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Biomedical subjects

E W Martin

Publications and source records attributed to E W Martin.

At least 55 records · Page 3Linked to original sources
PubMed1995

Radioimmunoguided surgery in primary colorectal carcinoma: an intraoperative prognostic tool and adjuvant to traditional staging.

BACKGROUND: The prognostic value of traditional staging classification for colorectal cancer has changed little since Dukes created the first staging scheme. Some patients with known metastatic disease are long-term survivors, while other patients with local disease die early. New intraoperative cancer detection technology, the radioimmunoguided surgery (RIGS) system, is being studied as a tool to aid in prediction of patient outcome. PATIENTS AND METHODS: Thirty-one patients with primary colorectal cancer were injected with the monoclonal antibody CC49, which was radiolabeled with iodine 125 (125I). A hand-held gamma-detecting probe was used at surgery to detect the radiolabeled antibody. Patients were classified as to the presence or absence of 125I-CC49-positive residual tissue at the close of surgery. Patient survival was analyzed. RESULTS: Follow-up ranged from 30 to 54 months. Survival of 11 stage I or II patients was longer than in 20 stage III or IV patients (P = 0.019). All 14 patients cleared of RIGS-positive tissue were alive at last follow-up, while 15 of 17 RIGS-positive patients died of their disease (P < 0.0001). CONCLUSIONS: The RIGS system used during surgery provides the surgeon with immediate prognostic information on patients with colorectal cancer and supplements traditional pathologic staging.

Adult↗
PubMed1995

Pilot study evaluating the intraoperative localization of radiolabeled monoclonal antibody CC83 in patients with metastatic colorectal carcinoma.

BACKGROUND: CC83, a second-generation monoclonal antibody (MAb) against tumor-associated glycoprotein TAG-72 has been shown to have a higher affinity constant than the anti-TAG MAbs CC49 and B72.3. Clinical studies have shown the effectiveness of both CC49 and B72.3 radiolabeled MAbs in localizing colorectal carcinoma with a hand-held gamma-detecting probe during operation. This current study was designed to assess the safety and tumor-binding ability of radiolabeled CC83 MAb in this setting. METHODS: Seventeen patients with recurrent colorectal cancer underwent intravenous injection with CC83 MAb radiolabeled with iodine 125 (2.0 mCi125I/0.2 mg CC83 MAb). Exploratory laparotomy was carried out 21 to 28 days after injection, consisting of a thorough traditional exploration followed by a survey with a hand-held gamma-detecting probe. All traditionally suspicious and probe-positive tissue was either biopsied or resected and subsequently examined for the presence of carcinoma by using routine histochemical staining techniques. RESULTS: Thirty-two sites were identified as suspicious for cancer by traditional surgical exploration and 39 through intraoperative survey with a hand-held gamma-detecting probe in the seventeen patients completing the study. Biopsy or resection yielded 27 tumor sites when tissue was evaluated by using routine hematoxylin-eosin staining. All 27 tumor sites were localized by the radiolabeled CC83 MAb, whereas 12 additional sites were RIGS positive but hematoxylin-eosin negative, resulting in a sensitivity and positive predictive value of 100% and 69%, respectively. Traditional methods of exploration detected 23 of 27 tumor sites (85% sensitivity), and nine false-positive sites were recorded (72% positive predictive value). Occult tumor was found by using CC83 MAb in four (15%) of 27 sites, altering the surgical plan in three patients. CONCLUSIONS: This initial study indicates that CC83 MAb, when used with RIGS, is safe and sensitive in detecting recurrent intraabdominal colorectal cancer.

Adult↗
PubMed1995

Radioimmunoguided Surgery system improves survival for patients with recurrent colorectal cancer.

BACKGROUND: Advanced colorectal cancer is fatal. No systemic therapies have resulted in increased patient survival. METHODS: One hundred thirty-one patients with recurrent colorectal cancer enrolled in two prospective nonrandomized studies using Radioimmunoguided Surgery (RIGS) system from May 1986 to April 1992 have been analyzed. Eighty-six patients were injected with the anti-tumor-associated glycoprotein (TAG) antibody B72.3, and 45 patients were injected with the second-generation anti-TAG monoclonal antibody CC49. Both monoclonal antibodies were radiolabeled with iodine 125. Both traditional and RIGS explorations were used to determine resectability. Follow-up was a minimum of 28 months. RESULTS: Forty-nine (37.4%) of the 131 patients underwent a curative resection. Twenty-seven of the patients (55%) are alive 2 to 8 years after operation. The cancers of the remaining 82 patients were unresectable, and only two patients (2%) are alive. In this unresectable group alternative intraoperative therapeutic methods (intraoperative radiation therapy, intraperitoneal hyperthermic perfusion, hepatic lines, and brachytherapy) were tried in 11 patients with two survivors. There were no survivors in 18 patients whose cancers were found to be traditionally resectable but unresectable with RIGS or in the 53 patients whose cancers were clearly unresectable by traditional exploration. Patients selected for curative resection had significantly increased survival (p < 0.0001). CONCLUSIONS: As an intraoperative tool RIGS significantly improves the selection of patients for curative resection.

Adenocarcinoma↗
PubMed1995

Expansion of mucin-reactive T-helper lymphocytes from patients with colorectal cancer.

The ability to identify and expand effector cells with reactivity against tumor-associated antigens (TAA) is critical for effective adoptive cellular therapy. The purpose of this study was to assess lymph node lymphocytes sensitized in vivo to the shed TAA TAG-72 as a potential source of cells for adoptive cellular therapy. Lymph nodes containing microscopic tumor and/or shed TAG-72+ mucin were localized using radiolabeled CC49 monoclonal antibody and a gamma detector at the time of exploratory colorectal surgery. Lymph nodes containing microscopic tumor and shed mucin exhibited approximately 40-fold expansion in short-term (< 21 days) cultures with either IL-2 or IL-1 plus IL-2; the combination of IL-2/anti-CD3 monoclonal antibody (mAb) resulted in significantly higher expansion. Cultures generated with IL-2 alone favored the expansion of CD8+ and CD56+ cells, whereas addition of IL-1 or anti-CD3 mAb to IL-2 promoted outgrowth of CD4+ T-cells. The IL-2/anti-CD3 expanded cells exhibited low levels of cytolytic activity in vitro against autologous and allogeneic colon tumor targets. However, CD4+ cells expanded in IL-2/anti-CD3 retained the ability to proliferate in response to TAG-72 mucin-expressing autologous tumor as well as bovine submaxillary mucin (BSM) a soluble TAG-72+ mucin. In addition, CD4+ cells expressed mRNA for IL-2, IL-4, tumor necrosis factor-beta and IFNg, and retained the ability to secrete IL-2 after expansion. Thus, noncytolytic, cytokine-secreting, mucin-reactive T- cells can be expanded from lymph nodes of patients with colorectal cancer.(ABSTRACT TRUNCATED AT 250 WORDS)

Antigens, Neoplasm↗
PubMed1995

Phase I trial of escalating doses of interleukin-1 beta in combination with a fixed dose of interleukin-2.

PURPOSE: Interleukin-1 (IL-1) and IL-2 have synergistic antitumor and myelostimulatory activities. We investigated the clinical and biologic effects of IL-1/IL-2 therapy. PATIENTS AND METHODS: Twenty patients with metastatic cancer, divided into five cohorts, were treated with escalating doses of IL-1 beta (0.005 to 0.2 micrograms/kg/d) administered as a 30-minute intravenous (IV) infusion on days 1 to 4, combined with a fixed dose of IL-2 (0.1 mg/m2/d) administered by continuous IV infusion on days 1 to 4. The 4-day cycles were repeated weekly for up to 8 weeks in the absence of toxicity and/or progressive disease. RESULTS: Patients tolerated up to 0.2 microgram/kg/d of IL-1 beta in combination with IL-2 without severe adverse effects. Peripheral-blood CD4-to-CD8 ratios and lymphokine-activated killer (LAK) activity were higher at the lower doses (0.005 to 0.05 microgram/kg/d) of IL-1 beta and higher than that of a cohort of patients treated with IL-2 alone. WBC counts, primarily neutrophils, increased significantly with higher doses of IL-1 beta (0.1 to 0.2 microgram/kg/d). Platelet counts were not significantly altered. Increases in serum IL-6, interferon gamma (IFN-gamma), and soluble IL-2 receptor levels were observed, but did not vary with IL-1 beta dose. Tumor regressions were observed in patients with colorectal cancer, melanoma, and renal cell carcinoma. CONCLUSION: IL-1 beta cancer be administered in combination with IL-2 with acceptable toxicity. Our results suggest that the addition of even low-dose IL-1 beta to IL-2 may be associated with potentially beneficial biologic activity; higher doses of IL-1 beta (0.1 to 0.2 microgram/kg/d) may add potentially beneficial hematologic activity.

Adjuvants, Immunologic↗
PubMed1994

Identification of occult micrometastases in pericolic lymph nodes of Duke's B colorectal cancer patients using monoclonal antibodies against cytokeratin and CC49. Correlation with long-term survival.

BACKGROUND: Patients with transmurally invasive, lymph node negative colorectal carcinoma (Dukes' B) have a 5-year survival rate ranging from 53.9% to 84.9%. The authors postulate that patients with Dukes' B colon cancer who die of their disease have occult micrometastases in their pericolic lymph nodes at the time of original diagnosis. In an attempt to identify these occult micrometastases, pericolic lymph nodes from Dukes' B colon cancer resections were stained retrospectively with antibodies against cytokeratin (anti-keratin AE1/AE3, Boehringer Mannheim, Indianapolis, IN) and CC49 (a second-generation monoclonal antibody directed against TAG-72. METHODS: The authors reviewed all Dukes' B (transmurally invasive, lymph node negative) primary colorectal carcinoma resection specimens from the surgical pathology files of the Ohio State University Hospitals between 1984 and 1987. Survival data were obtained from the Tumor Registry of the Arthur G. James Cancer Hospital and Research Institute, Columbus, Ohio. The results were analyzed by univariate and multivariate analysis. RESULTS: Fifty cases with 568 lymph nodes (11.3 per case) were examined with each antibody using standard immunoperoxidase techniques. Positive staining for cytokeratin was seen in 14 patients (33 lymph nodes), 6 of whom died of colon cancer within 66 months (43%). Only 1 of the 36 patients with cytokeratin-negative lymph nodes died of colon cancer over the same time period (3%, P = 0.0009 univariate, P = 0.0013 multivariate). There was no significant difference in survival between the CC49-positive and CC49-negative groups. CONCLUSION: Immunoperoxidase techniques are capable of identifying micrometastatic disease in lymph nodes missed by routine hematoxylin and eosin staining. Further, the presence of cytokeratin-positive cells within lymph nodes correlated with a significantly poorer prognosis. Therefore, cytokeratin staining of pericolic lymph nodes in patients with Dukes' B colorectal cancer is recommended. Larger multicenter studies are needed, however, to confirm these results and to evaluate the appropriateness of adjuvant chemotherapy in patients whose disease is upstaged by immunohistochemical staining.

Antibodies, Monoclonal↗
PubMed1994

Localization of tumor-reactive lymph node lymphocytes in vivo using radiolabeled monoclonal antibody.

BACKGROUND: Lymph node lymphocytes vary in their responsiveness to tumor. A technique has been developed that uses radiolabeled monoclonal antibody (MoAb) against the tumor-associated mucin, TAG-72, and a gamma-detecting probe by which lymph nodes containing microscopic tumor and/or shed TAG-72 can be identified in vivo. The immunologic characteristics of these lymph nodes were examined. METHODS: Patients with colon cancer received 125I-labeled MoAb CC49 by intravenous injection preoperatively. During laparotomy lymph nodes that appeared normal on inspection and palpation but which contained radiolabeled MoAb were identified using a hand-held gamma-detecting probe. These lymph nodes and other lymph node and tumor specimens were resected for analysis. RESULTS: Lymph nodes identified by the probe were found by immunohistochemical studies to contain microscopic tumor and/or shed antigen associated with germinal centers. They were characterized by greater CD4+:CD8+ ratios, rates of expansion, and cytolytic activity compared with lymphocytes from lymph nodes with macroscopic tumor, noninvolved lymph nodes, and tumors. All lymph node lymphocytes identified by the probe demonstrated significant proliferative responses to autologous tumor and, in contrast to lymphocytes from noninvolved lymph nodes, significant proliferative responses to allogeneic TAG-72+ tumor cells and to soluble TAG-72+ mucin. CONCLUSIONS: By locating lymph nodes with microscopic tumor and/or shed antigen, the use of radiolabeled MoAb in vivo can be used to reproducibly identify tumor-reactive lymph node lymphocytes. This technique may be useful in identifying cells for use in adoptive immunotherapy programs and in studying the regulation of immune responses in vivo.

Antibodies, Monoclonal↗
PubMed1993

Radioimmunoguided radical prostatectomy and lymphadenectomy.

BACKGROUND: The feasibility of using radioimmunoguided surgery (RIGS) (Neoprobe Corp., Columbus, OH) for intraoperative detection of prostate cancer was examined in a pre-Phase I clinical study involving 10 patients having radical prostatectomy and lymphadenectomy. METHODS: Patients were injected with iodine 125-radiolabeled B72.3 monoclonal antibody, which has been shown previously to bind to TAG-72, a pancarcinoma and oncofetal antigen. At a mean of 26 days after injection, RIGS was performed with a specially designed intraoperative gamma-detecting probe. RESULTS: By comparing probe counts with counts of appropriate background tissues, the RIGS system successfully localized tumor to the prostate of all 10 patients. Clinically occult and histologically confirmed bilateral intraprostatic tumor was identified in three patients. One additional patient had bilateral positive intraprostatic probe count ratios with the RIGS technique; on histologic examination, tumor was identified unilaterally, and extensive high-grade prostatic intraepithelial neoplasia was found on the contralateral side. Probe count ratios were positive in the lymph nodes of three patients; two had tumor confirmed histologically. CONCLUSIONS: The current investigation supports the feasibility of the RIGS technique and the need for additional studies.

Antibodies, Monoclonal↗
PubMed1993

Evaluation of NR-LU-10 with the Neoprobe gamma detector in a mouse model.

The Neoprobe Model 1000 hand-held gamma detector, in combination with the murine monoclonal antibody (MAb) B72.3 can successfully intraoperatively target both primary and recurrent colorectal cancer. Because of the shortcomings of this system (length of time needed to clear unbound MAb and heterogeneous staining of cancer cells), new MAbs are under investigation. NR-LU-10 IgG and its FAB fragment were evaluated with the Neoprobe gamma detector in a nude mouse model. NR-LU-10 is a pancarcinoma IgG2b antibody that recognizes an oncofetal glycoprotein antigen that is expressed by most carcinomas. Animals were injected intraperitoneally with 125I-labeled IgG, 125I, or technetium 99m (99mTc)-labeled Fab fragment. The Neoprobe gamma detector and standard gamma well counts provided biodistribution and pharmacokinetic data. The Fab fragment achieved a 5:1 tumor to blood-pool background (BPB) ratio in only 66 hr, whereas the whole MAb required 14 days. Technetium did not appear to be an adequate isotope for this system because of its short half-life. Autoradiographs performed for both the 125I-labeled NR-LU-10 IgG and its 125I-labeled Fab fragment (but not 99mTc-labeled Fab) localized well in this model and gave adequate tumor to BPB and tissue ratios. Use of the 125I-labeled Fab significantly decreased the time required for clearance of the MAb radionuclide complex from the blood and tissue background, thus providing earlier tumor localization in the Radioimmunoguided Surgery (RIGS) system.

Animals↗
PubMed1993

Role of carcinoembryonic antigen in predicting resectability of recurrent colorectal cancer.

The reported low resectability rate for patients with recurrent colorectal cancer who have carcinoembryonic antigen (CEA) levels > 11 has led us to perform this study. One hundred twenty-four patients who underwent Radioimmunoguided Surgery (RIGS) procedures for recurrent colorectal cancer from 1986 to the present were studied. In surgery, all patients underwent a traditional exploration followed by survey with a hand-held, gamma-detecting probe to detect preinjected radiolabeled monoclonal antibodies attached to cancer cells. Sites of metastases included: 72 liver (58.1 percent), 23 pelvis (18.5 percent), 15 distant lymph nodes (12.1 percent), 2 anastomotic (1.6 percent), and 12 other sites (9.7 percent). The resectability rate was 43.5 percent (54 patients). The mean preoperative CEA level for patients with resectable disease was significantly lower than for patients with unresectable disease (P = 0.017): unresectable--mean, 87.1; SD, 141.0; minimum, 0.3; maximum, 501; resectable--mean, 36.6; SD, 59.3; minimum, 0.3; maximum, 329. The CEA level for patients with liver metastasis did not vary significantly from those patients without metastasis: 70 vs. 58.2 (P = 0.58). Those patients with resectable liver tumors had lower mean CEA levels than those with unresectable liver, approaching significance: 41.6 vs. 91.9 (P = 0.065). Other metastatic sites had a mean CEA level of: pelvic, 72.6; distant lymph nodes, 47.8; anastomotic, 2.7; and other sites, 53.8. These data suggest that there is a significant difference between the preoperative CEA level of the resectable and unresectable recurrent colorectal cancer patients, but the large standard deviation does not justify abandonment of exploration for any CEA level.

Antibodies, Monoclonal↗
PubMed1993

Intraoperative localization of neuroendocrine tumors with 125I-TYR(3)-octreotide and a hand-held gamma-detecting probe.

BACKGROUND: This study evaluates a novel method of intraoperative localization of endocrine gastroenteropancreatic tumors with a hand-held gamma-detecting probe to detect in situ tumor binding of the radioiodinated somatostatin analog 125I-TYR(3)-octreotide. METHODS: Seven patients with biochemical and radiologic evidence of a specific endocrine tumor, one patient with biochemical evidence of gastrinoma but no tumor localized by conventional imaging techniques, and four patients with equivocal preoperative biochemical or radiologic study results but suspected of harboring a neuroendocrine tumor underwent abdominal exploration with intraoperative injection of 125I-TYR(3)-octreotide. 298 +/- 63 microCi. A hand-held gamma-detecting probe was used during operation to determine whether gross tumor accumulated the radiolabeled analog and occult tumor could be detected. Positive uptake was defined as tumor/background ratios exceeding 2:1. RESULTS: The tumor in all seven patients with gross disease accumulated 125I-TYR(3)-octreotide. Occult tumor beyond that appreciated with preoperative imaging or by routine operative exploration was detected in a patient with carcinoid tumor. In the patient with the occult gastrinoma the probe detected the lesion within the duodenal bulb before duodenotomy and also predicted what proved histologically to be positive peripancreatic adenopathy. There was a single false-positive reading from the stomach in a patient with suspected carcinoid tumor in whom no tumor could be found grossly or histologically. A pancreatic mass that probed negative proved to be an adenocarcinoma of ductal origin. CONCLUSIONS: Tumor-specific peptide-receptor binding can be detected in situ with 125J-TYR(3)-octreotide and a hand-held gamma-detecting probe. This technique may facilitate neuroendocrine tumor localization and operative cytoreduction.

Adult↗
PubMed1993

Radioimmunoguided surgery for colorectal cancer.

This article provides a basic understanding of the RIGS (radioimmunoguided surgery) technique and reviews the evolution of the technology from its inception as an experimental technique in animal models to the current clinical trials in patients. A review of published data from the laboratory and from preclinical and clinical trials is updated by a statement of the current status of RIGS. A look at the future of RIGS as an experimental and clinical tool highlights current areas of investigation based on this technology.

Animals↗
PubMed1993

Adjuvant treatment for rectal cancer: current status.

Surgery is still the cornerstone of curative treatment for rectal cancer. A combination of postoperative radiation and chemotherapy is the preferred adjuvant treatment for TNM stages II and III rectal cancer. Although studies combining 5-fluorouracil (5-FU) and the investigational agent semustine (methyl-CCNU) with radiation showed some survival benefit, preliminary results of recent studies suggest that radiation with 5-FU alone is an effective substitute. Preoperative radiation treatment has several advantages over postoperative radiotherapy. The major disadvantage, that tumors may be downstaged, preventing exact evaluation of treatment results, may be overcome by using rectal ultrasound for preoperative staging. Another promising treatment is preoperative radiation combined with 5-FU as a radiosensitizer and for possible increased systemic effect. Studies are needed to find a better, less toxic radiosensitizer, to explore new chemotherapy combinations with 5-FU (such as levamisole), and to define the proper dose sequence and integration.

Combined Modality Therapy↗
PubMed1992

Intraoperative detection of colorectal cancer with radioimmunoguided surgery and CC49, a second-generation monoclonal antibody.

Radioimmunoguided surgery (RIGS) has been employed intraoperatively in cases of colorectal cancer to assess the extent of local tumor spread and metastatic disease. This technique uses radiolabeled monoclonal antibodies (MAbs) directed against tumor-associated antigens, and a hand-held gamma-detection probe to detect the radiolabel fixed to tumor tissue. Recently introduced is an MAb directed against tumor-associated glycoprotein (anti-TAG), CC49. Sixty patients were entered into the initial study. Eighteen of 21 (86%) primary tumors were localized by the CC49 MAb and the gamma-detecting probe. Twenty-nine of 30 (97%) recurrent tumors were localized. Antibody dose did not affect localization. Specimens were divided into tissue types I through IV, based on antibody localization and hematoxylin and eosin (H&E) staining: type I, RIGS (-) and histologically (-); type II, RIGS (-) and histologically (+); type III, RIGS (+) and histologically (-); type IV, RIGS (+) and histologically (+). Type IV tissue were further classified by whether they were grossly apparent, IVa, or grossly inapparent, IVb (occult). Occult tumor found by RIGS and confirmed by H&E staining (type IV) had localization ratios similar to RIGS-positive, histology-negative tissue (type III). Traditionally found cancer (type IV) had significantly higher ratios. In 12 of 24 patients (50%) with primary tumors and 14 of 30 patients (47%) with recurrent tumors, RIGS with CC49 altered the planned operative procedure. Radioimmunoguided surgery with CC49 provides useful, immediate intraoperative information not available by other techniques.

Adult↗
PubMed1992

Radioimmunoguided surgery challenges traditional decision making in patients with primary colorectal cancer.

BACKGROUND: Initial experience with the radioimmunoguided surgery system (RIGS) has been found to impact on decision making in patients with recurrent colorectal cancers. Reported here is experience with RIGS-influenced therapeutic decisions in patients with primary colorectal cancer. METHODS: Thirty-six evaluable patients with primary cancers were injected with the second-generation anti-tumor-associated glycoprotein antibody CC49 labeled with 1 to 2 mCi iodine 125. Pharmacokinetic determination and precordial counts were obtained after injection and weekly until levels were less than 20 counts/2 sec. At surgery abdominal and pelvic explorations were performed, first traditionally by inspection and palpation and then with the hand-held, gamma-detecting probe. RIGS-positive tissue was considered cancerous and removed if possible. RESULTS: Thirty patients (83%) had positive antibody localization at surgery. Of those patients with localization, in 24 (80%) additional information was obtained at the time of surgery. In 11 patients (34%) staging changes were made as a result of RIGS exploration. New findings resulted in operative changes in nine patients (25%). Eleven (30%) of the original 36 patients became eligible for adjuvant chemotherapy based on current recommendations because of RIGS findings. CONCLUSIONS: In conclusion, the RIGS system provides immediate staging information that impacts on therapeutic interventions, challenging the adequacy of traditional procedures alone for primary colorectal cancer exploration.

Colonic Neoplasms↗