Biomedical subjects

T Olencki

Publications and source records attributed to T Olencki.

18 recordsLinked to original sources

PubMed2000

A phase II pharmacodynamic study of pyrazoloacridine in patients with metastatic colorectal cancer.

PURPOSE: To perform a phase II trial of pyrazoloacridine (PZA), a novel DNA intercalator, in patients with metastatic colorectal carcinoma and no previous therapy. METHODS: PZA was administered at a dose of 750 mg/m2 intravenously over 3 h every 21 days. Pharmacokinetic studies to determine PZA plasma concentrations were performed. RESULTS: No responses were seen in 14 response-evaluable patients. Patients received a median of two cycles of PZA (range 1-6). Toxicity included neutropenia and neurologic side-effects, which were > or = grade III in 73% and 14%, respectively. High plasma concentrations of PZA (Cmax) correlated with low neutrophil counts (P = 0.04). CONCLUSIONS: PZA is inactive at this dose and schedule in colorectal cancer, and produces moderately severe toxicity.

Acridines↗

PubMed1999

Interferon-gamma and CXC chemokine induction by interleukin 12 in renal cell carcinoma.

Interleukin 12 (IL-12) is known to play an important role in the development of an antitumor response. Its activity has been shown to be dependent upon the intermediate production of IFN-gamma and the influx into the tumor of CD8 lymphocytes. In a murine model, tumor regression induced by IL-12 treatment correlated with IFN-gamma, IP-10, and Mig expression in the tumor bed and was abrogated by antibodies to both chemokines. Here we examined the effects of rHuIL-12 on IFN-gamma and CXC chemokine gene expression in patients with renal cell carcinoma (RCC) in an attempt to determine whether a similar series of molecular events leading to IL-12-mediated tumor regression in mice is also detectable in humans. As in the murine RENCA model, cultured RCC cells themselves could be induced by IFN-gamma to synthesize IP-10 and Mig mRNA. Explanted RCC produced IFN-gamma and IP-10 mRNA in response to IL-12 treatment, which was consistent with the finding that biopsied RCC tumors from IL-12-treated patients also variably expressed augmented levels of those molecules after therapy. Although Mig mRNA was present in the majority of biopsied tumors prior to treatment, both the Mig and IP-10 chemokines as well as IFN-gamma were induced in the peripheral blood mononuclear cells of IL-12-treated patients. Skin biopsies of IL-12-treated patients also all synthesized IP-10 mRNA. This study demonstrates that recombinant human IL-12 therapy of patients with RCC has the potential to induce the expression of gene products within the tumor bed that may contribute to the development of a successful antitumor response.

Animals↗

PubMed1998

Should continent diversion be performed in patients with locally advanced bladder cancer?

OBJECTIVES: To assess the effect of local, regional, and distant recurrence on pouch function in patients with locally advanced bladder cancer treated by cystectomy and continent diversion. METHODS: A review of 64 consecutive patients undergoing orthotopic (n = 40) or continent cutaneous (n = 24) urinary diversion was performed; 25 patients (39.1%) had locally advanced cancers as defined by deep muscle invasion, extension into perivesical fat, stromal invasion of the prostate, or node-positive disease. Patients were followed at 6-month intervals with physical examination, assessment of voiding function, and computed tomography (CT) scans. RESULTS: The pelvic recurrence rate was 4.7% in the overall group and 12% in patients with locally advanced disease. In the 39 patients with organ-confined tumors, 34 (87%) are alive without evidence of recurrence and have normal pouch function with a median follow-up of 27 months. Four patients in this group receiving systemic chemotherapy for clinical recurrences have retained normal pouch function until last follow-up or death. In the 25 patients with locally advanced tumors, 15 (60%) are alive without evidence of recurrence and have normal pouch function with a median follow-up of 15 months. Seven patients in this group received a median three cycles of adjuvant chemotherapy, and 4 patients received chemotherapy for clinically evident recurrences. Surgical recovery did not delay the onset of adjuvant therapy in any patient, nor did problems specifically related to the presence of a continent pouch delay any cycle of chemotherapy in those patients treated for recurrent disease in either group. Only 1 patient (1.5%) experienced treatment-related toxicity related to the presence of a continent diversion. CONCLUSIONS: This experience suggests that the use of orthotopic or continent cutaneous diversions after cystectomy in patients with locally advanced bladder cancer is safe, does not interfere with the delivery of subsequent therapy, and allows most patients to anticipate normal pouch function even in the presence of recurrent disease.

Adult↗

PubMed1998

Phase I trial of subcutaneous recombinant human interleukin-12 in patients with advanced renal cell carcinoma.

Patients with advanced renal cell carcinoma were treated in a Phase I trial with escalating doses of recombinant human interleukin-12 (rHuIL-12) given on days 1, 8, and 15 of each 28-day cycle. Treatment in the initial dose scheme consisted of a fixed dose with dose levels of 0.1, 0.5, and 1.0 microg/kg given to cohorts composed of three or six patients. On the basis of the toxicity profile, a second scheme (up-titration) was undertaken wherein rHuIL-12 was escalated for each patient from week 1 to week 2, to a target dose given week 3 and thereafter; cohort target dose levels were 0.5, 0.75, 1.0, 1.25, and 1.5 microg/kg. Fifty-one patients were treated: 32 (63%) had prior cytokine therapy and 19 (37%) had received no prior systemic therapy. The maximum tolerated dose for the fixed dose scheme was 1.0 microg/kg. Dose-limiting toxicities included increase in transaminase concentration, pulmonary toxicity, and leukopenia. The most severe toxicities occurred with the first injection and were milder upon further treatment. With the up-titration dose scheme, the maximum tolerated dose was reached at 1.5 microg/kg, and dose-limiting toxicity consisted of an increase in serum transaminase levels. At the maximum tolerated dose of 1.5 microg/kg, serum IL-12 levels increased to a mean peak level of 706 pg/ml. Serum levels of IFN-gamma increased to a mean peak level of about 200 pg/ml at 24 h after the first maintenance dose of 1.5 microg/kg. The best responses were as follows: one patient had complete response, 34 patients were stable, 14 patients showed progression, and 1 patient was inevaluable. In conclusion, rHuIL-12 was relatively well tolerated when administered by s.c. injection. The recommended dose according to the up-titration schedule of rHuIL-12 (microg/kg) for Phase II trials was as follows: cycle 1, 0.1 (day 1), 0.5 (day 8), 1.25 (day 15); cycle 2 onwards, 1.25. Phase II trials of rHuIL-12 were initiated in previously untreated patients with renal cell carcinoma and in patients with melanoma.

Adolescent↗

PubMed1998

Signal transduction abnormalities in T lymphocytes from patients with advanced renal carcinoma: clinical relevance and effects of cytokine therapy.

Studies have demonstrated abnormalities of the CD3/T-cell antigen receptor (TCR) and pathways of signal transduction in T lymphocytes from animals and patients with advanced malignancy. Diminished expression of TCRzeta and p56(lck) that are associated with the TCR and reduced nuclear localization of RelA containing nuclear factor kappaB (NFkappaB) complexes have been noted. These defects have been described in T cells from patients with malignant melanoma, renal cell carcinoma (RCC), ovarian cancer, and colorectal cancer. Preliminary observations also indicate possible correlation with clinical variables such as stage in selected instances. To further characterize altered expression of TCRzeta, p56(lck), and impaired activation of NFkappaB, T lymphocytes were obtained from 65 patients with RCC, the majority of whom were receiving combination cytokine therapy [interleukin (IL)-2, IFN alpha-containing regimens] and 37 control individuals. In 29 of these patients, levels of TCRzeta and p56(lck) were determined by Western blots of T-cell lysates and semiquantitated using densitometry. Relative levels were then correlated with a series of clinical variables including response to therapy, performance status, survival, disease sites, age, and others. In another group of 28 patients (three individuals from the first group), the frequency of abnormal NFkappaB activation was studied using electrophoretic mobility shift assays after activation of T cells with phorbol myristate acetate/ionomycin or anti-CD3 monoclonal antibody. Changes in these signaling molecules during cytokine treatment were also investigated. TCRzeta and p56(lck) were detected in the peripheral blood T cells in 27 of 29 patients, and overall, reduced levels were noted visually in 12 of 29 (41%) and 13 of 29 (45%) individuals, respectively. When levels were semiquantitated using densitometry, significant decreases of TCRzeta (P = 0.029) and p56(lck) (P = 0.029) but not CD3epsilon (P = 0.131), compared with control levels, were found. In patients treated with IL-2/IFN alpha-based therapy, relative levels of TCRzeta increased significantly (P = 0.002) on day 15 of cycle one compared with the baseline. Correlations of TCRzeta or p56(lck) levels with response or disease variables, except for lower TCRzeta levels (P < 0.001) in the presence of bone metastases, were not found. Abnormal NFkappaB activation after stimulation with phorbol myristate acetate/ionomycin and/or anti-CD3 monoclonal antibody was found in 59% of patients (17 of 28) and was not accounted for by the advanced age of the study cohort. Activation of NFkappaB in peripheral blood T cells was inducible during cytokine therapy in four of six individuals who displayed impaired NFkappaB activity prior to therapy. Moreover, impaired activation of NFkappaB does not appear linked to a reduction of TCRzeta expression, because in five patients, normal TCRzeta levels were present although kappaB binding was not inducible. In the majority of patients with advanced RCC, peripheral blood T cells express TCRzeta and p56(lck), and in a subset, reduced levels of these TCRzeta associated molecules are seen that may increase during cytokine-based therapy. Abnormal activation of NFkappaB is also present in >50% of patients and may also revert to normal during IL-2/IFN alpha-based treatment. This alteration in NFkappaB activation occurred in the presence of normal expression of TCRzeta-associated signaling elements. The clinical significance of these findings remains unclear.

Carcinoma, Renal Cell↗

PubMed1997

Randomized trial of carboplatin plus amifostine versus carboplatin alone in patients with advanced solid tumors.

BACKGROUND: To test the hypothesis that the cytoprotectant amifostine attenuates the thrombocytopenia produced by carboplatin, the authors performed a randomized trial comparing treatment with carboplatin alone versus the combination of amifostine and carboplatin. METHODS: Patients with refractory or carboplatin-sensitive malignancies were randomized to receive either carboplatin, 500 mg/m2 alone or carboplatin, 500 mg/m2 in conjunction with 2 doses of amifostine of 910 mg/m2 each. RESULTS: Fifty-five patients with a variety of malignancies were entered on this study. One patient withdrew from each arm prior to the administration of any therapy, leaving 30 evaluable patients treated with carboplatin alone and 23 treated with the combination of amifostine and carboplatin. For 82 cycles of therapy with amifostine plus carboplatin, the median platelet nadir was 127 x 10(9)/L while the median platelet nadir was 88 x 10(9)/L over the 80 courses of therapy with carboplatin alone (P = 0.023). The median platelet nadir after the first cycle of therapy was 144 x 10(9)/L for patients treated with amifostine plus carboplatin and 85 x 10(9)/L for patients treated with carboplatin alone (P = 0.24). The median survival for 9 patients with advanced nonsmall cell lung carcinoma treated with carboplatin alone was 39 weeks whereas the median survival for 12 such patients treated with amifostine plus carboplatin was 52 weeks (P = 0.116). CONCLUSIONS: These data support the hypothesis that amifostine attenuates the myelosuppression of carboplatin. Additional studies of amifostine in combination with carboplatin-containing chemotherapy regimens are warranted.

Adult↗

PubMed1997

Phase II trial of interleukin-2 and interferon-alpha in patients with renal cell carcinoma: clinical results and immunologic correlates of response.

A phase II trial was conducted in patients with metastatic renal cell carcinoma, to assess the clinical efficacy and immunoregulatory effects of continuous-infusion recombinant interleukin-2 (rIL-2) (9.0 x 10(6) IU/m2/day on days 1-5, 8-12, 15-19, and 22-26) and subcutaneously administered recombinant human interferon-alpha 2b (rHuIFN alpha 2b) (10.0 x 10(6) U/m2/day TIW). Thirty-six patients with metastatic renal cell carcinoma, performance status of 0-1, and measurable disease who had not received prior rIL-2, rHuIFN alpha 2b, or chemotherapy were treated. Patients with CNS metastases, active infections, history of another malignancy within 3 years, and those requiring corticosteroids were ineligible. Cycles of rIL-2 and rHuIFN alpha 2b were administered in the outpatient department every 6-8 weeks in stable or responding patients until patient tolerance or a complete response were reached. Doses were modified for grade III or IV toxicity. Ancillary studies included three-color immunocytometric analysis of peripheral blood lymphocytes, repetitive tumor biopsies for immunohistologic analysis of infiltrating cells and proliferative responses of tumor infiltrating lymphocytes, and preliminary studies of changes in peripheral blood T-lymphocyte signal transduction molecules [T-cell receptor (TCR)-zeta, p56ick, p59fyn]. Thirty-six eligible patients were treated, with 6 of 36 patients (17%, 95% confidence interval 6-33%) responding (3 complete response, 3 partial response). In two of the partial responders, and in an additional three patients with either minimal tumor regression (one patient) or stable disease (two patients), surgical removal of residual disease was undertaken. The median survival of all patients was 14 months. The toxicity of this regimen was severe, but outpatient administration was possible in most instances. Immunoregulatory effects on T-cell subsets included increases in various CD3+ CD25+/- HLADr+/- subsets unrelated to response. Tumor biopsies before and/or during therapy were obtained in 17 patients, and no consistent alterations in the degree of T-lymphocyte or macrophage infiltrates could be detected. In a subset of patients, tumor infiltrating lymphocyte proliferative responses and levels of peripheral blood T-cell signal transduction molecules (TCR-zeta, p56lck, p59fyn) were investigated. Abnormalities were found in selected patients, which improved during rIL-2/rHuIFN alpha 2b therapy. This cytokine combination produces tumor regression in selected patients with metastatic renal cell carcinoma. Surrogate immunologic markers associated with response were not identified; however, preliminary studies demonstrate investigation of immune defects and their reversal with cytokine therapy is possible.

Adult↗

PubMed1996

Phase II trial of subcutaneously administered granulocyte-macrophage colony-stimulating factor in patients with metastatic renal cell carcinoma.

BACKGROUND: Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a cytokine that is involved in the differentiation and proliferation of various hematopoietic precursors. It also has been reported to enhance the antitumor activity of various mature effector cells. Previous reports have noted preclinical antitumor activity in a murine model utilizing genetically engineered tumor cells and instances of tumor regression in patients with solid tumors receiving GM-CSF. In the present study, a Phase II trial of human recombinant GM-CSF (GM-CSFrh) in patients with metastatic renal cell carcinoma (RCC) was conducted to investigate further the potential antitumor activity of this cytokine. METHODS: Twenty-six eligible patients with metastatic RCC received 3 microgram/kg of GM-CSFrh subcutaneously for 14 days, with cycles repeated every 28 days. RESULTS: Two of 26 patients (8%; 95% confidence interval 1-25%) demonstrated partial tumor responses during GM-CSFrh therapy. Both individuals who responded had received prior therapy. A median of three cycles per patient were administered, and toxicity was mild. CONCLUSIONS: GM-CSFrh may mediate tumor regression in patients with metastatic RCC; however, the level of activity in previously treated patients is low.

Adult↗

PubMed1996

Immunomodulatory effects of interleukin-2 and interleukin-4 in patients with malignancy.

A phase I trial of simultaneously administered recombinant interleukin-2 (rIL-2) and recombinant human IL-4 (rHuIL-4) was conducted to evaluate the toxicity and the clinical and immunologic effects of this cytokine combination. Thirty-nine eligible patients with refractory malignancy were treated at eight different dose levels (1A to 3B): 1-3 of rIL-2 [3.0, 12.0, and 48.0 x 10(6) IU/m(2) i.v. three times weekly (TIW)] and A-C of rHuIL-4 (40, 120, and 400 mu g/m(2) s.c. TIW). The toxicity of these two cytokines was moderate and was comparable with that seen with rIL-2 alone. The maximal tolerated dose (MTD) of the combination was not reached because of lack of sufficient rHuIL-4 but is at least 48.0 x 10(6) IU/m(2) of rIL-2 and 120 mu g/m(2) of rHuIL-4. Two patients with melanoma had partial responses. The immunologic effects included increases in absolute lymphocyte numbers, and the CD3- /CD56+/ CD2+, total CD56+, CD8+, and CD16c+ lymphocyte subsets with increasing rIL-2 dose levels, but not with rHuIL-4. This increase in natural killer (NK) cells in the peripheral blood was accompanied by an increase over baseline in NK lytic activity against K562 targets; however, concomitant increases in lymphokine-activated killer (LAK) activity (Daudi targets) were not seen. The CD3+, CD4+, and CD3+/CD25+/HLA-Dr+ T-cell subsets also increased, and these increases were related to both increasing rIL-2 and rRuIL-4 doses. Finally, in four of six patients, serial tumor biopsies demonstrated increases in major histocompatibility complex (MHC) class I or II antigen expression on tumor cells or increasing T-cell infiltrates during cytokine therapy or both. This trial demonstrated that rIL-2 and rHuIL-4 can be administered simultaneously with acceptable toxicity. The immunologic findings demonstrated the expected rIL-2-associated increases of CD56+ and CD16c+ lymphocytes and NK activity, and interestingly, no development of LAK activity. These findings suggest regulatory effects of rHuIL-4 on rIL-2-related effects in vivo.

Adjuvants, Immunologic↗

PubMed1996

Phase I trial of subcutaneous interleukin 3 in patients with refractory malignancy: hematological, immunological, and pharmacodynamic findings.

We conducted a Phase I trial of s.c. recombinant human interleukin 3 (rhIL-3) to evaluate the toxicity, maximal tolerated dose, pharmacokinetics, and in vivo biological effects of this cytokine. Thirty-one patients with refractory cancer were entered into the study between November 1991 and June 1993. Therapy consisted of s.c. rhIL-3 daily for 15 days administered to cohorts of three to nine patients at dose levels of 60-4000 microgram/m2/day. Cycles were repeated at intervals of 28 days. Seventy-five cycles of rhIL-3 were administered (median, two per patient) and the maximal tolerated dose was 2000 microgram/m2/day. Toxicity was moderate, with most patients developing chills, fever, and myalgia. Dose-limiting toxicity consisted of diarrhea (two patients) and headache (one patient). Hematological effects of rhIL-3 included significant dose-related increases of WBC (P < 0.001), neutrophils (P < 0.001), and eosinophils (P < 0.001). Platelet counts and absolute lymphocyte numbers also increased. Various CD3(+) lymphocyte subsets increased; however, lytic activity (natural killer and lymphokine-activated killer) of peripheral blood lymphocytes was not enhanced. Serum levels of the soluble IL-2 receptor increased in a dose-related fashion, and IL-2-induced lymphocyte proliferation also was increased variably. Pharmacokinetic studies were performed in 13 patients, and area under the curve and maximal concentration values increased with increasing rhIL-3 dose levels (P < 0.001) and correlated with maximal changes from baseline in WBC, neutrophils, and eosinophils. rhIL-3 antibodies were detected in 8% of patients by day 29 of cycle 1 but were not neutralizing. rhIL-3 is well tolerated when administered s.c. and has reproducible hematological and immunological effects. The pleiotropic effects of this cytokine on various in vivo biological parameters were demonstrated clearly. Further studies of its immunoregulatory effects are warranted.

Adult↗

PubMed1995

Selective cytokine gene expression in renal cell carcinoma tumor cells and tumor-infiltrating lymphocytes.

The progression of tumors such as renal cell carcinoma (RCC), despite the presence of substantial lymphocytic infiltrates (TIL), suggests that the ability of the local immune response to control tumor growth is impaired. Cytokine gene expression was examined to further investigate the nature of this response. Initial studies were performed with frozen tumors using PCR-assisted mRNA amplification with cytokine-specific primers for interleukin 10 (IL-10), interleukin 2 (IL-2) and interferon-gamma (IFN-gamma). IL-2 mRNA was not detected, despite the presence of T cells as defined by the expression of CD3 gamma mRNA. In contrast, mRNA for IFN-gamma was expressed in 4/9 and for IL-10 in 5/9 tumors. To confirm this, 5 fresh tumor specimens were examined, and PCR demonstrated that IL-10 mRNA was detectable in 4/5 tumors from which RNA was isolated at the time of nephrectomy. In these experiments multiple cycles and dilutions were employed to semi-quantitate the expression of IL-10. To identify potential sources of this cytokine in the tumor bed, IL-10 mRNA expression in freshly isolated lymphocytes and tumor cells, TIL lines, cultured RCC and established RCC lines was examined. Our studies demonstrate that within the tumor TIL may be one source of IL-10. Lymphocyte-enriched populations from 4/5 tumors expressed IL-10 mRNA as did 4/6 freshly isolated tumor cell preparations. IL-10 gene expression was not detected, however, in tumor cells after one passage in vitro in short-term cultured RCC tumor cells (passages 2-5) or in established RCC tumor cell lines. Finally, 4/9 CD4+ and 2/5 CD8+ TIL lines expressed IL-10 mRNA either constitutively or after stimulation with anti-CD3 antibody. This finding was associated with IL-10 production in vitro. Our studies demonstrate that IL-10 mRNA is frequently present in RCC tumors and may originate from the tumor-infiltrating mononuclear cell population.

Base Sequence↗

PubMed1994

Amifostine: potential for clinically useful cytoprotection.

The ability to target malignant cells for cytotoxicity while sparing normal host tissues has proven to be limited. These limitations have resulted in unacceptable toxicity or insufficiently effective therapy. Continuing investigation of new, potentially useful cytotoxic agents must continue. An alternative approach, also worthy of study, is the selective protection of normal tissues. This approach, used in conjunction with available therapeutic agents, may open the therapeutic window and incrementally enhance the effectiveness of cytotoxic therapy. A variety of methods have been used to protect normal tissues selectively. Regional protection can be used for certain organ systems, such as the oral mucosa. Selective protection on a systemic level is more difficult but agents that seem to protect normal but not malignant tissues selectively are being developed. Among these is amifostine, which was originally selected by the U.S. defense department for study as a radioprotectant. Pre-clinical studies have suggested that amifostine is differentially concentrated in normal tissues but not in malignant tissues. Tissue-specific differences in the activity of alkaline phosphatase, which dephosphorylates amifostine to its active metabolite WR-1065, and in pH are thought to be involved in this relative specificity. Clinical studies indicate that amifostine can reduce the myelosuppression produced by cyclosphosphamide, the combination of cyclophosphamide and cisplatin, and, perhaps, carboplatin. The protective effects of amifostine on nonhematopoietic toxicities are being investigated. Future trials will investigate the integration of amifostine with cytokine-based supportive care in order to define the role of this potentially clinically useful cytoprotectant agent.

Amifostine↗

PubMed1994

Pleiotropic effects of cytokines: clinical and preclinical studies.

Cytokines have diverse and pleiotropic effects including immunologic, hematopoietic and pro-inflammatory activities. A total of 135 patients have been treated in a series of phase I clinical trials utilizing five different recombinant cytokines: granulocyte-macrophage colony-stimulating factor (rhuGM-CSF), interleukin 3 (rhIL-3) interleukin 4 (rhuIL-4), and interleukin 6 (rhIL-6). The toxicity, maximum tolerated dose and biologic activities were determined. Hematopoietic, immunologic and pro-inflammatory effects were noted during therapy with these agents. Prominent effects on lymphocyte and monocyte functional activities were demonstrated. The diversity of biologic effects in vivo demonstrates the pleiotropic nature of the cytokines investigated and the difficulties encountered in their in vivo evaluation.

Blood Cell Count↗

PubMed1993

Interleukin-2: use in solid tumors.

Recombinant interleukin-2 (rIL-2) is a cytokine that has a central immunoregulatory role in controlling T cell function and growth. Clinical trials of rIL-2 regimens in various solid tumors have been initiated, and 337 patients at the Cleveland Clinic Foundation have been treated in a sequence of trials. The studies have involved rIL-2 or polyethylene-glycol conjugated rIL-2 (PEG-IL-2) as single agents, combinations of rIL-2 with recombinant interferon alpha, IL-4, or doxorubicin, and trials of rIL-2 with tumor infiltrating lymphocytes (TILs). These studies are summarized and involve Phase I or Phase II investigations in patients with renal cell carcinoma (191 patients), malignant melanoma (49 patients) or miscellaneous solid tumors (97 patients). Response rates in each category, respectively, were 12%, 20% and 2%. Toxicity varied depending on the regimen and generally reflected the dose and schedule of rIL-2 being employed. This series of clinical studies demonstrates the role of rIL-2 in various malignancies and documents the activity in patients with malignant melanoma and renal cell carcinoma. Additional studies to investigate potential mechanisms of antitumor activity and response determinants are underway.

Clinical Protocols↗

PubMed1988

Linitis plastica of the esophagus.

A 62-yr-old woman was evaluated for a 2-wk history of regurgitation and weight loss. Radiologic studies demonstrated a stenotic region in the distal third of the esophagus. Multiple endoscopic biopsies were nondiagnostic. Esophagectomy and esophagogastrostomy revealed a diffusely infiltrating adenocarcinoma ("linitis plastica") of the distal esophagus, sparing the gastroesophageal junction and stomach. Despite the absence of metastatic disease at laparotomy, the patient developed metastases unresponsive to chemotherapy. The pathologic, radiographic, and endoscopic findings are consistent with primary linitis plastica of the esophagus.

Adenocarcinoma↗

PubMed1988

Interleukin-3 (IL-3) stimulates the clonal growth of pulmonary alveolar macrophage of the mouse: role of IL-3 in the regulation of macrophage production outside the bone marrow.

Interleukin-3 (IL-3) is one of the hematopoietic growth factors that regulates the growth and differentiation of pluripotent stem cells, thereby leading to the production of all the major blood cell types. The role of IL-3 in the regulation of pulmonary alveolar macrophage (PAM) production was investigated. IL-3 stimulated the proliferation and clonal growth of murine PAM with a dose-response curve similar to that of bone marrow granulocyte-macrophage colony-forming cells. The IL-3-induced colony formation by cells outside the bone marrow appeared to be unique to PAM; IL-3 failed to cause colony formation by both peritoneal exudate macrophages (PEM) and blood monocytes. Unlike bone marrow stem cells, PAM are unipotential and in vitro gave rise to only mononuclear phagocytes under the influence of IL-3. Nevertheless, cells derived from PAM cultures in media containing IL-3 displayed a high degree of heterogeneity in terms of their Fc receptor-mediated phagocytic activity. At low concentrations, IL-3 induced a synergistic response with colony-stimulating factor 1 (CSF-1), which resulted in an enhanced proliferative capacity of PAM. A synergistic effect was also observed by short-term exposure of PAM to IL-3 followed by incubating with CSF-1 alone. This study shows that IL-3 exhibited a macrophage growth factor activity unique to PAM.

Animals↗

PubMedDate not supplied

Phase II trial of circadian infusion floxuridine (FUDR) in hormone refractory metastatic prostate cancer.

Circadian administration of chemotherapy has been reported to decrease toxicity and possibly enhance efficacy. Between March 1991 and December 1993, 18 evaluable patients with progressive, hormone-refractory metastatic prostate cancer were treated in this phase II trial of circadian infusion floxuridine (FUDR). The drug was delivered through a central venous catheter using a CADD-Plus computerized pump such that approximately 70% of the drug was administered between 3 and 9 p.m. and the rest (30%) was administered between 9 p.m. and 3 p.m. The dose of FUDR was 0.15 mg/kg/day x 14 days every 4 weeks. A total of 79 complete cycles was administered. Two of 18 evaluable patients (11.1%) had decreases in PSA lasting five and eight months. No objective responses or improvement in bone scans was noted. The major toxicity observed was diarrhea. Although circadian infusion FUDR is feasible and tolerable, it has limited activity in hormone refractory prostate cancer.

Antimetabolites, Antineoplastic↗

PubMedDate not supplied

Phase 1 trial of subcutaneous IL-6 in patients with refractory cancer: clinical and biologic effects.

The authors evaluated the clinical and biologic effects of human recombinant interleukin-6 (rhIL-6) in patients with refractory cancer. A phase 1 trial using escalating doses of rhIL-6 (1-50 microg x kg(-1) x d(-1), Monday through Friday for 4 weeks) was performed in 30 patients. Toxicity was moderate and the maximum tolerated dose was determined to be 25 microg x kg(-1)x d(-1) based on cardiac and neurocortical toxicity in one patient each and thrombocytosis (platelets > 800,000/microL) in three patients. One patient with non-small-cell lung cancer had a partial response after three cycles of therapy. The biologic effects of rhIL-6 included anemia and dose-related thrombocytosis. Various proinflammatory activities were induced and included dose-related cyclical increases in peripheral blood monocytes and the CD14+/CD45RB+ +/- CD16C+ mononuclear cell populations. These increases were accompanied by increased levels of C-reactive protein, serum neopterin, and type I soluble tumor necrosis factor receptor. In contrast, rhIL-6 did not affect lymphocyte numbers or function (cytotoxicity, cytokine levels, immunoglobulin levels), with the possible exception of IL-2Ralpha mRNA induction in peripheral blood lymphocytes. rhIL-6 has pleiotropic proinflammatory actions in vivo and moderate toxicity when administered as long-term therapy.

Acute-Phase Reaction↗