[Iron-deficiency anaemia: a sign that requires an adequate explanation]. / IJzergebreksanemie: zoeken naar een overtuigende verklaring.

In three patients, aged 79, 58 and 59 years, respectively, iron-deficiency anaemia (IDA) was diagnosed. All three had a right-sided colonic adenocarcinoma. In the first patient, a cardiologic cause was looked for instead of a simple laboratory investigation of the anaemia. The second patient received iron supplementation without sufficient diagnostic evaluation, and in the third patient the abdominal X-ray was inadequate for evaluation of the ascending colon; moreover, she responded well to iron supplementation therapy. IDA is a common problem in clinical practice that may have various causes. In the Netherlands, gastrointestinal bleeding is the major cause of IDA in men and women over 50 years of age. The three patients described illustrate that IDA should be considered a clinical sign. An accurate evaluation of the IDA to detect a convincing explanation is therefore necessary. Various causes can be found on duodenoscopy and colonoscopy, e.g. neoplasms, ulcers, angiodysplasia or polyps. Carcinoma of the ascending colon is a frequent cause of IDA, especially in those over 50 years of age and without upper gastrointestinal symptoms. Evaluation to exclude a right-sided carcinoma of the colon has a high priority in these cases.

[Compartment syndrome in both lower legs after prolonged surgery in the lithotomy position]. / Compartimentsyndroom van beide onderbenen na langdurige chirurgie in steensnedenligging.

A 35-year-old man developed bilateral compartment syndrome in the lower legs after prolonged colorectal surgery in the lithotomy position. This complication of a prolonged non-physiological operation position is a rare event and the diagnosis is therefore often delayed, with sometimes serious irreversible neuromuscular damage. In this case the complication was successfully treated by four-compartment fasciotomy and forced diuresis (to prevent renal insufficiency caused by myoglobin nephrosis).

Old age is not a contra-indication for surgery in patients with primary hyperparathyroidism.

OBJECTIVE: Neck exploration for hyperparathyroidism is sometimes withheld from elderly patients out of concern for the risks. The question whether this concern is founded in fact was examined in a consecutive series of 18 patients aged 70 years or older who were operated for primary hyperparathyroidism in the period 1988-1993. The patients were referred by 6 institutions. RESULTS: Thirteen patients were considered symptomatic and 5 asymptomatic. The most common presenting symptoms were fatigue (n = 8), skeletal changes (n = 4), bone pain (n = 4) and polyuria (n = 4). Urolithiasis occurred in 2 patients. After operation with excision of all enlarged parathyroid glands serum calcium concentrations normalised in all patients. There was no mortality and the only complication was a late haematoma in a patient who used anticoagulants. The median postoperative hospital stay was 5 days (range 2-8 days). CONCLUSION: The high cure rate, the low morbidity, the low mortality and the short hospital stay favor neck exploration as the treatment of choice also in the elderly patient.

[Unnecessary localization studies in primary hyperparathyroidism]. / Onnodig lokaliserend onderzoek bij primaire hyperparathyreoïdie.

OBJECTIVE: To determine how often preoperative localisation tests are performed on patients suffering from primary hyperparathyroidism (pHPT) without previous neck surgery and to analyse the predictive value of such tests. DESIGN: Retrospective study. SETTING: University Hospital Utrecht, the Netherlands. METHODS: From 1988 to 1993 50 patients suffering from pHPT underwent initial surgical exploration of the neck. Clinical data, performed tests and results, findings at surgery, histological findings and clinical result were recorded. RESULTS: Localisation tests were performed 41 times on 27 patients (54%): 19 times ultrasonography, 14 times scintigraphy, 7 times computer tomography and once, venous sampling. Independent of preoperative testing, all patients underwent systematical, bilateral exploration of the neck. In 49 patients a total of 53 enlarged parathyroid glands were removed, all patients became normocalcaemic. Exploration revealed no abnormalities in 1 patient, who received no further surgical treatment. In 15 patients (56%) the localisation tests predicted the correct side of the enlarged glands, in 5 patients the wrong side was predicted and in 7 patients no prediction was possible. CONCLUSION: These results are in accordance with the poor predictive value of localisation tests prior to initial neck exploration as mentioned in other studies. The success rate of operation by an experienced parathyroid surgeon is 95-99 per cent. Preoperative localisation studies in patients with primary hyperparathyroidism without previous neck surgery are not only of poor predictive value, but should even be discouraged, because they may mislead the operating surgeon.

[(Procto)colectomy with permanent ileostomy versus restorative proctocolectomy in ulcerative colitis; the past as background for the present]. / (Procto)colectomie met permanent ileostoma versus restauratieve proctocolectomie, bij colitis ulcerosa; het verleden als achtergrond voor het heden.

In the University Hospital of Utrecht, in order to assess the value of 'restorative' proctocolectomy, the early and late complications after 'classical' (procto)colectomy with establishment of a permanent ileal stoma were evaluated retrospectively over the period 1969-1988. The inclusion criteria were: having undergone a (procto)colectomy with establishment of an ileal stoma because of pathologico-anatomically confirmed ulcerative colitis, with follow-up in the clinic mentioned. Data on the preoperative period, on the operation and on the early and late complications were collected of 101 patients. Immediately postoperative complications were encountered in 50% of the patients. Mortality was 2% in the group as a whole and 5% after emergency surgery. Late complications occurred in 62% of the patients, and in 45% of the patients they necessitated one or several reoperations. Sources of late complications included: the rectal stump left in situ, the perineal wound area, the stoma and the formation of abdominal adhesions. Classical (procto)colectomy with establishment of a permanent ileal stoma entails a large proportion of early and late postoperative complications. It is asserted that the complications at present observed after restorative proctocolectomy must not prompt a return to classical proctocolectomy as the standard surgical treatment of ulcerative colitis.

Local conditions in the host influence immunotherapy with interleukin-2 and LAK cells.

Production of biological response modifiers through recombinant techniques has stimulated interest in immunotherapy of cancer. One of these, interleukin-2 (IL-2), will induce in vivo as well as in vitro proliferation of noncommitted T lymphocytes into lymphokine-activated killer (LAK) cells: cells cytolytic for a broad range of tumor cells. We have demonstrated earlier that immunotherapy with IL-2 and LAK cells will reduce tumor load and prolong survival in a significant way in an intraperitoneal (ip) tumor model as well as in other models. Nevertheless, mice die of one or two metastases escaping immunotherapy. Activation of the host immune system might boost endogenous IL-2 production. Activation might also enhance immunotherapy by increasing the necessary cofactors. Loco-regional allogeneic pretreatment ip 14 days prior to syngeneic tumor challenge did not enhance, but completely abrogated, ip IL-2 and LAK cell therapy (peritoneal cancer index, 0.6 +/- 0.3 vs 2.6 +/- 0.2, P2 = 0.003). Tumor bulk is not the reason for escape of immunotherapy either. One week after intracutaneous (ic) tumor inoculation a noncurative or sham tumor resection was performed, followed by IL-2 and LAK cell therapy either ip or in and around the tumor nodule. No significant difference in tumor diameter or survival of mice was seen. Allogenic tumor cells admixed with syngeneic tumor cells will induce an inflammatory reaction locally and regionally. This inflammatory reaction in the syngeneic host will enhance the treatment with IL-2. The allogeneic (P815) and syngeneic (MCA-105) tumor cell mixture was injected ic. Growth rate was retarded and survival prolonged in a significant way when the cell mixture was treated with ip IL-2 injections; no difference was seen when the admixture was not treated or the syngeneic ic tumor alone was treated with IL-2. We conclude that host immune status and recruitment of immunocompetent cells locally to the tumor site determine the outcome of immunotherapy with IL-2 and LAK cells.

Fate of gamma-interferon-activated killer blood monocytes adoptively transferred into the abdominal cavity of patients with peritoneal carcinomatosis.

Five patients with colorectal cancer widely metastatic to peritoneal surfaces have been treated i.p. with infusions of autologous blood monocytes made cytotoxic by in vitro incubation with human gamma-interferon. The monocytes were purified by a combination of cytapheresis and counter-current centrifugal elutriation procedures; each week approximately 350 million activated monocytes were given to patients as adoptive immunotherapy by a single i.p. instillation. On the eighth cycle of treatment the trafficking of i.p. infused blood monocytes was studied in two patients by prelabeling the cells with 111In. These activated cells became distributed widely within the peritoneal cavity. Two and 5 days after infusion their position within the peritoneum had not changed. When peritoneal specimens were obtained 36 h after 111In-labeled monocyte infusion, labeled monocytes were demonstrated to be associated with the serosal surfaces by autoradiographic analysis. Scintiscanning structures outside the abdominal cavity revealed that 111In-labeled monocytes infused i.p. did not traffic to other organs during the 5 days of the study. We conclude that i.p. adoptive transfer of autologous killer blood monocytes is an effective way of delivering these cytotoxic cells to sites of tumor burden on peritoneal surfaces in these cancer patients.

Augmentation of interleukin-2 immunotherapeutic effects by lymphokine-activated killer cells and allogeneic stimulation in murine tumor cells.

Interleukin-2 (IL-2) and lymphokine-activated killer (LAK) cells were used in intraperitoneal and pulmonary tumor models in C57BL/6 mice. To maintain the immunotherapeutic effects of IL-2 plus LAK treatment but reduce its toxicity, ways were sought to augment IL-2 effects. The investigation showed that the adoptive transfer of LAK cells was a prerequisite for successful therapy of intraperitoneal cancer. When LAK cells were given on consecutive days within one course of immunotherapy, antitumor efficacy was augmented with additional doses of LAK cells. However, with the reduction of 1 complete cycle of IL-2 + LAK cells, no further reduction in intraperitoneal tumor was observed as compared to the reduction after 2 or 4 cycles. LAK cells generated from splenocytes of mice that had received an allogeneic tumor challenge 1 week earlier exerted a highly increased cytotoxicity as compared to normal LAK cells. Furthermore, the potentiation effect of an allogeneic response of the host at the tumor site was demonstrated by decreased numbers of lung implants and improved survival in mice given mixtures of syngeneic and allogeneic tumor cell suspensions. An alloimmune response within the microenvironment of tumor tissue markedly enhanced the antitumor effect of IL-2 against the syngeneic tumor. It was concluded that there is a fundamental need to improve the recruitment of adoptively transferred LAK cells or LAK precursors into tumor tissue. This may be the next step required in the further development of IL-2 and LAK immunotherapy.

The requirements for successful immunotherapy of intraperitoneal cancer using interleukin-2 and lymphokine-activated killer cells.

In a significant proportion of patients with gastrointestinal and ovarian malignancy the peritoneal cavity is a prominent site at which surgical treatment fails. Adjuvant treatments directed at this site should be investigated in an attempt to improve survival in patients with these cancers. In the study reported here, a model of intraperitoneal tumor in the mouse was established and shows the effectiveness of lymphokine activated killer (LAK) cells and exogenous interleukin-2 (IL-2) in the control of intraperitoneal tumor. A standard regimen was used to treat seven different tumors in three different mouse strains. In all seven cases a significant reduction in the intraperitoneal tumor mass was observed when LAK cells plus IL-2 were used as immunotherapy. A prolonged survival was also demonstrated in mice with intraperitoneal tumor. The relevance of these observations to patients with cancer was demonstrated in that allogeneic and syngeneic LAK cells were equally effective, LAK cells generated from normal and from tumor-bearing donors showed equal reactivity, and this treatment was successful in the immuno-compromised host. Both IL-2 derived from an IL-2-producing subline of the EL-4 thymoma and recombinant IL-2 were equally effective in the control of intraperitoneal tumor. The local-regional effects of the intraperitoneal administration of IL-2 were demonstrated by high levels of LAK cell cytotoxicity in peritoneal exudate cells. Intraperitoneal IL-2 or IL-2 plus LAK cell regimens should be investigated in the treatment of malignancy that spreads by implantation onto peritoneal surfaces.

Immunotherapy of intraperitoneal cancer with interleukin 2 and lymphokine-activated killer cells reduces tumor load and prolongs survival in murine models.

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.

Liver transection: a controlled study of four different techniques in pigs.

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.

Treatment of proximal biliary tract carcinoma: an overview of techniques and results.

Proximal biliary tract cancer carries a dismal prognosis. Few patients have a curative option. However, worthwhile palliation can be achieved in many patients by relieving obstructive jaundice. An overview is presented to place in perspective the treatment methods described and the results obtained.

Hepatic resection of colorectal metastases. Influence of clinical factors and adjuvant intraperitoneal 5-fluorouracil via Tenckhoff catheter on survival.

This report analyzes an experience with 33 hepatic resections for metastatic colorectal cancer over a 7-year period and with intraperitoneal 5-FU administered as a postresection adjuvant in 21 of these patients. Particular emphasis is placed on the identification of clinical determinants of postresection survival. There was no operative mortality in this series. Postoperative complications occurred in 27% of patients, and the incidence of complications correlated with intraoperative blood loss (p = 0.002). Two- and 4-year estimated survivals were 72% and 53%, respectively. Patients with three or fewer metastases resected or with unilobar disease had improved survival when compared with patients having more than three metastases or bilobar disease, respectively (p less than 0.05). Disease-free survival was improved in patients with microscopically negative resection margins (p = 0.019). Dukes' stage of the primary lesion, interval between bowel resection and detection of hepatic metastases, method of detection of metastases, preoperative CEA level, and type of operation performed were not predictive of postresection survival. Intraperitoneal 5-FU was well tolerated. There was a trend toward improved survival in patients receiving adjuvant chemotherapy, but this was not statistically significant. It is concluded that the number of metastases resected, the distribution of the metastases, and the technical adequacy of the excision are all predictive of outcome following hepatic resection of colorectal metastases. Encouraging results with the use of intraperitoneal 5-FU as a postresection adjuvant have led to the initiation of a prospective randomized trial investigating this modality at the NCI.