Biomedical subjects
Publications and source records attributed to E D Holyoke.
In the resection of mesenteric tumors or primary malignant lesions of the small bowel, exposure of the superior mesenteric vessels is important. This is the necessary criterion of resectability and the condition of obtaining maximal margins in the lymphatic drainage area. It also helps avoid unnecessary sacrifice of branches and tributaries to the superior mesenteric vessels from uninvolved portions of the bowel.
Chemotherapy was administered in the immediate postoperative period to seventy patients (52 with melanomas and 18 with sarcomas) after a total of eighty-seven major operations, with no morbidity or mortality traceable to the chemotherapy. There was no apparent interference with wound healing or what would be considered a normal postoperative course. Fourteen of these patients (5 with melanomas and 9 with sarcomas) received a combination of radiation anc chemotherapy initiated in the postoperative period, and it was tolerated well. This combination appears to be safe, provided the field of radiation is not so large that is may add significantly to the myelosuppressive effect of chemotherapy and the dosage of concomitantly administered radiopotentiating agent(s) is reduced. Sixteen patients had Bacillus Calmette-Gúerin (BCG) immunotherapy in the immediate postoperative period without complications. This policy of a tight interweaving of modalities is safe, has the theoretic advantage of an earlier concerted attack on microscopic residual tumor, and appears particularly promising in sarcomas.
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Histologic grading of the histiolymphocytic reaction in nodules of T241 or B16 murine tumors in 94 C57BL/6J mice was performed at various time intervals post-inoculation. The infiltrate occurring in the first four days was generally sparse and no significant difference was observed between two different dose control inocula, suggesting a weak primary localization. Comparison between control inocula, and challenge inocula in mice harboring the same tumor for 10 days, showed a somewhat denser infiltrate initially in the challenge inocula. Despite the immunogenicity of these tumors, as shown by concomitant immunity, lymphocytic infiltration was generally sparse, consistent with an hypothesis of deficient localization of immunocompetent cells at tumor sites.
The leukocyte adherence inhibition (LAI) microassay detects tumor-associated antigen(s). Extracts of colon carcinoma (MCA-38 and B16 melanoma tumors, both syngeneic to the C57BL/6J mice) are recognized only by peritoneal cells from mice bearing the corresponding tumor. To ascertain whether this in vitro antigenic recognition correlates with the ability of the host to recognize and reject a tumor in vivo, serial LAI microassays were performed synchronously with experiments designed to test the ability of mice bearing tumors to reject live secondary tumor challenges. Concomitant tumor immunity was present in the MCA-38 tumor-bearing mice on 3 occasions from 5 to 15 days from primary inoculation. In the B16 system, concomitant immunity was present on one occasion 10 days after primary inoculation. These results in turn were paralleled with the specific in vitro recognition of tumor antigens as detected by the LAI microassays. Loss of immunity in the "eclipse" phase of tumor development, as detected by concomitant tumor immunity, was paralleled by nonreactivity of the indicator cells in the LAI microassay.
To study the cellular basis for specific antigen-induced leukocyte adherence inhibition, enriched populations of B-cells, T-cells, and monocytes were prepared by a two-stage adherence separation procedure from spleen cells of normal C57BL/6J mice and mice bearing progressively growing MCA-38 tumors. The reactor cell undergoing specific antigen-induced adherence inhibition was identified as a monocyte (esterase positive, did not respond to mitogens, and did not bear Thy 1.2 antigen or surface immunoglobulin). Furthermore, an enriched population of MCA-38-sensitized B-cells could program normal monocytes to undergo specific antigen-induced adherence inhibition. In contrast, enriched populations of MCA-38-sensitized T-cells could not program normal nylon wool-adherent cells to undergo antigen-specific adherence inhibition. Programming of normal monocytes by MCA-38-sensitized B-cells occurs through a soluble mediator and not by direct cell contact. The soluble mediator appears to be immunoglobulin in nature and induced both adherence inhibition and the inhibition of adherence. Thus, in this murine tumor model, leukocyte adherence inhibition appears to be due to programming of monocytes by a secretory product of specifically sensitized B-cells.
This paper gives a detailed description of the microtest leukocyte adherence inhibition technique, as well as the results obtained with blood specimens coded by impartial observers. Three coded blood specimens from patients with colon cancer, pancreatic cancer, and melanoma were tested against crude membrane preparations of pancreatic and colon adenocarcinoma tumors. No tissue type-specific reactivity was observed. The inability to demonstrate specific reactivity was due to extensive variability observed within each test. The extensive variability resulted from time constraints of the workshop that necessitated deviations from the normal procedure.
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Tourniquet infusion chemotherapy involves the direct injection of a chemotherapeutic drug into the main artery of an extremity with prior application of an external tourniquet proximally on this extremity set at above the level of systolic pressure for ten minutes. Thus, the drug is not diluted and pushed by the blood into the venous circulation before diffusion into the tissues has occurred. This technique, applied in seven patients for a total of 40 instances, proved to be safe. Skin erythema and blisters, which are reversible, occur in the treated area. Complete clinical regression was achieved in all six patients with evaluable tumor, with high percentages of tumor necrosis. It was possible to avoid amputation in five of the seven patients treated. This technique appears superior to perfusion, but the long term permanence of regression has not yet been ascertained.
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CEA plasma levels obtained prior to definitive surgery in patients with colorectal cancer in our hands have predictive ability. An elevated CEA greater than 2.5 ng/ml recorded by our laboratory means an increased risk of subsequent local recurrence or of later metastatic disease. The question as to whether or not this is additive as a prognostic variable when tested against careful histopathological staging remains. As a monitor, CEA will detect recurrence. Again, the problem as to how accurate this is remains. If we use two consecutive elevations of plasma CEA greater than 2.5 ng/ml as a criteria, we encounter about 15% false positives which must be weighed against finding disease significantly earlier in about one-third of the patients followed. Our data for second-look procedures indicate clearly that when used in patients with an elevated CEA laparotomy may be useful and further studies showed the presence of disease in 11 of 14 patients with an elevation following surgery for two consecutive tests were greater than 2.5 ng/ml. Two were operable. The significance of these findings is described.
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Ascitic fluid from a patient with carcinoma of the pancreas was fractionated by ammonium sulfate precipitation. The fraction precipitated between 25 and 50% saturation of ammonium sulfate was sequentially chromatographed on Sephadex G-200 and Sepharose 6B. A macromolecular fraction (greater than 10(6) daltons) obtained was found to react with both antihuman IgM and antiserum to carcinoembryonic antigen (CEA). This fraction was further purified by adsorption with protein A-Sepharose CL-4B and chromatography on DEAE-Sephacel. The purified macromolecular fraction had a sedimentation value of 28S as determined by ultracentrifugation. Upon dissociation of the purified macromolecule at pH 2.3 and purification of the dissociated components on Sepharose CL-2B and BioGel A 1.5M, a 19S protein and a 5S protein were recovered. The 19S protein showed a complete line of identity with a reference human IgM when reacted with antihuman IgM in gel diffusion, whereas the 5S protein showed a partial immunologic identity with colon CEA against anti-CEA. These results indicated the existence of an IgM-containing macromolecular complex with an anti-CEA cross-reactive substance in the extracellular fluid of human pancreatic cancer.
Thirty patients with locally advanced, nonresectable, nonmetastatic cancer in the peripancreatic region, stomach and colorectum-anus, to be treated with radiation therapy with or without adjuvant chemotherapy, were randomized to receive standard diet and either usual between-meal feedings or 300 calories tid of a high nitrogen elemental diet. Although weight loss associated with radiation therapy was not significantly reduced in those receiving the nutritional supplement, delayed hypersensitivity skin test responses tended to improve in patients receiving the elemental dietary supplement and to deteriorate in controls. Planned radiation therapy was completed in all nutritionally supported patients. One control patient expired shortly after treatment was halted abruptly, and three other control patients required rescue by total parenteral nutrition.
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