Mechanisms of depressed reactivity to dinitrochlorobenzene and ultraviolet-induced tumors during ultraviolet carcinogenesis in BALB/c mice.
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Biomedical subjects
Publications and source records attributed to J M Jessup.
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In these experiments, we tested in various in vivo assays the immune responses of inbred C3H/HeN(MTV-) (C3H-) mice during carcinogenesis by chronic exposure to UV irradiation. Although the UV-treated mice were unable to reject syngeneic UV-induced tumor transplants, they rejected H-2-incompatible tumor allografts and H-2-compatible skin allografts. The primary hemagglutinin response to sheep red blood cells was normal in these mice, as were the induction of a local graft-versus-host reaction with lymphoid cells from UV-irradiated donors and the induction of an inflammatory response to dimethyl sulfoxide in the footpads of UV-treated mice. An early transient depression of two reactions in UV-irradiated mice occurred: delayed hypersensitivity to dinitrochlorobenzene measured by footpad swelling and the graft-versus-host reaction in UV-irradiated recipients measured by the use of the popliteal lymph node weight gain assay. Both of these reactions returned to a normal level before the development of primary tumors. We conclude that the inability of UV-irradiated mice to reject syngeneic and autochthonous UV-induced tumors was not due to a generalized immunosuppressive effect of chronic UV irradiation.
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In the murine model presented for tumor-associated immune suppression, normal BALB/c mice displayed significant foodpad swelling when sensitized on the flank with 2 mg dinitrochlorobenzene (DNCB) dissolved in dimethyl sulfoxide and challenged in a footpad with 0.05 mg DNCB 10 days later. This reaction in challenged footpads seemed to be a classic delayed hypersensitivity reaction, since it took 24 hours to develop and included an extensive mononuclear infiltrate. The reaction was transmissible from sensitized to normal mice by the transfer of lymphoid cells but not to serum. When sensitized 10 days after tumor inoculation, mice bearing either an allogeneic melanoma or a syngeneic lymphoma or fibrosarcoma did not demonstrate delayed hypersensitivity to DNCB.
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Multimodality therapy has not reproducibly improved the survival of patients with gastric adenocarcinoma. This is largely because the staging of disease has been imprecise and because the current regimens have only limited efficacy against advanced disease. Until staging is improved and active regimens are found, it will be difficult to identify synergism between surgery and other treatment modalities.
Carcinoma of the pancreas has an especially grim prognosis. Only 1-3% of patients survive for 5 years. Radical pancreaticoduodenectomy, especially for minimal disease, is currently the only chance for cure. While radiation therapy does not improve overall survival, it may improve local control following radical resection and decrease pain in locally advanced cancers. Although chemotherapy has led to significant improvements in survival in patients with locally advanced disease, the overall effect is small. When surgery, radiotherapy, and chemotherapy are administered to localized carcinomas in randomized, prospective trials, survival is significantly lengthened. Similar trials in locally advanced, unresectable pancreatic cancer also confirm the concept of synergistic interaction between therapies. Thus, pancreas carcinoma is one neoplasm where multimodality therapy has had a demonstrable, although small effect.
An emphasis on careful surgical staging of adenocarcinoma of the colon has improved the predictive value of tumor staging systems. As a result of improved staging and carefully conducted randomized clinical trials, adjuvant therapy of locally advanced colon cancer, based on 5-fluorouracil chemotherapy, has been proven to substantially reduce recurrence rates and significantly increase overall survival for selected patients. Improved treatments and schedules are currently being studied in randomized trials and may increase the efficacy of this adjuvant therapy. Radiation therapy has not as yet been integrated into the adjuvant treatment of colon carcinoma. The application of a combined approach of surgery and chemotherapy in selected patients with liver metastases may also improve cure rates and long-term survival. The developing understanding of molecular determinants for the biological behavior of these cancers will increase the opportunities to identify, on the one hand, those patients who will benefit from specific therapies, and, on the other hand, new therapeutic strategies and treatments.
The goals of the conservative management of adenocarcinoma of the distal rectum are to preserve rectal sphincter function and achieve excellent local tumor control. Multimodality therapy for more advanced disease suggests that these goals will be met by conservative surgery combined with radiation therapy and chemotherapy. Over 100 patients with T0-3 N0-1 lesions have been treated in prospective single institution trials with either local excision or anterior resection with coloanal anastomosis, usually combined with chemotherapy and radiotherapy. The typical criteria for local excision have been for lesions to be 4.0 cm or less, mobile, and not poorly differentiated or mucinous. Patients with larger or more advanced lesions may undergo anterior resection with coloanal anastomosis. Following resection, radiotherapy is delivered to the pelvis and tumor bed often with concomitant chemotherapy. The overall rate of local failure in the trials in which local excision is performed with postoperative chemoradiotherapy is 3% for T1 lesions, 5% for T2 lesions, and 30% for T3 lesions with a median follow-up of at least 25 months. Local failure in patients with a coloanal anastomosis is 9% overall. Salvage was successful in about half of the patients who failed locally. Importantly, nearly all patients remained continent. These institutional studies show that sphincter preservation can be used in patients who are objectively selected for this procedure. However, before this multimodality approach may be considered standard therapy the rate of local control must be confirmed in a large, Phase II, multicenter, prospective trial such as that now underway in many of the cooperative groups.
The treatment of locally advanced rectal carcinoma is one of the more complicated problems in the management of colorectal carcinoma. More than any other site successful treatment requires a multimodality approach as surgery alone is frequently insufficient to completely eradicate all disease. This review focuses primarily on the management of patients who present without prior treatment and discusses the role of preoperative radiation therapy as well as intraoperative radiation therapy. Although much less gratifying, patients who present after failing previous therapy may also benefit from an aggressive multimodality approach.
Molecular prognostic markers are molecules produced by either the tumor or the host (patient) whose expression is associated with the clinical outcome. Three types of molecular markers exist that characterize different aspects of the tumor : host relationship: (1) tumor biology, (2) tumor burden and (3) host response. The first type of marker is measured within the primary or metastatic tumor mass and defines the aggressiveness of the cancer and its ability to respond to therapy. The other two types of markers are usually measured in the blood and assess concentrations of circulating tumor products or cytokines that may be involved in host resistance to the cancer. In this brief review we will define each type of marker, provide examples of their current utility and then describe how these markers may be useful.
The effect of a continuous infusion of a soybean oil emulsion on immune function was evaluated in 40 malnourished patients who were randomized to receive preoperatively either a 25% glucose-5% amino acid solution (group G) or a 15% glucose-3.3% Intralipid-5% amino acid solution (group G-F). Average length of total parenteral nutrition (TPN) was 10.3 +/- 0.9 days for group G and 9.0 +/- 0.8 days for group G-F. Initial nutritional status and response to TPN were similar for both groups. Immune function was assessed before TPN and after nutritional repletion prior to surgery for each patient. The levels of immunoglobulins, C3, C4, circulating B lymphocytes and T lymphocytes, suppressor T lymphocytes, natural killer cell activity, and monocytes were normal before TPN and after nutritional therapy. However, the total number of T cells and helper T cells were low before TPN and remained so after TPN. In addition, lymphocyte function measured by the lymphocyte blastogenic response to phytohemagglutinin and pokeweed mitogen was depressed prior to TPN and was not improved by either regimen. Neutrophil chemotaxis and bactericidal activity were not affected by either nutritional regimen while neutrophil phagocytosis was enhanced before TPN and remained elevated throughout TPN with either regimen. There were no differences in infection rates during TPN. The addition of Intralipid to the TPN regimen did not alter immune function in these patients who showed depressed cell-mediated immunity before TPN compared with the standard glucose TPN regimen.
The National Cancer Data Base, a joint project of the American Cancer Society and the American College of Surgeons Commission on Cancer, provides a mechanism for periodic assessment of hospital-based cancer patient care. From its annual summary, health care professionals can evaluate trends in patient care to make more efficient treatment decisions. This article provides a first look at highlights from the 1996 annual summary.
In summary, the ability to decrease the mortality of colorectal carcinoma is increasingly within the grasp of clinicians. With accurate family and personal history, it is possible to estimate the risk of colorectal cancer and initiate FOBT and colonoscopy where appropriate. In the future, germline and even somatic genetic testing will further increase our ability to diagnose cancers before they become widely invasive. As molecular biology unravels the cause of what currently appears to be the majority of sporadic cancers, it may be possible to characterize more colorectal cancers that are caused by novel, as yet not recognized mutator genes. Unfortunately, a set of patients is likely to exist who remain to be diagnosed by symptoms caused by advanced cancer. The goal for the clinician is to decrease this subset to as small a group as possible.
The following highlights summarize the principle findings of the NCDB, which are presented in more detail in other reports, some of which have been published and others of which are in press or submitted awaiting review. Collectively, these findings present a broad pattern of NCDB assessment of cancer patterns of care. In addition to the resulting journal publications, 1,600 NCDB participating hospitals receive a customized summary of similar patterns of care and outcome at their facility compared with national norms, which is then used for quality assurance purposes.
Rapid progress in understanding the biology of colorectal carcinoma has occurred in the last decade. During this time, the importance of tumor suppressor genes has been delineated. Mutations in proto-oncogenes, and some of the genetic and epigenetic defects that occur during neoplastic transformation, have been characterized. The very recent identification of a technology that detects some mutations in genes by analyzing fecal specimens offers the real prospect of effective, low-cost screening of large segments of the population at risk for the development of large bowel cancer. A better understanding of the mechanisms involved in metastasis is slowly leading to better methods of prognostication for patients with carcinoma of the colon or rectum. This is important because a better biologic identification of patients at high risk for subsequent metastasis will help determine which patients should receive adjuvant therapy. Further, the development of new approaches to inhibit various aspects of the cascade of events necessary to produce metastasis, notably the inhibition of neovascularization, suggests the real possibility that established metastases may be treated by relatively nontoxic medical therapies. As a result, further knowledge of the biology of colorectal cancer will translate into strategies that will continue to improve the control of this prevalent carcinoma.
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