Barrett's esophagus: treatment with 5-aminolevulinic acid photodynamic therapy

Barrett's esophagus has been identified as the premalignant precursor of esophageal adenocarcinoma. The eradication of metaplastic or dysplastic columnar-lined (Barrett's) esophagus may prevent progression to esophageal adenocarcinoma. 5-Aminolevulinic acid photodynamic therapy is a simple method for the mucosal ablation of the abnormal segment. Areas of metaplastic epithelium may remain buried after treatment and continued surveillance is necessary. Repeated treatments often are necessary but are very well tolerated with few complications.     

Photodynamic diagnosis using 5-aminolevulinic acid (5-ALA) for minimally-invasive treatment of cancer

Summary

Preclinical and clinical studies on 5-aminolevulinic acid (5-ALA) induced protoporphyrin IX (PPIX) are currently being performed at various departments, following promising clinical results for the detection of bladder cancer in urology. This paper provides an overview on the progress of 5-ALA assisted fluorescence diagnosis in urology, pulmonology, neurosurgery, gynaecology and ENT, coordinated by the Laser Research Laboratory of the Ludwig-Maximilians-University in Munich. 5-ALA can be applied either topically or systemically to induce an intracellular accumulation of fluorescing PPIX. With appropriate dosage of 5-ALA, malignant tissue can be stained selectively, and irradiation with violet light excites a bright red fluorescence of the tumour, visible to the naked eye. Optical properties of the tissue tend to hamper the precise identification and demarcation of suspect areas in fluorescence images. Multicolour remission and fluorescence imaging, therefore, should improve tumour localisation in future.     

Photodynamic therapy of early squamous cell cancers of the esophagus

The conventional treatment for the cure of esophageal cancer is surgical resection. Esophageal cancer, when detected at an early stage, has a very good probability of being eradicated by less aggressive procedures, and photodynamic therapy has proven to be a safe and effective treatment modality in some carefully selected patients. The indications, outcomes, and future considerations regarding the use of photodynamic therapy for the treatment of superficial squamous cell carcinomas of the esophagus are discussed in this article.     

Staging and neoadjuvant therapy of squamous cell carcinoma of esophagus

Once the diagnosis of esophageal cancer is established, the decision on treatment will depend on the stage of the disease. Since improvement of prognosis can only be expected in patients with complete removal of their tumor, preoperative staging plays a pivotal role in the decision-making process. Preoperative diagnostic procedures should define the tumor in its relation to the tracheal bifurcation (site), determine the depth of tumor invasion (T status), evaluate regional lymph node metastases (N1 disease) and exclude distant metastases (M1 disease). Endosonography represents currently the most accurate imaging technique for detecting the correct T stage over the correct N stage. A higher accuracy rate may be achieved by combining endosonography with other staging modalities such as computed tomography. Chest x-ray, and percutaneous ultrasonography (abdominal, neck) form the diagnostic basis in staging M1 disease. Computed tomography (neck, chest and abdomen) is currently the best method to detect metastases in the liver and in celiac nodes. Staging laparoscopy when combined with laparoscopic ultrasonography shows a higher sensitivity than ultrasonography and computed tomography in the diagnosis of smaller metastases and peritoneal seedings. En bloc esophagectomy together with the regional lymph nodes remains the treatment of choice in medically fit patients with localized esophageal carcinoma (Stage I-IIB, T1-T2/N0-N1/M0). Due to early involvement of mediastinal structures, curative resection is unlikely to be achieved in patients with locally advanced esophageal carcinoma (Stage III, T3-T4/N0-N1/M0). Most available data indicate that neoadjuvant radiochemotherapy leads in a significant number of patients to downstaging of the tumor, increases the rate of R0 resection, improves local tumor control, and prolongs the recurrence free interval. However, neoadjuvant radiochemotherapy resulted in a marked increase of morbidity and postoperative mortality without improvement of survival. At present, neoadjuvant therapy is still experimental and there is no consensus for an optimal treatment regimen. Its use outside of an investigational setting can not be recommended. Future research must focus on more effective and less toxic neoadjuvant modalities (e.g. new chemotherapy agents, hyperthermia).     

Poor results of 5-aminolevulinic acid-photodynamic therapy for residual high-grade dysplasia and early cancer in barrett esophagus after endoscopic resection

BACKGROUND AND STUDY AIMS: The aim of the study was to evaluate the efficacy of photodynamic therapy (PDT) in the treatment of residual high-grade dysplasia or early cancer (HGD/EC) after endoscopic resection in Barrett esophagus. PATIENTS AND METHODS: Study patients were separated into group A, with proven residual HGD/EC, and group B with possible HGD/EC (positive lateral margins in the endoscopic resection specimen, without HGD/EC in the remaining Barrett esophagus). PDT treatment consisted of 5-aminolevulinic (5-ALA) photosensitization (40 mg/kg) followed by illumination of the Barrett esophagus with a total light dose of 100 J/cm (2). Complete remission was defined as the absence of HGD/EC in biopsies taken in two consecutive follow-up endoscopies. The percentage regression of Barrett esophagus, as well as the recurrence rate of HGD/EC, was calculated. RESULTS: 20 patients underwent PDT (group A, 11; group B, 9). Mild complications were seen in 4/26 procedures. The overall success rate was 15/20 (75 %). There was a significant difference in success rate between group A (55 %) and group B (100 %); P = 0.03. All patients had residual Barrett esophagus after PDT; the median regression percentage was 50 % (IQR 25 - 70 %). Recurrence of HGD/EC occurred in four patients (two each in groups A and B) after a median follow up of 30 months. CONCLUSIONS: In this selected group of patients, the addition of 5-ALA-PDT after endoscopic resection for HGD/EC had a disappointing success rate in patients who had residual HGD/EC after endoscopic resection. Most patients undergoing 5-ALA-PDT have residual Barrett mucosa after PDT and 5-ALA-PDT does not seem to prevent recurrences during follow-up.     

Intraepithelial high-grade neoplasia and early adenocarcinoma in short-segment Barrett's esophagus (SSBE): curative treatment using local endoscopic treatment techniques

BACKGROUND AND STUDY AIMS: In recent years, short-segment Barrett's esophagus (SSBE) has attracted increasing attention in the context of reflux disease. However, there is continuing controversy regarding its potential for malignant transformation. PATIENTS AND METHODS: Between October 1996 and September 1999, 50/115 patients (43 %) with intraepithelial high-grade neoplasia or early Barrett's adenocarcinoma, who underwent local endoscopic treatment, had developed a malignant lesion in an (SSBE). In the framework of a prospective observational study, 28 patients were treated with endoscopic mucosal resection (EMR), 13 with photodynamic therapy, and three with argon plasma coagulation; six patients received combinations of these treatments. RESULTS: Complete local remission was achieved in 48/49 patients (98 %). One patient switched to surgery after the first EMR, because there was submucosal tumor infiltration, and in one patient out of 50 local endoscopic treatment failed. A mean of 1.7 +/- 1.4 treatment sessions was required for local endoscopic treatment. The method-associated mortality was 0 %. The rate of relevant complications (stenosis, bleeding) was 6 % (3/50 patients). No cases of severe hemorrhage (Hb fall >2 g/dl) or perforation occurred. During a mean follow-up period of 34 +/- 10 months, metachronous intraepithelial high-grade neoplasms or early adenocarcinomas were seen in 11/48 patients (23 %), who received further successful endoscopic treatment. Four patients died during the follow-up period, but in only one patient was this due to his Barrett's adenocarcinoma (this was the patient who underwent esophageal resection). CONCLUSIONS: The malignant potential of short-segment Barrett's esophagus must not be underestimated. Organ-preserving local endoscopic treatment shows good acute-phase and long-term results. Local endoscopic treatment represents an alternative to esophageal resection in the case of intraepithelial high-grade neoplasia and selected early adenocarcinomas in Barrett's esophagus.     

Head and neck cancer arising after endoscopic mucosal resection for squamous cell carcinoma of the esophagus

BACKGROUND AND STUDY AIMS: It is well known that patients with head and neck cancer often have synchronous or metachronous squamous cell carcinoma of the esophagus. However, the prevalence of subsequent head and neck cancer in patients with early-stage esophageal cancer is still unknown. The aims of this study were to analyze the frequency of metachronous head and neck cancer after endoscopic mucosal resection (EMR) for esophageal cancer and to investigate whether minute iodine-unstained areas, often associated with squamous cell carcinomas, would be an index for metachronous head and neck cancer. PATIENTS AND METHODS: 99 patients with esophageal squamous cell carcinoma who underwent EMR were studied. Based on the iodine-staining pattern at initial EMR, they were categorized into those with uniform (group U) and scattered (group S) types of background mucosa. Patients were monitored endoscopically and otolaryngologically (group U, median 46 months, range 12-83 months; group S, median 44 months, range 13-80 months). RESULTS: In total, 5/99 patients (5.1 %) were found to have metachronous head and neck cancer during the follow-up, including 4/20 patients (20 %) in group S. In three cases laryngeal or hypopharyngeal cancer was found by endoscopic examination. The cumulative proportion of metachronous head and neck cancer-free subjects was significantly lower in group S than group U (P = 0.0007). CONCLUSIONS: Among patients who undergo EMR for esophageal carcinoma, those with scattered-type iodine staining of the background mucosa have an increased risk of metachronous head and neck cancer, and should therefore be closely observed. Careful endoscopic observation led to early detection of laryngeal and hypopharyngeal cancer.     

Investigations on the formation of urinary coproporphyrin isomers I-IV in 5-aminolevulinic acid dehydratase deficiency porphyria, acute lead intoxication and after oral 5-aminolevulinic acid loading

OBJECTIVES: Investigation of the metabolism of the four urinary coproporphyrin isomers I-IV in the extremely rare 5-aminolevulinic acid dehydratase (ALAD) deficiency porphyria (syn.: Doss porphyria), in acute lead intoxication, and after oral 5-aminolevulinic acid (ALA) loading. DESIGN AND METHODS: We analyzed the excretion of total urinary coproporphyrins and the composition of the respective isomers I-IV with ion-pair HPLC methods in these conditions. RESULTS: The concentration of total coproporphyrins was about 30-fold increased in patients with ALAD deficiency porphyria and acute lead intoxication as compared with controls. In addition, the proportion of coproporphyrin III as well as that of the atypical isomers II and IV were significantly elevated at the expense of isomer I. After oral ALA administration to normal volunteers, a 10- to 15-fold increase in the maximal concentration of total urinary coproporphyrins was observed within 12 to 24 h. Urinary levels were back to normal after another 24 h. The excretion pattern of the individual urinary coproporphyrin isomers I-IV after ALA ingestion revealed a dynamic process: initially isomer III was preferentially formed, followed by a 3-fold increase of isomers II and IV via non-enzymatic rearrangement of isomer III, and finally normalization of all four isomers occurred within 48 h. CONCLUSIONS: These results demonstrate that oral ALA loading can be used as an in vivo model to study the metabolism of the four urinary coproporphyrin isomers I-IV especially in ALAD deficiency porphyria and in acute lead poisoning.     

血清SCC-Ag检测在宫颈鳞癌患者的治疗与病情监测中的临床价值

目的探讨血清鳞状上皮细胞癌抗原(SCC-Ag)指标在宫颈鳞癌的治疗与病情监测中的临床意义。方法回顾2084例不同临床分期的宫颈鳞癌患者的SCC-Ag水平并作统计处理;对手术前后5d内或放/化疗前后20d内均有SCC-Ag测定的患者进行治疗前后的对比及Ⅰa～Ⅱa期手术患者有无淋巴转移的病倒进行SCC-Ag值比较,同期收集90例健康体检者及1175例包括宫颈上皮细胞不典型增生、子宫肌瘤等妇科良性肿瘤病例的SCC-Ag值作为对照。结果按FIGO临床分期,SCC-Ag水平随病情分期进展而递增(P0.01),各期与妇科良性肿瘤组(1175,1.17±0.76ng/ml)和健康体检组(90,0.77±0.26ng/ml)相比均有明显差异(P0.01);统计显示疾病较早期(Ⅰa期～Ⅱa期)患者其手术后SCC-Ag水平(1.28±1.81ng/ml)比手术前(4.63±8.13ng/ml)有明显下降(P0.05);疾病较晚期(Ⅱb～Ⅳ期)患者其放/化疗后SCC-Ag水平(11.01±8.44ng/ml)对比放/化疗前(23.39±23.71ng/ml)有明显下降(P0.05);956例行根治术(子宫切除+盆腔淋巴结清扫)的患者,有淋巴转移的与无淋巴转移的,两者比较有差异(P0.01)。结论 SCC-Ag是宫颈鳞癌较特异的肿瘤标志物,是宫颈鳞癌的临床分期、疗效观察、治疗方案及病情监测状态中的重要参考指标。     

Comparative evaluation of serum C-reactive protein (CRP) levels in the different histological subtypes of esophageal cancer (squamous cell carcinoma and adenocarcinoma of esophagus)

Elevated C-reactive protein (CRP) levels have been found in patients with several malignancies. The aim of the present study was to analyze the diagnostic and prognostic values of CRP levels measurement in esophageal cancer (EC) patients in relation to its different histological subtypes (squamous cell carcinoma-ESCC and adenocarcinoma-AC of esophagus) and compared them with classic tumor markers-carcinoembryonic antigen (CEA) and squamous cell cancer antigen (SCC-Ag). The diagnostic sensitivity, specificity, and the areas under receiver operating characteristic curves (AUC) for all the proteins tested were defined. Serum CRP levels were statistically higher in EC, ESCC, and AC patients compared to healthy subjects and significantly increased in EC and ESCC patients with the presence of lymph node and distant metastases. The percentage of elevated CRP results in all the analyzed subgroups (EC, ESCC, and AC) was higher than CEA and SCC-Ag, similarly as AUC for CRP in comparison to SCC-Ag. Serum CRP level was a significant predictor of EC and ESCC patients' survival in univariate analysis. In conclusion, these results indicate that CRP can be used as an adjunct in evaluating the tumor markers-CEA and SCC-Ag and may improve the clinical diagnosis and follow-up of EC patients, especially for ESCC subgroup.     

血清中肝细胞生长因子含量对食管鳞状细胞癌的影响

目的探讨血清中肝细胞生长因子（HGF）含量对食管鳞状细胞癌的影响。方法用ELISA方法研究6例食管良性疾患和42例食管鳞状细胞癌患者血清中肝细胞生长因子（HGF）含量。结果12例正常健康体检和6例食管良性疾患病人血清中都有一定量的肝细胞生长因子（HGF）,而食管鳞状细胞癌患者血清中HGF含量（397．4±339．9pg／ml）明显高于正常健康人和食管良性疾患患者（P〈0．05）,其含量与病理类型、病理组织分级和临床病理分期、淋巴结转移情况无关。3年随访36例病例中死亡（23例）,其血清HGF含量明显高于生存（30例）者（P〈0．05）。结论增高的血清HGF在食管鳞状细胞癌中预示了一种更具有侵袭性的生物学行为。血清HGF含量水平可作为食管鳞状细胞癌的高危因素指标。     

葡萄糖调节蛋白78在人食管鳞状细胞癌中的表达及意义——附59例检测报告

目的：探讨葡萄糖调节蛋白78（glucose-regulatedprotein 78,GRP78）在人食管鳞状细胞癌中的表达情况,并了解其与食管鳞状细胞癌临床、病理特征的关系。方法：食管鳞状细胞癌手术切除标本59份,距癌组织5em以上的手术远端切缘的食管正常鳞状上皮组织20份,用免疫组织化学方法检测GRP78的表达情况,并分析GRP78的表达与临床、病理特征的关系。结果：食管鳞状细胞癌组织中GRP78的阳性表达率明显高于食管正常鳞状上皮组织（P〈0．01）;GRP78的表达程度随着浸润深度的增加而增高;随着分化程度的降低而增高;病理分期高者表达高于病理分期低者;有淋巴转移者明显高于无淋巴转移者（P〈0．05～0．01）。GRP78表达与患者性别及肿瘤长度无关（P〉0．05）。结论：食管鳞状细胞癌患者多呈GRP78的阳性表达,说明GRP78可能参与了人类食管鳞状细胞癌的发生、发展。     

细胞角蛋白19与鳞状细胞癌抗原联合检测在宫颈癌早期筛查及疗效评估中的应用

目的：探讨细胞角蛋白19片段（CYFRA21‐1）与鳞状上皮细胞癌抗原（SCCAg）联合检测在宫颈癌早期诊断、疗效评估中的价值。方法选择2010年8月至2013年8月达州华康医院收治的宫颈癌患者97例,子宫颈上皮非典型增生（CIN ）患者45例,并选择体检的健康妇女50例作为对照组;采用电化学发光免疫分析对CY‐FRA21‐1、SCCAg水平进行检测,比较各组水平。结果与对照组及CIN组相比,宫颈癌患者血清CYFRA21‐1、SCCAg水平显著升高,差异有统计学意义（P＜0．05）;其中宫颈癌Ⅲ～Ⅳ期血清CYFRA21‐1、SCCAg水平及其阳性检出率明显高于Ⅰ～Ⅱ期,组间相比差异具有统计学意义（ P＜0．05）;两者联合检测敏感度升高至62．47％。放化疗后各宫颈癌分期患者血清CYFRA21‐1、SCCAg水平显著降低,与放化疗前相比差异具有统计学意义（P＜0．05）。结论血清CYFRA21‐1、SCCAg检测对宫颈癌早期诊断、疗效评估等方面具有重要的参考价值。     

基于SEER数据库分析手术治疗和内镜切除治疗表浅食管鳞癌的长期疗效

目的 基于SEER数据库分析Tis及T1期食管鳞癌患者接受手术或内镜治疗后的生存情况,以期为食管癌的早期治疗提供参考.方法 从美国SEER数据库获取2004年至2012年初次病理确诊为食管鳞癌的病例,均有完整T及N分期信息、无远处转移、预后和随访信息完整、肿瘤原发灶治疗信息完整.主要结局为食管癌特异性死亡.用Cox回归...     

5-氨基酮戊酸光动力效应对体外培养人恶性黑素瘤细胞的物理学干预特征

目的:探讨5-氨基酮戊酸(5-ALA)光动力学效应(5-ALA-PDT)对体外培养人恶性黑素瘤细胞的物理学干预作用,为进一步进行体内的实验研究提供实验依据。方法:实验于2004-04/11在解放军第三军医大学西南医院中心实验室将体外培养的人黑素瘤A-375细胞分别加入不同浓度的5-ALA(0.5,1,1.5,2mmol/L)孵育6h,予波长652nm半导体激光照射,照射的功率密度为15.6mW/cm2,照射剂量分别为0,2,5,10,20J/cm2,继续孵育12h,用四唑盐(MTT)比色法测定细胞存活率。结果:①5-ALA作为内源性光敏剂原卟啉IX(PpIX)的前体物被黑素细胞瘤摄取后产生过量的原卟啉IX,用652nm的激光照射能对黑素瘤A-375产生杀伤作用,其杀伤细胞的程度与5-ALA的浓度和光照剂量成正相关(P<0.01),但是当5-ALA的浓度达到1.5mmol/L以上时其杀伤细胞的作用无显著增加。②在加入5-ALA而无激发光源的情况下,细胞所产生的原卟啉IX对细胞的生存不产生明显影响(P>0.05)。结论:5-氨基酮戊酸在体外可以对黑素瘤细胞产生光动力学效应。     

Accelerated fractionation radiation therapy for advanced squamous cell carcinoma of the head and neck

We treated 14 patients who had advanced head and neck cancer with an accelerated fractionation schedule of irradiation consisting of two fractions given 6 hours apart. In the morning a volume of 1.7 Gy was given to an area that encompassed the entire tumor, enlarged lymph nodes, and all areas at risk for microscopic disease. Six hours later, 1.1 Gy was given to an area that included only the tumor and any enlarged lymph nodes, with a 2-cm margin. The treatment was well tolerated; of the 13 patients who completed therapy, six did not require a break in therapy, and seven patients did. The median rest period was 2 days. There was no grade 4 toxicity. Grade 3 toxicity included skin changes (one case), mucositis (two), dysphagia (two), weight loss (three), and a decrease in the hemoglobin level (one case). The response rate in the 13 who completed therapy was 13/13 (100%); 11 of the 13 (83%) had a complete response. Only one of the 11 who achieved a complete response had failure at the primary site. At a median follow-up of 24 months, the absolute survival was 7/13 (54%) and the corrected survival was 7/10 (70%). This technique permits radiation therapy to be given on an accelerated schedule without a planned break in treatment. The overall response rate and survival at 2 years was excellent.