶数目没有增加,骨骼病灶情形也没有恶化。
  
  副作用包括于注射部位产生一个硬的5 公厘大小的肿块合并局部淋巴病变,这个肿块发生溃疡且自发性地愈合,留下一个很小的疤痕。
  
  这是第一个使用于副甲状腺癌,成功地以免疫方式对抗PTH的病例,导致荷尔蒙与生化正常化以及肿瘤消退。研究人员评论指出,即使2年后病患状况仍然很好,但由于这种病灶的生长速度非常缓慢,因此长期预测是不可行的。
  
  在其它副甲状腺肿瘤病患使用类似的免疫疗法,必须要以成功率与风险、利益间的比值作考量;研究人员表示,这项疗法令人满意的结果与良性的副作用,暗示这样的考量应该优先于病患情况恶化或是接受,破坏颈部淋巴组织治疗,包括反覆的颈部手术之前。

PTH Immunization Shrinks Tumor

By Yael Waknine
Medscape Medical News

July 23, 2004 — Parathyroid hormone (PTH) immunization results in tumor regression and normalization of clinical, hormonal, and biochemical parameters in patients with metastatic parathyroid carcinoma, according to a case study presented in the July issue of the Journal of Clinical Endocrinology and Metabolism.

"In metastatic parathyroid carcinoma, the main problems stem from the uncontrolled effects of excess PTH, and the main causes of morbidity and mortality are hypercalcemia and bone disease," write D. Betea, MD, and colleagues at the University of Liége's Centre Hospitalier Universitaire Sart Tilman in Liége, Belgium. "Treatment options for refractory and metastatic disease are limited because parathyroid carcinoma is largely unresponsive to chemo- and radiotherapy."

To investigate the possibility of PTH immunization, investigators recruited a female patient aged 50 years and diagnosed as having refractory parathyroid carcinoma with pulmonary metastases. The patient was immunized eight times over the course of 34 months with bovine and modified human PTH fragments and intact human PTH, mixed with Freund's adjuvant.

Antibodies to all PTH fragments were identified from two weeks after the second immunization onward. A sustained reduction in PTH and serum calcium levels was observed after the fourth immunization, with PTH decreasing from 191 ng/L to 84.5 ng/L and total calcium concentration decreasing from 12.12 mg/dL to within normal range (9.48 mg/dL) by the time of the fifth immunization a month later.

During this time span, the patient showed dramatic improvement in severity of asthenia, nausea, and muscle weakness. During the next three months she regained a normal appetite and 10 kg of body weight. Fluid intake was 2 L daily and furosemide was discontinued.

Ionized and total calcium levels remained normal for more than 24 months of follow-up, whereupon the patient developed mild hypocalcemia with a PTH of 48.8 ng/L.

Computed tomography at 21 months showed a significant decrease in the size of pulmonary metastases from baseline (range, 39.2% - 71.4%; P < .05). There was no increase in number of pulmonary lesions and no progression of skeletal lesions.

Adverse events included firm 5 mm nodules that developed at the injection site in conjunction with local lymphadenopathy. The nodules ulcerated and healed spontaneously, leaving small scars.

"[T]his is the first case of successful immunization against PTH in a patient with parathyroid carcinoma, in which hormonal and biochemical normalization was accompanied by tumor regression," the authors comment, noting that while the patient has been well for more than two years, long-term predictions are not possible due to the slow-growing nature of the lesions.

"Similar immunotherapy in other patients with parathyroid carcinoma needs to be considered both in terms of the possibility of success and the risk/benefit ratio," the authors advise, adding that the satisfactory outcome and benign adverse effects suggest such consideration prior to the patient becoming terminally ill or undergoing "treatments that destroy cervical lymphoid tissues, including repeated cervical surgery."

The authors have no financial conflicts to disclose.

J Clin Endocrinol Metab. 2004;89:3413-3420

Reviewed by Gary D. Vogin, MD

    
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