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Biomedical subjects

H D Bear

Publications and source records attributed to H D Bear.

68 records · Page 4Linked to original sources
PubMed1990

Cyclophosphamide and abrogation of tumor-induced suppressor T cell activity.

Previously we have demonstrated that the in vitro generation of P815-specific anti-tumor cytotoxic T lymphocytes (CTL) was suppressed by splenic suppressor T cells from late tumor-bearing hosts (TBH). Suppression is not caused by in vitro growth of P815 from splenic metastases, since suppression was also seen with spleen cells from late TBH mice bearing a hypoxanthine/aminopterin/thymidine-sensitive subline (PHS-5) of P815 in the presence of HAT. Cyclophosphamide has been shown to inhibit the induction of suppressor cells selectively in a number of immune responses, but evidence that it can inhibit active tumor-induced suppressor T cells is limited. We have found that suppressor T cells already induced by P815 in syngeneic late TBH are sensitive to low doses of cyclophosphamide (50 mg/kg) given 1 day before spleen harvest, but the in vitro CTL response of late TBH spleen cells could not be restored by pretreating the mice with cyclophosphamide, even when exogenous interleukin-2 was added to the cultures. Although 50 mg/kg cyclophosphamide did not inhibit the CTL response of spleen cells from mice immunized with P815 + Corynebacterium parvum, the same dose of cyclophosphamide eliminated the CTL response of spleen cells from early TBH. Interleukin-2 (IL-2) did not overcome this effect of cyclophosphamide, suggesting a direct effect on CTL. "Ultra-low" -dose cyclophosphamide (10 mg/kg) did not adversely effect early TBH CTL but was still able to eliminate suppressor T cell activity from late TBH. Nevertheless, late TBH CTL remained unresponsive after pretreatment of mice with ultra-low-dose cyclophosphamide, even when exogenous IL-2 was added in vitro. CTL precursor frequency analyses demonstrated that cyclophosphamide pretreatment had little or no effect on the numbers of CTL precursors from early TBH. Late TBH CTL precursor cells were not detectable in these studies, with or without suppressor T cell inhibition by cyclophosphamide pretreatment. Thus, it appears that most CTL precursor cells may be lost or irretrievably inactivated in the spleens of late TBH mice.

Animals↗
PubMed1989

Treatment of biliary obstruction caused by metastatic cancer.

Over an 8-year period, among 41 patients with obstructive jaundice caused by metastases to the liver or lymph nodes adjacent to the porta hepatis, palliative biliary decompression was established surgically in 11, by percutaneous transhepatic biliary drainage (PTBD) in 25, and by both methods in 2. Three patients had no drainage procedure performed. Early mortality after drainage occurred in 6 of 38 patients, and the median survivals (actuarial) for the remaining 32 patients were 4.5 months for the surgical group (range 2 to 21 months) and 4 months for the PTBD group (range 2 to 14 months). Although there were trends toward more frequent hospital readmissions and episodes of cholangitis in the PTBD group, the only statistically significant difference was in the number of catheter manipulations required. We concluded that when patients develop obstructive jaundice as a manifestation of metastatic cancer, useful palliation can be achieved by either surgical or percutaneous decompression.

Adult↗
PubMed1989

Management of biliary obstruction in patients with unresectable carcinoma of the pancreas.

Clinical and pathologic data from 73 patients with unresectable carcinoma of the pancreas treated from 1980 to 1987 were reviewed to evaluate the efficacy of biliary enteric bypass and percutaneous transhepatic biliary drainage (PTBD) in the treatment of malignant biliary obstruction. Fifty-two patients underwent biliary enteric bypass with no operative deaths and with a 15% operative morbidity. These patients had a median postoperative hospitalization of 12 days. Four patients (8%) eventually developed recurrent jaundice, and three of these were successfully treated with PTBD. The median survival for these 52 patients was 7 months. Twenty-one patients underwent PTBD with an 81% technical-success rate. These patients had a 33% early complication rate and a 33% in-hospital mortality. The median hospitalization was 13 days postdrainage. Of the 14 patients surviving the initial hospitalization, 86% developed late complications requiring 16 hospital admissions and ten emergency room visits for a total of 155 days of hospitalization. The median survival for those patients undergoing PTBD was 4 months from the time of diagnosis and 2 months from the time of catheter drainage. Surgical bypass offers excellent palliation for malignant biliary obstruction with extremely low morbidity and mortality in properly selected patients; PTBD is useful in the treatment of those patients with extensive disease, who are poor surgical candidates, or who have failed previous surgical drainage. There is a role for both of these palliative procedures in the management of patients with biliary obstruction from pancreatic cancer.

Adenocarcinoma↗
PubMed1988

Phenotype of syngeneic tumor-specific cytotoxic T-lymphocytes and requirements for their in vitro generation from tumor-bearing host and immune spleens.

Cells required for the in vitro generation of syngeneic cytotoxic T-lymphocytes (CTL) against the P815 mastocytoma in the DBA/2 mouse strain were investigated. For both immune and tumor-bearing host spleen cells, CTL effector cells were eliminated by treatment with anti-Thy1.2, anti-Lyt1.1, or anti-Lyt2.1 and C', but were resistant to anti-L3T4 (GK1.5). Thus, CTL effectors (and their precursors) were Lyt1+2+, L3T4-. However, P815-specific CTL could not be generated in the absence of L3T4+ cells, whose function could be replaced with exogenous interleukin-2 (IL-2). When monoclonal antibodies against L3T4 were added to mixed leukocyte tumor cultures, CTL generation was markedly inhibited. Depletion of accessory cells also led to a marked reduction in CTL generation, which could be restored to control levels by adding adherent cells from normal spleens or with exogenous IL-2, but not with IL-1. Thus, accessory cells are apparently required to present the tumor antigens of this Ia-negative tumor to T-helper cells.

Animals↗
PubMed1987

Production of tumor-specific suppressor T cell hybridomas.

Spleen cells from late tumor-bearing host mice (TBH) with progressive P815 tumors have been shown to suppress the generation of cytotoxic T lymphocytes (CTL) from spleens of syngeneic immune or early TBH mice in vitro. This suppression is antigen-specific and is mediated by T lymphocytes. By positive selection, a highly enriched population of T cells was obtained from late TBH spleens and fused with the BW5147 HAT-sensitive thymoma. Cloned hybrid cell lines were obtained which released soluble antigen-specific factors capable of suppressing anti-P815 CTL generation. Similar T cell hybrids with suppressive activity were also derived from the fusion of spleen cells of TBHs bearing a HAT-sensitive subline of the P815 tumor.

Animals↗
PubMed1986

Tumor-specific suppressor T-cells which inhibit the in vitro generation of cytolytic T-cells from immune and early tumor-bearing host spleens.

Spleen cells from DBA/2 mice, after immunization with syngeneic P815 mastocytoma cells and Corynebacterium parvum, respond to P815 in vitro with a brisk, secondary-type generation of cytotoxic cells. This cytotoxicity is mediated by antigen-specific T-lymphocytes and correlates with resistance to in vivo challenge. This model confirms the observations of previous investigators made in semisyngeneic hosts using an in vivo transfer model. Spleen cells from "early" tumor-bearing hosts (TBHs), 7-12 days after intradermal (i.d.) inoculation of 10(6) P815 cells alone, made a similar, but generally higher, cytotoxic T-lymphocyte (CTL) response in vitro. Spleen cells from "late" TBHs (18-28 days) completely suppressed the in vitro CTL response of immune cells (e.g., from 71% specific release in controls down to 8% at an effector: target ratio of 40:1). Early i.d. TBH spleen cells, because of their higher level response, appeared to be resistant to this suppression (85% release for controls and 84% when suppressor cells were added at 40:1). By testing early TBH CTL at lower effector: target ratios, however, suppression by late TBH spleen cells could be readily demonstrated. When TBHs were inoculated s.c. instead of i.d. or with lower doses of tumor cells, responses were lower and susceptibility of splenic CTLs to suppression was increased. At intermediate times after tumor inoculation (14-20 days), spleen cells from TBHs still can respond in vitro, but they are completely suppressed by spleen cells from late TBHs. The suppressor cells are antigen-specific, radiation-sensitive, Thy1+ cells.

Animals↗
PubMed1985

Prognosis of level V malignant melanoma.

Level V melanomas have been reported to have a poor prognosis, but in-depth analyses of prognostic factors and treatment have not been reported. From 1952 through 1982, 41 patients presented with primary Clark's Level V melanomas. There were 23 patients who presented with clinical Stage I disease and 18 with Stage II. Among Stage I patients, 9 were treated by wide excision alone and 13 underwent wide excision plus prophylactic regional lymph node dissection (RLND); 8 of 13 patients had histologically positive nodes. Twelve Stage II patients were treated by wide excision and RLND (including three hemipelvectomies), and four refused surgery. The 5-year survival was 52%. For Stage I patients, survival was 62% and disease-free survival (DFS) 28% at 5 years; 6 of 10 recurrences were local or regional only. Prophylactic RLND reduced the incidence of recurrence but did not appear to influence survival rates. Among 14 evaluable Stage II patients, overall survival was 60% and DFS 42% at 3 years; of 4 patients who subsequently had a recurrence, 3 had distant metastases. All seven patients with distant metastases at the time of first recurrence died of disease within 14 months (median, 4 months) of detection of metastatic disease. Primary melanomas of the foot (11 patients) and trunk (4 patients) appeared to have a worse prognosis than other sites. Ulceration (seen in 21 patients) did not appear to significantly influence outcome. These data suggest that most patients with Level V melanoma present with clinically localized disease. Prophylactic RLND did not significantly affect overall survival. The invasiveness of these deep tumors appears to reduce the influence of other factors, including primary site, sex, race, and ulceration. The prognosis of patients with Level V melanoma, even with clinically or histologically positive lymph nodes, is not hopeless, and these patients should be treated aggressively.

Actuarial Analysis↗
PubMed1984

Colon and rectal carcinoma in the west of Scotland. Symptoms, histologic characteristics, and outcome.

Multiple clinical and pathologic factors have been analyzed retrospectively for a group of 456 patients with colon and rectal cancer treated in Glasgow over a span of 4 years. Sixty-five percent of these patients underwent curative resection, and another 16 percent had palliative resection. Obstruction and perforation (present in 19 and 5 percent, respectively) were associated with the highest operative mortality (17 percent for both) of any presenting symptom. However, when only patients who survived curative resection were considered, obstruction carried only a slightly lower 5 year survival than did other common symptoms, whereas perforation still led to only a 10 percent 5 year survival. Neither mucin production nor degree of differentiation influenced survival significantly. Adherence of the primary tumor to an adjacent organ was associated with a very poor prognosis (9 percent 5 year survival), but curative resection of the involved organs with the primary tumor increased the 5 year survival to 34 percent. Patterns of recurrence were noted to be markedly different for each primary site and for different stages. Dukes' stage was the most important overall determinant of prognosis.

Actuarial Analysis↗
PubMedDate not supplied

Biologic therapy of melanoma with cytokines and lymphocytes.

Melanoma has a somewhat unpredictable behavior, and spontaneous regressions do occasionally occur. Many have surmised that these are the result of immunologic attack by the host. Immunologic treatment has been more successful for melanoma than for most other neoplasms, even with relatively crude therapies, such as bacterial products. With the availability of recombinant cytokines, immunotherapy for melanoma has entered a new era. Interleukin-2 (IL-2), which acts entirely through immunologic mechanisms, has been tested extensively, either alone, in combination with other cytokines, or with adoptive cellular therapy. Alone, it has only modest antitumor activity, even at high doses. Its utility may be greater when combined with immunocompetent cells, especially tumor-sensitized T lymphocytes, in adoptive immunotherapy. On the other hand, nonspecific lymphokine-activated killer (LAK) cells do not appear to add significantly to the efficacy of IL-2 alone. Interferon-alpha (IFN-alpha) [corrected] also has had fairly limited activity in the advanced disease setting, but, on the basis of a recently completed randomized trial, has arguably become the "standard of care" in the adjuvant setting for patients with high-risk melanoma, particularly node-positive patients. A number of regimens combining IL-2, IFN-alpha, and chemotherapeutic agents have yielded striking response rates in small trials and await confirmation in larger studies. With better delineation of the host immune response and definition of relevant tumor antigens, we can look forward to exciting results with combinations of vaccines, cytokines, and adoptive cellular approaches, particularly in patients with micrometastatic disease.

Adjuvants, Immunologic↗