Physiology and pathophysiology of the 5-HT3 receptor.

The 5-HT3 receptor is a ligand-gated cation channel located in the central and peripheral nervous system; it has also been detected on a variety of other cells. In the periphery, it is found on autonomic neurons and on neurons of the sensory and enteric nervous system. In the CNS, the 5-HT3 receptor has been localized in the area postrema, nucleus tractus solitarii, nucleus vaudatus, nucleus accumbens, amygdala, hippocampus, entorhinal, frontal, cingulate cortex, and in the dorsal horn ganglia. Further extraneuronal locations include among others lymphocytes, monocytes, and foetal tissue. 5-HT3 receptors modulate the release of neurotransmitters and neuropeptides like dopamine, cholecystokinin, acetylcholine, GABA, substance P, and serotonin itself. They have been demonstrated to be involved in sensory transmission, regulation of autonomic functions, integration of the vomiting reflex, pain processing and control of anxiety. While the physiologic functions of the 5-HT3 receptor are discrete and difficult to detect, it plays a key role in certain pathologic situations related to increased serotonin release. Clinical development of 5-HT3 receptor antagonists revealed a remarkable range of activities. 5-HT3 receptor antagonists do not modify any aspect of normal behaviour in animals or induce pronounced changes of physiological functions in healthy subjects. Clinical efficacy was shown for various forms of emesis like chemotherapy-induced, radiotherapy-induced, and postoperative emesis, diarrhoea-predominant irritable bowel syndrome, anxiety, chronic fatigue syndrome, alcohol abuse, and in pain syndromes such as fibromyalgia and migraine. Most recent data also suggest that 5-HT3 receptor antagonists are effective for the treatment of other rheumatic diseases such as rheumatoid arthritis, tendinopathies, periarthropathies, and myofascial pain. Other possible indications under discussion are chronic heart pain and bulimia. Unfortunately, experimental findings do not yet provide a homogenous conception of the significance of 5-HT3 receptors in all investigated fields; in nociception, for example, contradictory observations are still inadequately explained and complicated by bell-shaped dose-response curves. Further elucidation and better understanding of the serotonergic neuronal network remains a task for the next decade.

Expression of 5-HT3A receptors in cells of the immune system.

There is evidence from both human and animal research that 5-hydroxytryptamine3 (5-HT3) receptor antagonists, particularly tropisetron, exert analgesic and antiinflammatory effects. However, the underlying mechanisms of these effects including the expression of 5-HT3 receptors in cells of the immune system have not yet been investigated in detail. Therefore, we investigated the expression of the 5-HT3A receptor in primary human monocytes, chondrocytes, T-cells, dendritic cells, and synovial tissue. We found that 5-HT3A receptors are expressed in monocytes, chondrocytes, T-cells, and synovial tissue but not in dendritic cells. Our data show that 5-HT3A receptors are widely expressed in cells of the immune system and that they might play an important role in inflammatory events and in the observed antiphlogistic effects of 5-HT3 receptor antagonists.

Spectrum of use and tolerability of 5-HT3 receptor antagonists.

Several 5-HT3 receptor antagonists are available (tropisetron, ondansetron, granisetron, dolasetron, and palonsetron), and further compounds are in clinical development. These substances show only minor differences in the activity profile regarding their affinity for particular receptors. 5-HT3 receptor antagonists are primarily used and found effective in the prevention and treatment of chemotherapy-induced nausea and emesis, and in postoperative nausea and vomiting (PONV). Antagonism of the 5-HT3 receptors in the peripheral and central nervous system is a probable mechanism of action. The substances are suitable as first-line therapy (combined with a corticosteroid) for the prevention of acute nausea and vomiting in patients treated with moderately to severely emetogenic chemotherapeutic agents. This combination is also moderately effective in the prevention of delayed nausea and vomiting. 5-HT3 receptor antagonists are an important constituent in the prevention and treatment of emesis and nausea caused by radiation therapy, especially in patients receiving whole body or upper abdominal treatment. Alosetron was found clinically effective in diarrhoea-predominant irritable bowel syndrome, whereas tropisetron in fibromyalgia and related pain disorders. Further indications for such treatment include anxiety disorders, alcohol dependence, drug withdrawal, and psychosis related to treatment of Parkinson's disease. 5-HT3 receptor antagonists are well tolerated with the most frequently reported adverse effects being headache, constipation, dizziness, tiredness, and gastrointestinal disturbances such as abdominal pain or constipation. Intravenous administration of serotonin induces the Bezold-Jarisch reflex and causes small reversible changes in electrocardiogram (ECG) parameters.

Antiinflammatory effects of 5-HT3 receptor antagonists in lipopolysaccharide-stimulated primary human monocytes.

There is evidence from both human and animal research that 5-hydroxytryptamine (5-HT)3 receptor antagonists, particularly tropisetron, exert analgesic and antiinflammatory effects. However, the underlying mechanisms of these effects have not yet been investigated in detail. Therefore, the antiinflammatory effects of tropisetron and ondansetron were investigated in human monocytes. In human monocytes, both lipopolysaccharide (LPS)-stimulated tumour necrosis factor (TNF)-alpha and interleukin (IL)-1beta secretion were dose-dependently inhibited by tropisetron starting at a concentration of 5 microg/mL and reaching maximal levels at 25 microg/mL (IC50: 32 microg/mL and 12 microg/mL, respectively). LPS-induced IL-6 and PGE2 release was only slightly inhibited at high doses, whereas LPS-induced release of IL-8 and matrix metalloprotease (MMP)-9 was not affected. In conclusion, our data show that the binding of tropisetron to 5-HT3 receptors results in antiinflammatory effects through inhibition of TNF-alpha/IL-1beta, which might explain the antiphlogistic effects of 5-HT3 antagonists.

Influence of tropisetron on the serum substance P levels in fibromyalgia patients.

BACKGROUND: Substance P is found at an elevated level in the cerebrospinal fluid of fibromyalgia (FM) patients. Treatment with tropisetron leads in a subgroup of FM patients to pain reduction. The question arises of whether the substance P level in the serum can be changed by tropisetron treatment. METHOD: Twenty patients with FM diagnosed according to the ACR criteria were treated for 5 days with a 5 mg tropisetron intravenous (i.v.) bolus injection daily. Before the first injection, 3 h later, and before and 3 h after the last injection, the serum levels of substance P were determined. The determination of this substance was carried out by means of an immunoassay from Assay Design Biotrend, Cologne. To evaluate the success of the tropisetron treatment, patients made a global assessment as 'clearly better', 'better', 'unchanged', or 'poor'. Patients who answered 'clearly better' and 'better' were regarded as responders. RESULTS: Of the 20 patients, ten reported a good or very good influence on their pain (responders). In these responders, the means of the serum substance P levels were elevated in comparison with the non-responders, though the difference was not significant. In responders, the 5-HT3 receptor antagonist tropisetron produced a significant decrease in the serum substance P levels, while this did not occur in the non-responders. CONCLUSION: It is possible that the responders to tropisetron represent a subgroup of FM patients for whom substance P and 5-HT3 receptors play key roles in the development of the pain symptoms.

Treatment of fibromyalgia with tropisetron--dose and efficacy correlations.

Previous studies evaluating the efficacy and tolerance of tropisetron for the treatment of fibromyalgia (FM) used the drug either intravenously or orally, and at different dosage levels ranging from 2 mg to 15 mg daily. The shortest treatment was a single dose and the longest treatment period covered 28 days. A significant reduction of the pain intensity was achieved by using tropisetron 5 mg per day. Apart from the fact that treatment periods were different, the efficacy of oral and intravenous administration did not differ significantly. Tropisetron was well tolerated; but in the 15 mg group in one of the studies, the decrease in pain was less than in the placebo group, however, the frequency of constipation and other gastrointestinal symptoms increased. Furthermore, it was hypothesized that due to the impacts of CYP2D6 activities, a daily dose of tropisetron 2 mg may be efficacious in slow metabolizers only. Although tropisetron proved to be efficacious in a group of fibromyalgia patients, the dose-response curves cannot yet be explained in a fully satisfactory manner, which may encourage research focusing on possible subgroups of FM.

Efficacy and tolerability of intravenous tropisetron in the treatment of fibromyalgia.

OBJECTIVE: To determine the efficacy of a serotonin receptor (5-HT(3)) antagonist in the treatment of fibromyalgia (FM) in a prospective, randomized, double-blind, placebo-controlled, multicentre trial. METHODS: Twenty-one female patients (age 21-63 years) with FM according to the American College of Rheumatology classification criteria for FM were assigned randomly to either a placebo group or to receive a daily intravenous bolus injection of 5 mg tropisetron for 5 days. RESULTS: In patients receiving tropisetron, the visual analogue scale (VAS) score for pain decreased by 28.9 compared with a decrease of 6.8 in the placebo group [probability (p)=0.063; effect size: 0.794]. Similar results were obtained using a body diagram pain score as a secondary efficacy parameter: mean pain reduction was 27.2 in the tropisetron group, versus 2.8 in the placebo group (p=0.038; effect size: 0.902). CONCLUSION: 5-HT(3) receptor antagonists provide significant pain relief for a group of FM patients.

[A randomized, double-blind, placebo-controlled, phase 3 trial comparing SMS 201-995 pa LAR plus tamoxifen versus tamoxifen plus placebo in women with locally recurrent or metastatic breast cancer]. / Palliative Therapie bei metastasiertem Mammakarzinom mit Tamoxifen und hochdosiertem Octreotid (Somatostatin-Analog) - Ergebnisse einer multizentrischen Phase-III-Studie.

UNLABELLED: A randomized, double-blind, placebo-controlled, phase 3 trial comparing SMS 201-995 pa LAR plus tamoxifen versus tamoxifen plus placebo in women with locally recurrent or metastatic breast cancer. PATIENTS AND METHODS: Numerous studies have proved the efficacy of tamoxifen treatment in women with receptor-positive breast cancer. Preclinical and phase I/II-studies showed that tumor control can be improved if Octreotid is added. In this randomized controlled double blind phase III study women received 20 mg tamoxifen daily and either 160 mg Octreoid-Depot i. m. injection once a month or a placebo injection. Until 1998 a total of 263 women were randomized. RESULTS: The study medication was tolerated well by all patients in the treatment group (n = 133). The most frequent moderate side effects were diarrhea (n = 73), nausea (n = 26), abdominal pain (n = 19), bone pain (n = 24) and fatigue (n = 20). No patient dropped out because of these side effects. Surprisingly, several complete remissions occured. Neither the total survival nor the progression free survival was significantly different between groups. Therefore the study was stopped before the originally planned number of patients (n = 416) had been enrolled. CONCLUSION: Octreotid plus tamoxifen does not improve tumor control. It is necessary to define subgroups that might benefit from Octreotid.

Fibromyalgia treatment with intravenous tropisetron administration.

A prospective, randomized, placebo-controlled, multicenter, double-blind trial in fibromyalgia patients demonstrated that peroral daily treatment with 5 mg tropisetron for 10 days produced a significant reduction in pain and other symptoms. The aim of the present study was to determine whether intravenous administration of 2 mg tropisetron daily for a limited period of time would produce quicker and more favorable results. In the first cohort 18 fibromyalgia patients received a single intravenous injection of 2 mg tropisetron. In the second cohort 24 fibromyalgia patients were treated with 2 mg intravenous tropisetron daily for 5 days. Pain intensity was measured with the visual analog scale and the pain score. Pain at tender and control points (dolorimeter) as well as 17 ancillary symptoms before and after treatment were evaluated. Pain intensity was followed-up by means of a patient diary until recurrence. Dolorimetry revealed that a single intravenous injection of 2 mg tropisetron significantly reduced pain and enhanced pain threshold. These effects, however, lasted for only a few days. Of 18 patients in the first cohort, only three showed no response to therapy. Of the 24 patients in the second cohort, 23 showed pain reduction when 2 mg tropisetron was administered daily for 5 days. Pain relief lasted for 2 weeks to 2 months in 20 of these patients. Two patients stopped filling in the pain diary. Twelve ancillary symptoms such as sleep disturbances, fatigue, morning stiffness were also significantly improved by the latter treatment. In the global assessment 16 out of 24 patients showed significant improvement and seven showed slight improvement. Only one patient experienced no improvement. Tolerability was good. In conclusion, intravenous injection of 2 mg of the 5-hydroxytryptamine3 receptor antagonist tropisetron once daily for 5 days produced a longer-lasting therapeutic effect on fibromyalgia symptoms than did peroral daily treatment with 5 mg of this drug. The results achieved are currently being evaluated in a randomized, placebo-controlled, double-blind trial.

Granulocyte/macrophage-colony-stimulating-factor plus interleukin-2 plus interferon alpha in the treatment of metastatic renal cell carcinoma: a pilot study.

Granulocyte/macrophage-colony-stimulating factor (GM-CSF) plays a central role in the differentiation and function of dendritic cells, which are crucial for the elicitation of MHC-restricted T cell responses. Preclinical and the first clinical data provide a rationale for the application of GM-CSF in immunotherapy of cancer. Ten patients with renal cell carcinoma stage IV (Holland/ Robson) were treated in this pilot study. Therapy was started with GM-CSF alone (2 weeks). Interleukin (IL-2) and interferon alpha (IFNalpha) were added sequentially (3 weeks GM-CSF plus IL-2 or IFNalpha, 3 weeks GM-CSF plus IL-2 plus IFNalpha). Therapy was performed on an outpatient basis. The cytokine regimen was evaluated for toxicity, clinical response and immunomodulatory effects [fluorescence-activated cell sorting analysis of peripheral blood mononuclear cells (PBMC), mixed-lymphocyte reaction and cytotoxicity of PBMC]. GM-CSF treatment caused a significant increase in the number of PBMC expressing costimulatory molecules. Addition of IL-2 and IFNalpha led to an increase in CD3 , CD4+, CD8+ and CD56+ PBMC in week 9. In an autologous mixed-lymphocyte reaction a 2.1-fold increase in T cell proliferation was observed after 2 weeks of GM-CSF treatment, and cytotoxicity assays showed changes in natural-killer-(NK)- and non-NK-mediated cytotoxicity in some patients. Two patients achieved partial remission, one patient had a mixed response. The toxicity of the regimen was mild to moderate with fever, flu-like symptoms and nausea being observed in most patients. Severe organ toxicity was not observed. We conclude that GM-CSF might be useful for immunotherapy of renal cell carcinoma, especially in combination with T-cell-active cytokines. Further studies are warranted.

Oral treatment of fibromyalgia with tropisetron given over 28 days: influence on functional and vegetative symptoms, psychometric parameters and pain.

The 5-HT3 receptor antagonists are a novel therapy for patients suffering from fibromyalgia, although the optimal duration of treatment is still unclear. The objective of this phase II study was to evaluate whether prolonging treatment with tropisetron to 4 weeks is tolerable and correlated with an improved clinical benefit. Thirty female patients with fibromyalgia received oral tropisetron (5 mg) daily for 28 days in an open-label fashion. Treatment resulted in significantly decreased pain as measured by visual analog scale (VAS), with a mean reduction of 59.7% and an absolute median change of -25.0 from baseline to day 28 (p<0.0001). A similar, significant reduction of 55.7% and absolute median change of -31.0 was observed in the painscore (p<0.0001). The response rate with patients showing a > or = 35% reduction in individual pain scores was 72.4% at day 28. The pressure tolerance of tender-points was slightly increased at the end of the treatment period. In addition, significant improvements were observed in the State-Trait-Anxiety-Inventory (STAI), scales of von Zerssen (Bf-S) and Beck Depression Index (BDI). Functional symptoms were compared with the results from a 10-day, randomized, double-blind phase III study of tropisetron in 418 fibromyalgia patients. In both studies several functional symptoms such as sleep disturbances and dizziness improved significantly (p<0.05). In the 28 days study, the number and extent of improvement in functional symptoms was increased compared with the shorter trial. Tolerability and safety of tropisetron was good, and typically for 5-HT3-receptor antagonists, gastrointestinal symptoms and headache were the most frequently reported events. In conclusion, 28 days treatment of fibromyalgia patients with 5 mg tropisetron resulted in significant pain reduction, which was most pronounced after 10 days with a further reduction up to day 28. Psychometric tests showed significant improvements in depression and anxiety state scores, while functional symptoms improved with extended tropisetron treatment.

Treatment of irradiation-induced mucositis with growth factors (rhGM-CSF) in patients with head and neck cancer.

BACKGROUND: Mucositis is a frequent side-effect of radiotherapy which often causes interruption of therapy and consequently decreases the probability of remission or cure, rhGM-CSF may ameliorate symptoms of mucositis by increasing the immune response via macrophage activation and stimulation of secondary cytokines. PATIENTS AND METHODS: 32 patients with locally advanced head and neck cancer were treated with adjuvant local radiotherapy after surgery (60 Gy in 30 dose fractions). In a pilot study, 16 patients received rhGM-CSF for five days, starting after a radiation dose of 20 Gy. These patients were compared retrospectively with a control group of 16 matching patients. Patients were assessed according to the Oral Assessment Guide (OAG), the Composite Mucositis Score (CMS) and the Common Toxicity Criteria (CTC) for severity of mucositis and pain. RESULTS: When compared with controls, patients on rhGM-CSF treatment showed decreased OAG, CMS and CTC scores. During the following irradiation courses mucositis was less severe in patients previously treated with rhGM-CSF. With regard to pain relief, rhGM-CSF-treated patients demonstrated a statistically significant improvement (p = 0.011), compared with controls. CONCLUSION: rhGM-CSF affected the severity of oral mucositis and reduced the related pain. As rhGM-CSF was well tolerated, this effect will be further investigated in prospective, controlled study.

A phase II study of high-dose octreotide in patients with unresectable pancreatic carcinoma.

This report describes the results of a phase II trial to evaluate the safety, feasibility and response of patients with irresectable, histologically proven, stage II-IV adenocarcinoma of the pancreas receiving high-dose octreotide treatment. Octreotide was self-administered subcutaneously (3 x 2000 micrograms per day) by 49 patients. Therapy was discontinued after progression of the disease. Due to the subseqment diagnosis of bile duct carcinoma and stage I disease, 2 patients were excluded, leaving 47 evaluable patients with measurable disease. The median Karnofsky score was 80%. 3 patients had stage II (6%), 19 stage III (40%), and 25 (53%) stage IV disease. Octreotide treatment resulted in stable disease in 9 patients (19%) for more than 12 weeks. No complete or partial response was observed. The median overall survival was 21.4 weeks and the median progression-free survival 9.0 weeks. Therapy with high-dose octreotide is feasible, well tolerated and might prolong survival. In a placebo-controlled phase III study the effects of octreotide in patients with pancreatic cancer will be confirmed.

Recombinant human granulocyte and granulocyte-macrophage colony-stimulating factor (G-CSF and GM-CSF) administered following cytotoxic chemotherapy have a similar ability to mobilize peripheral blood stem cells.

The availability of hematopoietic growth factors has greatly facilitated the mobilization and collection of peripheral blood stem cells (PBSC). It was the aim of this double-blind study to compare the PBSC-mobilizing efficacy of recombinant human G-CSF and GM-CSF when administered post-chemotherapy. Twenty-six patients with relapsed Hodgkin's disease were included in the study. Their median age was 31 years (range, 22-59) and 14 patients were males and 12 were females. Patients were pretreated with a median of eight cycles of cytotoxic chemotherapy, while 18 patients had undergone extended field irradiation. The patients received dexamethasone 24 mg days 1-7, melphalan 30 mg/m2 day 3, BCNU 60 mg/m2 day 3, etoposide 75 mg/m2 days 4-7, Ara-C 100 mg/m2 twice daily days 4-7 (Dexa-BEAM). Twelve patients were randomized to receive 5/microg/kg/day G-CSF and 14 patients to receive 5 microg/kg/day GM-CSF, both administered subcutaneously starting on day 1 after the end of Dexa-BEAM. Primary endpoints of the study were the number of CD34+ cells harvested per kg body weight on the occasion of six consecutive leukaphereses and the time needed for hematological reconstitution following autografting. Twenty-one patients completed PBSC collection, and six patients of the G-CSF group and nine of the GM-CSF group were autografted. No difference was observed with respect to the median yield of CFU-GM and CD34+ cells: 32.5 x 10(4)/kg vs 31.3 x 10(4)/kg CFU-GM, and 7.6 x 10(6)/kg vs 5.6 x 10(6)/kg CD34+ cells, for G-CSF and GM-CSF, respectively (U test, P= 0.837 and 0.696). High-dose chemotherapy consisted of cyclophosphamide 1.7 g/m2 days 1-4, BCNU 150 mg/m2 days 1-4, etoposide 400 mg/m2 days 1-4. All patients transplanted with more than 5 x 10(6) CD34+ cells/kg had a rapid platelet recovery (20 x 10(9)/l) between 6 and 11 days and neutrophil recovery (0.5 x 10(9)/1) between 9 and 16 days, while patients transplanted with less than 5 x 10(6)/kg had a delayed reconstitution, regardless of the kind of growth factor used for PBSC mobilization. In conclusion, our data indicate that in patients with Hodgkin's disease G-CSF and GM-CSF given after salvage chemotherapy appear to be not different in their ability to mobilize PBSC resulting in a similar time needed for hematological reconstitution when autografted following high-dose therapy.

Downregulation of the proinflammatory cytokine response to endotoxin by pretreatment with the nontoxic lipid A analog SDZ MRL 953 in cancer patients.

Interfering with the endotoxin-mediated cytokine cascade is thought to be a promising approach to prevent septic complications in gram-negative infections. The synthetic lipid A analog SDZ MRL 953 has been shown to be protective against endotoxic shock and bacterial infection in preclinical in vivo models. As part of a trial of unspecific immunostimulation in cancer patients, we conducted a double-blind, randomized, vehicle-controlled phase I trial of SDZ MRL 953 to investigate, first, its biologic effects and safety of administration in humans and, second, its influence on reactions to a subsequent challenge of endotoxin (Salmonella abortus equi). Twenty patients were treated intravenously with escalating doses of SDZ MRL 953 or vehicle control, followed by an intravenous application of endotoxin (2 ng/kg of body weight [BW]). Administration of SDZ MRL 953 was safe and well-tolerated. SDZ MRL 953 itself increased granulocyte counts and serum levels of granulocyte colony-stimulating factor (G-CSF) and interleukin-6 (IL-6), but not of the proinflammatory cytokines tumor necrosis factor-alpha (TNF-alpha), IL-1beta, and IL-8. Compared with vehicle control, pretreatment with SDZ MRL 953 markedly reduced the release of TNF-alpha, IL-1beta, IL-8, IL-6, and G-CSF, but augmented the increase in granulocyte counts to endotoxin. Induction of tolerance to the endotoxin-mediated cascade of proinflammatory cytokines by pretreatment with SDZ MRL 953 in patients at risk may help to prevent complications of gram-negative sepsis.

The effect of recombinant human granulocyte macrophage colony stimulating factor after chemotherapy of various tumors.

Recombinant human granulocyte macrophage colony stimulating factor (rhGM-CSF) has been successfully used in different clinical settings. We evaluated the tolerability of rhGM-CSF treatment in addition to its efficacy in preventing myelosuppression and reducing infectious complications after standard-dose chemotherapy of various tumors. Of the patient group analyzed (n = 308), 75% had solid tumors and 25% had hematological malignancies. In 27.9% of these patients an infection occurred after the first cycle of chemotherapy and between 8.2 and 19.0% in later cycles with a mean duration of fever (above 38.5 degrees C) of 3.6 days. Treatment with rhGM-CSF was well-tolerated. After the completion of treatment, the investigators assessed the efficacy of rhGM-CSF in 83.7% of the patients as 'very good' or 'good', and as 'moderate' or 'bad' in only 11.5% of patients as well as the tolerability as 'very good' or 'good' in 87.0% of the patients and in 9.4% 'moderate' or 'bad'. We conclude that rhGM-CSF proved to be an effective and well-tolerated tool in preventing myelosuppression and infectious complications after standard-dose chemotherapy of various tumors.

Treatment of prolonged chemotherapy induced severe thrombocytopenia with recombinant human interleukin-3--a report on four cases.

Interleukin-3 (IL-3) is a multipotent hematopoietic growth factor, which exhibits stimulatory effects on leucocytes, reticulocytes and platelets. Due to its pronounced induction of megakaryopoiesis, IL-3 is thought to be a cytokine with the potential to prevent and to overcome chemotherapy-induced thrombocytopenia. We report on four cases (two of metastatic breast cancer, one of metastatic ovarian cancer and one of Hodgkin's disease) with prolonged chemotherapy-induced thrombocytopenia in whom rhIL-3 in combination with either recombinant human (rh) granulocyte macrophage colony stimulating factor (GM-CSF) or rh granulocyte colony stimulating factor (G-CSF) was administered. In all cases, a steady and clinically significant increase in platelet counts could be observed. No major side effects, neither due to the application of rhIL-3 nor due to rhGM-CSF or rhG-CSF, occurred; only flu-like symptoms were seen, which could effectively be treated with paracetamol. This report highlights the efficacy of combined treatment with rhIL-3 plus rhGM-CSF or rhG-CSF in chemotherapy-induced thrombocytopenia, where megakaryopoiesis could be stimulated efficiently by rhIL-3. Based on this experience, the authors conclude that established thrombocytopenia as a major side effect of myelosuppressive chemotherapy should be considered as an indication for the use of rhIL-3 in interventional treatment. Further investigations in this area are encouraged.

Regression of a distal bile duct carcinoma after treatment with octreotide for 6 months.

We report the case of a 66-year-old male who was admitted for obstructive jaundice presenting with an enlargement of the pancreatic head on CT scan. During exploratory laparotomy an invasion of the retropancreatic mesenteric vessels was found. Subsequently, the patient was included in a multi-center trial of subcutaneous high-dose octreotide in irresectable pancreatic cancer. After 6 months there was no tumour detectable on routine CT follow-up. One year after commencing octreotide treatment the patient underwent Whipple resection; the specimen showing a small T1N0M0 distal bile duct carcinoma. Taking into account that somatostatin receptors have been found on bile duct cancer cells our observation might warrant a controlled clinical trial.

Chemotherapy-induced severe thrombocytopenia in gynecologic oncology and its treatment with interleukin-3.

Six patients suffering from various gynecologic malignancies developed severe thrombocytopenia (WHO IV) after normal-dose chemotherapy. All patients were treated with platelet transfusions but the results on hematopoietic recovery were not satisfactory. Therefore treatment with a new hematopoietic substance (rh interleukin-3) was initiated. All patients received a dosage of 5 mu g/kg/bw daily s.c. up to 10 days depending on the response of platelet counts. In two women, who had suffered from severe hemorrhage (epistaxis resp. ankle joint hematoma), symptoms disappeared after approximately three days of rhIL-3 use. Whereas platelet transfusions were ineffective in all patients, IL-3 led to a significant increase of the platelet count after 3-5 days of application. Side-effects were mild, when seen in one case, where G-CSF was given at the same time. Our experience supports the idea of using new growth factors like rhIL-3 to cure chemotherapy-induced myelosuppression, such as severe thrombocytopenia.