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An assay which uses two differentially labeled cell populations was used to characterize the preferential localization of passively transferred syngeneic cells immunized to specific alloantigens. Splenocytes cytotoxic to B10.D2 and B10.BR alloantigens were harvested from (C57BL/6 X A/J)F1 (B6AF1) donors bearing acutely rejected skin allografts. One population was labeled in vitro with 3H-thymidine and the other with 14C-thymidine. The labeled cells were pooled and then transferred i.v. into B6AF1 hosts bearing 5-day-old skin grafts from B10.D2 and B10.BR donors. After 48 hr the mice were killed, and the relative amount of cells present in the skin grafts and draining axillary lymph nodes was derived by comparing the 3H:14C ratios of the harvested tissues. The results of these studies indicated that cytotoxic splenocytes harvested from donors bearing acutely rejected skin allografts preferentially localize to the relevant skin allograft after passive systemic transfer. The homing behavior of these splenocytes was augmented by T cell enrichment and significantly diminished by pretreatment with anti-Thy-1.2 serum plus rabbit complement. There was no evidence of preferential homing within the draining axillary lymph nodes. It can be concluded that a T cell population derived from in vivo sensitized splenocytes exhibits preferential homing to relevant skin allografts upon passive transfer.

We have previously shown that the in vivo administration of ABPP, an interferon inducing pyrimidinone, generates activated killer cells that can lyse fresh tumor cells in vitro in 4-h 51chromium release assays. The administration of this agent however has no effect on established tumor. In this communication we show that ABPP, when used in combination with low or moderate doses of cyclophosphamide, can be quite effective against early established (day 3) tumor as well as against advanced, grossly visible (day 8-10) tumor in both the i.p. and pulmonary metastasis model. The synergistic antitumor activity of this chemoimmunotherapeutic regimen was very strong against immunogenic tumors but rather weak against nonimmunogenic tumors. Two treatment cycles were significantly more effective than one and multiple cycles even cured the majority of mice with established i.p. tumor. These experiments demonstrate the potential of chemoimmunotherapeutic regimens and highlight the efficacy of multiple treatment cycles.

The use of total parenteral nutrition (TPN) in patients with advanced, untreatable cancer is controversial. Occasionally, however, damage to bowel by tumor, radiation, or surgery renders these patients unable to eat and TPN may be indicated to prevent premature death from starvation. We have used Home Parenteral Nutrition (HPN) to support three patients with advanced, untreatable abdominal cancer and inability to eat. Morbidity was minimal and survival times were 24, 6 and 1.5 months. Payment was covered by third party agencies. All patients and their families were gratified by the ability to return home with nutritional support. HPN can be used to support terminal cancer patients with bowel obstruction and may afford them longer survival. Ideally, patients considered for this should be well motivated, with good support systems, and with survival estimated to be at least months.

In 60 computed tomographic examinations of the liver and spleen in 55 patients, a new intravenous lipoid contrast material, Ethiodized Oil Emulsion 13, was used. This organ-specific contrast material, retained by the reticuloendothelial cells of the liver and spleen, caused marked increase in the attenuation of the liver and spleen, but did not appreciably change the attenuation of the tumor involving these organs, thereby significantly increasing the density differential between normal and abnormal tissue. Toxicity was considered to be well within tolerable limits with the most frequently noted untoward side effects of chills, fever, headaches, and foul metallic taste. Ethiodized Oil Emulsion 13 holds the promise to become a valuable clinical tool by which hepatic and splenic imaging may be significantly improved and lesions less than 1 cm in diameter demonstrated in the liver and spleen.

We have previously reported the results of a randomized trial that demonstrated the survival benefit of adjuvant chemotherapy in the treatment of patients with high-grade extremity sarcomas compared with no chemotherapy. This regimen included doxorubicin, cyclophosphamide, and methotrexate. This report updates and extends our experience. The median follow-up of this trial is now 7.1 years and reveals a 5-year disease-free survival of 75% and 54% for chemotherapy and no chemotherapy groups, respectively (two-sided P [P2] = .037). The 5-year overall survival for patients in this trial was 83% and 60% for the chemotherapy and no chemotherapy groups, respectively, with a trend towards improved survival in the chemotherapy arm (P2 = .124). Because of doxorubicin-induced cardiomyopathy we performed a subsequent randomized trial comparing this high-dose regimen to reduced cumulative doses of doxorubicin and cyclophosphamide without methotrexate. Eighty-eight patients were entered into this trial which has a median follow-up of 4.4 years. The 5-year disease-free and overall survival for patients treated with the reduced doses of chemotherapy was 72% and 75%, respectively, and was not significantly different from the high-dose regimen. No patients developed congestive heart failure on this study. We conclude that adjuvant chemotherapy improves disease-free survival in patients with extremity soft-tissue sarcomas. The overall survival advantage in patients receiving adjuvant chemotherapy in our initial randomized high-dose chemotherapy trial has diminished though it continues to favor the chemotherapy group. A reduced-dose chemotherapy regimen was found to be comparable to the high-dose regimen.

Adoptive immunotherapy with lymphokine activated killer (LAK) cells and recombinant interleukin-2 (IL-2) is successful in a variety of tumour models in both the normal and the immunocompromised mouse. We investigated the effects of an immune response to an allogeneic challenge on the metabolism of IL-2. Serum IL-2 levels at different time points after the administration of 20,000 units of IL-2 intraperitoneally were 2-4 fold higher in normal mice than in recently alloimmunized mice. In an intraperitoneal tumour model the alloimmunization of mice with allogeneic P815 tumour cells or splenocytes IP prior to the intraperitoneal inoculation of syngeneic tumour significantly diminished the anti-tumour effects of IL-2 and LAK cell immunotherapy in 7 consecutive experiments. High doses of IL-2 or pretreatment with cyclophosphamide restored the efficacy of IL-2 and LAK cell immunotherapy. From these results we hypothesize that T cells, activated by the allogeneic challenge, consume IL-2 and thus inhibit the effects of IL-2 and LAK cell treatment by competitive inhibition. LAK cell activity with reduced levels of IL-2 cannot be maintained and anti-tumour effects are lost. High doses of IL-2 were shown to overcome the competition for IL-2. Alternatively activated T-cells could be eliminated by pretreatment with cyclophosphamide and anti-tumour effects restored. These results are important in that they provide an alternative explanation as to the mechanism of non-specific cell mediated suppression and may in part explain the failure of some cancer patients to respond to treatment with IL-2 plus LAK immunotherapy.

In the past, most work in tumor immunology involved attempts to demonstrate tumor-specific transplantation antigens; however, recent in vitro work has shown that it is not necessary to sensitize to a specific tumor antigen to achieve lysis of syngenic tumor cells. Responder spleen cells from B6AF1 mice (H-2a,b) were sensitized in mixed lymphocyte cultures (MLC) to alloantigens on spleen cells from B10.D2 (H-2d) mice. In cell-mediated lympholysis (CML) assays the relevant allogenic P815 (H-2d) tumor targets and B10.D2 lymphoblast targets were lysed. In addition, the semisyngenic tumor target EL-4 (H-2b) was lysed but RDM-4 (H-2k) was not. B10.BR (H-2k), C57BL/6 (H-2b) and B6AF1 lymphoblasts were not lysed. If lymphocytes were added as cold targets to the CML assay, B10.D2 lymphocytes completely absorbed lytic activity when B10.D2 lymphoblasts were the target. If B10.D2 lymphocytes were added when P815 was the target, lysis was reduced but could not be abolished. When B10.D2 lymphocytes were added with EL-4 as a target, lysis doubled. These experiments show that the neoplastic determinant on tumor cells recognized by alloantigen-activated lymphocytes does not cross-react with stimulator cell alloantigen and is not an alien histocompatibility antigen. These observations should be considered when in vivo attempts are made to control tumor with in vitro activated lymphocytes; transfer of not only in vitro activated cells but also allogenic stimulator cells to the tumor site may be necessary for maximal tumor destruction.

Twenty patients with known liver metastases were evaluated by unenhanced computed tomography (CT), scans enhanced with ethiodized oil emulsion-13 (EOE-13), and magnetic resonance (MR) imaging with three pulse sequences. Spin-echo (SE) 300/26 (repetition time/echo time, in msec) images prospectively demonstrated 95.4% of the detectable liver metastases; inversion recovery (IR) 1,500/100 (repetition time/inversion time, in msec) images revealed 90.8%; and EOE-13-enhanced CT scans showed 87.1%. SE 2,000/80 images showed 51.4%, and unenhanced CT scans 49.6%, of the metastases. The relationship of vascular anatomy to metastatic foci was best seen on SE 300/26 images and EOE-CT scans. SE 300/26, IR 1,500/100, and EOE-CT studies particularly improved detection of lesions in the 1-2-cm range compared with SE 2,000/80 imaging or unenhanced CT scanning. SE 300/26 and IR 1,500/100 sequences appear comparable to EOE-CT scans in demonstrating liver metastases and significantly superior to conventional CT scans. Because EOE-13 is generally not available, these MR sequences should be the procedure of choice for the diagnosis of liver metastases.

Reports of prolonged survival in patients with recurrent colon or rectal cancer following a reoperative surgery suggest that early diagnosis of locally persistent or limited metastatic disease may save some patients. To determine which laboratory and radiologic tests were useful, a prospective comparison of all currently available modalities was begun in 1978. Sixty-six patients at high risk for recurrent large-bowel cancer were studied. At present, mean follow-up is at 4 1/2 years. Protocol studies included monthly carcinoembryonic antigen (CEA) assays for 3 years and then at 3-month intervals for 2 more years. A review of symptoms and a physical examination were performed every 4 months for 3 years and then every 6 months for 2 more years. Computerized tomograms of the abdomen, full lung tomograms, and liver/spleen scintigrams were obtained every 4 months for 3 years and then annually for 2 more years. Intravenous pyelography, barium enema, and bone scintigraphy were performed yearly for 5 years. Thirty-three recurrences were observed in 31 patients. A progressive rise in serial CEA values was the first indication of recurrence in 22 of 33 patients (67%), review of symptoms and physical examination in seven of 33 (21%), CT scan in two of 33, and bone scintigraphy and full lung tomography each in one of 33 patients. Serial CEA assays and routine visits to a physician's office were the most useful tests in this study population. Use of a simplified follow-up plan will result in the earliest detection of recurrent colon cancer.

Sixty-four patients were entered into a randomized trial that evaluated intra-arterial (I.A.) versus intravenous (I.V.) 5-fluorodeoxyuridine (FUDR) for colorectal liver metastases. There was a significant improved response rate for I.A. (62%) compared with I.V. (17%) treatment (p less than 0.003). However, the improved response rate for patients in whom I.A. therapy was used did not translate to a significantly improved survival rate. The 2-year actuarial survival rates for the groups for which I.A. and I.V. therapy was used were 22% and 15% respectively, with the survival curves not differing significantly (p = 0.27). These results may have been due to the inclusion of patients with tumor in draining hepatic lymph nodes. The presence of tumor in hepatic lymph nodes was associated with a poorer prognosis. Analysis of a subgroup of patients with negative hepatic lymph nodes suggested an improved actuarial survival rate in patients for whom I.A. versus I.V. therapy was used (p less than 0.03). The toxicity of I.A. FUDR was considerable, and side effects included chemical hepatitis (79%), biliary sclerosis (21%), peptic ulcers (17%), and gastritis/duodenitis (21%). The only major effect of toxicity of I.V. FUDR was severe diarrhea (59%). Regional I.A. FUDR allowed more drug delivery to liver tumors, which resulted in increased tumor responses when compared with use of systemic therapy. However, the small gain in survival seen in a select subgroup of patients with negative hepatic nodes appeared to be offset by the toxicity of I.A. FUDR.

No new chemotherapy agents have been developed in the recent past that present hope for improving survival in patients with colon or rectal cancer. This study was undertaken to investigate a new route of administering an old drug, 5-fluorouracil (5-FU). When 5-FU is delivered by the intraperitoneal (IP) route the tolerable dose of drug was markedly increased without an increase in adverse side effects. The natural history of surgically treated disease was changed by reducing the incidence of peritoneal carcinomatosis, but time to relapse and survival was not improved. Intraperitoneal 5-FU may be recommended for investigation in patients with perforated colon cancer, peritoneal implants, or as one part of a multimodality treatment protocol for colorectal cancer. If 5-FU is given to patients with gastrointestinal malignancy, the IP route should be strongly considered.

Serial CEA radioimmunoassays were performed on 16 patients receiving preoperative radiation therapy of rectal cancer or irradiation of recurrent or metastatic colorectal cancer. Radiation therapy of localized colorectal cancer reliably reduced previously elevated circulating CEA titers. Significant decrease of elevated CEA titers with accumulating doses of irradiation may indicate that the bulk of CEA-producing tumor is within the radiation treatment portal and assist in patient management decisions. The decrease of circulating CEA with preoperative radiation therapy was of short duration and may indicate that surgical resection should not be delayed more than 6-8 weeks after irradiation. Because of the high frequency of false positive and false negative results, CEA must be used only in conjunction with other clinical and laboratory parameters.

Death from colorectal cancer frequently results from manifestations of recurrent local or metastatic disease following initial 'curative' therapy. Presently, the attempted curative treatment of recurrent colorectal cancer lays in the hands of the surgeon. This paper reviews the natural history of surgically treated large bowel cancer and summarizes published and National Cancer Institute experience with the surgical therapy of recurrent disease. A schema with rationale is offered for follow-up of the patient following 'curative' bowel resection. The treatment of recurrent disease incorporating the use of CEA initiated second-look laparotomy is advocated. Hepatic and pulmonary resections for metastatic disease are accepted as important therapeutic endeavours, and are discussed in some detail. It is concluded that of all patients diagnosed as having large bowel cancer, roughly 70% are resectable for cure at time of presentation, and 45% will indeed be cured by primary resection. Of the 25% who fail primary therapy, approximately 20% (5% of all colorectal cancer patients) can be cured by local re-resection or hepatic or pulmonary resection.

Anatomic localization of the tip of a colonoscope without the aid of fluoroscopy is adequate in a majority of patients. External check points of transilluminated light within the colon on the abdominal wall, characteristic internal appearance of the colon and gross anatomic landmarks have been used. An improved technique for advancement results if a routine sequence of maneuvers is used in a similar manner in all patients.

The optimal method of transecting liver parenchyma has not been established and presently a variety of methods are in use. In a controlled study in pigs standard resections were performed with four different transection techniques: ultrasonic dissection, suction dissection, electrocautery, and sharp dissection. The blood loss, number of vessels identified before their division, need for additional hemostatic measures, and time for each procedure were evaluated. Also, the histologic appearance of the fresh and the healing cut surface of the liver was studied. The blood loss was the lowest when ultrasonic dissection was used (median blood loss of 58 ml per resection). The comparisons with suction dissection (median blood loss of 87 ml) and cautery (median blood loss of 79 ml) were not significant. The ultrasonic and suction dissection techniques were both effective in isolating vessels, but the ultrasonic dissector did this more atraumatically. Cautery and ultrasonic dissection had a hemostatic effect on the parenchyma in that a significantly smaller number of vessels needed to be clipped or tied. On histologic study of the fresh cut liver surface, a smooth surface was seen with ultrasonic dissection, parenchymal hemorrhage after suction dissection, and coagulation necrosis after electrocautery. Ultrasonic dissection was the only technique that combined lowered blood loss because medium- and large-size vessels were dissected free and ligated before transection and a hemostatic effect on small vessels.

Controversies exist regarding the surgical treatment of the ovaries in women with primary colorectal cancer. A review of the authors' experience and the surgical literature reveals an incidence of ovarian metastases from colorectal cancer of approximately 6 percent. This problem may occur somewhat more frequently in premenopausal women. Resection of the ovaries at the time of colectomy is unlikely to affect survival. Removal of the ovaries at the time of bowel resection will prevent repeat laparotomy to resect an ovarian mass in approximately 2 percent of women with large bowel cancer. Oophorectomy should be performed in all postmenopausal females at the time of primary resection. Oophorectomy should be performed in premenopausal women if any gross abnormality of the ovary is detected or if peritoneal implants are seen at the time of primary resection.

Technical aspects of the clinical management of 69 patients who had a Tenckhoff catheter implanted for chemotherapy infusion were reviewed. Catheter placement under local anesthesia was performed using a trochar. Three patients had intestinal perforation. Also, bacterial peritonitis occurred in three patients, an incidence of 10 per cent per catheter year. Peritonitis responded to antibiotic treatment without catheter removal. If the catheter failed to infuse or drain, irrigation and instrumentation were used to reopen the catheter. An absolute indication for catheter removal was infection of the Dacron cuff. Intraperitoneal chemotherapy was thought to be a safe way in which to deliver high concentrations and large amounts of drug to the abdominal cavity. In selected tumors, there may be a significant pharmacologic advantage over conventional routes of administration. Proper catheter insertion and maintenance were required to keep complications of this treatment modality to a minimum.

The control of malignancy disseminated within the peritoneal cavity is an important problem in the management of low-grade gastrointestinal and ovarian neoplasms. A model of peritoneal carcinomatosis in the mouse was used to investigate the potential of lymphokine-activated killer (LAK) cells and exogenous interleukin 2 (IL-2) to control intraperitoneal tumor. LAK cells are splenocytes activated in vitro by IL-2. C57BL/6 mice were injected intraperitoneally with a lethal inoculum of syngeneic MCA-105 tumor. Three days later, the established tumor was treated with adoptively transferred LAK cells and/or exogenous IL-2 administration. LAK cells alone were ineffective in reducing intraperitoneal tumor. Administration of IL-2 alone resulted in limited tumor reduction. Treatment with exogenous IL-2 in conjunction with LAK cells resulted in the greatest reduction of intraperitoneal tumor. The larger the number of LAK cells given, the greater the reduction in tumor. Frequent intraperitoneal bolus administration of IL-2 was more effective than a single daily intraperitoneal injection and intraperitoneal administration of IL-2 and LAK was more effective than systemic treatments. Marked prolongation of life was seen in mice treated with LAK cells plus exogenous IL-2. We conclude that intraperitoneal LAK cells plus exogenous IL-2 is an effective treatment regimen for reducing intraperitoneal tumor in this murine model.

Pseudomyxoma peritonei is an unusual malignancy arising from the goblet cells of the large bowel or appendix. Its characteristic clinical features are low histologic grade of malignancy and widespread dissemination throughout the abdominal cavity. In a clinical study of 14 patients, the most common initial symptoms were abdominal distention or right lower quadrant pain suggestive of appendicitis. All patients underwent radical procedures in an attempt to surgically remove all gross disease from the abdomen. Six patients had small-bowel obstruction and five of these had bowel function restored. All of eight patients had relief from bulky intra-abdominal tumors. Six cycles of intraperitoneal 5-FU and three doses of mitomycin C were used following cytoreductive surgery in seven patients. Five of these seven patients are disease free following staging by celiotomy with two- to four-year follow-up. This new treatment strategy, designed to cure some patients with pseudomyxoma peritonei, has given favorable results in a disease that previously had a uniformly lethal outcome.

The resection of hepatic metastases in patients with extrahepatic disease is of no proven benefit. Preoperative identification of extrahepatic disease may prevent unnecessary laparotomy. Preoperative evaluation including physical examination, computed tomography of the abdomen, full lung tomography or chest-computed tomography, and radionuclide bone scanning identified extrahepatic metastases, most commonly in the lung, in 25 of 132 patients with purported isolated liver metastases. Of 107 patients with negative staging evaluations, intra-abdominal extrahepatic metastases were found in 26 percent (28 of 107) at laparotomy, most commonly in portal and celiac lymph nodes. The presence of extrahepatic disease correlated with greater than 25 percent hepatic replacement by tumor, presence of symptoms, and Dukes' C primary lesions; however, none was predictive. We were unable to develop a model to preoperatively predict the presence of intra-abdominal extrahepatic disease. The authors recommend a preoperative evaluation including physical examination, and computed tomographic scans of the abdomen and chest. A bone scan is required only in patients with symptoms referable to bone. Despite a negative preoperative evaluation, however, a considerable proportion of patients with colorectal hepatic metastases will have extrahepatic disease at the time of abdominal exploration.

Often, maintenance of fluid and electrolyte homeostasis is the most challenging dilemma posed by short bowel syndrome. This report describes the management of a patient with intractable, dehydrating, salt-wasting diarrhea after small and large bowel resection for Crohn's disease complicated by rectal cancer. Intraperitoneal fluid and electrolyte therapy delivered through a Tenckhoff catheter was used to achieve long-term outpatient stability without chronic intravenous therapy. The concept of intraperitoneal fluid and electrolyte therapy is discussed and its potential role in the treatment of short bowel syndrome is described.

In this report, we have presented the first patient treated with a discontinuous myocutaneous flap for coverage of a hemipelvectomy combined with buttockectomy. This procedure allows circumferential excision of all tissues anterior and posterior to the hemipelvis. The circular defect that extends from the anus to anterior abdominal wall is covered with fresh tissue obtained from the anterior thigh just above the knee and supported on the superficial femoral artery. The major principles to be emphasized are the use of uninvolved tissues, as well as obtaining adequate tumor-free margins.

No new chemotherapy agents have been developed recently that present hope for improving survival in patients with colon or rectal cancer. We undertook this study to investigate a new route of administering an old drug, 5-fluorouracil (5-FU). Sixty-six patients with advanced primary colon or rectal cancer were randomized to receive 12 cycles with increasing dosages of intravenous (IV) or intraperitoneal (IP) 5-FU; the mean follow-up time was three years. The maximal tolerable dose and objective adverse side effects were prospectively recorded. The mean daily dose of 5-FU given by the IV route was 904 mg; for the IP route it was 1361 mg (p2 less than 0.0001). Two of ten patients had recurrent peritoneal carcinomatosis when treated with IP 5-FU; ten of eleven patients treated with IV 5-FU developed peritoneal implants (p2 less than 0.003). The incidence of serious complications was the same, but hematologic toxicity and hepatic toxicity were significantly reduced in patients who received IP 5-FU. When 5-FU is delivered by the IP route, the tolerable dose of drug was markedly increased without an increase in adverse side effects. The natural history of surgically treated disease was changed by reducing the incidence of peritoneal carcinomatosis but time to relapse and survival was not improved. IP 5-FU may be recommended for investigation in patients with perforated colon cancer, peritoneal implants, or as one part of a multimodality treatment protocol for colorectal cancer. If 5-FU is given to patients with gastrointestinal malignancy, the IP route should be strongly considered.

Monthly serial postoperative CEA determinations, three-monthly system review plus physical examination, and a battery of six-monthly laboratory and radiologic tests were compared in order to evaluate each in detection of recurrent colorectal cancer. Twelve of the 33 patients studied prospectively developed recurrent disease. In this study CEA was found not to be a substitute for careful clinical follow-up, but if used in a serial manner it was a useful adjunct for detection of early recurrent cancer, especially intra-hepatic and retroperitoneal disease recurring in patients with elevated pretreatment CEA levels. The other laboratory and radiologic tests employed were often useful to confirm progressing disease, but they did not reveal any first evidence of recurrent disease.

Portal venous infusion of chemotherapy may prove to be an important treatment effective in diminishing the incidence of hepatic metastases from colorectal cancer. To infuse drugs safely and reliably, we have cannulated major branches of the portal vein exposed during right or left colectomy. To prevent bleeding into the free peritoneal cavity upon catheter removal, the cannula is secured with elastic suture material. The technique has been used in 30 patients without complication.