[Granulomatous mastitis: a rare cause of breast swelling]. / Een zeldzame oorzaak van een mammagezwel: granulomateuze mastitis.

Three women, aged 37, 39 and 29 years, presented with unilateral painful swelling of the breast. Ultrasound revealed inflammation with abscess formation. Histological biopsies contained granulomatous tissue without necrosis. Corynebacterium species were cultured in the first two patients. All 3 patients were diagnosed with granulomatous mastitis and were successfully treated with doxycycline. Granulomatous mastitis is a rare disorder that may mimic breast carcinoma. It occurs most frequently in fertile women. Diagnosis is based on histological biopsy which shows granulomas without necrosis, while other causes of granulomatous inflammation, especially tuberculosis, have been excluded. The aetiology is not fully understood. It is hypothesised that the granulomatous mastitis is caused by a type IV allergic reaction. Recently an association with Corynebacterium species was suggested. Best practice treatment methods are unclear. Most patients are treated with surgical intervention and steroids, but the rate of recurrence is high (50%). Treatment with doxycycline must be considered in patients with cultured Corynebacterium species.

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.

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.

Conservative treatment for closed fifth (small finger) metacarpal neck fractures.

BACKGROUND: Subcapital fractures of the fifth metacarpal bone, meaning fractures just below the knuckle of the little finger, account for approximately 20% of all hand fractures. Currently, there is no consensus concerning the optimal management of these fractures. Traditionally, treatment consists of closed reduction and external splinting in a neutral position using plaster of Paris (POP), involving the metacarpal joint, the proximal interphalangeal joint and the carpo-metacarpal joint. An alternative treatment strategy is functional treatment using taping or bracing that does not restrict movement. OBJECTIVES: To compare functional treatment with immobilization, and to compare different periods and types of immobilization, for the treatment of closed fifth metacarpal neck fractures in adults. SEARCH STRATEGY: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialized Register (July 2004), the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 3, 2004), OVID OldMEDLINE (1951 to 1965), OVID MEDLINE (1966 to July 2004), OVID MEDLINE In-Process (July 2004), EMBASE (1988 to 2004, week 29), the Internet, and reference lists of articles. No language restrictions were applied. SELECTION CRITERIA: All randomized and quasi-randomized controlled trials which compare functional treatment with immobilization or different types of immobilization for closed fifth metacarpal neck fractures. DATA COLLECTION AND ANALYSIS: Two review authors assessed abstracts of all studies identified by the initial search, identified studies meeting the selection criteria, independently assessed the quality of the trial reports, and extracted and analysed the data. MAIN RESULTS: Five studies met the inclusion criteria including a total of 252 participants. Most studies were of poor quality. The primary outcome measure, function of the hand, was not used in any studies. There was no evidence that any of the treatment modalities was statistically significantly superior. AUTHORS' CONCLUSIONS: No included studies reported our primary outcome measure of interest, validated hand function. There was heterogeneity between the studies, which were of limited quality and size. No single non-operative treatment regimen for fracture of the neck of the fifth metacarpal can be recommended as superior to another in result. Further research is definitely warranted.

Laparotomy enhances intraperitoneal tumor growth and abrogates the antitumor effects of interleukin-2 and lymphokine-activated killer cells.

The interrelationship between host resistance to cancer and the trauma of a surgical procedure is the subject of much speculation. Extensive study of animal models and human subjects is required to define these effects and to provide a theoretical model by which to interpret these data. We used a murine model of intraperitoneal cancer to demonstrate the augmentation of tumor growth by surgical trauma. In this intraperitoneal tumor model, a surgical procedure that included entry into the abdominal cavity resulted in augmented tumor growth; a surgical incision on the skin of the animal's back did not promote tumor growth. The immunotherapeutic effects of interleukin-2 and lymphokine-activated killer cells were significantly reduced by the performance of a laparotomy. This abrogation of the effects of the immunotherapeutic regimen was observed for up to 14 days after laparotomy but was lost by days 35 to 42. Healing tissue may promote tumor growth, and these effects are dominant over immunotherapy with interleukin-2 plus lymphokine-activated killer cells.

A nonelemental versus an elemental diet for early postoperative enteral feeding by needle catheter jejunostomy.

In a prospective randomised study the use of an elemental versus a nonelemental diet for early postoperative enteral feeding by needle catheter jejunostomy was investigated. After extensive gastrointestinal surgery, 25 patients received an elemental and 24 patients a nonelemental diet. The incidence of diarrhoea, the effects of the feeding and the costs were evaluated. The occurrence of diarrhoea was observed more frequently in the elemental diet group (14 25 ) compared to the nonelemental diet group (7 24 ), although this difference was statistically not significant (p > 0.05). No difference was found between the two groups in postoperative restoration of total protein and serum albumin levels and the extent of the postoperative weight loss. The costs showed a clear difference: the nonelemental diet was three times cheaper than the elemental diet. For early postoperative enteral feeding by needle catheter jejunostomy we therefore recommend the use of a nonelemental diet.

[A Turkish man with Behçet disease and recurrent acute abdomen]. / Een Turkse man met de ziekte van Behçet en een recidiverende acute buik.

Following a total hip prosthesis, a 52-year-old Turkish man with Behçet's disease developed persistent ileus due to intestinal perforations. Resection of the intestine was followed by new perforations, resulting in resection of another portion of the intestine and the start of immunosuppressive medication. Following the 5th resection for a perforated ulcer in the space of two weeks, an ileostomy was performed. One year later the stoma could be eliminated and the patient remained symptom-free. Behçet's disease is relatively rare in the Netherlands. However, the gastrointestinal complications may be life-threatening. Surgical intervention is then often necessary. Complications and recurrences are frequent.

Local regional promotion of tumor growth after abdominal surgery is dominant over immunotherapy with interleukin-2 and lymphokine activated killer cells.

Various investigators have shown that tumor growth can be facilitated by surgery, that an operation can suppress immune functions, and that these phenomena may be related. With a murine intraperitoneal (i.p.) tumor model, we investigated whether an operation could promote tumor growth and, if so, whether this effect could be successfully overcome by immunotherapy with interleukin-2 (IL-2) and lympokine activated killer (LAK) cells. Treatment with IL-2 and LAK cells was highly effective in unoperated mice. When a laparotomy was done 4 days before i.p. tumor inoculation, tumor growth was enhanced in all experiments, and the effect of immunotherapy was completely abrogated. This effect was local regional; an incision on the back of the mice did not affect tumor growth or outcome of treatment. Tumor growth in the scar area was usually excessive. Furthermore, these effects were found to be temporary. Promotion of tumor growth and abrogation of IL-2 + LAK effects were seen only from 4 days to up to 2 weeks after laparotomy but were lost 5 weeks after surgery. These results suggest that growth factors present in healing wounds may cause promotion of tumor growth and are dominant over the effects of IL-2 and LAK cell therapy.

Recruitment of inflammatory cells to a tumor deposit potentiates the immunotherapeutic effects of interleukin-2.

Interleukin-2 (IL-2) is a potent immunotherapeutic agent in murine models of intraperitoneal, pulmonary, and hepatic tumor implantation. Because of the systemic toxicity documented at doses of IL-2 required to control tumor growth, potentiation of the effects of low dose IL-2 is an important problem in immunotherapy. To address this problem, we attempted to recruit lymphocytes into a tumor mass. Allogeneic P185 (H-2d) tumor was mixed with MCA-105 (H-2b) tumor and injected s. c. into C57BL/6 (H-2b) mice. Mice were treated with 50,000 units of IL-2 twice daily from day 0 to day 6. When IL-2 alone was used to treat s. c. tumor, there was no reduction in the size of tumor implants. When allogeneic tumor was mixed with syngeneic tumor, there was a reduction in tumor size at the high dose of allogeneic tumor but not at the low dose. When allogeneic tumor was mixed with syngeneic tumor and the mice treated with IL-2, the immunotherapeutic effects of IL-2 were markedly increased. These studies show that an immune response to alloantigens, generated within tumor tissue can augment the immunotherapeutic effects of exogenous IL-2.

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.

Inhibitory effects of alloimmune T cells on the generation of cytolytic responses of lymphokine-activated killer cells.

Not all cancer-bearing hosts respond to interleukin-2 (IL-2) and lymphokine-activated killer (LAK) cell immunotherapy. We wished to determine if modification of the host could change the immunotherapeutic effects. Alloimmunization of the host was used to study the suppression observed when LAK cells were generated in the presence of cytotoxic T lymphocytes (CTL). If C57BL/6 (BL/6, H-2b) mice were given P815 (H-2d) tumor prior to syngeneic tumor challenge, the immunotherapeutic effects of IL-2 were lost. Cells taken from mixed lymphocyte culture and incubated 3 days in IL-2 showed a reduced capability of generating LAK. However, their cytotoxicity toward an alloimmunogeneic target was markedly increased by 3 days of incubation in IL-2. In mixing experiments alloimmune cells from in vitro culture were markedly inhibitory to normal splenocytes in the generation of LAK cell cytotoxicity; they also interfered with the maintenance of LAK cell cytotoxicity. A T cell was responsible for the suppressive effects on LAK generation because suppression was abrogated by treatment of alloimmune cells with anti-T serum plus complement. The cytotoxic T cell did not lyse the LAK cell. If IL-2 was serially diluted and incubated with CTLs, the IL-2 titer was substantially reduced by 72 h incubation. If supernatants from CTLs were added to serially diluted IL-2, the IL-2 titer increased; this suggested that a soluble suppressor factor produced by CTLs did not cause the diminished IL-2 plus LAK effects. These in vitro experiments suggest that CTLs compete with normal lymphocytes or LAK cells for IL-2 and thereby suppress LAK cell responses. These studies are important in attempting to elucidate the role the host's immune system may play in IL-2 plus LAK immunotherapy of cancer or infectious disease processes.

Alloimmune cells consume interleukin-2 and competitively inhibit the anti-tumour effects of interleukin-2.

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.

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.

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.