Inherited predisposition to pancreatic adenocarcinoma: role of family history and germ-line p16, BRCA1, and BRCA2 mutations.

Susceptibility to pancreatic adenocarcinoma appears to be linked to germ-line mutations in genes causing various familial cancer syndromes. The objectives of this study were to estimate the proportion of unselected pancreatic cancer patients belonging to hereditary cancer syndrome families and to determine the frequency ofp16, BRCA1, BRCA2, hMSH2, and hMLH1 germ-line mutations in patients with a personal or family history of cancer. The study population consisted of 102 patients with histologically verified pancreatic adenocarcinoma, unselected for age, sex, family history, or ethnic origin. Patients completed a family history questionnaire and provided blood for mutation analysis. Three-generation pedigrees were constructed and classified as high risk/familial, intermediate risk/ familial, intermediate risk/nonfamilial, or low risk according to defined criteria. High- and intermediate-risk cases were analyzed for germ-line mutations using a combination of methods. Thirty-eight of 102 (37%) patients were characterized as high or intermediate risk, and the remainder were classified as low risk. Germ-line mutations were identified in five (13%) of these cases [one in p16 (I49S); one in BRCA1 (5382 insC); and three in BRCA2 (6174delT)]. The BRCA1 and BRCA2 mutations were identified in Ashkenazi Jewish patients. Four of the mutation carriers had strong family histories of the syndromes associated with the mutated genes. No mutations were identified in patients in whom the sole risk factor was a family history of pancreatic cancer, and only one mutation was found among patients with early-onset disease. We conclude that known causes of genetic predisposition are an important risk factor in a small proportion of pancreatic cancer patients, especially if associated with a strong family history of syndromes associated with the disease. The lack of detectable germ-line mutations in most high- and intermediate-risk cases suggests that there are probably additional, as yet unidentified genes predisposing to this disease.

Pre-operative assessment of axillary lymph node status in patients with breast adenocarcinoma using intravenous 99mtechnetium mAb-170H.82 (Tru-Scint AD).

Immunoscintigraphy of the axilla has potential utility for the diagnostic and prognostic assessment of patients with breast adenocarcinoma. mAb-170H.82 is a murine monoclonal antibody (mAb) derived against synthetic Thomsen-Friedenreich (TF) antigen. Tru-Scint AD, a 99mTc-mAb-170H.82 immunoconjugate, has previously been shown to localize in various human adenocarcinomas. The purpose of this study was to evaluate the accuracy of this immunoconjugate in the pre-operative assessment of axillary lymph nodes in patients with known breast adenocarcinoma. Sixteen patients with documented primary breast cancer were injected intravenously with 1 mg of immunoconjugate (radioactivity 1.8 GBq) and imaged 22-24 hrs post-injection. Both planar and single photon emission computed tomographic (SPECT) images were obtained and reviewed in a blinded fashion. Imaging results were compared with surgical and pathological findings. Seven of 16 patients were found to have histologically positive axillary nodes: 5 of these sites were detected by immunoscintigraphy (sensitivity = 71%). Nine patients had pathologically disease-free axillary nodes: only 1 of these was misidentified as positive by immunoscintigraphy (specificity = 89%). These results suggest that immunoscintigraphy with 99mTc-mAb-170H.82 has promise in the detection of axillary lymph node involvement in patients with breast cancer. Further studies are warranted to define the role of immunoscintigraphy in axillary staging.

Compartmental analysis of the pharmacokinetics of radioiodinated monoclonal antibody B72.3 in colon cancer patients.

Sixteen patients with colorectal cancer were administered 37-74 MBq (1 mg) of radioiodinated B72.3 monoclonal antibody. Pharmacokinetic analysis was carried out on plasma and urine samples. Elimination from the plasma was biexponential with a mean T1/2 alpha of 3.7 h and T1/2 beta of 62.4 h. The plasma clearance was fit to a two-compartmental model. This was combined with a previously reported model for radioiodine to construct a composite model. There was a good correlation (r = 0.952) between the model-predicted and observed excretion of radioiodine suggesting that the composite model is compatible with the pharmacokinetics of the radiolabelled antibody.

Comparative dual label study of first and second generation antitumor-associated glycoprotein-72 monoclonal antibodies in colorectal cancer patients.

Radiolabeled first-generation anti-tumor-associated glycoprotein-72 (TAG-72) monoclonal antibody (MAb), B72.3, has proven useful in detecting primary and secondary colorectal carcinoma. It has been anticipated that the development of second-generation, higher affinity, anti-TAG-72 MAbs, CC49 and CC83, would be of greater use in cancer detection and of value in radioimmunotherapy of human cancer. We compared the pharmacokinetics, biodistribution, and immune responses of 131I-labeled CC49 and CC83 to 125I-labeled B72.3 by preoperatively coninjecting dual-labeled MAbs into 16 colorectal cancer patients. The imaging properties of radiolabeled CC49 and CC83 were also assessed. Pharmacokinetics of all three MAbs were identical, and there were no differences in the uptake of any of three MAbs in tumor and normal tissues. Maximum tumor uptake was 0.0041% of the injected dose/g for 125I-B72.3, 0.0024% for 131I-CC49, and 0.0029% for 131I-CC83. Radiolabeled CC49 and CC83 detected most known tumor sites on scintigrams without any clear advantage for either MAb. Nonspecific splenic and testicular uptake was frequently observed. Anti-idiotypic human anti-mouse antibody responses were seen more frequently with B72.3 than with CC49 or CC83. We conclude that higher affinity, radiolabeled anti-TAG-72 MAbs can detect colorectal cancer but do not penetrate these tumors more effectively than B72.3. Improvements in tumor detection and radioimmunotherapeutic strategies will likely require the administration of smaller fragments of MAb molecules or novel delivery systems rather than the continued development of higher affinity MAbs.

Extended cervical mediastinoscopy. A single staging procedure for bronchogenic carcinoma of the left upper lobe.

Despite a common misconception, bronchogenic carcinoma of the left upper lobe frequently metastasizes to lymph nodes not only in the anterior mediastinum (para-aortic and subaortic) but also in the superior mediastinum. Anterior (parasternal) mediastinotomy can be used to assess only the former compartment. This procedure alone, if not done in conjunction with standard cervical mediastinoscopy, will fail to disclose technically unresectable N2 or N3 disease of the left upper lobe involving the superior mediastinum. We have developed a technique to explore and sample nodes from both regions by extending a standard cervical mediastinoscopy, eliminating the need for a second incision when the anterior mediastinal compartment requires assessment. We have prospectively analyzed the first 100 procedures that we performed. This technique has been found to be accurate and exceptionally safe with one superficial wound infection as the only complication. We can recommend this single staging procedure for preoperative assessment of bronchogenic carcinomas of the left upper lobe.