Minimal deviation melanoma.

Minimal deviation melanomas (MDM) are poorly characterized, uncommon naevomelanocytic tumours that are thought to represent part of the continuum from benign atypical naevi to frank malignant melanomas. Exactly where on that continuum they stand and who is most affected remains controversial. The few studies classifying MDM pointed to a less aggressive nature. Furthermore, it is thought that MDM affects patients in the fourth and fifth decades of life. In a recent review conducted at our institution, medical records of all patients with melanoma diagnosed at a tertiary care university medical center between January 1997 and May 2000 were reviewed to identify those with MDM. Those with MDM were examined to determine subtype, age and sex distributions, and location of tumour and findings were compared to those in the published literature. Unlike previous studies, the mean age of patients with MDM was 27 years with 20/31 being under 30 years old. Our results support prior findings that MDM is less aggressive than typical malignant melanomas in that only 1/5 undergoing lymphatic mapping had a positive node. Despite its description more than 30 years ago, MDM remains a poorly understood pathologic entity. Further study in such techniques as sentinel lymph node mapping and determination of angiogenesis factors is warranted to give insight as to what features predict an aggressive nature and to identify prognostic factors.

Evaluation and treatment of the patient with early melanoma.

In summary, prospective studies within the last 10 years have made a significant impact on our understanding of the natural history of early melanoma. Surgeons can now excise the melanoma with narrower and more selective margins that preserve function and cosmetic appearance. Early melanomas are now, and will continue to be the most common presentation of this cutaneous malignancy. This reflects an enhanced awareness of the public and the medical community about the value of increased detection, and serious attempts at protection from intense ultra-violet light exposure. Current research is now focusing on the inherited forms of melanoma, the effects of ultra-violet light on melanocytes and the immune cells of the skin, and the molecular measurement of the abnormal cytogenetics seen in malignant melanocytes. These studies will allow physicians to detect a melanoma at an earlier and earlier time point in its natural history, and perhaps prevent or reverse the formation of melanoma early in life.

Characteristics of cancer cells in gastrointestinal lavage specimens.

Cancer cells from the effluent stools resulting from oral gastrointestinal lavage were analyzed. Cellular preparation were done by cytocentrifugation. The method produced cellular preparations that contained from none to 205 cells per slide; the average number was 28. Single cells predominated over groups. The average number of single cells was 13, while three groups were identified on the average slide. The cells were small and averaged 13 microns in diameter and 149 microns 2 in area. The nuclei averaged 8 microns in diameter and 61 microns 2 in area. The nuclear chromatin pattern varied from dense to clumped to vesicular, with the clumped pattern predominating. The technique is simple and easily adaptable and holds promise as a screening technique for gastrointestinal cancer.

Surgical treatment of enteric 'bud' fistulas in contaminated wounds. A riskless extraperitoneal method using split-thickness skin grafts.

We describe methods and results of a local extraperitoneal method of repairing enterocutaneous "bud" fistulas in abdominal-wall defects. The method is performed with local anesthesia and involves an extraperitoneal closure with skin-graft coverage. Of the nine fistulas so treated, five healed. No patient's postoperative course was set back by the repairs that failed since the method precludes intraperitoneal entrance. Two of three high-output fistulas were successfully repaired with the extraperitoneal method, reversing an otherwise stormy clinical course. We conclude that for epithelialized enterocutaneous fistulas, little is lost if our method of repair fails and much is gained if it is successful in these critically ill patients.

Effects of pharmacologic agents on human keloids implanted in athymic mice. A pilot study.

The treatment of keloids remains difficult. In experimental studies, lathyrogenic agents and colchicine have been shown to be effective in keloid prevention. Recently, a study was published of a new animal model utilizing human keloids implanted in athymic mice. We used the same model to compare the effects of penicillamine, acetylcysteine, colchicine, and triamcinolone acetonide. Unexpectedly, all keloids implanted showed a growth peak at 4 weeks and then regression in size. Histologic sections of the implanted keloids revealed peripheral vascularity, collagen bundles similar to the parent keloids, and no evidence of implant rejection. After 8 weeks, the mice treated with the lathyrogenic agents exhibited a higher rate of regression when compared with the control mice. While triamcinolone acetonide may have prevented keloid implant growth, drug toxic reaction may have been a factor.

Increased cisplatin tissue levels with prolonged arterial infusion in the rat.

Prolonged arterial infusions of cisplatin (DDP) have been effective in the treatment of regionally confined malignancies. It is unclear whether the route or schedule of DDP administration was responsible for the observed therapeutic benefit. To resolve this issue, tumor and normal tissue platinum (Pt) levels were determined in rats bearing hind-limb rat mammary tumors after intravenous (IV) and intra-arterial (IA) DDP infusions of constant dose and varying lengths. Infusions of DDP at 6 mg/kg were conducted IA over 30 minutes, and 3, 6, 24, and 48 hours and IV over 30 minutes and 48 hours. After infusion, Pt concentrations in solubilized tissue homogenates were measured by flameless atomic absorption spectroscopy. Maximum tumor Pt levels were seen after 48-hour IA infusion (29.3 micrograms Pt/mg tissue). IA infusions of 24 hours or less resulted in significantly lower Pt levels. Maximum tumor Pt concentration after IV administration was only 0.98 micrograms/mg tissue (48-hour infusion). Muscle Pt levels adjacent to the tumor were highest in the IA infused extremities, but at the 48-hour interval, were 53-fold less than tumor levels. Tumor and adjacent muscle Pt levels were not significantly different from each other after IV administration. This study provides pharmacologic evidence that lengthening the duration of IA DDP infusion increases tumor levels of Pt over that of IV or rapid IA administrations. The benefit of prolonged IA DDP infusions is dependent upon both route and schedule of drug administration.

Effects of intracarotid and intravenous infusion of human TNF and LT on established intracerebral rat gliomas.

The effects of recombinant human tumor necrosis factor (TNF) and lymphotoxin (LT) were investigated against two different established rat gliomas. Single preestablished intracarotid (ic) or intravenous (iv) doses (1.5-2.0 x 10(6) units) were administered to Wistar rats with intracerebral C6 gliomas and Fischer 344 rats with intracerebral T9 gliomas. Five days after cytokine treatment, animals were sacrificed and tumor size determined by histopathologic techniques. In Wister rats, ic TNF produced a greater reduction in size of C6 tumors than iv TNF. Experiments with Fischer rats showed that both TNF and LT were more effective when administered ic compared to iv. Furthermore, LT induced a greater reduction in tumor size than TNF. Additional studies on the age-related susceptibility of these gliomas revealed early, 8-day tumors were more sensitive to ic LT than advanced, 14-day tumors. No direct toxicity of these cytokines against the tumor cells was detected in vitro indicating their autitumor effect was mediated by alternate mechanisms in vivo. Thus for regionally confined gliomas ic therapy was superior to iv therapy and LT was more effective than TNF. Cytokine treatment was most effective on earlier tumors and there appeared to be differences in efficacy related to the tumor-host combination.

Rat mitogen-stimulated lymphokine-activated T killer cells: production and effects on C6 glioma cells in vitro and in vivo in the brain of Wistar rats.

An in vitro technique was developed to generate activated rat T cells, with antitumor activity. Splenic mononuclear cells (SMC) from outbred Wistar and inbred Wistar-Munich rats were stimulated with Concanavalin A and recombinant human interleukin-2 (rIL-2) in vitro for 48 h. After 2 days, the nonadherent cells began proliferating and were maintained in rIL-2 for up to 18 days in vitro. FACScan analysis revealed that SMC was a mixture of cell types; however, CD5+ T cells rapidly increased and became the predominant cell type after 5 days in culture. SMC induced cytolysis of YAC-1, but not C6 glioma cells in 4 h 51Cr release assays. In contrast, 5- and 9-day T cells lysed C6 glioma and YAC-1 cells. The C6 cells were admixed with cultured effector cells at various effector-to-target (E:T) ratios and were injected into the right cerebral hemisphere of Wistar and Wistar-Munich rats for a Winn assay. Histopathologic evaluations revealed that a) SMC had no effect; b) 2- and 5-day T cells, injected at E:T ratios greater than 5:1, caused significant reduction in tumor size; and c) 2- or 5-day T cells, at a 40:1 E:T ratio, resulted in little or no histologic evidence of tumor. Eighty-three percent of animals receiving C6 and 5-day mitogen-stimulated lymphokine activated killer cells at an E:T ratio of 40:1 were alive 120 days postinjection (p less than 0.05).

Murine monoclonal antibodies to human pancreatic cancer: specificity and sensitivity.

Pancreatic carcinoma (n = 7), pancreatitis tissue (n = 4), normal pancreas tissue (n = 5), colonic adenocarcinoma (n = 4) and in vitro human pancreatic cancer cell lines (n = 6) were studied with the murine monoclonal antibodies (MAbs) 3DS2A, AR1-28, AR2-20, Ca19-9 and CA17-1A to determine their immunohistologic specificity and sensitivity for use as radiolabeled diagnostic imaging agents. Using the avidinbiotin-immunoperoxidase staining technique, MAbs 3DS2A and AR1-28 stained 86 and 100% of pancreatic cancer specimens, respectively. MAbs 3DS2A and AR1-28 are suitable agents for use as radiolabeled diagnostic imaging agents in patients with pancreatic cancer.

A prospective, randomized clinical investigation of cholecystoenterostomy and choledochoenterostomy.

A prospective, randomized clinical trial was conducted to assess the efficacy of bilioenteric bypass in noncalculous distal biliary obstruction. Thirty-one patients required bypass for either malignant obstruction or chronic pancreatitis and were randomized into two groups: cholecystoenterostomy or choledochoenterostomy with cholecystectomy. Nine bypasses failed after cholecystoenterostomy and two after choledochoenterostomy (p less than 0.04). Eight of the 9 failures occurred in the subgroup of 22 patients with malignant biliary obstruction. In this subgroup, five bypasses failed within 90 days of operation, all after cholecystoenterostomy (p = 0.03 compared with choledochoenterostomy). The results indicate that choledochoenterostomy is the superior operation for malignant distal biliary obstruction. Additional studies will be necessary to identify the procedure of choice for benign noncalculous obstructions.

Malignant cystosarcoma phyllodes metastatic to the maxilla.

A case of malignant cystosarcoma phyllodes metastatic to the maxilla is reported, representing the only known case with a maxillary metastasis.

The pharmacokinetics of cisplatin in experimental regional chemotherapy.

Cisplatin (DDP) is attractive for use in regional chemotherapy because of its tendency for protein binding. A study of regional chemotherapy was conducted in rabbits bearing the VX-2 carcinoma. Modes of therapy examined were intravenous (IV), intra-arterial (IA), IA with stopflow, IA with outflow occlusion, and isolation-perfusion (I-P). Each mode was evaluated by examining the pharmacokinetics of DDP in systemic and regional administration and measuring tissue concentrations of DDP. It was observed that the systemic exposure to DDP was significantly less for IA with outflow occlusion and I-P when compared to IV, IA, or IA with stopflow occlusion (P = 0.003). Tumor concentrations were highest with IA infusion with outflow occlusion (P = 0.002) and IA stopflow occlusion (P = 0.03). Tumor tissue concentrations were always higher than adjacent muscle DDP concentrations. The authors conclude that significant pharmacologic advantage can be demonstrated for certain modes of DDP administration in this rabbit model, and that these promising results should be followed by clinical trials.

The effect of tumor CEA content and tumor size on tissue uptake of indium 111-labeled anti-CEA monoclonal antibody.

This study was undertaken to determine the effect of tumor size and tumor carcinoembryonic antigen (CEA) content on the uptake of indium 111 (111In)-labeled anti-CEA monoclonal antibody in nude mice bearing xenografts. The tumor cell lines were WiDr, SW403, and LS174T, human colon cancer derivatives. The murine breast carcinoma cell line EMT-6 was used as a control. Tumor CEA levels (ng/g of tumor +/- standard error of the mean [SEM], measured by enzyme immunoassay (EIA) were: EMT-6, 0; WiDr, 105 +/- 5.7; LS174T, 2052 +/- 198; SW403, 17,575 +/- 1,785. The 111In-labeled monoclonal antibody was injected intravenously into mice bearing a single tumor. At 48 hours postinjection, scintiscan was performed, and the mice were killed so that biodistribution studies could be performed. The uptake of the monoclonal antibody was expressed as percent injected counts per minute per gram of tissue +/- SEM. The non-CEA-producing tumor, EMT-6, showed the lowest tumor uptake (1.4 +/- 0.3). WiDr, an intermediate CEA-producing tumor, showed some tumor uptake (16.4 +/- 1.5). The high CEA-producing tumors, SW403 and LS174T, had high tumor uptake (29.5 +/- 5.0 and 51.1 +/- 6.1, respectively). Biodistribution and scintiscan quality were closely related. Although LS174T had the best tumor uptake, SW403 had the highest CEA tumor content, indicating tumor CEA content cannot entirely predict scintiscan and biodistribution results. Tumor-to-blood (T/B), tumor-to-liver (T/L), and liver-to-blood (L/B) ratios were calculated for each animal and compared with tumor size. It was found that T/L had a negative correlation with tumor size (r = -0.72) and L/B had a positive correlation with tumor size (r = 0.94). These ratios may be useful clinically to follow response to therapy.

Complications of pelvic exenteration.

This report is based on a retrospective review of 104 patients who had undergone pelvic exenteration for advanced malignancy over a 29-year period (1956 to 1984, inclusive). Fifty-one patients (49%) developed major complications of the operative field involving the gastrointestinal tract (fistula or obstruction), the urinary tract (fistula, infection, or obstruction), or the wound (abscess, dehiscence/necrosis, or hemorrhage). No association was identified between the complication rate and organ of primary disease, extent of disease, tumor histology, or extent of resection. Patients receiving pelvic radiotherapy prior to exenteration had a much higher complication rate (39/58, 67%) than patients having had no radiotherapy (12/46, 26%). Reconstruction of the irradiated pelvis after exenteration by omental flap, colonic advancement, and/or myocutaneous flaps decreased the complication rate from 82% (27/33) to 48% (12/25). The operative mortality of pelvic exenteration was 2.9% and the actuarial five-year survival rate was 27%.

High-specific-activity 111In-labeled anticarcinoembryonic antigen monoclonal antibody: improved method for the synthesis of diethylenetriaminepentaacetic acid conjugates.

A new method has been developed for conjugating diethylenetriaminepentaacetic acid (DTPA) to proteins using the N-hydroxysuccinimide active ester of DTPA. The DTPA-active ester was prepared using diisopropylcarbodiimide in a simple single step synthesis. DTPA-conjugated proteins were prepared by adding the DTPA-active ester reaction mixture to protein solutions (5 mg/ml) buffered at pH 7.0 and purified by Sephadex G-50 chromatography. A monoclonal antibody directed against carcinoembryonic antigen was reacted with four different amounts of the DTPA-active ester. Solid-phase enzyme immunoassay showed that the immunological activity of the antibody conjugate was not altered when the active ester: antibody molar ratio was 36:1 or 72:1; however, it decreased when the ratio was 180:1 or 360:1. The antibody heavy and light chains had slightly decreased electrophoretic mobilities when analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, a result consistent with the covalent attachment of DTPA to the protein. Sephadex G-200 chromatography showed that the native and conjugated antibodies were the same size. When the DTPA-conjugated antibody was incubated with 10, 50, and 100 microCi of 111In/micrograms of protein, specific activities of 9.8, 43.1, and 56.3 microCi/micrograms were obtained. Enzyme immunoassay and radioimmunoassay of the 111In-labeled antibody showed that it retained its full immunological activity. The high specific activity of the 111In-labeled antibody makes it suitable for imaging carcinoembryonic antigen-bearing tumors using low doses of antibody.

High-specific-activity 111In-labeled anticarcinoembryonic antigen monoclonal antibody: biodistribution and imaging in nude mice bearing human colon cancer xenografts.

Tumor imaging and biodistribution of an indium-labeled monoclonal antibody (MAB) to carcinoembryonic antigen (CEA) [anti-CEA MAB-diethylenetriaminepentaacetic acid (DTPA)-111In] have been investigated using LS174T human colon cancer xenografts in nude mice. Antibody specificity, dose, and specific activity were examined with respect to tumor uptake and quality of scintiscans at different times following injection. The CEA-bearing LS174T tumors were imaged specifically with anti-CEA MAB-DTPA-111In. Using 62.5 ng of indium-labeled MAB (50 microCi/micrograms) the ratio of activity in tissue expressed as a percentage of the total radioactive dose injected into the animal per gram tissue for tumor:blood increased from 0.66 +/- 0.02 (SE) at 1 h to 14.8 +/- 1.1 at 72 h. Scintiscan quality improved with the rise in tumor:blood ratio until 48 h. At longer intervals insufficient counts remained for imaging. The tumor:blood ratio and the scintiscan quality were not improved by increasing the MAB dose to 625 or 6250 ng but good images were obtained at longer times postinjection. By decreasing the 111In from 50 to 10 microCi/micrograms of MAB, the unbound 111In was decreased from 7 microCi/micrograms (14%) to 0.2 microCi/micrograms (2%). Even with the lower specific activity (9.8 microCi/micrograms) of the 10-microCi/micrograms preparation, scintiscan quality at the 62.5-ng dose was maintained. This anti-CEA MAB-DTPA-111In preparation was stable, retained immunological activity, did not require column chromatography to remove unbound 111In, was specific for a CEA-bearing tumor, and was effective for tumor imaging over a wide range of antibody doses (3 to 300 micrograms MAB/kg body weight). This anti-CEA MAB-DTPA-111In preparation is feasible and practical for imaging CEA-bearing tumors in humans.