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Biomedical subjects

M B Orringer

Publications and source records attributed to M B Orringer.

At least 37 records · Page 2Linked to original sources
PubMed1999

Transhiatal esophagectomy: clinical experience and refinements.

OBJECTIVE: To review the authors' clinical experience with transhiatal esophagectomy (THE) and the refinements in this procedure that have evolved. BACKGROUND: Increased use of THE during the past two decades has generated controversy about the merits and safety of this approach compared with transthoracic esophageal resection. The authors' large THE experience provides a valuable basis for benchmarking data regarding the procedure. METHODS: The results of THE were analyzed retrospectively using the authors' prospectively established esophageal resection database and follow-up information on these patients. RESULTS: From 1976 to 1998, THE was performed in 1085 patients, 26% with benign disease and 74% with cancer. The procedure was possible in 98.6% of cases. Stomach was the esophageal substitute in 96%. The hospital mortality rate was 4%. Blood loss averaged 689 cc. Major complications were anastomotic leak (13%), atelectasis/pneumonia (2%), intrathoracic hemorrhage, recurrent laryngeal nerve paralysis, chylothorax, and tracheal laceration (<1% each). Actuarial survival of patients with carcinoma equaled or exceeded that reported after transthoracic esophagectomy. Late functional results were good or excellent in 70%. With preoperative pulmonary and physical conditioning, a side-to-side stapled cervical esophagogastric anastomosis (<3% incidence of leak), and postoperative epidural anesthesia, the need for an intensive care unit stay has been eliminated and the length of stay reduced to 7 days. CONCLUSION: THE is possible in most patients requiring esophageal resection and can be performed with greater safety and fewer complications than the traditional transthoracic approaches.

Adolescent↗
PubMed1999

Detection of erbB-2 amplifications in tumors and sera from esophageal carcinoma patients.

We used TaqMan PCR to detect quantitative anomalies of tumor markers in both tumor and serum DNA from esophageal cancer patients. We demonstrated the potential of this methodology by detecting erbB-2 amplifications in a plurality of esophageal tumor samples. These amplifications were corroborated by Southern blots. We then showed the potential of this methodology to detect quantitative anomalies of erbB-2 in serum DNA from individuals with a corresponding amplification in the tumor. The capability of TaqMan PCR to detect abnormalities in serum of esophageal cancer patients creates an opportunity to diagnose esophageal cancer and to monitor the outcome of treatment with a blood test.

Adenocarcinoma↗
PubMed1998

A novel amplicon at 8p22-23 results in overexpression of cathepsin B in esophageal adenocarcinoma.

Cathepsin B (CTSB) is overexpressed in tumors of the lung, prostate, colon, breast, and stomach. However, evidence of primary genomic alterations in the CTSB gene during tumor initiation or progression has been lacking. We have found a novel amplicon at 8p22-23 that results in CTSB overexpression in esophageal adenocarcinoma. Amplified genomic NotI-HinfI fragments were identified by two-dimensional DNA electrophoresis. Two amplified fragments (D4 and D5) were cloned and yielded unique sequences. Using bacterial artificial chromosome clones containing either D4 or D5, fluorescent in situ hybridization defined a single region of amplification involving chromosome bands 8p22-23. We investigated the candidate cancer-related gene CTSB, and potential coamplified genes from this region including farnesyl-diphosphate farnesyltransferase (FDFT1), arylamine N-acetyltransferase (NAT-1), lipoprotein lipase (LPL), and an uncharacterized expressed sequence tag (D8S503). Southern blot analysis of 66 esophageal adenocarcinomas demonstrated only CTSB and FDFT1 were consistently amplified in eight (12.1%) of the tumors. Neither NAT-1 nor LPL were amplified. Northern blot analysis showed overexpression of CTSB and FDFT1 mRNA in all six of the amplified esophageal adenocarcinomas analyzed. CTSB mRNA overexpression also was present in two of six nonamplified tumors analyzed. However, FDFT1 mRNA overexpression without amplification was not observed. Western blot analysis confirmed CTSB protein overexpression in tumor specimens with CTSB mRNA overexpression compared with either normal controls or tumors without mRNA overexpression. Abundant extracellular expression of CTSB protein was found in 29 of 40 (72. 5%) of esophageal adenocarcinoma specimens by using immunohistochemical analysis. The finding of an amplicon at 8p22-23 resulting in CTSB gene amplification and overexpression supports an important role for CTSB in esophageal adenocarcinoma and possibly in other tumors.

Adenocarcinoma↗
PubMed1998

Lack of cell surface Fas/APO-1 expression in pulmonary adenocarcinomas.

The Fas receptor and ligand initiate an apoptotic pathway. Alterations in this pathway within tumor cells can result in escape from apoptosis and immune surveillance. We evaluated Fas protein expression in 42 primary pulmonary adenocarcinomas, and Fas expression and function in the lung adenocarcinoma cell lines A549 and A427. Immunohistochemical analysis demonstrated Fas protein expression in 47.6% of the tumors; however, Fas-positive tumors demonstrated cytoplasmic staining without cell surface expression. Northern blot analysis indicated that levels of Fas mRNA were similar in Fas protein-positive tumors to levels in normal lung tissue, but were reduced in Fas protein-negative tumors. Soluble form Fas was not detected in the majority of these tumors either by RT-PCR or Western blot analysis. Cell surface Fas protein expression was minimal in A549 and A427 cell lines as determined by flow cytometry. Both cell lines demonstrated Fas mRNA expression by Northern blot analysis and abundant protein expression by Western blot analysis. Transfection of the Fas cDNA derived from A549 cells induced surface Fas protein in COS cells; however, stable transfection of a native Fas cDNA into A549 cells failed to induce surface Fas protein expression. Parental A549 cells and A549 cells transfected with a Fas expression vector were resistant to Fas-mediated apoptosis. Transgenic expression of a FLAG-tagged Fas cDNA in A549 cells, with visualization of the Fas-FLAG protein using confocal microscopy, demonstrated that the Fas-FLAG protein was retained within cytoplasmic portions of the cell and was not translocated to the cell surface. These findings suggest that the Fas protein is reduced or not present on the cell surface in the primary lung tumors and is sequestered within A549 tumorigenic lung cells, and these alterations directly affect the cells resistance to Fas-mediated apoptosis.

Adenocarcinoma↗
PubMed1998

Distal chromosome 17q loss in Barrett's esophageal and gastric cardia adenocarcinomas: implications for tumorigenesis.

The molecular genetic mechanisms underlying esophageal cancer are poorly understood. However, a novel gene that may be involved in esophageal carcinogenesis was recently localized by others to distal 17q by linkage analysis of kindreds with palmoplantar keratoderma and squamous cell carcinoma of the esophagus. To help determine whether a distal 17q gene may also be involved in the pathogenesis of primary Barrett's esophageal and gastric cardia adenocarcinomas, we performed loss of heterozygosity (LOH) analysis of 21 Barrett's and 18 gastric cardia adenocarcinomas at loci spanning 17q: cen-BRCA1-SSTR2-D17S2058-D17S929-D17S722-+ ++D17S937-D17S802-tel. Over 50% of the Barrett's and cardia adenocarcinomas demonstrated loss of an allele at one or more informative distal 17q markers. One common overlapping region of loss involved loci mapped to distal 17q24-proximal 17q25, which tentatively defines a potential chromosomal region distal to BRCA1 involved in the pathogenesis or progression of both types of adenocarcinomas. LOH analysis of DNA from matched microdissected sections of Barrett's metaplasia suggested that loss of D17S2058 in this region may be an early event in the malignant transformation of Barrett's metaplasia. No statistically significant correlations between 17q LOH and tumor stage or patient survival were noted. In summary, LOH mapping of 17q in Barrett's and cardia adenocarcinomas suggests the existence of at least one putative distal 17q tumor suppressor gene involved in the pathogenesis of these tumors.

Adenocarcinoma↗
PubMed1998

Abundant expression of the intestinal protein villin in Barrett's metaplasia and esophageal adenocarcinomas.

Villin is a cytoskeletal protein that is involved in the formation of brush-border microvilli in normal small intestine and colon epithelium. This protein is present in Barrett's metaplasia but is reported not to be expressed in Barrett's adenocarcinoma. In this study, we analyzed villin protein expression in Barrett's metaplasia and in both Barrett's adenocarcinomas and tumors of the gastric cardia. Immunohistochemical analysis was used to evaluate the expression and cellular localization of the villin protein in 21 cases of Barrett's metaplasia, 30 cases of Barrett's adenocarcinoma, 16 cases of gastric cardia adenocarcinoma, and eight cases of adenocarcinoma of the distal esophagus. Southern, northern, and western blot analyses were used to evaluate the potential mechanisms for regulation of villin protein expression. Villin protein expression was observed in 21 of 21 cases (100%) of intestinal-type Barrett's metaplasia and in 28 of 30 cases (93%) of Barrett's adenocarcinoma and was thus highly expressed in these tumors. Northern blot analysis demonstrated villin mRNA (3.5 and 2.7 kb) in both villin-positive Barrett's metaplasia and adenocarcinomas. Western blot analysis with the antibody used for immunohistochemical analysis confirmed the presence of a single villin protein band of 95 kDa. Abundant villin expression also was present in both adenocarcinoma of the gastric cardia (13 of 16 cases; 81%) and distal esophageal adenocarcinomas of unknown origin (six of eight cases; 75%). The intestinal brushborder enzyme sucrase isomaltase was found to be present in only 22 of 46 cases (48%) of the adenocarcinomas that expressed villin. We concluded that the protein villin is highly expressed in Barrett's adenocarcinomas and is well maintained in these and other esophageal tumors.

Adenocarcinoma↗
PubMed1998

Unique expression patterns and alterations in the intestinal protein villin in primary and metastatic pulmonary adenocarcinomas.

The identification of markers that distinguish primary pulmonary adenocarcinomas from pulmonary adenocarcinomas secondary to the digestive tract would be clinically important. Villin, a specific marker in digestive-tract malignancies, was evaluated in 57 pulmonary adenocarcinomas, six samples of proximal bronchial tissue, and five metastatic pulmonary adenocarcinomas (three colon and two esophageal adenocarcinomas) by using immunohistochemical and molecular analyses. Villin was expressed in 31.6% (18 of 57) of the pulmonary adenocarcinomas and showed either a diffuse cytoplasmic pattern (10.5%) or a primary cytoplasmic pattern with minor brush-border staining (21.1%). However, none of those samples demonstrated the primary brush-border staining pattern that was characteristic of all five of the metastatic digestive-tract adenocarcinomas. There was a significant difference in the positive brush-border staining pattern between the primary and metastatic pulmonary adenocarcinomas (P < 0.002). Villin protein was expressed in bronchial epithelial cells, and villin mRNA was detected by reverse transcription-polymerase chain reaction. Northern analysis demonstrated 3.5- and 2.7-kb villin mRNAs in villin protein-positive tumors, but villin mRNA was not detected in non-tumorous lung tissue, indicating the transcriptional upregulation of villin in lung tumors. An additional smaller-sized mRNA (1.8 kb) was observed in six of 10 pulmonary adenocarcinomas and in the bronchoalveolar carcinoma cell line A549. Two small villin mRNAs were cloned from the cell line A549 and were found to represent an alternatively spliced (exon 8-exon 14) 1.85-kb mRNA and a 1.8-kb mRNA that was missing a portion of the 5' region (exon 1-exon 9) of the native villin mRNA. These studies demonstrated that the pattern of villin expression and the presence of altered villin mRNAs may be useful markers for pulmonary adenocarcinomas as well as provide support for the potential origin of villin-expressing tumors from bronchial epithelial cells.

Adenocarcinoma↗
PubMed1997

Fas/APO-1 (CD95) is not translocated to the cell membrane in esophageal adenocarcinoma.

This study describes Fas (CD95) expression in Barrett's esophagus, adenocarcinomas of the esophagus, and three esophageal adenocarcinoma cell lines. Immunohistochemical analysis of Barrett's esophagus demonstrated cell surface expression of Fas protein. In contrast, 30.5% of esophageal adenocarcinomas examined by immunohistochemical analysis demonstrated faint cytoplasmic staining, and 69.5% were negative for Fas. Similar levels of Fas mRNA were identified in tumors compared to mRNA levels in esophageal squamous mucosa or Barrett's esophagus. An approximately Mr 48,000 Fas protein was identified by Western blot analysis in tumors that were negative for Fas expression by immunohistochemical analysis. The esophageal adenocarcinoma cell line Seg-1 was negative for Fas expression by immunohistochemical analysis, but Western blot analysis demonstrated abundant, appropriately sized Fas protein. In agreement with the immunohistochemical analysis, flow cytometry of Seg-1 showed minimal amounts of Fas on the cell surface, which correlated with resistance to Fas-mediated apoptosis. No mutations in the Seg-1 Fas coding sequence or exon 1 were identified by sequence analysis. This was confirmed by transient transfection of COS cells with expression vectors generated from the Seg-1 Fas cDNA, which resulted in cell surface expression of the Fas protein. Stable transfection of Seg-1 with a Fas expression vector did not result in efficient Fas expression on the cell surface. Seg-1 cells, transiently transfected with a Fas-FLAG expression vector and examined for protein expression using confocal microscopy and an anti-FLAG antibody, showed that the Fas-FLAG protein was not present on the cell surface but was present in the cytoplasm. Taken together, these results indicate that expression of Fas on the cell surface by esophageal adenocarcinoma is reduced. In an esophageal adenocarcinoma cell line, wild-type Fas protein is retained in the cytoplasm, and this correlates with resistance to Fas-mediated apoptosis. The retention of wild-type Fas protein within the cytoplasm may represent a mechanism by which malignant cells evade Fas-mediated apoptosis.

Adenocarcinoma↗
PubMed1997

Functional outcome after surgical treatment of esophageal perforation.

BACKGROUND: The functional results after treatment of intrathoracic esophageal perforations have been poorly documented. METHODS: A retrospective review of 42 patients who underwent treatment of intrathoracic esophageal perforation associated with benign esophageal disease was performed. RESULTS: Of 42 patients treated for esophageal perforation, 25 underwent primary repair, 15 underwent esophagectomy and reconstruction, 1 underwent cervical esophagostomy and drainage followed by esophageal resection, and 1 had drainage alone followed by primary repair. Among the patients treated with primary repair, at least one additional operation was required in 13 patients. Of the 15 patients treated with esophagectomy and reconstruction, none required further operative treatment. Follow-up averaged 3.7 years, and of the 36 survivors available for follow-up, 18 (50%) required at least one esophageal dilation postoperatively, and 3 (8.3%) have required regular dilations. Subjectively, 19 of 36 patients (53%) indicate that their swallowing is better than before perforation, it was the same in 12 (33%), and worse in 4 (11%). CONCLUSIONS: In conclusion, approximately one third of patients surviving primary repair of esophageal perforations have continued difficulty with swallowing, which often requires esophageal dilations or esophageal reconstructive procedures, or a combination of both. Optimal long-term results are achieved when primary repair is performed in patients with motor disorders or a "normal" esophagus. Esophagectomy is a better option in those patients with strictures or diffuse esophageal disease.

Adult↗
PubMed1997

Intrapericardial paragangliomas (pheochromocytomas): imaging features.

OBJECTIVE: The imaging features of intrapericardial paragangliomas (pheochromocytomas) are described. MATERIALS AND METHODS: We conducted a retrospective study of the imaging features of all intrapericardial paragangliomas seen at our institution over the last 13 years. RESULTS: In this study, intrapericardial paragangliomas were typically located adjacent to or involved the left atrium. The diameter of the tumors ranged from 3 to 8 cm. Metaiodobenzylguanidine (MIBG) scintigraphy revealed 11 of 12 tumors (sensitivity = 92%). After MIBG scintigraphic location, dynamic contrast-enhanced CT revealed all 12 tumors. CONCLUSION: Intrapericardial paragangliomas are rare tumors, typically located adjacent to or involving the left atrium. For initial detection, regional location of these extraadrenal tumors, and detection of distant metastases, MIBG scintigraphy is recommended. Dynamic contrast-enhanced CT or MR imaging can then provide detailed anatomic delineation before surgical resection.

3-Iodobenzylguanidine↗
PubMed1997

Detection of p53 nuclear protein accumulation in brushings and biopsies of Barrett's esophagus.

Alterations in the tumor suppressor gene p53 may represent a useful prognostic marker of premalignant or malignant disease in Barrett's dysplasia or esophageal adenocarcinoma. Immunohistochemistry was used to establish the ability to detect nuclear accumulation of altered p53 protein in esophageal brushings as well as biopsies, and to examine for p53 alterations in a group of 18 patients with Barrett's esophagus enrolled in a surveillance and endoscopy program, p53 protein accumulation was easily detected in esophageal brushings, and the results correlated well with matched biopsies (9/11). In patients enrolled in surveillance endoscopy, 1 brushing of 22 was positive for p53 protein accumulation. In this patient, who received preoperative radiation and chemotherapy, the positive p53 result correlated with positive cytology for residual adenocarcinoma. All Barrett's esophagus brushings negative for p53 protein were benign by cytologic, morphologic criteria. The immunohistochemical detection of p53 alterations in esophageal brushing and biopsy specimens may provide useful information in patients undergoing surveillance for esophageal dysplasia and adenocarcinoma.

Adenocarcinoma↗
PubMed1996

Distribution of distant metastases from newly diagnosed non-small cell lung cancer.

BACKGROUND: The purpose of our study was to determine the incidence and locations of M1 disease at presentation in patients with non-small cell lung cancer to help design appropriate preoperative imaging algorithms. METHODS: All patients with non-small cell lung cancer seen between 1991 and 1993 were identified, and records were reviewed. For patients with M1 disease, the sites of distant metastases and the methods of diagnosis were recorded. RESULTS: Of 348 patients identified, 276 (79%) had M0 disease and 72 (21%) had M1 disease. In 40 of 72 patients (56%), M1 disease was detected via chest or abdominal computed tomography (CT). Brain, bone, liver, and adrenal glands were the most common sites of metastatic disease, in decreasing order. Brain metastases often occurred as an isolated finding, although isolated liver metastases were uncommon. CONCLUSIONS: M1 disease was common at presentation, and was often detectable via chest CT. The incremental yield of abdominal CT over chest CT was very small, and therefore abdominal CT is not an effective method of screening for metastases if chest CT has been performed.

Adenocarcinoma↗
PubMed1996

Detection of Barrett's adenocarcinoma of the gastric cardia with sucrase isomaltase and p53.

BACKGROUND: Routine surveillance for dysplastic epithelium in patients with Barrett's esophagus has markedly improved prognosis. Many patients with short segments of Barrett's mucosa near the esophagogastric junction remain undiagnosed and at risk for the development of Barrett's adenocarcinomas (BA). Sucrase isomaltase (SI), an intestinal enzyme, is highly expressed in intestinal-type Barrett's mucosa and frequently expressed in dysplastic Barrett's mucosa and BA. Sucrose isomaltase is not expressed in normal esophageal or gastric mucosa. Alterations in the p53 tumor suppressor gene are frequent events in dysplastic Barrett's mucosa and BA and result in nuclear protein accumulation. The purpose of this study was to determine the presence or absence of these markers of Barrett's mucosa in adenocarcinoma of the esophagogastric junction or cardia. METHODS: Expression of SI and p53 were examined in 40 BAs and 25 cardia adenocarcinomas using immunohistochemical techniques. RESULTS: Sucrose isomaltase analysis revealed positive staining in 55% (22/40) of the BAs and 44% (11/25) of the cardia adenocarcinomas. Of 14 cardia adenocarcinomas that were SI negative, 100% (14/14) had no associated Barrett's mucosa. However, in 21 cardia adenocarcinomas with no associated Barrett's mucosa, 7/21 (33%) were SI positive. This suggests that SI-positive tumors may represent BA without the standard definition of Barrett's esophagus being met. P53 was present in 65% of BAs and 64% of cardia adenocarcinomas, demonstrating the importance and similarity of this gene alteration in both tumor types. Staining was positive for SI or p53 in 77% (50/65) of all tumors. Tumors of lower stage expressed SI more often than higher stage tumors. CONCLUSIONS: These data suggest that a subset of cardia adenocarcinomas represent BAs. Surveillance endoscopy incorporating additional esophagogastric junction biopsies and assessment of SI or p53 may improve detection of intestinalized Barrett's mucosa and early dysplastic changes.

Adenocarcinoma↗
PubMed1996

Anterior mediastinal tracheostomy.

Anterior mediastinal tracheostomy is not a commonly performed operation. The procedure, however, clearly facilitates resection of cervicothoracic, tracheal, and esophageal malignancies. Of 49 cervical exenterations performed, in 35 (71%) a concomitant mediastinal tracheostomy was performed, similar to the 77% rate of mediastinal tracheostomy with cervical exenteration reported by Grillo and Mathisen. There is little question that anterior mediastinal tracheostomy combined with cervical exenteration, transhiatal esophagectomy, and a primary pharyngogastric anastomosis is a formidable technical exercise. Although this operative approach provides effective palliation and occasionally cure in patients with compromise of their airway, swallowing ability, or both, careful patient selection, meticulous attention to operative detail, and intensive postoperative care are mandatory in order to achieve a successful outcome with acceptable morbidity and mortality rates.

Adult↗