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Biomedical subjects

R Essner

Publications and source records attributed to R Essner.

53 records · Page 3Linked to original sources
PubMed1994

Interleukin 4 regulates G1 cell cycle progression in gastric carcinoma cells.

We have previously reported that interleukin 4 (IL-4) inhibits the growth of human gastric carcinoma cells. To investigate the mechanism for this inhibition we analyzed the effect of IL-4 on cell cycle progression of the IL-4-sensitive gastric carcinoma cell line, HTB-135. IL-4 significantly inhibited cell cycle G1-S-phase progression. To assess the postreceptor molecular events that transduced the negative-growth signals by IL-4, we analyzed the expression of cell cycle nuclear-regulating factors such as retinoblastoma gene product (Rbp), c-myc, c-myc protein (c-mycp), and cyclin D1 expression which are known to be regulators of G1-S-phase transition. IL-4 was found to induce an unphosphorylated form of Rbp within 24 h and significantly reduce the phosphorylated form at 48 h. The transition of Rbp to a hypophosphorylated form concurs with the decrease in c-myc gene expression and c-mycp. In addition, we demonstrated that IL-4 down-regulated p34cdc2, a kinase associated with Rbp phosphorylation and cyclin D1. Cyclin D1, considered as a critical nuclear regulatory factor of G0-G1 to S-phase transition was down-regulated 24 and 48 h post-IL-4 treatment as well. These studies suggest that IL-4 inhibits gastric cell proliferation by blocking cell cycle progression by down-regulating several key G0-G1 cell cycle nuclear-regulating factors.

Adenocarcinoma↗
PubMed1993

Intraoperative lymphatic mapping and selective cervical lymphadenectomy for early-stage melanomas of the head and neck.

PURPOSE: We developed intraoperative lymphatic mapping with selective lymphadenectomy (SLND) to identify micrometastatic spread of cutaneous melanoma to regional lymph nodes. This study was undertaken to assess the sensitivity and specificity of our technique in patients with clinical stage I (CS-I) melanoma of the head or neck. PATIENTS AND METHODS: Seventy-two CS-I melanoma patients underwent intraoperative lymphatic mapping of primary cutaneous melanomas located on the head, neck, or upper chest/back draining to the neck. Key (sentinel) cervical lymph nodes in the regional lymphatic drainage basin were identified, selectively excised during SLND, and examined for microscopic evidence of tumor cells. If these sentinel nodes were tumor-negative, the surgery was concluded; if the sentinel nodes were tumor-positive, all nodes in the drainage basin were removed during en bloc lymphadenectomy (LND). RESULTS: Intraoperative lymphatic mapping identified sentinel nodes in 90% of the regional drainage basins. Fifteen percent of these nodes were tumor-positive, indicating the need for LND. There were no false-negative sentinel nodes, and extended follow-up showed no local nodal recurrences in patients whose sentinel-node histology did not indicate the need for LND. CONCLUSION: Intraoperative lymphatic mapping and SLND is a minimally invasive and highly accurate screening technique for determining which patients with CS-I head and neck melanomas have subclinical node metastases and therefore might benefit from cervical LND.

Adolescent↗
PubMed1991

Reirradiation for extremity soft tissue sarcomas. Local control and complications.

The treatment for patients who have locally recurrent soft tissue sarcoma of the extremity after surgery and radiation therapy is primarily amputation. A second course of radiation and local excision is usually not considered because of two major concerns: radiation complications and inability to achieve local disease control. This study examines the clinical course of 32 patients who received a second course of radiation for soft tissue sarcoma. Four groups of patients were defined by the sequence of radiation (preoperative and postoperative) and surgery. Despite high cumulative doses of radiation, complications requiring amputation were rare. Local tumor control was achieved with a second course of preoperative radiation and wide local excision in 15 of 18 (84%). However, local excision and a second course of postoperative radiation resulted in eight of 14 (57%) local failure and cannot be recommended as a comparable therapy to amputation.

Adult↗
PubMed1991

Production of tumor necrosis factor alpha and interferon gamma in interleukin-2-treated melanoma patients: correlation with clinical toxicity.

Interleukin-2 (IL-2)-based immunotherapy regimens are accompanied by dose-limiting toxicity consisting of fever, tachycardia, chills and capillary leak syndrome. We hypothesized that the toxicity was caused by the induction and release of endogenous cytokines such as tumor necrosis factor alpha (TNF alpha) and interferon gamma (IFN gamma). We measured the serum levels of TNF alpha and IFN gamma in IL-2-treated melanoma patients and attempted a correlation with clinical toxicity. A total of 23 patients received either 6 x 10(6) IU or 12 x 10(6) IU Cetus IL-2/m2 by i.v. bolus daily for 5 consecutive days on weeks 1, 3 and 5. Serum TNF alpha and IFN gamma levels were measured by enzyme-linked immunosorbent assay. Clinical toxicity was scored each day by objective measurements of hypotension, tachycardia, fever and chills/rigors. Clinical toxicity and IFN gamma levels correlated nicely, peaking on the 5th day of each treatment cycle. The kinetics and magnitude of TNF alpha production, however, were not predictable and did not correlate with either IFN gamma or toxicity. Some patients had modest increases in TNF alpha production while others had markedly increased levels during the second and third treatment weeks. Remarkably, these high levels persisted during nontreatment weeks and after completion of therapy. This clinical study demonstrates novel kinetics for immunoreactive TNF alpha in IL-2 cancer patients, which do not correlate well with toxicity.

Humans↗
PubMed1990

Influences of interleukins 2 and 4 on tumor necrosis factor production by murine mononuclear phagocytes.

Administration of recombinant human interleukin 2 (IL-2) to mice gave rise to peritoneal macrophages and blood monocytes that were primed to produce large amounts of tumor necrosis factor (TNF). Macrophages from IL-2-treated athymic mice responded less well than those from euthymic mice. In addition to its in vivo priming effect, IL-2 was able to directly stimulate TNF production in vitro by purified monocytes. Macrophages responded to IL-2 generally less well than monocytes both in vitro and in vivo. In contrast to IL-2, recombinant murine interleukin 4 (IL-4) down-regulated TNF synthesis by macrophages. In vitro pretreatment of macrophages with IL-4 largely abolished their ability to synthesize TNF in response to IL-2 or lipopolysaccharide. Also, administration of IL-4 to mice blocked the ability of IL-2 and lipopolysaccharide to prime macrophages in vivo for TNF production. Overall, these results demonstrate that IL-2 and IL-4 can act antagonistically to regulate TNF production by macrophages. In spite of its down-regulatory action on TNF production, IL-4 was unable to protect mice against the lethal toxic effects of lipopolysaccharide or IL-2.

Animals↗
PubMed1990

Differential effects of granulocyte-macrophage colony-stimulating factor and macrophage colony-stimulating factor on tumor necrosis factor and interleukin-1 production in human monocytes.

Human peripheral blood monocytes (PBM) cultured in the presence of 100-5,000 u/ml granulocyte-macrophage colony-stimulating factor (GM-CSF) for 24 hr secreted small quantities of tumor necrosis factor (TNF), but not interleukin-1 (IL-1). The activation of PBM to produce TNF was weak and could be blocked by polyclonal anti-GM-CSF anti-serum. Neither LPS nor IL-2 were synergistic with GM-CSF in the production of TNF or IL-1. IFN gamma alone did not induce either cytokine, but in the presence of GM-CSF it caused a synergistic (100-fold) increase in TNF but not IL-1 production. Macrophage colony-stimulating factor (M-CSF) alone or in combination with LPS, IFN gamma or IL-2 did not stimulate PBM to produce TNF or IL-1 in 24 hr culture.

Granulocyte-Macrophage Colony-Stimulating Factor↗
PubMed1989

Genetic analysis of the human tumor necrosis factor alpha/cachectin promoter region in a macrophage cell line.

The 615-bp 5' flanking region of the human TNF-alpha/cachectin gene was isolated and ligated to the luciferase reporter gene. In addition, a series of truncated promoter constructs was generated by exonuclease III digestion. The promoter activity of these constructs was studied in a transient transfection system using the TNF-alpha-producing U937 cell line. Full-length and truncated TNF promoter constructions extending from -615 to -95 bp relative to the transcription start site (TSS) could be induced by phorbol esters. A construct truncated to within 36 bp of the TSS (and within 11 bp of the TATAA box) was inactive. Therefore, the phorbol ester responsive is localized in the TNF/cachectin promoter to a relatively short region proximal to the TATAA box.

Base Sequence↗
PubMed1989

IL-4 down-regulates IL-1 and TNF gene expression in human monocytes.

The effects of IL-4 on IL-1 and TNF gene expression in human peripheral monocytes (PBM) were examined. Highly purified PBM cultured for 24 to 96 h in the presence of IL-4 produce neither IL-1 nor TNF protein. RNA hybridization studies demonstrated that IL-4 does not induce transcription of IL-1 or TNF. Preincubation of PBM with IL-4 did, however, inhibit LPS-induced IL-1 and TNF production in a dose- and time-related fashion. Maximal inhibition occurred after 96 h of incubation with 200 U/ml IL-4. RNA hybridization studies demonstrated that IL-4 suppressed the expression of IL-1 alpha, IL-1 beta, and TNF mRNA. These results suggest IL-4 modulates monocyte production of TNF and IL-1 by down-regulation of gene expression. This unique property of IL-4 may be important in the regulation of the immune response.

Gene Expression Regulation↗
PubMed1989

Overview of biological response modifiers.

The immune system is regulated by a variety of lymphokines, monokines, and colony-stimulating factors. Most have now been cloned and it is clear that these cytokines have a broad range of overlapping immunological, inflammatory, and physiological properties. Some of these cytokines might favorably influence the biological therapy of cancer and they have been collectively referred to by clinicians as "biological response modifiers." This review summarizes current knowledge about the molecular biology and biological properties of most of the common cytokines and provides a brief survey of their therapeutic potential in patients with cancer.

Antineoplastic Agents↗
PubMed1989

Tumour necrosis factor production by IL-2-activated macrophages in vitro and in vivo.

Purified human and murine monocytes can be activated in vitro by human recombinant IL-2 to secrete tumour necrosis factor (TNF). TNF mRNA is detected within 4 h of addition of IL-2. Signal transduction does not appear to require expression of the Tac peptide of the IL-2 receptor. IL-2 does, however, induce Tac mRNA and Tac peptide expression on peripheral blood monocytes (PBM). In addition to these in vitro studies, PBM retrieved from IL-2-treated cancer patients and mice have been shown to have a greatly increased capacity for TNF production. These studies identify a pathway for macrophage activation by IL-2 both in vitro and in vivo. They also suggest a mechanism for some of the immunoregulatory and toxic effects of IL-2 based immunotherapy regimens.

Animals↗
PubMed1988

Prognostic significance of melanoma arising in the scalp.

Thirty-five patients with stage I melanoma of the scalp were retrospectively reviewed and compared with similar patients with melanoma of the extremity and trunk. Patients with melanoma of the scalp were predominantly male. The 5-year survival rate was 89 percent. This compared favorably with similar patients with melanoma arising either in the trunk or the extremity. The prognosis of patients with stage I melanoma of the scalp is no worse than that of patients with melanoma arising in the trunk or extremity; therefore, they should be treated in a comparable manner.

Abdomen↗
PubMedDate not supplied

Efficacy of lymphatic mapping, sentinel lymphadenectomy, and selective complete lymph node dissection as a therapeutic procedure for early-stage melanoma.

BACKGROUND: Lymphatic mapping, sentinel lymphadenectomy, and selective complete lymph node dissection (LM/SL/SCLND) is an increasingly popular alternative to elective lymphadenectomy (ELND) for patients with early-stage melanoma. Although several reports have demonstrated the accuracy of the LM/SL technique, there are no data on its therapeutic value. METHODS: We performed a matched-pair statistical analysis of 534 patients with clinical stage I melanoma; one half of the patients were treated with LM/SL and the other half were treated with ELND. Patients in the two treatment groups were matched for age (54% were < or =50 years of age), gender (63% were male patients), site of the primary melanoma (49% were on the extremities, 36% on the trunk, and 15% on the head and neck), and thickness of the primary melanoma (7% were < 0.75 mm, 42% between 0.75 and 1.5 mm, 43% between 1.51 and 4.0 mm, and 8% > 4 mm). Patients in the LM/SL group underwent complete regional lymphadenectomy (SCLND) only if the LM/SL specimen contained metastatic melanoma. RESULTS: The overall incidences of nodal metastases were no different (P = .18) between LM/SL (15.7%) and ELND (12%) groups, but the incidence of occult nodal disease was significantly (P = .025) higher among patients with intermediate-thickness (1.51-4.0-mm) primary tumors who underwent LM/SL (23.7%) instead of ELND (12.2%). Survival data were compared by the log-rank score test. LM/SL/SCLND and ELND resulted in equivalent 5-year rates of disease-free survival (79 +/- 3.3% and 84 +/- 2.2%, respectively; P = .25) and overall survival (88 +/- 3.0% and 86 +/- 2.1%, respectively; P = .98). The LM/SL and ELND groups also exhibited similar incidences of same-basin recurrences (4.8% vs. 2.1%, P = .10, respectively) and in-transit metastases (2.6% vs. 3.8%, P = .48) after tumor-negative dissections. Patients who underwent ELND showed a higher incidence of distant recurrences (8.9% vs. 4.0%, P = .03), but this may be related to the longer follow-up period for these patients (median, 169 months), compared with the LM/SL-treated patients (45 months). Among patients with tumor-positive nodal dissections, the 5-year overall survival rates were higher, and approached significance (P = .077) for patients treated by LM/SL/SCLND (64 +/- 12%) compared with ELND (45 +/- 10%). CONCLUSIONS: These findings suggest that LM/SL/SCLND is therapeutically equivalent to ELND but may be more effective for identifying nodal metastases in patients with intermediate-thickness primary tumors.

Biopsy↗
PubMedDate not supplied

Long-term survival after complete resection of melanoma metastatic to the adrenal gland.

BACKGROUND: Survival of patients with American Joint Committee on Cancer stage IV melanoma is generally poor, although there are occasional long-term survivors who have undergone surgical resection of a limited number of metastases. In the study, we examined the outcome of patients with adrenal gland metastases. METHODS: Eighty-three patients with adrenal metastases were identified from our computerized melanoma database of 8250 patients. Univariate and multivariate analyses for overall survival differences were performed by using proportional hazards modeling. RESULTS: Median survival for the 83 patients was 9.3 months (1-67 months). Of the 27 patients who underwent surgical exploration, 18 (66%) were rendered clinically free of disease by adrenalectomy alone (12 cases) or by adrenalectomy and resection of additional disease (6 cases). Nine patients underwent palliative adrenal resection. Median survival was 25.7 months after complete resection compared with 9.2 months after palliative resection (P = .02). CONCLUSIONS: Patients with adrenal metastases from melanoma, either isolated or with a limited number of additional metastases, may benefit from surgical resection if all visible disease can be removed. Patients with unresectable extra-adrenal disease achieve no survival benefit from adrenalectomy.

Adrenal Gland Neoplasms↗
PubMedDate not supplied

Functional interleukin-4 receptor and interleukin-2 receptor common gamma chain in human gastric carcinoma: a possible mechanism for cytokine-based therapy.

Interleukin (IL)-2 and IL-4 play a critical role in the regulation of the immune response. Yet both of the receptors for these cytokines have been found on nonhematopoietic cells, including human gastric carcinoma cell lines and tissue specimens. IL-4 causes G1 phase cell cycle arrest of gastric carcinoma; the effect directly correlates with the expression of IL-4 receptor (IL-4R) and is seen within 48 hours after treatment. Cells lacking IL-4R are unaffected by IL-4. We examined signal transduction pathways employed by IL-4 that may account for cell cycle arrest of an established human gastric carcinoma cell line, CRL 1739. Western blot analysis was performed on CRL 1739 cultured in the presence of IL-4 (500 U/ml). Cells were lysed, protein extracted, and electroblotted; blots were then probed with murine mono-clonal antibodies to specific intracellular proteins. Western blotting of CRL 1739 with antiphosphotyrosine antibody (4G10) demonstrated multiple (140 kDa and 65 kDa) phosphoproteins seen only in IL-4-treated CRL 1739. Immunoprecipitation and blotting of CRL 1739 with specific secondary antibodies demonstrated that the 140 kDa phosphoprotein was IL-4R", the 65kDa phosphoprotein was IL-2Rgc, the 130 kDa phosphoprotein was Janus kinase (JAK1), and the 116 kDa phosphoprotein was JAK3. Reverse transcription-polymerase chain reaction with specific primers demonstrated that multiple human gastric tumor specimens expressed IL-4R" and IL-2Rgc but did not express the leukocyte marker CD45. These results suggest that human gastric carcinomas may express functional cytokine receptors, including the IL-2Rgc commonly found in association with the lymphocyte IL-2R. These receptors may represent novel targets for directing cytokine-based therapy.

Biopsy↗
PubMedDate not supplied

Is the node of Cloquet the sentinel node for the iliac/obturator node group?

PURPOSE: Some surgeons question the survival advantage of ilioinguinal lymphadenectomy for metastatic melanoma because they believe that deep nodal involvement signifies a poor prognosis that is unchanged by surgery. However, several series, including our own, have reported 5-year survival rates reaching 30%. New adjuvant therapies may further improve survival after ilioinguinal lymphadenectomy, but this applies only to nodal basins with metastatic disease. We hypothesized that the node of Cloquet accurately reflects the pathologic status of the iliac/obturator nodes, allowing deep pelvic lymphadenectomy to be selectively performed. PATIENTS AND METHODS: Between 1972 and 1998, 691 patients with primary cutaneous melanoma underwent both elective and therapeutic complete (superficial and deep) ilioinguinal lymphadenectomy. Of the 204 (30%) patients with tumor-positive inguinal and/or iliac/obturator nodes, 68 had a node of Cloquet identified during pathologic review of the lymphadenectomy specimen. Chart and computer database review of these 68 patients was undertaken to determine the association between the tumor status of Cloquet's node and that of deep pelvic nodes. Immunohistochemical analysis was performed on eight of 11 negative Cloquet's nodes in patients with positive iliac/obturator nodes. Paraffin blocks of the other three negative nodes of Cloquet were unavailable for immunohistochemistry, and they were excluded from analysis. RESULTS: Tumor-positive deep nodes were identified in the lymphadenectomy specimen from 20 of 30 (67%) patients with a positive Cloquet's node and from eight of 35 (23%) patients with a negative Cloquet's node (P = 0.0019). Re-examination of these eight tumor-negative Cloquet's nodes using immunostaining with S-100 and HMB45 identified tumor in 3 nodes, increasing the sensitivity of Cloquet's node for predicting deep nodal metastases from 71% to 82%. The 6.8 odds ratio of positive iliac/obturator nodes given a positive node of Cloquet increased to 12.4 after immunohistochemical analysis. The positive and negative predictive values were also enhanced from 67% to 70% and 77% to 84%, respectively. DISCUSSION: The tumor status of the node of Cloquet significantly reflects the tumor status of the iliac/obturator nodes, particularly when Cloquet's node is examined by immunohistochemical analysis. The node of Cloquet assumes the role of the sentinel node in patients whose superficial inguinal lymph nodes drain through Cloquet's node to the iliac/obturator nodes.

Adult↗
PubMedDate not supplied

Universal application of intraoperative lymphatic mapping and sentinel lymphadenectomy in solid neoplasms.

PURPOSE: Regional lymph node involvement is the most important prognostic indicator in patients with solid tumors. Conventional lymph node dissection has not been shown to affect survival and is often associated with considerable morbidity. Intraoperative lymphatic mapping and sentinel lymph node dissection were therefore designed as a minimally invasive alternative to routine elective lymph node dissection in patients with primary cutaneous melanoma. This study examined whether introperative lymphatic mapping and sentinel lymph node dissection were accurate in staging patients with other solid malignancies. PATIENTS AND METHODS: Between 1985 and 1998, 107 patients with breast cancer, 17 with thyroid tumors, 14 with gastrointestinal/gynecologic cancers, six with Merkel cell cancers, and five with squamous cell carcinomas of the head and neck have undergone mapping and sentinel lymph node dissection at the John Wayne Cancer Institute. RESULTS: The sentinel node was identified in 96% of patients (98% melanoma). In 36% of patients the sentinel node was the only tumor-positive node (71% melanoma). Eighteen percent of sentinel nodes were negative by hematoxylin and eosin staining but were positive by immunohistochemical staining (15% melanoma). CONCLUSION: These data suggest that many solid neoplasms have a primary lymphatic channel and lymph node to which it drains. Although sentinel lymph node dissection has been popularized in melanoma therapy, we have found it feasible for treatment of other solid malignancies. This technique may ultimately replace conventional dissection with more accurate staging.

Adult↗