Spatially resolved metabolomics to discover tumor-associated metabolic alterations.

Characterization of tumor metabolism with spatial information contributes to our understanding of complex cancer metabolic reprogramming, facilitating the discovery of potential metabolic vulnerabilities that might be targeted for tumor therapy. However, given the metabolic variability and flexibility of tumors, it is still challenging to characterize global metabolic alterations in heterogeneous cancer. Here, we propose a spatially resolved metabolomics approach to discover tumor-associated metabolites and metabolic enzymes directly in their native state. A variety of metabolites localized in different metabolic pathways were mapped by airflow-assisted desorption electrospray ionization mass spectrometry imaging (AFADESI-MSI) in tissues from 256 esophageal cancer patients. In combination with in situ metabolomics analysis, this method provided clues into tumor-associated metabolic pathways, including proline biosynthesis, glutamine metabolism, uridine metabolism, histidine metabolism, fatty acid biosynthesis, and polyamine biosynthesis. Six abnormally expressed metabolic enzymes that are closely associated with the altered metabolic pathways were further discovered in esophageal squamous cell carcinoma (ESCC). Notably, pyrroline-5-carboxylate reductase 2 (PYCR2) and uridine phosphorylase 1 (UPase1) were found to be altered in ESCC. The spatially resolved metabolomics reveal what occurs in cancer at the molecular level, from metabolites to enzymes, and thus provide insights into the understanding of cancer metabolic reprogramming.

Strategy for Global Profiling and Identification of 2- and 3-Hydroxy Fatty Acids in Plasma by UPLC-MS/MS.

2-Hydroxy fatty acids (2-OHFAs) and 3-hydroxy fatty acids (3-OHFAs) with the same carbon backbone are isomers, both of which are closely related to diseases involving fatty acid oxidation disorder. However, the comprehensive profiling of 2- and 3-OHFAs remains an ongoing challenge due to their high structure similarity, few structure-informative product ions, and limited availability of standards. Here, we developed a new strategy to profile and identify 2- and 3-OHFAs according to structure-dependent retention time prediction models using ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Both accurate MS and MS/MS spectra were collected for peak annotation by comparison with an in-house database of theoretically possible 2- and 3-OHFAs. The structures were further confirmed by the validated structure-dependent retention time prediction models, taking advantage of the correlation between the retention time, carbon chain length and number of double bonds, as well as the hydroxyl position-induced isomeric retention time shift rule. With the use of this strategy, 18 2-OHFAs and 32 3-OHFAs were identified in the pooled plasma, of which 7 2-OHFAs and 20 3-OHFAs were identified for the first time in this work, furthering our understanding of OHFA metabolism. Subsequent quantitation method was developed by scheduled multiple reaction monitoring (MRM) and then applied to investigate the alteration of 2- and 3-OHFAs in esophageal squamous cell carcinoma (ESCC) patients. Finally, a potential biomarker panel consisting of six OHFAs with good diagnostic performance was achieved. Our study provides a new strategy for isomer identification and analysis, showing great potential for targeted metabolomics in clinical biomarker discovery.

[Diagnosis and long-term results of surgical resection of early cardiac adenocarcinoma].

OBJECTIVE: To summarize therapeutic experience and the long-term results of early cardiac adenocarcinoma with surgical resection. METHODS: Ninety cases were diagnosed with early cardiac adenocarcinoma during endoscopic screening in high incidence rate area of esophageal cancer from 1972 to 1997. All of the patients accepted surgical treatment. Cardiectomy included partial stomach and esophagus was performed through left thoracotomy in all patients. Esophagogastrostomy was carried out in the infra-aortic region and thoracoabdominal lymphatic dissection was performed in all cases. RESULTS: The resection rate was 100%. One patient died in one month after the operation. Postoperative complications occurred in 4 cases (4.4%). Pathological examination of cancer specimens showed that 46 cases (51.1%) were intramucosal carcinoma without lymphatic metastasis and 44 cases (48.9%) were submucous infiltrating carcinoma with lymphatic metastasis in 5 (11.4%). The patients were followed-up to 2002, and the overall 5, 10, 15, 20 and 25 year survival rates were 91.9%, 83.6%, 69.6%, 49.8% and 16.6%, respectively. CONCLUSIONS: Early diagnosis and early treatment may be the best approach for promoting the survival of the cardiac cancer. Surgical resection of early cardiac carcinoma provides excellent long-term survival.

[Surgical treatment of primary esophageal adenocarcinoma].

OBJECTIVE: To summarize the surgical treatment and clinical bio-characteristics of primary esophageal adenocarcinoma (PEAC). METHODS: Clinical data of 43 cases with PEAC who had undergone operation from February 1980 to December 2000 in Linzhou City Esophageal Tumor Hospital were retrospectively analyzed. RESULTS: Forty-three cases PEAC were reported in this study, which were 0.8% out of 5638 cases pathologically confirmed esophageal carcinoma treated during this period. Twelve cases (27.9%) were in the middle 1/3 of esophagus, thirty-one cases (72.1%) in the lower 1/3, which were significantly different from esophageal squamous cell carcinoma (ESCC). Fourteen cases were pure esophageal adenocarcinoma (32.6%), twenty-nine cases were adenosquamous cell carcinoma and adenoacanthoma cell carcinoma (67.4%). The ratio of lymph node metastasis of PEAC was higher than that of ESCC (65.1% vs. 31.6%, P < 0.001). The overall survival rates of 1, 3 and 5-year of PEAC were 81.4%, 46.5% and 28.2%, respectively, which were lower than those of ESCC (89.7%, 68.2% and 39.4%, respectively; chi 2 = 4.846, P = 0.028). CONCLUSIONS: Compared with ESCC, PEAC, mainly located in the inferior 1/3 of esophagus, is a malignant disease with higher frequency of lymph node metastasis and poor prognosis. Surgical resection should be the first choice of treatment. Early diagnosis and early treatment as well as curative operation could improve prognosis. The long-term survival may be increased by adjunct multi-modality treatment.

[Surgical treatment of severe cicatricial anastomotic stricture after esophagectomy for esophageal and cardiac cancer].

OBJECTIVE: To review the experience of the surgical procedure in the treatment of postoperative severe cicatricial anastomotic stricture for esophageal cancer and cardiac cancer. METHODS: Twenty-four cases with severe anastomotic strictures and dysphagia after esophagectomy underwent second operation. The anastomosis was opened by two small transverse incisions about 1-2 mm above and below the anastomotic line. The esophageal and gastric walls were half opened. Then the circular cicatricial tissue was partially removed. The re-anastomosis was performed with a one layer, intermittent technique. RESULTS: The second operations were successfully completed in 24 cases, cervical anastomotic leakage happened in 1 case and no operative mortality. All cases were followed up for 2-3 years. All patients can eat soft and common diet smoothly. No anastomotic strictures were found and the quality of life was significantly improved. CONCLUSION: The second surgery with partial removal of the narrow cicatricial ring and reanastomosis for postoperative severe anastomotic stricture after esophagectomy is feasible, and the result is satisfactory.

Long-term results of operation for 420 patients with early squamous cell esophageal carcinoma discovered by screening.

BACKGROUND: Cancer of the esophagus is one of the most commonly seen malignancies in China. From 1959 to 1981, mass screening of esophageal cancer disclosed that the age-adjusted incidence in the 40- to 69-year-old population in Lin County, Henan Province, was 470/10(5) In its northern part, an even higher incidence of 760/10(5)was found. As they were discovered by mass screening, most of them were found to have early lesions. Surgical treatment was done in attempt to find out the feasibility of managing esophageal carcinoma by early diagnosis and early treatment. This paper is the result of the long-term follow-up. METHODS: Since 1972, a total of 17 extensive mass screening has been conducted among more than 160,000 participants in the rural areas in Henan, Hebei, and northern Jiangsu provinces, sorting out more than 30,000 high-risk individuals. Among these individuals, 24,600 were examined by endoscopy, discovering 2,094 patients with carcinomas in the esophagus or gastric cardia; 757 of these 2,094 patients were found to have superficial esophageal cancer; 420 patients accepted surgical treatment. Esophagectomy with gastric replacement was performed through left thoracotomy in all patients. Cervical anastomosis 94 (22.4%), intrathoracic supraaortic anastomosis 307 (73.1%), and infra-aortic anastomosis 19 (4.5%) were done. Double thoracoabdominal lymphatic dissection was performed. RESULTS: The resection rate was 100%. One-month operative mortality occurred in 5 (1.2%). Postoperative complications developed and were satisfactorily treated in 28 patients (6.7%). Pathology of the cancer specimens showed that there were carcinoma in situ in 76 (all without lymphatic metastasis), intramucosal (TI) carcinoma in 126 (2 [1.6%] with lymphatic metastasis), and submucous infiltrating (TI) carcinoma in 218 (34 [15.6%] with lymphatic metastasis). All these 420 patients have been followed up to 2001 with a follow-up rate of 94.1%. Those who were lost to follow-up were taken as censored cases. The survival rates were calculated by the life-table method. The 5-, 10-, 15-, 20-, and 25-year survival rates were 86.14%, 75.03%, 64.48%, 56.17%, and 49.93%, respectively. CONCLUSIONS: Esophageal balloon cytology, endoscopy, mucosa 1.2% iodine stain, and multipoint biopsy may be the best approach for early diagnosis of esophageal carcinoma. Surgical resection of superficial esophageal cancer provides excellent long-term survival with acceptable quality of life. It was discovered that carcinoma in situ and intramucosal carcinoma gave far better results than the submucosal infiltrative carcinoma, as the latter tends to have a higher frequency of lymphatic metastasis.