The use of interleukin 2 (IL-2) as an antineoplastic agent has been limited by the serious toxicities that accompany the doses necessary for a tumor response. Elevation of nitric oxide (NO) and tumor necrosis factor (TNF) both have been implicated in IL-2 toxicities. CNI-1493, a tetravalent guanylhydrazone, is an inhibitor of macrophage activation including the synthesis of TNF and other cytokines. Doses of CNI-1493 as low as 1 mg/kg/day conferred complete protection against fatal toxicity of IL-2 with IL-2 doses tenfold higher than the safely tolerated level in Sprague-Dawley rats. Moreover, typical pathologic changes in the lungs, kidneys, and the liver caused by IL-2 infusion were blocked by cotreatment with CNI-1493. When animals bearing established hepatomas were given IL-2 and CNI-1493 combination therapy, 10 of 10 hepatomas regressed from 1 cm3 to <1 mm3. Intracytoplasmic TNF levels were increased in normal tissues from IL-2 treated animals, and treatment with CNI-1493 maintained TNF at control levels. The degree of apoptosis measured by terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling staining of tumors following IL-2 therapy was not reduced compared with IL-2 cotreated with CNI-1493. In contrast, apoptosis in the liver and lung parenchyma following IL-2 therapy was blocked completely by cotreatment with CNI-1493. Taken together, these data showed that low and infrequent doses of CNI-1493 markedly protected animals from IL-2 systemic toxicities whereas not affecting tumor response to IL-2 therapy. With the protection afforded by CNI-1493 treatment, IL-2 therapy dose levels could be increased to provide significant antitumor effects in animals with established hepatomas.
The development of adenocarcinoma or carcinoid tumors in atrophic gastritis is widely documented. We report the simultaneous occurrence of gastric adenocarcinoma and carcinoid (composite tumor) in atrophic gastritis, a finding reported only twice before in the literature. This 52-yr-old man with rectal bleeding, epigastric pain, and iron deficiency anemia was noted to have multiple polypoid masses on upper endoscopy. Biopsy revealed features of both adenocarcinoma and carcinoid tumor in a background of atrophic gastritis, leading to a total gastrectomy, lymph node dissection, and liver biopsy. The gastrectomy specimen was characterized by a 6 cm pedunculated polyp and multiple sessile nodular masses between 0.4 and 2.5 cm in the background of a granular mucosa. On microscopic examination, the large polypoid mass corresponded to a well-differentiated adenocarcinoma, intestinal type, infiltrating the wall. The smaller nodules were composed of carcinoid tumors, restricted to the mucosa, or infiltrating the gastric wall. Carcinoid tumor was also seen in the large polypoid mass closely intermingled with adenocarcinoma. The carcinoid tumor metastasized to the liver. Lymph nodes showed both adenocarcinoma and carcinoid tumor. The gastric mucosa was characterized by atrophic gastritis with intestinal metaplasia, neuroendocrine hyperplasia, and microcarcinoids. The adenocarcinoma stained strongly for CK7, CK 20, MIB-1, and focally for chromogranin and synaptophysin. The carcinoid tumor was negative for CK7, CK 20 and MIB-1, and was positive for chromogranin and synaptophysin. Overexpression of p53 was noted only in the adenocarcinoma. Electron microscopy revealed neurosecretory granules in the carcinoid characteristic of a neuroendocrine tumor. Composite tumor can occur in the setting of atrophic gastritis. The findings in this patient reinforce the concept that the epithelial and neuroendocrine cells of the gastrointestinal tract both result from multidirectional differentiation of a primitive cell.
GOLD, JONATHAN W. M. M.D.1; WEIKEL, CYNTHIA S. M.D.1; GODBOLD, JAMES PH.D.2; GARCIA, CARLOS M.D.3; URMACHER, CARLOS M.D.3; CUNNINGHAM-RUNDLES, SUSANNA PH.D.4; KOZINER, BENJAMIN M.D.4; POLLACK, MARILYN PH.D.4; GALLO, ROBERT C. M.D.5; SARNGADHARAN, M. G. PH.D.6; ARMSTRONG, DONALD M.D.1 Author Information
There is an increasing awareness of local procedures to treat early stage rectal cancer. Abdominoperineal resection (APR) or low anterior resection (LAR) has been recommended if adverse pathologic findings are encountered in the local excision specimen. No data compare the impact on survival of "immediate" resection for adverse features vs. "salvage" resection for clinical recurrence.We reviewed retrospectively 155 patients who underwent initial curative treatment of invasive rectal cancer by excision (91), snare-cautery (44), and fulguration (20).Twenty-one patients underwent APR/LAR immediately after initial local treatment, whereas another 21 patients underwent salvage APR/LAR for local recurrence. The disease-free survival after APR/LAR was 94.1 percent for the immediate group and 55.5 percent for the delayed group (P < 0.05).This decreased survival observed after delayed resection supports the recommendation for immediate APR/LAR when adverse pathologic features are present in the excision specimen.
A 75‐Year‐old while woman was referred to Memorial Sloan‐Kettering Cancer Center for evaluation of a slowly enlarging, asymptomatic plaque that had been present on the left breast for several years. She had developed hypothyroidism and hypertension. There was no personal or family history of skin cancer or broast disease. Results of mammography, performed 1 month earlier, were normal. Physical examination revealed an elderly, moderately obose white woman. Examination of the breasts did not reveal any masses, and there were no palpable axillary lymph nodes. On the left breast, tbere was a well circumscribed, orangered plaque, 3 cm in diameter, with a peripheral collarette scale. The lesion was located 2 cm from the areola, in the medio‐inferior quadrant of the breast (Fig. 1). A punch biopsy of the lesion showed atypical cells in the epidermis characterized by abundant pale cytoplasm (Fig. 2). Result of PAS stain for glycogen was only weakly positive, and results of all stains for mucin were negative. A lichenoid lymphohistiocytic infiltrate was seen in the dermis. A complete excision of the lesion was performed, revealing Bowen's disease. The specimen contained areas of pagetoid cells (Fig. 2) as well as more typical areas of Bowen's disease (Fig. 3).
The treatment of difficult wounds remains a considerable clinical challenge. The goal of this study was to determine whether genetic augmentation of dermal cells on resorbable matrices can stimulate the healing process, leading to increased tissue repair in a rat full-thickness excisional wound repair model. The human platelet-derived growth factor B (PDGF-B) gene was the initial gene chosen to test this hypothesis. The human PDGF-B gene was obtained from human umbilical vein endothelial cells (HUVEC) by reverse transcriptase-polymerase chain reaction, cloned into retroviral vectors under control of either the cytomegalovirus promoter or the rat beta-actin promoter, and introduced into primary rat dermal cells. In vitro results demonstrate that rat dermal cells are transduced and selected readily using retroviral vectors, and engineered to secrete PDGF-B at a steady-state level of approximately 2 ng per milliliter culture per 1 million cells per 24 hours. Seeding of the gene-modified cells onto polyglycolic acid (PGA) scaffold matrices and introduction into the rat model resulted in substantially increased fibroblast hypercellularity over control wounds at both 7 and 14 days posttreatment. Our results demonstrate that gene augmentation of rat dermal fibroblasts with the PDGF-B gene introduced into this animal model via PGA matrices modulates wound healing and suggests that experimentation with additional genes for use separately or in combination with PDGF-B for additional, improved wound healing is warranted.
