Pancreaticoduodenectomy and palliation in pancreatic carcinoma.
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Humans↗
Biomedical subjects
R H Hruban
Publications and source records attributed to R H Hruban.
Genomic sequencing of DPC4 in the analysis of familial pancreatic carcinoma.
A first-degree relative with pancreatic cancer is found in 5% to 10% of patients with pancreatic carcinomas, suggesting an inherited predisposition for this neoplasm. The recently identified DPC4 tumor suppressor gene is a strong candidate for the gene responsible for the familial form of pancreatic carcinoma. DPC4 was identified in a consensus area of homozygous deletion in pancreatic carcinomas, and it is biallelically inactivated in approximately 50% of sporadic pancreatic carcinomas. The coding sequence of this gene is 1660 nucleotides in length, covering 11 exons. We describe optimized primers and conditions used in polymerase chain reaction and cycle sequencing of the entire DPC4 coding sequence of 25 individuals (eight with pancreatic carcinoma) from 11 kindreds with a familial aggregation of pancreatic carcinoma. No mutations in the coding sequences of the DPC4 gene were found; hence, it appears that germline mutations in DPC4 cannot account for many of the familial aggregations of pancreatic carcinoma.
Carcinoma↗
The structural basis of molecular genetic deletions. An integration of classical cytogenetic and molecular analyses in pancreatic adenocarcinoma.
Molecular genetic alterations are known to be important in human carcinoma, but the structural basis of these changes is largely unknown. To examine the basis of these changes, we compared the karyotypic chromosomal abnormalities of primary pancreatic adenocarcinomas with the molecular changes identified in these same cancers. In 14 cancers with abnormal karyotypes, 65% (123 of 188) of the chromosomal arms with molecular loss of heterozygosity (LOH) were associated with karyotypic structural anomalies. Karyotypic changes accounting for these molecular allelic losses included 83 chromosome losses, 18 partial deletions, nine isochromosomes, eight additions, and five translocations. Eight bomozygous deletions were also identified by molecular analyses. Of the three homozygous deletions identified at 9p21, the only karyotypic change was a single case in which one entire copy of chromosome 9 was deleted. Of the four homozygous deletions identified at 18q21.1, one showed a loss of both copies of chromosome 18, two showed a loss of one copy of chromosome 18, and the fourth had two structurally normal copies of chromosome 18. One homozygous deletion was identified at 13q12.3, and the karyotype revealed the loss of one entire copy of chromosome 13. The second copy of chromosome 13 in this carcinoma was structurally normal. These results indicate that chromosomal structural anomalies can account for two-thirds of the LOH in pancreatic adenocarcinomas and that most homozygous deletions are likely to be interstitial chromosomal deletions that are below the detection limit of conventional karyotypic analyses. Some of the molecular deletions detected as LOH on chromosomes with karyotypically normal structure can be explained by chromosomal loss with reduplication of the remaining chromosome.
Adenocarcinoma↗
Images in clinical medicine. A metastasis caught in the act.
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Adenocarcinoma↗
Germline BRCA2 gene mutations in patients with apparently sporadic pancreatic carcinomas.
Germline mutations in BRCA2 predispose carriers to the development of breast, ovarian, and a variety of other cancers. The original localization of the BRCA2 gene was aided by its homozygous deletion in a pancreatic carcinoma; indeed, an excess of pancreatic carcinoma has been seen in some BRCA2 cancer families. To determine the involvement of BRCA2 in pancreatic carcinomas, we screened for BRCA2 alterations in an unselected panel of 41 adenocarcinomas of the pancreas (30 pancreatic adenocarcinoma xenografts and 11 pancreatic cancer cell lines). Of the 15 (27%) that had allelic loss at the BRCA2 locus, 4 (9.8%) had abnormalities in the second allele upon screening of the entire BRCA2 gene by in vitro synthesized protein assay. Three of the four mutations were considered germline in origin (7.3% overall; two were confirmed in normal tissue, and one was the 6174delT mutation from the pancreatic cancer cell line CAPAN-1, for which normal tissue was unavailable). The identification of two 6174delT mutations in this series prompted us to evaluate the prevalence of this mutation in an overlapping consecutive series of 245 patients who underwent pancreatoduodenectomy for adenocarcinoma of the pancreas. Sequence analysis of this limited region of the gene identified two additional mutations: (a) one additional germline 6174delT mutation (2 of 245, 0.8% overall); and (b) a second nearby germline 6158insT mutation. One of the patients with a germline mutation had a single relative with breast cancer, and another had a single relative with prostate cancer. None had a family history of pancreatic cancer. The incidence of germline BRCA2 mutations in apparently sporadic pancreatic cancer may be at least as high as in breast or ovarian cancer. Our results suggest that some familial risks for carcinoma will be evident only through a population-based application of gene screening techniques because a low disease penetrance of the germline mutations in some families often evades clinical suspicion.
Adenocarcinoma↗
DPC4 gene in various tumor types.
We recently identified a novel tumor-suppressor gene, DPC4, at chromosome 18q21.1 and found that both alleles of DPC4 were inactivated in nearly one-half of the pancreatic carcinomas. Here, we analyzed 338 tumors, originating from 12 distinct anatomic sites, for alterations in the DPC4 gene. Sixty-four specimens were selected for the presence of the allelic loss of 18q and were further analyzed for DPC4 sequence alterations. An alteration of the DPC4 gene sequence was identified in one of eight breast carcinomas and one of eight ovarian carcinomas. These results indicate that whereas DPC4 inactivation is prevalent in pancreatic carcinoma (48%), it is distinctly uncommon (< 10%) in the other tumor types examined. The tissue restriction of alterations in DPC4, as in many other tumor-suppressor genes, emphasizes the complexity of rate-limiting checkpoints in human tumorigenesis.
Chromosomes, Human, Pair 18↗
K-ras oncogene activation in atypical alveolar hyperplasias of the human lung.
Atypical alveolar hyperplasia (AAH) is a potential precursor lesion from which lung adenocarcinomas arise and may be a good target for studying the early events of lung tumorigenesis. A common genetic alteration in lung adenocarcinomas is mutational activation of K-ras. To determine the timing of K-ras activation, we evaluated formalin-fixed and paraffin-embedded tissue samples of 41 AAHs and their paired lung neoplasms from 28 patients for codon 12 point mutations of the K-ras oncogene. K-ras codon 12 mutations were detected using PCR followed by allele-specific oligonucleotide hybridization. Mutations were found in 16 (39%) of the 41 AAHs, 8 (42%) of the 18 adenocarcinomas, and none (0%) of the 5 lung neoplasms that were not adenocarcinomas. Of the 18 patients with both an AAH and a synchronous lung adenocarcinoma, 6 had K-ras mutation in the adenocarcinoma but not in the AAH, 6 had mutations in the AAH but not in the adenocarcinoma, 4 did not harbor mutations in either the AAH or the adenocarcinoma, and 2 had mutations in both their AAH and their synchronous adenocarcinoma. In just 1 of the 18 patients was the same K-ras mutation present in the AAHs and adenocarcinoma of the patient. The detection of independent activating point mutations in a cancer-causing gene points to the neoplastic nature of AAH and suggests that glandular neoplasms of the lung arise from a background of field cancerization.
Adenocarcinoma↗
Early evaluation of abdominal/hepatic irradiation and 5-fluorouracil/leucovorin infusion after pancreaticoduodenectomy.
PURPOSE: To describe the toxicities of a combined modality adjuvant regimen for patients with resectable periampullary adenocarcinoma. METHODS AND MATERIALS: Fourteen patients with surgically resected periampullary adenocarcinoma were treated with adjuvant therapy consisting of prophylactic hepatic irradiation and pancreatic bed irradiation and concurrent infusional 5-fluorouracil and leucovorin (5-FU/LV). Starting within 60 days of surgery, patients received radiation treatments of 1.8 Gy per fraction to the liver and pancreatic bed (13 fractions), followed by 1.8 Gy per fraction to the pancreatic region (15 fractions). All radiation treatments were given with infusional 5-FU (200 mg/m2/day) and leucovorin (5 mg/m2/day) for 5 out of every 7 days during the 38-day treatment sequence. After a 1-month break, patients were scheduled to receive four cycles of infusional 5-FU/LV (2 weeks on/2 weeks off). RESULTS: All 14 patients completed the initial combination treatment. Toxicities were tolerable; three patients had Grade 3/4 toxicities that were primarily gastrointestinal in nature. Six patients required hospitalization during therapy for treatment-related toxicities. Two patients required radiation treatment breaks of less than 1 week, and two others had radiation held for 2-4 weeks. Three patients required chemotherapy dose reductions secondary to toxicities. Toxicities in the subsequent chemotherapy-alone cycles were few and primarily manifested by Grade 2 rises in liver injury tests. Higher toxicity grades were associated with tumor progression. Twelve patients have developed recurrent disease with an equal number of recurrences occurring in the pancreatic bed as in the liver over the 12-month median follow-up. Median survival for this cohort is 417 days, not significantly different from previously reported adjuvant trials in this patient population. CONCLUSION: These data indicate that adjuvant therapy with concomitant large-field radiation and infusional chemotherapy is feasible and associated with mangeable toxicities in patients undergoing pancreaticoduodenectomy for periampullary adenocarcinoma. Improvement in survival over other adjuvant regimens has not thus far been observed. Modification of this strategy may be required.
Adenocarcinoma↗
Homozygous deletion map at 18q21.1 in pancreatic cancer.
Absolute genetic differences between neoplastic and nonneoplastic cells can be discerned at sites of homozygous deletions. These deletions are of critical interest because they might be useful in the identification of defective biochemical pathways in neoplastic cells, and subsequently for the development of new treatment strategies in human cancer. We identified an area at 18q21.1 involved by homozygous deletions in 30% of pancreatic carcinomas. To characterize the homozygous deletions, we constructed a detailed physical map of nearly 2 Mb, containing yeast artificial chromosomes, P1-derived artificial chromosomes, cosmids and 24 sequence-tagged sites. The homozygously deleted are contained a new candidate tumor-suppressor gene (DPC4). To date, 23 (64%) of 35 pancreatic carcinomas carry at least one homozygous deletion at a published locus. The study of the total gene content of these loci, facilitated by the sequence-tagged site markers and maps of these regions, should help to reveal the absolute biochemical differences between neoplastic and nonneoplastic cells for a common human tumor.
Alleles↗
DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1.
About 90 percent of human pancreatic carcinomas show allelic loss at chromosome 18q. To identify candidate tumor suppressor genes on 18q, a panel of pancreatic carcinomas were analyzed for convergent sites of homozygous deletion. Twenty-five of 84 tumors had homozygous deletions at 18q21.1, a site that excludes DCC (a candidate suppressor gene for colorectal cancer) and includes DPC4, a gene similar in sequence to a Drosophila melanogaster gene (Mad) implicated in a transforming growth factor-beta (TGF-beta)-like signaling pathway. Potentially inactivating mutations in DPC4 were identified in six of 27 pancreatic carcinomas that did not have homozygous deletions at 18q21.1. These results identify DPC4 as a candidate tumor suppressor gene whose inactivation may play a role in pancreatic and possibly other human cancers.
Alleles↗
Tropical pyomyositis: imaging findings and a review of the literature.
Tropical pyomyositis is a rare cause of multiple abscesses of skeletal muscle. The entity is rare in temperate climates and, as its name suggests, is more common in areas such as the tropics and South Pacific. Staphylococcus aureus is the most common cause of infection. Therapy is aggressive, with surgical debridement and drainage followed by antibiotics. We report an unusual case of tropical myositis which simulated tumor recurrence in a patient without the typical risk factors associated with tropical pyomyositis.
Abscess↗
One-month histologic response of transmyocardial laser channels with molecular intervention.
BACKGROUND: Transmyocardial revascularization reduces the symptoms and morbidity of patients with endstage ischemic heart disease. The mechanism is postulated to be the formation of transmural left ventricular channels through which oxygenated blood directly perfuses the myocardium. New techniques for molecular enhancement of angiogenesis and endothelial cell motility may represent strategies to augment this clinical benefit. METHODS: Triads of transmyocardial revascularization channels were placed in eight separate nonischemic sites on the hearts of 7 pigs weighing 68 to 78 kg, which were allowed to recover and were then sacrificed at 28 days. In addition, one triad pair was injected with vascular endothelial growth factor, and two triad pairs received an adenovirus vector with or without the gene encoding for human profilin, which increases endothelial cell motility and adhesion. The remaining triad pair stood untreated (laser only). The histologic changes were graded (0 through 3) by an independent pathologist without knowledge of the treatment modality. Profilin production and vascular endothelial growth factor activation using a tyrosine kinase assay were monitored. RESULTS: Transmyocardial revascularization alone resulted in a significant injury response (p < 0.01), including increased vascularity without patent channels. Vascular endothelial growth factor increased surrounding inflammation (p < 0.01) without improving vascularity or patency. Profilin content in tissues was increased but nonspecifically because inflammation resulting from adenovirus also induces higher profilin concentrations. CONCLUSIONS: The clinical benefit of transmyocardial revascularization may result simply from a nonspecific histologic response to injury. Molecular interventions appear to stimulate more inflammation but no additional angiogenesis. Further improvement in the clinical benefit of transmyocardial revascularization awaits the successful stimulation of a true angiogenic response.
Adenoviridae↗
The WAF1-mediated p53 growth-suppressor pathway is intact in the coronary arteries of heart transplant recipients.
It has been suggested that the interaction of cytomegalovirus (CMV) with the p53 tumor suppressor gene product plays a role in the development of coronary artery restenosis after angioplasty. CMV nucleic acids have been observed in the coronary arteries of allografted hearts, suggesting a possible role for the interaction of CMV with p53 in the development of accelerated graft arteriosclerosis in transplant recipients. Formalin-fixed, paraffin-embedded sections of coronary arteries from 19 transplanted hearts were immunostained for the p53 gene product using Target Unmasking Fluid (TUF)-mediated immunohistochemistry and the anti-p53 antibodies CM1 and DO7. Fresh-frozen sections of coronary arteries were also available from six of the 19 hearts, and these fresh-frozen sections were immunostained for the p53 gene product with the DO7 antibody and for WAF1 using the anti-WAF1 antibody EA10. Focal and weak staining for p53 was observed in smooth muscle and endothelial cells in two of 19 vessels, whereas the remaining 17 did not stain. CMV nucleic acids were previously shown in six of 13 of these hearts by in situ hybridization. The fresh-frozen sections of coronary arteries also did not stain for p53, but the smooth muscle cells in these vessels did stain intensely for WAF1. These results suggest three possibilities: (1) CMV-p53 interactions are not important in the development of accelerated graft arteriosclerosis; or (2) there is an interaction, but it is transient and not detectable at the time points examined in this study; or (3) there is an interaction, but binding of CMV to p53 leads to accelerated degradation of p53, as occurs with HPV-E6. The expression of WAF1 further suggests that the WAF1-mediated antiproliferative signal is intact in these vessels.
Coronary Artery Disease↗
Immunohistochemical evaluation of HER-2/neu expression in pancreatic adenocarcinoma and pancreatic intraepithelial neoplasms.
Although several morphological and molecular genetic studies have implicated various grades of pancreatic duct hyperplasia as precursor lesions to infiltrating pancreatic adenocarcinoma, the identity of preinvasive pancreatic neoplasms remains controversial. In the present study, the authors examined the expression of the epidermal growth factor receptor homologue, HER-2/neu (c-erbB-2), in pancreatic duct lesions adjacent to infiltrating pancreas cancers in a series of 19 cases of pancreatic duct adenocarcinoma. HER-2/neu expression was examined because it has been identified in a proportion of infiltrating pancreas cancers and because it may provide early neoplasms with a growth advantage over adjacent nonneoplastic epithelium. In normal pancreatic ducts and ductules, HER-2/neu expression was absent in all but one case. By contrast, HER-2/neu was expressed in 82% (P = .008 vs normal ) of ducts with flat mucinous hyperplasia, 86% (P = .03 vs normal) of ducts with papillary mucinous hyperplasia without atypia, 92% (P = .001 vs normal) of ducts with atypical papillary mucinous hyperplasia, and all specimens with carcinoma in situ. HER-2/neu expression was observed in 69% (P = .002 vs normal) of the moderately differentiated infiltrating carcinomas and none of the poorly differentiated infiltrating carcinomas. These data establish HER-2/neu as a potential mediator of growth factor-related signal transduction in pancreatic duct lesions, and provide additional support for the hypothesis that lesions formerly regarded as various grades of hyperplasia instead may represent intraepithelial neoplasms with the potential for subsequent invasion and metastasis.
Adenocarcinoma↗
Partial T-cell receptor gene rearrangement. A source of pseudo-clonal populations in thymomas and other thymic tissues.
The differentiation of thymocytes into mature post-thymic T cells requires rearrangement of T-cell antigen receptor genes from germline to a spectrum of spliced configurations encoding functional receptors. In the T-cell receptor beta chain locus, this process occurs via a hierarchical series of recombination events, linking "diversity" and "joining" segments, then "variable" and "diversity" segments. The authors report Southern blot analysis of the T-cell receptor beta locus in normal human thymic tissue after restriction digestion with Bam HI identifying rearranged DNA fragments in 5 of 6 samples, which probably represent an intermediate deletion joining D beta 1 to a J beta 2 segment without rearrangement of the upstream V region. Hybridization intensity was in the range of 5% to 30% of represented DNA. Reduction of signal from bands containing C beta 1 and J beta 2 sequences after Eco RI and Hind III digestion was consistent with this model. A probe specific for J beta 1 did not hybridize with the rearranged fragment while J beta 2 specific sequences did not hybridize with the rearranged fragment while J beta 2 specific sequences did, indicating a deletion of the region of J beta 1, but limited to sequences upstream of J beta 2. Most peripheral lymphoid specimens do not demonstrate similar rearranged DNA fragments, however T-cell-rich populations may do so. Analysis of 31 additional surgically resected thymic tissues and three polyclonal T-cell-rich peripheral lymphoid specimens revealed a similarly rearranged fragment in 13 of 14 thymuses with follicular hyperplasia; 6 of 9 thymomas; 5 of 6 malignant (invasive) thymomas; 0 of 2 thymic carcinomas; and, at very low abundance, in 3 of 3 peripheral T-cell populations. Because this nongermline T-cell receptor gene apparently reflects polyclonal incomplete rearrangement, rather than clonality, awareness of this phenomenon may help prevent erroneous diagnosis of T-cell lymphoma for mediastinal lymphoid lesions with an apparent "clonal" T-cell receptor gene rearrangement. If the intermediate deletion is derived from an ongoing process, the data suggest that in many cases neoplastic thymic epithelium may retain functions necessary not only to support a resident thymocyte population, but also to activate ongoing T-cell differentiation. Alternatively, the intermediate deletion may derive from abandoned non-productive rearrangements.
Blotting, Southern↗
Pancreaticoduodenectomy. Does it have a role in the palliation of pancreatic cancer?
OBJECTIVE: The authors define the role of palliative pancreaticoduodenectomy in patients with pancreatic carcinoma. BACKGROUND: Decreases in perioperative morbidity and mortality and improved long-term survival associated with pancreaticoduodenectomy for patients with pancreatic carcinoma have clearly established a role for this operation when performed with curative intent. However, most surgeons remain hesitant to perform pancreaticoduodenectomy unless surgical margins are widely clear, choosing rather to perform palliative biliary and gastric bypass. METHODS: A single-institution retrospective review was performed comparing the outcome of 64 consecutive patients undergoing pancreaticoduodenectomy for pancreatic carcinoma with gross or microscopic evidence of adenocarcinoma at the surgical resection margins, and 62 consecutive patients found to be unresectable at the time of laparotomy because of local invasion without evidence of metastatic disease (stage III). Combined biliary and gastric bypass were performed in 87% of patients not resected. RESULTS: The two groups were similar with respect to age, gender, race, and presenting symptoms. The hospital mortality rate was identical in both groups (1.6%). Fifty-eight percent of patients undergoing pancreaticoduodenectomy had an uncomplicated postoperative course compared with 68% of patients undergoing palliative bypass (not significant). The length of postoperative hospital stay after pancreaticoduodenectomy was 18.4 days, which was significantly longer (p < 0.05) than for patients undergoing palliative bypass (15.0 days). The overall actuarial survival (Kaplan-Meier) was improved significantly in patients undergoing pancreaticoduodenectomy (p < 0.02). Postoperative chemotherapy and radiation therapy improved survival in both groups. CONCLUSIONS: Pancreaticoduodenectomy can be performed with a similar perioperative morbidity and mortality and only a minimal increase in hospital stay when compared with traditional surgical palliation. Pancreaticoduodenectomy with postoperative chemotherapy and radiation therapy is associated with improved long-term survival when compared with patients treated with surgical bypass. These data support the role of palliative pancreaticoduodenectomy in patients with pancreatic carcinoma and with local residual disease.
Adenocarcinoma↗
Cholangiocarcinoma. A spectrum of intrahepatic, perihilar, and distal tumors.
OBJECTIVE: The objective of this article is to introduce a simple method for classifying cholangiocarcinomas and to apply this system to analyze a large number of patients from a single institution. SUMMARY BACKGROUND DATA: For the past 2 decades, most western reports on cholangiocarcinoma have separated intrahepatic from extrahepatic tumors and have subclassified this latter group into proximal, middle, and distal subgroups. However, "middle" lesions are uncommon and are managed most often either with hilar resection or with pancreatoduodenectomy. The spectrum of cholangiocarcinoma, therefore, is best classified into three broad groups: 1) intrahepatic, 2) perihilar, and 3) distal tumors. These categories correlate with anatomic distribution and imply preferred treatment. METHODS: The records of all patients with histologically confirmed cholangiocarcinoma who underwent surgical exploration at The Johns Hopkins Hospital over a 23-year period were reviewed. RESULTS: Of 294 patients with cholangiocarcinoma, 18 (6%) had intrahepatic, 196 (67%) had perihilar, and 80 (27%) had distal tumors. Age, gender, race, and associated diseases were similar among the three groups. Patients with intrahepatic tumors, by definition, were less likely (p < 0.01) to be jaundiced and more likely (p < 0.05) to present with abdominal pain. The resectability rate increased with a more distal location (50% vs. 56% vs. 91%), and resection improved survival at each site. Five-year survival rates for resected intrahepatic, perihilar, and distal tumors were 44%, 11%, and 28%, and median survival rates were 26, 19, and 22 months, respectively. Postoperative radiation therapy did not improve survival. In a multivariate analysis resection (p < 0.001. hazard ratio 2.80), negative microscopic margins (p < 0.01, hazard ratio 1.79), preoperative serum albumin (p < 0.04, hazard ratio 0.82), and postoperative sepsis (p < 0.001, hard ratio 0.27) were the best predictors of outcome. CONCLUSIONS: Cholangiocarcinoma is best classified into three broad categories. Resection remains the primary treatment, whereas postoperative adjuvant radiation has no influence on survival. Therefore, new agents or strategies to deliver adjuvant therapy are needed to improve survival.
Bile Duct Neoplasms↗
CT of the stomach: spectrum of disease.
In evaluation of gastric disease, computed tomography (CT) has proved to be a valuable adjunct to barium studies and endoscopy. CT clearly demonstrates the primary pathologic condition and shows extension of disease to adjacent or distant structures. Useful in staging gastric cancer, CT has also proved valuable in detecting and defining the extent of other gastric neoplasms such as lymphoma, leiomyosarcoma, and metastasis to the stomach. Recent advances in CT technology such as spiral CT-coupled with air contrast gastric studies and a better understanding of the need to optimize CT protocols-suggest that the value of CT in these applications will increase. CT has also been shown to be valuable in detection and differentiation of other gastric conditions such as benign tumors, Helicobacter pylori and other infections, various forms of gastritis (radiation, eosinophilic, and emphysematous), ulcer disease, Ménétrier disease, and varices. Adequate gastric distention is essential for successful gastric CT.
Adult↗