Outcome of neoadjuvant treatment for pancreatic cancer in elderly patients: comparative, observational cohort study.

BACKGROUND: Use of neoadjuvant therapy for elderly patients with pancreatic cancer has been debatable. With FOLFIRINOX (folinic acid, 5-fluorouracil, irinotecan, oxaliplatin) or gemcitabine plus nab-paclitaxel (GnP) showing tremendous effects in improving the overall survival of patients with borderline resectable and locally advanced pancreatic cancer, there is no definitive consensus regarding the use of this regimen in the elderly. METHODS: This study evaluated the eligibility of elderly patients with borderline resectable or locally advanced pancreatic cancer for neoadjuvant therapy. Patients registered in the database of pancreatic cancer at the University of Colorado Cancer Center, who underwent neoadjuvant treatment between January 2011 and March 2019, were separated into three age groups (less than 70, 70-74, 75 or more years) and respective treatment outcomes were compared. RESULTS: The study included 246 patients with pancreatic cancer who underwent neoadjuvant treatment, of whom 154 and 71 received chemotherapy with FOLFIRINOX and GnP respectively. Among these 225 patients, 155 were younger than 70 years, 36 were aged 70-74 years, and 34 were aged 75 years or older. Patients under 70 years old received FOLFIRINOX most frequently (124 of 155 versus 18 of 36 aged 70-74 years, and 12 of 34 aged 75 years or more; P < 0.001). Resectability was similar among the three groups (60.0, 58.3, and 55.9 per cent respectively; P = 0.919). Trends towards shorter survival were observed in the elderly (median overall survival time 23.6, 18.0, and 17.6 months for patients aged less than 70, 70-74, and 75 or more years respectively; P = 0.090). After adjusting for co-variables, age was not a significant predictive factor. CONCLUSION: The safety and efficacy of multiagent chemotherapy in patients aged 75 years or over were similar to those in younger patients. Modern multiagent regimens could be a safe and viable treatment option for clinically fit patients aged at least 75 years.

Cytoreductive surgery and HIPEC improve survival compared to palliative chemotherapy for biliary carcinoma with peritoneal metastasis: A multi-institutional cohort from PSOGI and BIG RENAPE groups.

BACKGROUND: Peritoneal metastasis from biliary carcinoma (PMC) is associated with poor prognosis when treated with chemotherapy. OBJECTIVE: To evaluate the impact on survival of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), and compare with conventional palliative chemotherapy for patients with PMC. MATERIAL AND METHODS: A prospective multicenter international database was retrospectively searched to identify all patients with PMC treated with a potentially curative CRS/HIPEC (CRS/HIPEC group). The overall survival (OS) was compared to patients with PMC treated with palliative chemotherapy (systemic chemotherapy group). Survival was analyzed using Kaplan-Meier method and compared with Log-Rank test. RESULTS: Between 1995 and 2015, 34 patients were included in the surgical group, and compared to 21 in the systemic chemotherapy group. In the surgical group, median peritoneal cancer index was 9 (range 3-26), macroscopically complete resection was obtained for 25 patients (73%). There was more gallbladder localization in the surgical group compared to the chemotherapy group (35% vs. 18%, p = 0.001). Median OS was 21.4 and 9.3 months for surgical and chemotherapy group, respectively (p=0.007). Three-year overall survival was 30% and 10% for surgical and chemotherapy group, respectively. CONCLUSION: Treatment with CRS and HIPEC for biliary carcinoma with peritoneal metastasis is feasible and may provide survival benefit when compared to palliative chemotherapy.

Cigarette smoking is strongly associated with mutation of the K-ras gene in patients with primary adenocarcinoma of the lung.

BACKGROUND: The majority of lung carcinoma cases occur in current or former smokers. K-ras gene mutations are common in lung adenocarcinoma and have been associated with cigarette smoking, asbestos exposure, and female gender. METHODS: In the current study, the authors examined the contribution of cigarette smoking to K-ras gene mutations in patients with primary lung adenocarcinoma. Smoking histories were obtained from 106 prospectively enrolled patients with primary adenocarcinoma of the lung. RESULTS: K-ras mutations were detected in the primary tumor using an allele-specific ligation assay. Ninety-two of the 106 patients (87%) with lung adenocarcinoma were smokers. Nonsmokers with this tumor were more likely to be women (11 of 14; 79%), whereas the majority of smokers (57%) were men. K-ras mutations were detected in 40 of 106 tumors (38%) and were significantly more common in smokers compared with nonsmokers (43% vs. 0%; P = 0.001). CONCLUSIONS: The results of the current study confirm and extend previous observations that smokers with adenocarcinoma of the lung are more likely to have K-ras mutant tumors compared with nonsmokers. The strong link between cigarette smoking and K-ras mutations in adenocarcinoma of the lung supports the role of specific tobacco carcinogens in the etiology of this malignancy.

O(6)-Methylguanine-DNA methyltransferase promoter hypermethylation shifts the p53 mutational spectrum in non-small cell lung cancer.

The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) removes mutagenic adducts from the O6 position of guanine, thereby protecting the genome against G to A transition mutations. MGMT is inactivated by promoter hypermethylation in many human cancers and has been associated with G to A mutations in K-ras in colorectal cancer. We hypothesized that MGMT promoter hypermethylation would be associated with an increase in G to A transitions in the p53 gene in non-small cell lung cancer (NSCLC). p53 mutations were detected by both dideoxy sequencing and p53 GeneChip analysis in 92 patients with primary NSCLC. Methylation of the promoter region of the MGMT gene was determined using methylation-specific PCR and was present in 27 of 92 (29%) tumors. Hypermethylation of the MGMT promoter was more common in adenocarcinoma than in other histological types of NSCLC and was also more common in poorly differentiated tumors. MGMT promoter hypermethylation was present significantly more often in tumors with a G to A mutation in p53 (9 of 14; 64%) than in tumors with other types of p53 mutations (11 of 41; 27%; P = 0.02) or in tumors with wild-type p53 (7 of 37; 18%; P = 0.006). MGMT promoter hypermethylation was also strongly associated with G to A transitions at CpG sites. Inactivation of the MGMT gene by promoter hypermethylation alters the pattern of p53 mutation in NSCLC.

Surgical therapy of iatrogenic lesions of biliary tract.

Iatrogenic injuries of the biliary tract have increased in incidence over the past decade with the introduction of laparoscopic cholecystectomy. Although a number of factors have been identified with a higher risk of injury (male gender, complicated gallstone disease, aberrant anatomy) and a number of technical steps have been emphasized to avoid these injuries, the incidence of bile duct injuries has reached a steady-state at least double the rate observed with open cholecystectomy. Most patients sustaining a bile duct injury are recognized in the weeks following laparoscopic cholecystectomy. Careful preoperative preparation should include control of sepsis by draining any bile collections or fistulas and complete cholangiography. Long-term results are best achieved in specialized hepatobiliary centers performing biliary reconstruction with a Roux-en-Y hepaticojejunostomy. Success rates over 90% have been reported from several centers to date with intermediate follow-up.

Increased loss of chromosome 9p21 but not p16 inactivation in primary non-small cell lung cancer from smokers.

Epidemiological studies have demonstrated a causal association between tobacco use and carcinoma of the lung, and some genetic targets of the carcinogens in cigarette smoke have been defined recently. We further examined the effect of cigarette smoking on the frequency of allelic losses on chromosome 9p21 and the incidence of p16 inactivation. Chromosomal loss at 9p21-24 was determined by microsatellite analysis using 14 markers in 47 patients with non-small cell lung cancer. In addition, p16 gene inactivation was determined by DNA sequence analysis, methylation-specific PCR, and immunohistochemistry. Tumors from a group of nonsmokers (n = 14) were compared with tumors from a group of smokers (n = 33) matched for cell type, tumor stage, and gender. Allelic loss encompassing the p16 locus was present significantly (P = 0.01) more often in smokers (23 of 33 smokers, 70%) than in nonsmokers (4 of 14 nonsmokers, 28%). No significant differences in the frequency of p16 inactivation were observed between smokers and nonsmokers (45% versus 36%). However, homozygous deletion of the p16 gene locus and point mutation of p16 gene were only observed in tumors from smokers, whereas the p16 gene was inactivated in tumors from nonsmokers only through promoter hypermethylation. Thus, inactivation of the p16 gene is a common event in all non-small cell lung cancer, but the mechanism of gene alteration differs between smokers and nonsmokers. The significant link between tobacco and loss of the p16 locus identifies additional genetic targets of smoking in the pathogenesis of lung cancer.

Chromosomal alterations in lung adenocarcinoma from smokers and nonsmokers.

The etiology of lung tumors arising in nonsmokers remains unclear. Although mutations in the K-ras and p53 genes have been reported to be significantly higher in smoking-related lung carcinomas, in the present study we performed a more comprehensive analysis in search of additional genetic changes between lung adenocarcinoma from tobacco- and non-tobacco-exposed patients. We selected a matched cohort of 18 lifetime nonsmoking and 27 smoking patients diagnosed with primary adenocarcinoma of the lung and searched for chromosomal alterations in each tumor by testing normal and tumor tissue with 54 highly polymorphic microsatellite markers located on 28 different chromosomal arms. Allelic losses or gains at chromosomal arms 3p (37 versus 6%), 6q (46 versus 12%), 9p (65 versus 22%), 16p (28 versus 0%), 17p (45 versus 11%), and 19p (58 versus 16%) were present significantly more often in adenocarcinomas from smokers than from nonsmokers. Chromosomal arms showing allelic imbalance in lung tumors from nonsmokers were rare but occurred more often at 19q (22%), 12p (22%), and 9p (22%). The FAL (fractional allelic loss or gain) is defined as the percentage of chromosomal arm losses/gains among the total informative chromosomal arms. Tumors from smokers harbored higher levels of FAL (13 (48%) of 27 showed FAL > or = 0.3) compared with the lung tumors from the nonsmoker patients (2 (11%) of 18 showed FAL > or = 0.3; P = 0.02; odds ratio, 0.13; 95% confidence interval, 0.01-0.79). Our data demonstrate that widespread chromosomal abnormalities are frequent in lung adenocarcinoma from smokers, whereas these abnormalities are infrequent in such tumors arising in nonsmokers. These observations support the notion that lung cancers in nonsmokers arise through genetic alterations distinct from the common events observed in tumors from smokers.

Cholangiocarcinoma.

Despite overall advances in the ability to diagnose and treat patients with cholangiocarcinoma, the prognosis for patients with this malignancy remains poor. Further improvements in the survival of patients with cholangiocarcinoma will come with the early diagnosis of these lesions. New molecular techniques should improve the ability to screen high-risk patients, such as those with primary sclerosing cholangitis, hepatolithiasis, choledochal cysts, and ulcerative colitis. Improvements in imaging will continue, and spiral CT scanning, duplex ultrasonography, MR imaging and, perhaps, PET scans will improve the ability to stage patients with cholangiocarcinoma noninvasively. Complete surgical resection remains the only curative treatment for malignancies of the biliary tract. Aggressive surgical approaches are likely to continue, and the challenge remains in being able to perform these procedures safely in jaundiced and sometimes septic patients. For patients with unresectable lesions, the optimal form of palliation, whether surgical or nonsurgical, remains to be defined. Finally, multicenter, prospective, randomized trials of chemoradiation need to be performed to delineate an effective adjuvant therapy more precisely, and to improve the overall prognosis of patients with cholangiocarcinoma.

Immunohistochemistry and molecular detection of nodal micrometastases in pancreatic cancer.

PURPOSE: Assays based on polymerase chain reaction (PCR) demonstrate mutated Kiras in the regional nodes of a majority of patients with node-negative stage I or II (T(1-3), N(0), M(0)) pancreatic adenocarcinoma. The hypothesis that the presence of mutated Kiras equates with micrometastases has not been validated by detailed histologic examination nor has an impact on survival been demonstrated. METHODS: We examined the paraffin blocks of the primary tumor and regional lymph nodes from all 30 patients from 1984 to 1998 with resected pN(0) stage I or II pancreatic adenocarcinoma. DNA was analyzed for mutations in codon 12 of the Kiras oncogene by PCR and restriction digest with BstN1 (RFLP). All nodes were examined by histology of 4 hematoxylin and eosin-stained step sections and immunohistochemistry (HPE/IHC) with AE3/AE1 epithelial cell marker antibody. RESULTS: Examination of the regional lymph nodes of the 30 patients demonstrated nodal metastases in 9 (30%) by step-section histology alone, 14 (46.7%) by HPE/IHC, 19 (63.3%) by PCR/RFLP, and 25 (83.3%) by a combination of PCR/RFLP and HPE/IHC. Seven cases were HPE/IHC positive yet PCR/RFLP negative while 10 cases were PCR/RFLP positive and HPE/IHC negative. Median survival (months) did not differ if nodes were negative or positive by HPE/IHC (20.5 vs 17.5) or PCR/RFLP (20.0 vs 19.0) or a combination of these techniques (25 vs 18.5). CONCLUSIONS: A great majority (83.3%) of patients with pathologic stage I or II pancreatic cancer had metastases in their regional nodes. Step-sectioning with immunohistochemistry and PCR/RFLP are complementary tests in detection of metastatic cancer cells. Nodal micrometastases did not adversely influence survival.

Microsatellite instability at AAAG repeat sequences in respiratory tract cancers.

We surveyed the occurrence of novel alleles at microsatellite sequences in non-small cell lung cancers (NSCLC) using 61 tetranucleotide repeat markers. The presence of at least one new allele, consistent with microsatellite instability (MSI), was observed in 26 of 61 (43%) markers involving 30 of 47 (64%) NSCLC. Twelve of the 26 markers detected new alleles in 2 or more tumors and 11 of these 12 markers contained an AAAG repeat sequence. Using this panel of 12 markers, MSI was detected in 24 of 47 (51%) NSCLC and 10 of 18 (56%) head and neck cancers but was only observed in 8 of 38 (21%) bladder cancers and 3 of 25 (12%) kidney cancers. Our results suggested that about 50% of respiratory tract cancers exhibited microsatellite instability predominantly at AAAG sequences. This distinct type of instability was termed EMAST for elevated microsatellite alterations at selected tetranucleotide repeats. The identification of markers with EMAST should have potential application for the molecular detection of respiratory tract cancers.

p21WAF1 expression is associated with improved survival after adjuvant chemoradiation for pancreatic cancer.

BACKGROUND: Cell cycle arrest after DNA damage is partly mediated through the transcriptional activation of p21(WAF1) by the p53 tumor suppressor gene. p21(WAF1) and p53 are both critical in maintaining cell cycle control in response to DNA damage from radiation or chemotherapy. Therefore, we examined the role of p21(WAF1) and p53 in the determination of outcome for patients who receive radiation and/or chemotherapy for pancreatic cancer. METHODS: p21(WAF1) and p53 protein expression were determined (with the use of immunohistochemistry) in specimens from 90 patients with pancreatic cancer. Forty-four patients underwent surgical resection, and 46 patients had either locally unresectable tumors (n = 9 patients) or distant metastases (n = 37 patients). Seventy-three percent of the patients who underwent resection and 63% of the patients who did not undergo resection received radiation and/or chemotherapy. RESULTS: p21(WAF1) expression was present in 48 of 86 tumors (56%) and was significantly (P<.05) associated with advanced tumor stage. Median survival among patients with resected pancreatic cancer who received adjuvant chemoradiation with p21(WAF1)-positive tumors was significantly longer than in patients with no p21(WAF1) staining (25 vs. 11 months; P = .01). Fifty of 89 tumors (56%) stained positive for p53 protein. p53 overexpression was associated with decreased survival in patients who did not undergo resection. CONCLUSIONS: Normal p21(WAF1) expression may be necessary for a beneficial response to current adjuvant chemoradiation protocols for pancreatic cancer. Alternate strategies for adjuvant therapy should be explored for patients with pancreatic cancer who lack functional p21(WAF1).

Alcohol consumption and cigarette smoking increase the frequency of p53 mutations in non-small cell lung cancer.

Epidemiological studies have demonstrated a strong association between tobacco use and lung cancer; however, the genetic targets of these carcinogens and the role of other environmental agents in this process have yet to be defined. We examined the contribution of alcohol use and cigarette smoking top53 gene mutations in patients with non-small cell lung cancer. Mutations of the p53 gene were detected by sequence analysis in 105 patients with non-small cell lung cancer. Patient characteristics significantly associated with p53 gene mutations were determined using logistic regression. Mutations in the p53 gene were present in 53% of the patients (56 of 105). p53 mutations were more common in patients who used alcohol than in patients who consumed less than one drink per day (72 versus 39%; P = 0.003), and were detected more often smokers than nonsmokers (58% versus 10%, P = 0.02). Mutations in the p53 gene were present more often (P = 0.01) in alcohol drinkers who smoked cigarettes [76% (31 of 41)], than in nondrinkers (<1 drink per day) who smoked cigarettes [42% (20 of 48)] or in nondrinkers who did not smoke [14% (1 of 7)]. In conclusion, alcohol consumption and tobacco use are both associated with p53 mutations in non-small cell lung cancer. The link between exposure to both alcohol and tobacco and p53 mutations raises the possibility that alcohol may enhance the mutagenic effects of cigarette smoke in the lung.

Microsatellite instability at selected tetranucleotide repeats is associated with p53 mutations in non-small cell lung cancer.

Microsatellite alterations are useful clonal markers for the early detection of cancer. An increase in microsatellite instability has been observed at certain tetranucleotide repeat markers (AAAGn) in lung, head and neck, and bladder cancer. However, the genetic mechanism underlying these elevated microsatellite alterations at selected tetranucleotide repeat (EMAST) tumors is still unknown. The p53 gene plays an important role in maintaining genome integrity by repairing damaged DNA. Therefore, we tested 88 non-small cell lung cancers with a panel of 13 microsatellite markers previously shown to exhibit frequent instability and also performed p53 sequence analysis in these tumors. Thirty-one of these 88 cancers (35%) demonstrated a novel allele [EMAST(+)] in > or =1 of these 13 microsatellite markers. p53 mutations were detected in 50 of 88 (57%) cancers and were significantly (P = 0.001) more common in EMAST(+) tumors (25 of 31; 81%) than in EMAST(-) tumors (25 of 57; 44%). Among squamous cell cancers, p53 mutations were detected significantly (P = 0.04) more frequently in EMAST(+) tumors (17 of 19; 89%) than in EMAST(-) tumors (10 of 18; 55%). Similarly, among primary adenocarcinomas, p53 mutations were present in 67% of the EMAST(+) tumors and in 35% of EMAST(-) adenocarcinomas. None of the 31 EMAST(+) tumors demonstrated high frequency microsatellite instability when examined with a reference panel of five mono- and dinucleotide markers. Primary lung cancers with microsatellite alterations at selected tetranucleotide repeats have a high frequency of p53 mutations and do not display a phenotype consistent with defects in mismatch repair.

Iron deficiency diminishes gallbladder neuronal nitric oxide synthase.

BACKGROUND: Iron deficiency has been demonstrated in the prairie dog to result in cholesterol crystal formation and altered biliary motility. Gallbladder filling and emptying are influenced by both inhibitory and excitatory stimuli, with nitric oxide (NO) playing a key role in normal relaxation. Iron is a cofactor for nitric oxide synthase. Therefore, we tested the hypothesis that iron deficiency would result in diminished levels of gallbladder neuronal nitric oxide synthase (nNOS) but would not influence the gallbladder's response to excitatory stimuli. MATERIALS AND METHODS: Twenty adult female prairie dogs were fed either an iron-supplemented (Fe(+)) (200 ppm) control diet (n = 10) or an iron-deficient (Fe-) (8 ppm) diet (n = 10) for 8 weeks. Fasting gallbladder volume was measured. Gallbladder muscle strips were harvested for response to excitatory stimuli and measurement of nNOS protein levels by Western blotting. Muscle strip response to a spectrum of doses of cholecystokinin, acetylcholine, and electrical field stimuli was determined, and the areas under the response curves were calculated. RESULTS: Gallbladder volume increased in the iron-deficient prairie dogs compared with the iron-supplemented group (1.45 +/- 0.27 mL vs 0.80 +/- 0.13 mL, P < 0.05). Iron deficiency diminished the ratio of gallbladder nNOS to beta-actin protein levels (0.05 +/- 0.01 vs 3.48 +/- 1.02, P < 0.05) but resulted in a normal response to excitatory stimuli. CONCLUSIONS: We conclude that diminished gallbladder neuronal nitric oxide synthase contributes to the gallbladder stasis that occurs with iron deficiency. This phenomenon may contribute to the increased incidence of gallstones in premenopausal women.

p53 overexpression and K-ras gene mutations in primary sclerosing cholangitis-associated biliary tract cancer.

Cholangiocarcinoma occurs frequently in patients with primary sclerosing cholangitis (PSC). We evaluated the incidence and prognostic significance of p53 protein overexpression and K-ras gene mutations in patients with biliary tract cancer and PSC. p53 protein expression was determined in specimens from 12 patients with biliary tract cancer, using the antibody, D07. K-ras mutations were detected using DNA sequencing and a mutation ligation assay. Accumulation of p53 protein was detected in 6 of 12 tumors (50%). K-ras mutations were detected in 4 of 12 tumors (33%). Overall survival in patients with p53-negative tumors was significantly longer (P < 0.05) than that in patients with p53-positive (mutant) tumors. Similarly, overall survival was significantly longer (P < 0.05) in the absence of a K-ras mutation than in patients with a tumor containing a K-ras mutation. Mean interval from the time of diagnosis of PSC until the diagnosis of biliary tract cancer was significantly shorter (P < 0.05) in patients with p53 overexpression than in those patients without p53 overexpression (2 versus 47 months). p53 overexpression and K-ras mutations occur commonly in patients with PSC and biliary tract cancer and are associated with a shortened survival. Patients with longstanding PSC are less likely to have these genetic alterations and may have a better prognosis.

Diagnosis and management of cholangiocarcinoma in primary sclerosing cholangitis.

Cholangiocarcinoma remains difficult to diagnose and is a major cause of death in patients with primary sclerosing cholangitis. Recently serum carcinoembryonic antigen and carbohydrate antigen 19-9 (CA 19-9) levels have been reported to improve diagnostic accuracy in patients with cholangiocarcinoma and primary sclerosing cholangitis. We reviewed our experience with cholangiocarcinoma complicating primary sclerosing cholangitis to identify clinical factors associated with cholangiocarcinoma in patients with primary sclerosing cholangitis and to determine the appropriate management of patients with confirmed or suspected cholangiocarcinoma. Between 1984 and 1997, 25 patients (18%) were diagnosed with cholangiocarcinoma among 139 patients with primary sclerosing cholangitis. The diagnosis of primary sclerosing cholangitis was made coincident with the diagnosis of cholangiocarcinoma in 12 patients and preceded it by a mean of 62 months in the remaining 13 patients. The incidence of inflammatory bowel disease was higher (P <0.05) in patients with cholangiocarcinoma (80% vs. 61%). Nine patients (36%) with cholangiocarcinoma were managed with either extrahepatic bile duct resection and/or partial hepatic resection (n = 5) or liver transplantation (n = 4), and the remaining 16 patients were unresectable at presentation. Serum CA 19-9 was elevated in all six patients with cholangiocarcinoma who were analyzed and in none of the eight patients without cholangiocarcinoma who were tested (P <0.01). Actuarial 1- and 3-year survival rates in the resected patients (56% and 28%, respectively) were significantly longer (P <0. 02) than in the unresected patients (13% and 0%, respectively). The 10-year actuarial mortality rates for cholangiocarcinoma among all 139 patients was 25%. In summary, cholangiocarcinoma was the leading cause of death in patients with primary sclerosing cholangitis and was often diagnosed concurrently with or within months of its diagnosis. Early liver transplantation for patients with primary sclerosing cholangitis will not reduce the incidence of cholangiocarcinoma-related mortality in these patients.

The potential of molecular screening.

Clonal genetic alterations such as tumor suppressor, gene mutations, or microsatellite instability are a hallmark of human cancer. These genetic alterations can be detected in clinical samples using DNA amplification techniques and used for early detection of cancer. This article reviews molecular-based approaches for screening of malignancies commonly encountered by the practicing general surgeon.

Extended subcostal hinge incision for right hepatic lobectomy.

The safe performance of a right hepatic lobectomy requires adequate exposure of the hepatic veins and of the suprahepatic vena cava. An extended subcostal or midline incision is commonly used to provide exposure for this operation. The technique for an extended subcostal incision that uses the natural hinge mechanism of the rib cage to provide exposure to the right upper quadrant is described. This approach provides adequate exposure during a difficult hepatectomy, avoiding the need for a thoracotomy or sternotomy.

Utility of magnetic resonance cholangiography in the evaluation of biliary obstruction.

BACKGROUND: Evaluation of suspected biliary obstruction has traditionally involved a variety of imaging modalities including ultrasound, CT, and invasive cholangiography. These techniques have limitations because of poor visualization of intraductal stones (ultrasound and CT) and the need for an invasive procedure (ERCP and percutaneous transhepatic cholangiography). Magnetic resonance cholangiography (MRC) is a noninvasive imaging modality that provides good visualization of the hepatobiliary system. The aim of the present study was to determine the utility of MRC in evaluating patients with suspected biliary obstruction. STUDY DESIGN: One hundred forty-three patients were identified with suspected acute biliary obstruction and underwent MRC. Patient selection was based on clinical criteria including an elevation in serum liver chemistries or evidence of biliary ductal dilatation on conventional imaging. MRC was performed using a half-Fourier acquisition single-shot turbo spin-echo sequence involving single breath-hold rapid image acquisition. A final diagnosis was determined in each patient based on invasive cholangiography, findings at surgery, and clinical course. RESULTS: Of the 143 patients, 73 had an obstructing biliary lesion. A malignant process was identified in 25 patients with final diagnoses of pancreatic cancer (n = 15), ampullary cancer (n = 4), cholangiocarcinoma (n = 3), and hepatic or nodal metastases (n = 3). MRC correctly identified biliary obstruction in all these patients and accurately identified the level of biliary obstruction in 24 of 25 patients. Based on the MRC images alone, a malignant process was suspected in 21 of the 25 patients. Forty patients were found to have common bile duct stones and eight patients had a benign distal bile duct stricture. MRC correctly identified common bile duct stones in 37 patients with one false-positive exam (sensitivity = 92%; specificity = 99%). MRC also correctly identified distal biliary strictures in eight patients. In the remaining 70 patients, no definite biliary obstruction was identified by MRC, and in all patients the absence of mechanical obstruction was confirmed by invasive cholangiography or overall clinical course. CONCLUSIONS: This study demonstrates that MRC is able to accurately identify the level and cause of biliary obstruction in both malignant and benign disease. MRC may prove to be an important noninvasive tool in preoperative evaluation of patients with suspected biliary obstruction and identification of patients most likely to benefit from an invasive radiologic or surgical procedure.

Rapid p53 sequence analysis in primary lung cancer using an oligonucleotide probe array.

The p53 gene was sequenced in 100 primary human lung cancers by using direct dideoxynucleotide cycle sequencing and compared with sequence analysis by using the p53 GeneChip assay. Differences in sequence analysis between the two techniques were further evaluated to determine the accuracy and limitations of each method. p53 mutations were either detected by using both techniques or, if only detected by one technique, were confirmed by using mutation-specific oligonucleotide hybridization. Dideoxynucleotide sequencing of the conserved regions of the p53 gene (exons 5-9) detected 76% of the mutations within this region of the gene. The GeneChip p53 assay detected 81% of all (exons 2-11) mutations, including 80% of the mutations within the conserved regions of the gene. The GeneChip assay detected 46 of 52 missense mutations (88%), but 0 of 5 frameshift mutations. The specificity of direct sequencing and of the p53 GeneChip assay at detecting p53 mutations were 100% and 98%, respectively. The GeneChip p53 assay is a rapid and reasonably accurate approach for detecting p53 mutations; however, neither direct sequencing nor the p53 GeneChip are infallible at p53 mutation detection.