Challenges of utilizing immunostains to facilitate the diagnosis and management of metastatic adenocarcinoma.

Women presenting with metastases from an unknown primary site represent a growing diagnostic challenge. Treatment is based upon the results of several diagnostic radiographic modalities that may locate the occult primary and determine the extent of metastatic tumor burden. Immunostaining represents another modality that can be used to facilitate identification and management of occult primary carcinoma. In patients who present with advanced disease, combining standard techniques with immunostaining can usually aid in determining the most effective regimen for optimal palliation and, in some cases, prolonged survival. We describe metastatic adenocarcinoma of unknown primary presenting as a pericardial effusion and coincident supraclavicular adenopathy. The patient completed the chemotherapy and had stable metastatic tumor burden with an acceptable quality of life. Two years after initial diagnosis, the patient expired because of disease progression. Although immunohistochemical staining initially suggested metastatic breast carcinoma, her clinical course confirmed a lung primary.

Genomic instability of human aberrant crypt foci measured by inter-(simple sequence repeat) PCR and array-CGH.

Aberrant crypt foci (ACF) are the earliest identifiable neoplastic lesions in the colon. Thirty-two ACFs were examined for genomic instability in forms detectable either by inter-(simple sequence repeat) PCR or by array comparative genomic hybridization [array-CGH]. One-fourth of ACFs revealed moderate instability by inter-(simple sequence repeat) PCR; none showed amplifications or deletions on array-CGH. The absence of genomic events detectible by BAC array-CGH indicates early events in colorectal tumor progression are typically smaller than the approximate 150 kb size of a BAC clone insert.

A BALB/c murine lung alveolar carcinoma used to establish a surgical spontaneous metastasis model.

Line-1, a weakly immunogenic lung tumor cell line derived from the BALB/c mouse, metastasizes spontaneously to the lungs of mice following subcutaneous administration. The parameters that influence metastasis as well as the progression of metastatic lung disease following surgical resection of primary subcutaneous tumors were characterized. Histological analysis of the lungs obtained from mice bearing different size subcutaneous tumors demonstrated that >90% of the mice developed micrometastatic disease in the lungs when the tumor exceeded 650 mm3 in size. Surgical resection of subcutaneous tumors resulted in the cure of primary disease in 95% of the mice. Macroscopic tumor nodules were grossly visible in the lungs of 75% of the mice 5 weeks after surgery. Serum amyloid A level correlated with primary tumor burden and was diagnostic for the presence of metastatic disease. The efficiency of metastasis, post-surgical primary tumor recurrence and long-term survival were significantly different between BALB/c mice obtained from different suppliers. The Line-1-BALB/c surgical metastasis model provides a clinically relevant tool for the evaluation of anti-cancer therapies, especially those that are designed to target long-term suppression of minimal residual disease following surgical intervention.

Cancer immunotherapy with interleukin 12 and granulocyte-macrophage colony-stimulating factor-encapsulated microspheres: coinduction of innate and adaptive antitumor immunity and cure of disseminated disease.

Tumor cells, injected s.c., were maintained until spontaneous metastases to the lungs were established in all of the mice. Mice were then treated with a single dose of cytokine-encapsulated biodegradable microspheres injected directly into primary s.c. tumors to achieve a local and sustained release of interleukin 12 (IL-12), granulocyte-macrophage colony-stimulating factor (GM-CSF), or a combination of these cytokines to the tumor microenvironment. The s.c. tumors were surgically excised 6 days after microsphere injections, and the mice were monitored for recurrence of the primary tumor, survival, and progression of metastatic disease. Combined neoadjuvant treatment with IL-12 and GM-CSF microspheres was superior to all other treatments in reducing the recurrence of primary tumors, enhancing postoperative survival, and suppressing established metastatic disease. Long-term survival analysis demonstrated that intratumoral injection of IL-12 + GM-CSF-loaded microspheres resulted in the complete cure of disseminated disease in the majority of the animals. The addition of systemic low-dose IL-2 therapy to the treatment protocol resulted in the loss of the antitumor activity induced by IL-12 + GM-CSF treatment. In vivo lymphocyte subset depletions established that both T- and natural killer-cell subsets were required for the suppression of primary and metastatic tumors. Long-term, tumor-specific T-cell activity was demonstrated by immunohistochemical analysis of metastatic lesions, IFN-gamma enzyme-linked immunosorbent spot (ELISPOT) assays and tumor challenge studies. These results establish that neoadjuvant in situ tumor immunotherapy with IL-12 + GM-CSF microspheres induces both innate and adaptive antitumor immune responses resulting in the eradication of disseminated disease.

Predictive factors associated with long-term survival in patients with neuroendocrine tumors of the pancreas.

BACKGROUND: Neuroendocrine tumors of the pancreas are rare tumors. We identified predictive factors that are associated with long-term survival (> or=5 years). METHODS: Fifty patients with a diagnosis of neuroendocrine tumors of the pancreas were retrospectively evaluated. The following factors were evaluated for disease-specific mortality: age, sex, primary tumor location, functional status, type of primary tumor treatment, presence or absence of liver metastases, timing of liver metastases occurrence, and type of liver metastases treatment. Aggressive treatment of the liver metastases included surgery, chemoembolization, or intrahepatic arterial infusion chemotherapy. RESULTS: Twenty-three patients (47%) had tumor located in the head of the pancreas, and 29 patients (58%) had nonfunctioning tumor. Thirty-nine patients (78%) had liver metastases. The median follow-up for the entire group was 35 months (range,.76-206 months). The median survival for the entire group was 40 months, and the overall 1-, 2-, and 5-year survival rates were 84%, 69%, and 36%, respectively. Factors that had a significant favorable effect on survival included curative resection of the primary tumor, metachronous liver metastases, absence of liver metastases, and aggressive treatment of the liver metastases. CONCLUSIONS: Definitive surgical resection of the primary tumor, absence of liver metastases, metachronous liver metastases, and aggressive treatment of the liver metastases were predictors of long-term survival in patients with neuroendocrine tumors of the pancreas.

High-grade dysplasia within Barrett's esophagus: controversies regarding clinical opinions and approaches.

Barrett's esophagus with high-grade dysplasia is a well-known risk factor for the development of esophageal adenocarcinoma, which has become the predominant form of esophageal cancer in the United States. This review addresses four major fundamental issues that shape our treatment decisions regarding high-grade dysplasia within Barrett's esophagus: (1) the poorly defined natural history of high-grade dysplasia in its progression to adenocarcinoma, (2) the potentially high morbidity and mortality of esophageal resection for high-grade dysplasia, (3) the difficulty in detecting cancer among dysplastic cells during endoscopy, and (4) the controversial role of endoscopic mucosal ablative therapy for high-grade dysplasia. Until there are more accurate surveillance methods, better biochemical or molecular markers in predicting cancerous progression, or more effective minimally invasive methods of treatment, esophagogastrectomy must be considered the standard means of managing patients with Barrett's esophagus and high-grade dysplasia. Regular rigorous systematic surveillance and endoscopic mucosal ablation are alternative treatment options that are available but should be used only under strict conditions. The decision to proceed in a certain direction is quite complex and challenging and ideally requires the feedback of patients who are properly educated about the controversies surrounding this disease.