Specific neurotrophic factors support the survival of cortical projection neurons at distinct stages of development.

Repair of specific neuronal circuitry in the neocortex may be possible via neural precursor transplantation or manipulation of endogenous precursors in situ. These approaches will almost certainly require a detailed understanding of the mechanisms that control survival and differentiation of specific neuronal lineages. Such analysis has been hampered by the overwhelming diversity of neuronal types intermixed in neocortex and the inability to isolate individual lineages. To elucidate stage-specific controls over the survival of individual lineages of cortical neurons, we purified immature callosal projection neurons (CPN) at distinct stages of development from embryonic and postnatal mouse cortex by retrograde fluorescence labeling, followed by fluorescence-activated cell sorting. Purified CPN survive well in culture, acquire stage-specific projection neuron morphologies, and express appropriate neurotransmitters and growth factor receptors. Purified CPN are dependent on exogenous trophic support for survival in a stage-specific manner. Survival of postnatal day 2 (P2) to P3 and P6-P7 CPN is promoted by overlapping but distinct sets of neurotrophic factors, whereas embryonic day 19 CPN show less specificity of dependence on peptide factors. These studies demonstrate for the first time the stage-specific control by peptide growth factors over the survival of a specific cortical neuronal lineage. Such information may be critical for the future goal of directed differentiation of transplanted or endogenous precursors toward cellular repair of complex cortical circuitry.

Fluorodeoxyglucose positron emission tomography as an adjunct to carcinoembryonic antigen in the management of patients with presumed recurrent colorectal cancer and nondiagnostic radiologic workup.

BACKGROUND: The purpose of this study was to determine the role of fluorodeoxyglucose positron emission tomography (PET) in localizing disease in patients with colorectal cancer with radiologically occult symptomatology or increases in carcinoembryonic antigen (CEA) level. METHODS: Two hundred seventy-seven patients with colorectal cancer underwent PET scanning between November 1998 and September 2000 prompted by (1) increasing CEA level and nondiagnostic imaging or (2) symptoms with normal CEA level and nondiagnostic imaging. PET results were correlated with operative findings/histology, clinical follow-up data, and CEA level to determine PET's accuracy in determining the source of symptoms or CEA. RESULTS: Fifteen patients had increasing CEA levels, and 14 had abnormal PET. Two of these 14 were denied exploration because PET suggested widely metastatic disease. Nine patients underwent exploration with curative intent. In 1 patient, recurrence was not pathologically confirmed (false-positive rate, 8%). Two had disease beyond that predicted by PET, and 6 underwent complete resection and normalized their CEA levels. Four symptomatic patients with normal CEA levels and negative x-rays had abnormal PET; at exploration, 3 had no evidence of recurrence. CONCLUSIONS: PET imaging can often accurately localize the source of radiologically occult increases in CEA level and select that subset of patients eligible for therapeutic laparotomy. Symptomatic, PET-positive patients with normal CEA levels frequently undergo nontherapeutic laparotomy, and PET findings should be interpreted with caution in these patients.

Neural precursor differentiation following transplantation into neocortex is dependent on intrinsic developmental state and receptor competence.

Reconstruction of neocortical circuitry by transplantation of neural precursors, or by manipulation of endogenous precursors, may depend critically upon both local microenvironmental control signals and the intrinsic competence of populations of precursors to appropriately respond to external molecular controls. Dependence on the developmental state of donor or endogenous precursor cells in achieving appropriate differentiation, integration, and connectivity is not clearly understood. Recent studies have demonstrated the ability to generate expandable, often clonal neural precursors at various stages of development. Transplantation of a variety of these precursors suggests that precursor differentiation and integration within the central nervous system (CNS) may depend directly on the level of cellular maturation, with less differentiated, earlier stage precursors offering more flexible but less efficient integration and more differentiated, later stage precursors offering more efficient differentiation to specific phenotypes. To further investigate this hypothesis within neocortex, we used the relatively immature HiB5 multipotent neural precursor cell line derived from embryonic day 16 hippocampus, which is less mature than precursor types that have demonstrated neuronal differentiation in adult neocortex. HiB5 cells labeled fluorescently, radioactively, and genetically were transplanted into murine neocortex under three different conditions expected to offer varying levels of instructive and permissive microenvironmental signals: (1) the developing cortex in utero; (2) regions of adult neocortex undergoing targeted pyramidal neuronal degeneration in which developmental signals are upregulated and in which later stage precursors and immature neurons undergo directed pyramidal neuron differentiation; or (3) the intact adult neocortex. Differentiation and integration of transplanted cells were examined histologically and immunocytochemically by morphology and using neuronal- and glial-specific markers. We found that these precursors underwent differentiation toward cortical neuron phenotypes with characteristic morphologies when transplanted in utero, but failed to do so under either of the adult conditions. HiB5 precursors demonstrated highly immature characteristics in vitro, consistently expressing neuroepithelial but not glial or neuronal markers. Under all conditions, donor cells survived and migrated 1-2 mm from the injection track 2 to 4 weeks after transplantation. HiB5 neural precursors transplanted into the developing cortex of embryonic mice in utero migrated within the cortex, integrated well into the host parenchyma, and differentiated toward morphologically diverse, neuronal phenotypes. HiB5 cells transplanted into the intact cortex of adult mice survived, but did not show neuronal differentiation. In contrast to slightly later stage neural precursors and embryonic neurons used in previous transplantation studies, the HiB5 cells also failed to undergo neuronal differentiation after transplantation into regions undergoing induced apoptotic neuronal degeneration in adult cortex. These results suggested that these early hippocampal-derived precursors might not be fully competent to respond to later stage differentiation and/or survival signals important in neocortex and known to be upregulated in regions undergoing targeted neuronal apoptosis, including the TrkB neurotrophin receptor ligands BDNF and NT-4/5. We investigated this hypothesis and found that undifferentiated HiB5 cells lack catalytic trkB neurotrophin receptors at the mRNA and protein levels, while confirming that they express trkC receptors under the same conditions. Taken together, these findings support a progressive sequence of neural precursor differentiation and a spectrum of competence by precursors to respond to instructive microenvironmental signals. (ABSTRACT TRUNCATED)

Limitations with light microscopy in the detection of colorectal cancer cells.

PURPOSE: The failure of light microscopy to predict individual patient survival accurately in pStage I and II colorectal carcinoma can hinder planning postoperative therapy and follow-up. This study was designed and conducted in two parts to assess the influence of relative sensitivity of the light microscope on the pathologist's ability to detect malignant cells in lymph nodes. METHODS: The first part of the study examined the issue of sampling error as a fraction of the number of lymph node sections examined by asking the question, "Does increasing the number of sections (sampling) taken from the block increase tumor cell detection in a lymph node?" Three levels of five sections 4 to 5 microm thick separated by 15 to 20 microm were obtained from each of 494 blocks from 173 cases of pStage I and II colorectal carcinoma. A total of 1,721 lymph nodes were examined. Sections from each level were stained with hematoxylin and eosin and for the expression of cytokeratin. The second part of the study examined the relative sensitivity of the light microscope to detect tumor cells in a lymph node. To simulate lymph nodes, cell blocks were made that contained 10(6) or 10(7) mononuclear cells admixed with increasing numbers of SW480 tumor cells (0, 50, 10(2), 5 x 10(2), 10(3), and 5 x 10(3)). Three pathologists independently examined sections from ten control and ten experimental blocks. RESULTS: Results from the first part of the study demonstrated cytokeratin-positive cells in 278 lymph nodes from 102 of 172 (59 percent) cases. These cells were identified in the first level in 177 (64 percent) as compared with the second or third level or both in 101 (36 percent) of the lymph nodes. Results from the second part of the study demonstrated an overall sensitivity of light microscopic examination of hematoxylin and eosin-stained sections to be approximately 23 percent, representing tumor cells correctly detected in 7 sections of the 30 sections containing tumor cells. The overall specificity was 87 percent or 26 sections correctly classified as lacking tumor cells of a possible 30. Immunohistochemical staining for cytokeratin expression improved sensitivity of the light microscope to detect tumor cells to 18 of 30 (60 percent) and the specificity to 30 of 30 (100 percent). CONCLUSION: This study demonstrates several sources of variability that can induce errors in pathologic staging. These include 1) inadequate section, i.e., sampling, of lymph nodes, 2) use of only hematoxylin and eosin-stained sections, 3) samples with tumor cells below the level of detection sensitivity of the light microscope, and 4) observer variability.

Staging of colorectal cancer: biology vs. morphology.

PURPOSE: An accurate determination of the extent or staging of a disease is critical, because it provides the basis for making therapeutic decisions. Staging is a collaborative effort by the surgeon and the pathologist. Radioimmunoguided surgery has been evaluated for its ability to help surgeons determine the extent of disease during surgery, when management decisions have the most impact on patient care. This study was done to compare radioimmunoguided surgery "biostaging" with traditional pathologic staging (TNM) as predictors of survival in patients undergoing curative resections for colorectal cancer. METHODS: Ninety-seven patients with colorectal cancer were prospectively enrolled in radioimmunoguided surgery protocols. Evaluation of follow-up survival data was performed. All patients underwent exploratory laparotomy and radioimmunoguided surgery with resection of their primary colorectal tumor. Survival data were analyzed with the Kaplan-Meier method with log-rank comparisons. RESULTS: Of 97 patients enrolled in the study, 59 were evaluable and completely resectable by radioimmunoguided surgery. Mean follow-up was 62 months, with a range of 34 to 89 months. By traditional staging 13 patients were pStage I, 18 patients were pStage II, and 28 patients were pStage III. By radioimmunoguided surgery biostaging, 24 patients were radioimmunoguided surgery-negative whereas 35 patients were radioimmunoguided surgery-positive. Survival rates by pathologic stage approached a significant difference, but did not, as of the conclusion of the study period, reach it (P = 0.12). Survival rates based on radioimmunoguided surgery status demonstrated a highly significant difference (P = 0.0002). CONCLUSIONS: Radioimmunoguided surgery biostaging provides new information intraoperatively on cancer staging that has not been available before. This may lead to new strategies for therapy that can be individualized and optimized for each patient with cancer.

First results for resetting the antitumor immune response by immune corrective surgery in colon cancer.

BACKGROUND: A critical step for cancer recurrence is the failure of the cellular immune response. It is suspected that chronic humoral immune responses against some tumor-associated antigens (TAA) can contribute to that failure. METHODS: In this study, we tested the ability of an immune corrective surgical procedure to prevent recurrences of colon cancer in stages I, II, and III. Radiolabeled anti-TAG antibodies injected intravenously become concentrated on TAG-72 immune complexes presented by follicular dendritic cells, which are responsible for the persistent humoral response against TAG-72 TAA. Using a hand-held gamma probe, we can intraoperatively detect and remove lymph nodes involved in TAG-72 presentation. By removing these lymph nodes, together with the tumor tissue, presentation and source of TAG-72 are drastically reduced. RESULTS: The impact of this TAA suppression on the tumor recurrence process is analyzed in a sample of 24 patients. The immune corrective surgical procedure did not increase morbidity. Five years after surgery the following were disease free: 5 of 5 stage I, 6 of 6 stage II, and 10 of 13 stage III. The global survival of this group was 87.5%. Compared with the standard surgical treatment of colon cancer (58% survival for the same stages), this surgical immune corrective procedure introduces a statistically significant improvement of 29% (P <0.001). CONCLUSIONS: The surgical removal of lymph nodes involved in the persistent humoral immune response against TAA has an important beneficial impact on colon cancer treatment.

[Lymphadenectomy in colorectal carcinoma]. / Lymphadenektomie beim colorectalen Carcinom.

Recurrence of colorectal carcinomas occurs in about 50% of the cases with localized neoplasia. It is understood that the tumor recurrence is due to residual micrometastases not found during surgery or extraregional (peripheral blood or bone marrow). We developed a procedure to detect non-visible, abdominal metastases using a radiolabeled anti-tumor cell antibody injected before the operation (radioimmunoguided surgery RIGS). However, even with the best technique, it is not possible to remove all micrometastasis if a hematogenic dissemination happens. Based on the knowledge of disturbing humoral immune reaction is mounted against shed tumor associated antigens (TAA), we developed a new method to reduce and correct the B cell response and B cell recruitment due to chronic TAA immun complex presentation on follicular dendritic cells (immune corrective surgery, ICS). This method is based on a selective lymphadenectomy. The target lymph nodes were those loaded with TAA-immune complex. The detection method used was the injection of radiolabeled antibody able to recognize the immune complex. From 20 patients (stage I, II and III) treated with ICS, 17 survived more than 5 years 'showing a statistically significant increase of survival compared to patients treated with standard procedures. In conclusion, these data show that surgery of colorectal cancer should be selectively extended to specific anatomical regions in order to remove hidden micrometastases, and more importantly, correct postoperative immune processes that could suppress the T cell response against residual tumor cells.

Intra-abdominal patterns of disease dissemination in colorectal cancer identified using radioimmunoguided surgery.

PURPOSE: Patterns of metastatic spread are difficult to determine with routine postoperative follow-up. This study was undertaken to evaluate two selected populations of colorectal cancer patients injected and screened with anti-tumor antibody. METHODS: Eighty-six evaluable patients with colorectal cancer underwent exploratory laparotomy with both traditional surgical exploration and radioimmunoguided surgery (RIGS) following injection of 125I-labeled CC49 monoclonal antibody. RIGS-positive tissue detectable with a handheld gamma-detecting probe was defined as tissue involved with the disease process. Comparisons were made between extent of disease using traditional exploration and extent using RIGS. RESULTS: In 41 patients with primary disease, traditional exploration detected 45 sites of disease (1.1 sites/patient) compared with 153 RIGS-positive sites (3.7 sites/patient). In 45 patients with recurrent disease, traditional exploration found 116 sites (2.6 sites/patient) vs. 184 RIGS-positive sites (4.1 sites/patient). Involvement by selected anatomic sites is shown below [Table: see text]. CONCLUSION: RIGS detected more tissue involved in disease process for all sites in both primary and recurrent disease except liver metastases. Areas with highest proportion of RIGS-positive tissue, the gastrohepatic ligament and celiac nodes, are rarely resected and are not pathologically examined. Positive RIGS localization of tumor antigen in these areas suggests more extensive dissemination of disease process.

Radioimmunoguided surgery for colorectal cancer.

BACKGROUND: Operations for patients with colorectal cancer are based on traditions established by historical experience. Radioimmunoguided surgery (RIGS) provides new information that challenges these traditions. METHODS: Thirty-two patients with primary colorectal cancer underwent RIGS after being injected with anti-TAG-72 murine monoclonal antibody CC49 labeled with iodine-125. Sixteen of the patients had all gross tumor and RIGS-positive tissue removed (RIGS-negative group), and 16 had only traditional extirpation of the tumor because RIGS-positive tissue was too diffuse (RIGS-positive group). RESULTS: In the 16 patients having all RIGS-positive tissue removed, five had traditional regional en bloc resections and 11 had additional extraregional tissues resected. Identification of extraregional disease added two liver resections and 25 lymphadenectomies: 10 of the gastrohepatic ligament, five celia axis, six retroperitoneal, and four iliac. With a median follow-up of 37 months, survival in the RIGS-negative group is 100%. In 14 of 16 patients (87.5%) there is no evidence of disease. In the RIGS-positive group, follow-up shows 14 of 16 patients are dead and two are alive with disease (p < 0.0001). CONCLUSION: These results suggest that RIGS identifies patterns of disease dissemination different from those identified by traditional staging techniques. Removal of additional RIGS-positive tissues in nontraditional areas may improve survival.

Intraoperative detection of occult colon cancer micrometastases using 125 I-radiolabled monoclonal antibody CC49.

BACKGROUND: The detection of locally-disseminated disease is one of the principal goals of oncologic surgery. For this study, a hand-held, gamma-detecting probe was used intraoperatively to assess the extent of colorectal carcinoma in patients previously injected with radiolabeled antibody to the TAG-72 antigen (CC49); this technique is known as Radioimmunoguided Surgery (RIGS) (Neoprobe Corporation, Dublin, OH). RIGS-positive areas (i.e. those with increased signal over background) have previously been shown to contain carcinoma in a high proportion of cases. However, some RIGS-positive areas had no tumor detectable by clinical examination or routine histopathologic analysis. This study was undertaken to determine if the presence of occult metastases might account for this disparity. METHODS: A total of 57 regional lymph nodes (LN), resected from 16 patients with primary (9) or recurrent (7) colorectal carcinoma, were studied. The patients were injected with 125I labeled CC49 murine monoclonal antibody approximately 3 weeks prior to surgery. After routine histologic evaluation, the LN were analyzed for occult metastases; paraffin sections were cut at 5 levels (50 micron apart) and were examined by histology (hematoxylin and eosin stain [H & E]) and by immunohistochemistry (IHC) with a cocktail of monoclonal antibodies to cytokeratins. RESULTS: Fifty-seven LN were included in this study; 17 were H & E-positive (i.e., contained tumor by routine histologic examination [overt tumor]), while 40 LN were H & E-negative (i.e., no evidence of tumor after routine histologic examination). Thirty-nine LN were RIGS-positive, but only 14 of these were H & E-positive. Of the 25 RIGS-positive/H & E-negative LN, 10 (40%) demonstrated the presence of occult metastases after serial section/IHC analysis. Thus, a total of 27 LN contained metastatic carcinoma (17 overt, 10 occult); routine histologic analysis was able to identify tumor in only 17 of these 27 LN (63%), while the probe signaled the presence of tumor in 24 of these LN (89%). None of the RIGS-negative/H & E-negative LN were found to have occult metastases (0/15). Specific immunoreactivity with CC49 antibody was observed in 5 of 15 RIGS-positive/H & E-negative LN in which no tumor could be identified by any method (histopathology or IHC. CC49 immunoreactivity was not observed in 15 RIGS-negative/H & E-negative LN. CONCLUSIONS: The finding of a RIGS-positive LN had a significant association with the presence of tumor cells (P < 0.05). In this study, the RIGS procedure was more sensitive than clinical or histopathologic examination in detecting the regional spread of a tumor. Furthermore, in LN that showed no evidence of tumor by routine histopathologic examination, a positive RIGS reading was significantly associated with the presence of occult LN metastases (P < 0.01). This study is the first to demonstrate the detection of histologically occult tumor by a remote imaging device. RIGS assessment is a highly sensitive method for detecting occult tumor deposits, and may guide therapeutic intervention in patients with colorectal carcinoma.

Peritoneal carcinomatosis and radioimmunoguided surgery.

The Radioimmunoguided Surgery (RIGS) system was developed, in part, to detect occult tumor in patients with recurrent colorectal cancer. Unfortunately, however, patients are sometimes found to have unresectable peritoneal metastasis. For these patients, intraperitoneal hyperthermic perfusion (IPHP) with mitomycin C (MMC) was used as a novel treatment method. Thirty-six intraperitoneal hyperthermic perfusions with MMC were given over the course of several studies. A preliminary study delineated two groups as possible candidates for this treatment: patients with pseudomyxoma peritonei and patients with peritoneal metastasis < 0.5 cm. Intraperitoneal hyperthermic perfusion (IPHP) was conducted for 1 hour after achieving an abdominal temperature of 41 degrees C. A dose of 30 mg MMC in 31 Plasmalyte was injected followed by a second 30 mg dose given at 30 minutes. Plasma pharmacokinetics of IPHP with MMC indicate an advantage in the range of 100-fold enhancement of exposure compared with delivery in plasma. The method was found to be safe when flow was observed and dosage decisions were made during perfusion according to flow. A clinical study group consisting of 15 patients underwent cytoreductive surgery followed by IPHP. The majority of them had either gastrointestinal or urologic anastomoses. There were no complications. In every patient the CEA level decreased after surgery and IPHP, with a median response of 6 months. RIGS technology aided in the selection of IPHP as a treatment choice by demonstrating the presence of an occult tumor burden in those patients whose traditional explorations were deceiving. This chapter includes technical details and suggestions for improving and modifying the use of IPHP.

Intraperitoneal hyperthermic perfusion with mitomycin C for colorectal cancer with peritoneal metastases.

BACKGROUND: Intraperitoneal (i.p.) metastases pose a special problem for surgical treatment because of their multiplicity and microscopic size. This study was designed to examine the feasibility and safety of i.p. hyperthermic perfusion (IPHP) with mitomycin C (MMC) for treating recurrent colorectal cancer. METHODS: Fifteen patients with metastatic colon cancer were treated. All patients underwent cytoreductive procedures leaving only residual i.p. metastases < 1 cm in diameter. All patients had received prior systemic chemotherapy, but their disease had progressed. Intraperitoneal chemotherapy was administered through three large catheters (28 French) using a closed system of two pumps, a heat exchanger, and two filters. After the patient's abdominal temperature reached 41 degrees C, 45-60 mg of MMC was circulated intraperitoneally for 1 h. RESULTS: The majority of patients had various anastomoses: small bowel (n = 11), large bowel (n = 5), and urologic (n = 5). No anastomotic complications occurred in any of the patients. One patient experienced severe systemic MMC toxicity, which caused cytopenia and respiratory depression. In all patients the carcinoembryonic antigen (CEA) level decreased after surgery and IPHP. Median follow-up was 10 months, and recurrence was defined as an elevation in CEA level. Disease recurred in three patients within 5 months, and disease recurred in seven other patients over the next 3 months; one patient remains clinically free of disease after 8 months. CONCLUSION: Our data suggest that IPHP is a safe palliative method of treatment for patients with peritoneal carcinomatosis. The median patient response duration of 6 months may warrant consideration of a repeat IPHP procedure at that time.

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.

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.

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.

The significance of intraoperative periportal lymph node metastasis identification in patients with colorectal carcinoma.

BACKGROUND: Nine patients who underwent Radioimmunoguided Surgery (RIGS) (Neoprobe Corporation, Dublin, OH) procedures for colorectal cancer were found to have disease recurrence in the periportal area. This led to a retrospective study to determine whether periportal lymph node involvement could have been predicted intraoperatively for these patients. METHODS: One hundred twenty-four patients underwent second-look RIGS for recurrent colon and rectal cancer from 1986 to 1992. The monoclonal antibody (MAb) B72.3 was administered as the carrier agent to 87 patients and the CC49 second-generation MAb was administered to 37 patients. Both MAbs were radiolabeled with Iodine-125. RESULTS: Periportal lymph nodes with RIGS-positive tissue were found in 47 (38%) patients, hematoxylin and eosin-positive lymph nodes were found in 13 of 47, and in further immunohistochemical studies performed for 31 of the remaining 34 patients, positive lymph nodes were found in 8, resulting in an incidence of 48% (21/44). A critical review of the nine patients' charts who later presented with a tumor mass in the periportal area demonstrated intraoperative gamma-detecting probe counts in ratios three to five times that of the normal adjacent tissues in the periportal area at the time of first exploration. Probe-directed biopsy was reported to be histologically negative for tumor in these patients, and, thus, the surgeon proceeded assuming the periportal area to be negative. A retrospective study of the periportal lymph nodes of these patients using cytokeratin immunohistochemical analysis identified tumor in five (56%). CONCLUSIONS: These findings suggest that the RIGS system may be a valuable method of intraoperative prediction and detection of periportal lymph node metastasis.

PEG ileus. A preventable complication.

Percutaneous endoscopic gastrostomy (PEG) tube placement is an established procedure in the nutritional management of patients. There are numerous reports in the literature describing the techniques for placing PEG tubes. However, there are few reports that discuss the proper methods for removing these devices and the complications that may result from incorrectly removing a PEG tube. An increasing number of patients with PEG tubes are being cared for by individuals who are not familiar with these devices and their proper method of removal. The use of an incorrect method to remove a PEG tube may result in significant morbidity to the patient. We report a case of bowel obstruction resulting from the incorrect removal of a PEG tube that required laparotomy. To prevent similar complications, PEG tubes should be removed using the appropriate method by individuals familiar with the device.

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.

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.