Small cell carcinoma of the esophagus. The Memorial Hospital experience 1970 to 1987

During the period 1970 to 1987, 11 patients with small cell carcinoma of the esophagus were treated at Memorial Sloan-Kettering Cancer Center, New York. This rare tumor was responsible for 1.1% of all patients with esophageal tumors seen on the inpatient services during that period. Using a clinical staging system similar to that employed in small cell cancer of the lung, eight of 11 patients had extensive disease. Although responses were seen to multidrug combination chemotherapy regimens used alone or with sequential radiation, the overall prognosis for small cell esophageal cancer was poor, with a median survival of 7.5 months. Only one patient lived for greater than 2 years.     

Viral infections in the mouth

Oral hairy leukoplakia (OHL) and Kaposi's sarcoma (KS) are commonly encountered in the HIV-infected patient. A unique feature of OHL is non-cytolytic high level of replication of Epstein–Barr virus (EBV) in the glossal epithelium. The expression of viral-encoded anti-apoptotic proteins concomitant to replicative proteins probably underlies this phenomenon. The question of whether OHL arises from activation of EBV latent in the tongue, or from superinfection by endogenous EBV shed via non-glossal sites or by exogenous EBV remains unresolved. Human herpesvirus 8 (HHV8) is now seen as necessary but not sufficient cause of KS. Expression of HHV8-encoded oncogenic proteins in endothelial cells probably explains the aberrant proliferation of these cells in KS lesions. Studies into why KS is so commonly observed at the palate in HIV-infected patients may provide important clues to its pathogenesis.     

Interleukin-1-inhibitor activity induced by respiratory syncytial virus: abrogation of virus-specific and alternate human lymphocyte proliferative responses

Respiratory syncytial virus (RSV) infection has been shown to induce human mononuclear leukocyte (MNL) production of net interleukin-1 (IL-1)-inhibitor activity. In the current studies of IL-1-inhibitor effects, RSV-exposed cells were compared with autologous MNL that were sham-exposed or exposed to inactivated RSV or influenza virus (which induces net IL-1 activity and commonly elicits effective homotypic immunity). Exposure of MNL to influenza virus or inactivated RSV resulted in increased expression of human leukocyte antigen-DR, the IL-2 receptor, and the transferrin receptor and increased progression through the cell cycle by 3 days. In contrast, exposure to infectious RSV resulted in decreased marker expression and cell cycle arrest, with abrogation of proliferation in response to the virus or other stimuli. These data raise the possibility that a contributing mechanism for recurrence of RSV infection is early suppression of the clonal expansion of virus-specific lymphocytes due to net IL-1-inhibitor activity.     

Activation of the Ha-, Ki-, and N-ras genes in chemically induced liver tumors from CD-1 mice.

We compared the profile of ras gene mutations in spontaneous CD-1 mouse liver tumors with that found in liver tumors that were induced by a single i.p. injection of either 7,12-dimethylbenz(a)anthracene (DMBA), 4-aminoazobenzene, N-hydroxy-2-acetylaminofluorene, or N-nitrosodiethylamine. By direct sequencing of polymerase chain reaction-amplified tumor DNA, the carcinogen-induced tumors were found to have much higher frequencies of ras gene activation than spontaneous tumors. Furthermore, each carcinogen caused specific types of ras mutations not detected in spontaneous tumors, including several novel mutations not previously associated with either the carcinogen or mouse hepatocarcinogenesis. For example, the model compound DMBA is known to cause predominantly A to T transversions in Ha-ras codon 61 in mouse skin and mammary tumors, consistent with the ability of DMBA to form bulky adducts with adenosine. Our results demonstrate that the predominant mutation caused by DMBA in mouse liver tumors is a G to C transversion in Ki-ras codon 13 (DMBA is also known to form guanosine adducts), illustrating the influence of both chemical- and tissue-specific factors in determining the type of ras gene mutations in a tumor. 4-Aminoazobenzene and N-hydroxy-2-acetylaminofluorene also caused the Ki-ras codon 13 mutation. In addition, we found that N-nitrosodiethylamine, 4-aminoazobenzene, and N-hydroxy-2-acetylaminofluorene all caused G to T transversions in the N-ras gene (codons 12 or 13). This is the first demonstration of N-ras mutations in mouse liver tumors, establishing a role for the N-ras gene in mouse liver carcinogenesis. Finally, comparison of the ras mutations detected in the direct tumor analysis with those detected after NIH3T3 cell transfection indicates that spontaneous ras mutations (in Ha-ras codon 61) are often present in only a small fraction of the tumor cells, raising the possibility that they may sometimes occur as a late event in CD-1 mouse hepatocarcinogenesis.     

Pharmacokinetics of a 5-fluorouracil liposomal delivery system.

A liposomal delivery system was developed in an attempt to prolong ocular levels of 5-fluorouracil for glaucoma filtering surgery. The pharmacokinetics of the 5-fluorouracil liposomal delivery system were studied in normal pigmented rabbits with 5-fluorouracil labelled with carbon-14 (C-14). 14C 5-fluorouracil was incorporated into the liposomes at a concentration of 10 g/l and injected subconjunctivally in doses of 5 and 10 mg. Concentrations of 5-fluorouracil were assayed at 10 time intervals from 0.5 to 96 hours in cornea, sclera, and conjunctiva and at six time intervals from 0.5 to 12 hours in aqueous. Two peak concentrations were noted at approximately one and eight hours, with measurable levels present at 96 hours. This study demonstrates the ability of this liposomal delivery system to prolong levels of 5-fluorouracial in normal pigmented rabbits.     

Three-dimensional visualization of physiologically based kinetic model outputs.

Outputs from a physiologically based toxicokinetic (PB-TK) model for fish were visualized by mapping time-series data for specific tissues onto a three-dimensional representation of a rainbow trout. The trout representation was generated in stepwise fashion: 1) cross-section images were obtained from an anesthetized fish using a magnetic resonance imaging system, 2) images were processed to classify tissue types and eliminate unnecessary detail. 3) processed images were imported to a visualization software package (Application Visualization System) to create a three-dimensional representation of the fish, encapsulating five volumes corresponding to the liver, kidney, muscle, gastrointestinal tract, and fat, Kinetic data for the disposition of pentachloroethane in trout were generated using a PB-TK model. Model outputs were mapped onto corresponding tissues volumes, representing chemical concentration as color intensity. The workstation software was then used to animate the images, illustration the accumulation of pentachloroethane in each tissue during a continuous branchial (gill) exposure.     

Axillopopliteal bypass for limb salvage.

Forty-one axillopopliteal bypass grafts have been placed in 30 patients for limb salvage in the past 12 years. The mean patient age was 65.6 years; 8 were women; 19 smoked; and six had diabetes. Sixteen grafts were straight axillopopliteal bypass grafts, and 25 were sequential axillopopliteal bypass grafts. Cumulative life-table primary patency rates at 1, 2, and 3 years were 70%, 56%, and 43%, respectively; secondary patency rates were 73%, 57%, and 50%, respectively. Corresponding limb salvage rates were 86%, 69%, and 69%, respectively. Ringed polytetrafluoroethylene (PTFE) graft patency at 3 years was 61% versus 40% for unsupported PTFE grafts (p = 0.35). Ringed PTFE axillofemoral grafts with sequential femoropopliteal saphenous vein grafts had a 3-year patency of 67%. Graft patency was restored in 25% of occluded grafts by thrombectomy and in 80% of occluded grafts by thrombectomy with graft revision (p = 0.21). Cumulative 3-year patient survival was 48%. The 30-day operative mortality rate was 20%; patients operated on for graft infection had a 30-day operative mortality rate of 36%. The data support the use of axillopopliteal bypass for limb salvage when standard revascularization techniques are contraindicated. Long-term patency is enhanced by use of externally supported PTFE and sequential femoropopliteal saphenous vein.