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Background: We performed a phase-II-study combining 41.8 degrees C whole body hyperthermia with ICE chemotherapy, i. e., ifosfamide (5 g/m (2) on day 1), carboplatin (300 mg/m (2) on day 1) and etoposide (150 mg/m (2) on days 2 and 3), administered every 4 weeks, to assess the treatment benefit for patients with malignant pleural mesothelioma. To date this is mainly done by measurement of response rates and overall survival, as it can be widely found in the literature. In fewer cases there is also a quality of life assessment. Here we describe an instrument well-capable for a more comprehensive statement on the therapeutic benefit by linking several study end points including quality of life assessment, the Modified Brunner-Score (MBS)., Material and Methods: The Modified Brunner Score (MBS) was used for this assessment. MBS integrates progression free survival, change of physical performance (WHO-index), a quality of life self-assessment by the patient and toxicity. A positive score means a therapy benefit and vice versa., Results and Conclusions: Of 27 chemonäive, non-metastatic patients enrolled, 22 were evaluable for assessment. Overall survival and progression free survival for all patients was 76 weeks (95 % CI 65.4 weeks - 87.8 weeks) and 29.6 weeks (95 % CI 24.4 weeks - 34.7 weeks) respectively. Major treatment toxicities included grade 3/4 neutropenia and thrombocytopenia and affection of the GI tract, like mucositis, nausea and vomiting. Mean Improvement of Performance Index (WHO) was 0.29 points. The MBS showed a score of 4.21 points (- 4.43 - 16.45 range) for the overall study group. 16 of 22 evaluable patients achieved a positive score. MBS is a suitable tool to evaluate the treatment benefit especially in non-standard therapy approaches. For WBH plus ICE, it showed a beneficial effect on overall quality of life in the majority of patients. more...

We performed a phase II study combining 41.8 degrees C whole body hyperthermia with ICE chemotherapy, i.e. ifosfamide (5 g/m(2)), carboplatin (300 mg/m(2)) and etoposide (150 mg/m(2) on days 2 and 3), administered every 4 weeks, for patients with malignant pleural mesothelioma. Of 27 chemonäive, non-metastatic patients enrolled, 25 patients were evaluable for response. Overall response rate was 20% (five partial remissions; 95% CI 8.9-39.1%). Median survival time from the start of treatment for all patients was 76.6 weeks (95% CI 65.4-87.8 weeks). Progression free survival for all patients measured 29.6 weeks (95% CI 24.4-34.7 weeks). One year overall survival was 68% and 2 year overall survival was 20%. Major treatment toxicities included grade 3/4 neutropenia and thrombocytopenia in 74 and 33% of treatment cycles, respectively. One patient died due to sepsis. These promising results are consistent with continued clinical investigation; a phase III clinical trial with whole body hyperthermia as the independent variable has been initiated. more...

Background: Based on earlier clinical and preclinical studies, we conducted a phase II trial in metastatic sarcoma patients of the combination of 41.8 degrees C (x60 min) radiant heat (Aquatherm) whole-body hyperthermia (WBH) with 'ICE' chemotherapy. The ICE regimen consists of ifosfamide (5 g/m(2)), carboplatin (300 mg/m(2)) and etoposide (100 mg/m(2)), concurrent with WBH, with etoposide also on days 2 and 3 post-WBH., Methods: Therapy was delivered every 4 weeks for a maximum of 4 cycles. All patients received filgrastim or lenograstim., Results: Of 108 patients enrolled as of September 2001, 95 are evaluable for response. Of the evaluable patients (mean ECOG performance status approximately 1; mean age 42.3; 58% male) 33 had no prior therapy for metastatic disease, and 62 were pretreated (mean: 1.5 prior regimens). The overall response rate was 28.4% (4 complete remissions and 23 partial remissions) with stable disease (SD) in 31 patients. For no prior therapy, the response rate was 36%; in pretreated patients it was 24%. The median overall survival by Kaplan-Meier estimates was 393 days (95% CI 327, 496); the median time to treatment failure was 123 days (95% CI 77, 164). The major toxicity (287 cycles) was grade 3 or 4 neutropenia and thrombocytopenia seen in 79.7 and 60.6% of treatments respectively; there were 7 episodes of infection (grade 3/4) with 2 treatment-related deaths, bot involving disease progression and ureteral obstruction., Conclusion: These results are consistent with continued clinical investigation of this combined modality approach., (Copyright 2003 S. Karger AG, Basel) more...

Purpose: Diffuse malignant pleural mesothelioma is the most common primary pleural malignancy. At the beginning of the last century, this tumor was of minor incidence. Meanwhile, the use of asbestos has led to and is still leading to a rise in pleural mesothelioma incidence. There is no standard therapy for this highly aggressive disease and the development of new therapeutic strategies is imperative., Methods: We, therefore, investigated the morphological and pharmakokinetic effects of a combined thermochemotherapy consisting of the administration of different dosages of mafosfamide with and without the application of a 1-h hyperthermia at 41.7 degrees C on the human biphasic malignant pleural mesothelioma cell line MSTO-211H. After therapy, cells were prepared for light and electron microscopy. BrdU-incorporation for the S-phase fraction, TUNEL-labeling for detection of apoptosis, and quantitative assessments using the MTT assay were performed., Results: Our results demonstrate that the combination of mafosfamide with hyperthermia leads to qualitatively and quantitatively enhanced cellular damage compared to monotherapy. During combined thermochemotherapy, cell damage and death is already induced at lower mafosfamide concentrations than without hyperthermia which suggests an additive effect from hyperthermia to the action of the alkylating drug mafosfamide. Cell death thereby mostly occurs as necrotic cell death rather than as apoptosis, although in a combined thermochemotherapy apoptosis is induced temperature-dependently, when comparing temperatures from 37 degrees C to 43 degrees C., Conclusions: We suggest that the effect of substances such as ifosfamide and cyclophosfamide which are in clinical use, might be enhanced by the combination of local or regional hyperthermia in order to improve the therapeutical index of these substances in the treatment of pleural mesothelioma. more...

Metastatic cancer of the breast in postmenopausal women can be treated with a number of "hormone-active" substances. The drugs of first choice are still anti-estrogens. Today, the three highly selective oral aromatase inhibitors anastrozole, letrozole and exemestane are additionally available for use in continuing progression under anti-estrogen treatment. Roughly one woman in three derives benefit from these new medications as reflected by objective remission or stabilization of the disease for more than 6 months. Neither chemical structure (steroidal/non-steroidal), nor the different nature of inhibition of the active centre of the aromatase, nor whether the inhibition of the enzyme is reversible or irreversible, has any influence on the parameters: response rate, response duration and clinical benefit. more...

Pulmonary lesions and ureter involvement are rare complications of endometriosis. We describe the first case with an involvement of both sites in this condition. The radiographs showed "pulmonary metastases" together with clinical findings of a hydronephrosis, mimicing a malignant metastatic gynecologic tumor of unknown primary. A laparoscopy showed severe endometriotic lesions; therefore the findings were most likely related to the condition of endometriosis. The patient was treated with gosereline acetate for six months (Zoladex). Control radiographs showed complete regression of the pulmonary lesions and the patient is symptom free at 36 months after diagnosis. more...

Purpose: To study in vitro the effect of carboplatin and/or hyperthermia in relation to etoposide (VP-16) cytotoxicity in L929 cells., Methodology/results: Cell survival assays demonstrated that the addition of 41.8 degrees C (x60 min) hyperthermia and carboplatin to VP-16 produced an antagonistic effect relative to VP-16 cytotoxicity in L929 cells; administering carboplatin and hyperthermia 24 h before VP-16 reduced this drug resistance; administering carboplatin and hyperthermia 48 h before VP-16, however, produced a supra-additive cytotoxicity. In order to gain insight into the molecular basis for these observations, we investigated the effect of hyperthermia and/or carboplatin on the stress protein GRP78, which is known to affect VP-16 cytotoxicity. Results obtained were consistent with the hypothesis that carboplatin and hyperthermia perturbation of NAD + pools results in down-regulation of GRP78 with subsequent modulation of VP-16 cytotoxicity. To further explicate these results we studied G-361 as a control cell line that had significantly higher pretreatment NAD+ levels, which were not affected by carboplatin and/or hyperthermia. This cell line did not exhibit a down-regulation of GRP78 or modulation of VP-16 cytotoxicity as a function of carboplatin and hyperthermia., Conclusions: These data taken collectively, demonstrate a sequence effect (regarding the aforementioned antineoplastic agents), and provide a framework for future studies directed at the therapeutic optimization of the sequential application of carboplatin, hyperthermia, and VP-16. more...

We developed a mouse model in a representative human derived head and neck cancer cell line for preclinical studies to evaluate antitumor response, tumor-free survival and host toxicity of alkylating agents, antimetabolites, platinum analogs and taxanes alone or in combination. Ninety athymic NMRI mice were inoculated with human derived oral squamous cell carcinoma cells growing on the hind paw to an average volume of 180 +/- 80 mm3. Animals were stratified according to tumor volume into 10 groups (n=6-10) and treated with ifosfamide (65 mg/kg b.w.), docetaxel (24 mg/kg b.w.), cisplatin (2 mg/kg b.w.), carboplatin (6 or 10 mg/kg b.w.), methotrexate (1 mg/kg b.w.), and fluorouracil (15 mg/kg b.w.) intravenously in single agent or combination (ifosfamide plus docetaxel or ifosfamide plus carboplatin) treatment schedules or controls. Tumor volume was measured 3 times per week for 60 days. The average tumor volume, the overall survival time and the response rates (CR, PR) of the treated animals were compared with the data obtained from untreated controls and statistically evaluated. Untreated tumors showed rapid and exponential tumor growth. Single agent therapies with ifosfamide, cisplatinum, and docetaxel lead to significant tumor regression and improved overall survival. Low dose carboplatin monotherapy induced significant tumor growth delay, but not significant tumor regression. Most impressive tumor-free survival was achieved by combination treatment with ifosfamide and docetaxel. This preclinical study demonstrates an animal model capable of differentiating various chemotherapy regimens. more...

The aim of this study was to determine whether the addition of whole body hyperthermia (WBH) to carboplatin (CBDCA) can induce responses in patients with platinum-resistant ovarian cancer. 16 pretreated patients with platinum-resistant ovarian cancer were entered on a Systemic Hyperthermia Oncological Working Group (SHOWG) study; (14 patients were eligible with 14 evaluable for toxicity and 12 for response). The patients were treated with WBH (Aquatherm) 41.8 degrees C x 60 min in combination with carboplatin (CBDCA) (area under the curve (AUC) of 8) every 4 weeks. Disease status was evaluated every two cycles. Patients were treated for a maximum of six cycles. One patient had a complete response (CR) and 4 had a partial response (PR). 4 patients had stable disease (SD). 3 patients had progressive disease (PD). 2 patients were unevaluable: 1 had a bowel obstruction shortly after her first treatment; the second patient achieved a CR, but only had one treatment secondary to an idiosyncratic reaction to sedative drugs. 2 patients entered on study were ineligible, as they did not meet criteria for platinum resistance; 1 entered a CR and 1 had SD. Dose-limiting toxicity, which required CBDCA dose reductions, was grade 4 thrombocytopenia. Other toxicities included neutropenia (grade 3/4), and nausea and/or vomiting. Consistent with preclinical modelling, these results suggests that 41.8 degrees C WBH can overcome platinum resistance in ovarian cancer. These observations suggest further investigation of the therapeutic potential of WBH in a group of patients who historically fail to respond to salvage therapies is warranted. more...

Purpose: To investigate the feasibility and effectiveness of radiochemothermotherapy (triple-modality therapy) in patients with inoperable recurrent breast cancer., Patients and Methods: Patients with inoperable recurrent lesions, World Health Organization (WHO) performance status of 2 or greater, life expectancy of more than 3 months, adequate bone marrow, hepatic and renal function were eligible for this Phase I/II study. Conventionally fractionated or hyperfractionated radiotherapy (RT) was performed. Once-weekly local hyperthermia (HT) combined with chemotherapy (CT; epirubicin 20 mg/m(2), ifosfamide 1.5 g/m(2)) was applied within 30 min after RT., Results: Twenty-five patients, all heavily pretreated (18/25 preirradiated), received a mean total dose of 49 Gy. The median number of HT/CT sessions was 4. Skin toxicity was low, whereas bone marrow toxicity was significant (leucopenia Grade 3/4 in 14/1 patients). The overall response rate was 80% with a complete response (CR) rate of 44%. Response rates in patients with noninflammatory disease (n = 14; CR 10 patients, partial response [PR] 3 patients) were far better than in patients with inflammatory disease (n = 11; CR 1 patient, PR 6 patients)., Conclusions: In patients with recurrent breast cancer, triple-modality therapy is feasible with acceptable toxicity. High remission rates can be achieved in noninflammatory disease, however, local control is limited to a few months. Whether the addition of chemotherapy has a clear-cut advantage to radiothermotherapy alone remains an open question. more...

Patients with brain metastases in disseminated non-seminomatous germ cell cancer of the testis are treated by combined modality, e.g., cisplatin-containing chemotherapy, whole brain irradiation and/or surgical excision. However, cure rates of patients refractory to that standard treatment are low (5-year survival rate <30%). Preclinical data on the use of hyperthermia combined with selected cytotoxic drugs clearly show increased tumor cell killing compared to chemotherapy alone with no increase in toxicity to normal tissue. These results are consistent with the concept that whole body hyperthermia (WBH) at 41.8 degrees C is non-myelosuppressive and can potentiate the tumoricidal effects of specific chemotherapeutic agents, thus improving the therapeutic index. We report on a patient with embryonal testicular cancer presenting with lung, liver and brain metastases who initially underwent orchiectomy, whole brain irradiation and cisplatin-containing chemotherapy. Restaging revealed minor regression of brain and lung metastases and no change of liver metastases. However, beta-HCG values dropped from initial 400000 mIU/ml to 12 mIU/ml with a normal alpha-fetoprotein all the time. Then, two cycles of whole body hyperthermia (WBH) plus chemotherapy were performed, followed by one cycle of chemotherapy without WBH. Radiotherapy, WBH and chemotherapy were well tolerated, especially no neurologic sequelae occurred. After more than 5 years of follow-up, the patient is still alive and disease-free. WBH plus chemotherapy seems to be feasible and may contribute to long-term survival in patients with advanced stages of non-seminomatous germ cell cancer refractory to standard treatment. more...

Increased thrombin generation associated with resistance to activated protein C makes the latter a likely candidate for an increased risk of acute coronary events. Activated protein C resistance (factor V Leiden) on its own, however, appears to have no significant effect in this regard. We describe a case of recurrent myocardial infarction caused by coronary thrombosis in a patient with persistent thrombocytopenia who was found to have a coexistence of heterozygous factor V Leiden and primary antiphospholipid syndrome. Since both thrombophilic disorders interfere with the protein C anticoagulant system, the simultaneous existence of inherited and acquired resistance against activated protein C could account for an increased thrombophilia with manifestation in the coronary arteries. This case suggests that evaluation of patients who present with recurrent acute coronary events should also consider these coagulation defects. more...

We report on the analysis of a murine anaplastic lymphoid cell line TS1G6, established recently by interleukin (IL)-9 transfection. TS1G6 revealed a highly characteristic pattern of large anaplastic cells with mononuclear, binuclear, or multinuclear cells resembling Hodgkin (H) or Sternberg-Reed (SR) cells. This cell line is tumorigenous after injection of as few as 10(4) lymphoma cells into nude or immunocompetent C57Bl/6 mice and leads to death from progressive disease of all treated animals within a few weeks. The histological analysis of these tumors revealed a diffuse large cell malignant lymphoma that is morphologically almost identical to human anaplastic large cell lymphoma (ALCL). The lymphoma cells did not show overexpression of the anaplastic lymphoma kinase (ALK) gene, which is found in about 50% of the cases of human ALCL. Thus, this model may be an animal model for an important subset of human ALCL. The cytokine profile, which is of the T helper 2 type, showed strong parallels to the human lymphoma counterpart. Mice suffering from such lymphomas could not be cured with a regimen using high dose cyclophosphamide similar to many ALCL patients. Such an animal model for ALCL has not yet been recognized, but may provide the basis for investigating new antitumor immunotherapies in a fully immunocompetent host. more...

History and Clinical Findings: A 57-year-old man presented with dyspnoea, cough, fatigue and weight loss. He had been exposed to asbestos 30 years ago. Physical examination was unremarkable apart from a suspected pleural effusion., Investigations: Computed tomography (CT) of the thorax showed multiple pleural masses with pleural effusion on the left side. CT of the abdomen and bronchoscopy were normal. The patient underwent explorative thoracoscopy; biopsies were taken, and diffuse malignant pleural mesothelioma was demonstrated., Treatment and Course: The patient was evaluated at the University Hospital Lübeck for Phase II experimental therapy with whole-body hyperthermia (WBH). The pretreatment evaluation revealed normal cardiorespiratory function and a normal contrast-enhanced CT of the brain. The patient's haematologic profile and electrolytes were normal. The WBH-radiant heat device (RHD) used for therapy was Aquatherm provided by the Cancer Research Institute (CRI, New York, USA). The patient received ifosfamide (5 g/m2, day 1), carboplatin (300 mg/m2, day 1), etoposide (150 mg/m2, days 2-3) combined with WBH at 41.8 degrees C (for 60 minutes). Two cycles were applied without complications and a partial remission of the disease was observed., Conclusion: Radiant heat whole body hyperthermia, in conjunction with a defined anticancer treatment and pharmacological approach to sedation, was a safe and effective palliative treatment in this patient. more...

Although whole-body hyperthermia combined with specific genotoxic chemotherapy can be shown to enhance neoplastic cell killing without a concomitant rise in bone marrow toxicity, nephrotoxicity can become treatment-limiting. This study compares the kidney toxicity to the kidney of ifosfamide, carboplatin and etoposide (ICE) chemotherapy alone, and ICE chemotherapy combined with either extracorporeal (e-WBH) or radiant-heat-induced hyperthermia (r-WBH) in 43 patients with refractory sarcoma. Within 3 days of ICE chemotherapy treatment there was a significant increase in urinary protein excretion and a reduction of the glomerular filtration rate. These effects were more pronounced if WBH was added. The use of immunoluminometric assays revealed a predominance of low-molecular-mass proteins. This increase in protein excretion persisted in the e-WBH-treated group, whereas it vanished within 3 weeks in both the group treated with ICE alone and that treated with r-WBH. Our findings suggest that ICE chemotherapy causes transient tubular and glomerular damage, which is enhanced by WBH. In terms of long-term nephrotoxicity e-WBH was more nephrotoxic than r-WBH. This finding is consistent with our clinical observations. more...

As there is still a high mortality of the large cell anaplastic non Hodgkin lymphoma (ALCL) (between 40-70%, depending on prognostic factors) there is a need for new therapeutic approaches. Therefore, we studied different strategies for cancer immunotherapy in an immunogenic ALCL tumor model system: A murine IL-9 dependent T cell line was transfected with IL-9 cDNA, resulting in an autonomous growing T cell line designated G6BB, which had a high tumor incidence after injecting of as few as 10(4) cells subcutaneously into syngeneic C57Bl/6 mice. Tumor growth, dissemination, histology, and immunohistochemistry were similar to human ALCL. This mouse model provides an immunogenic in vivo system to investigate antitumor immunotherapies. In order to increase antigen recognition by T cells and T cell activation, we administered tumor bearing mice cell-based cancer vaccines with irradiated tumor cells alone or in combination with immunostimulating CpG-Oligonucleotides, a combination of Th1 cytokines and Th2 cytokine antibodies (IL-12, IFN-gamma, GM-CSF, Anti-IL-10) (after detecting a Th2 cytokine profile in G6BB), or the recall antigens diphtheria, pertussis, and tetanus. more...

Background: In a previous phase II trial of ifosfamide (IFO) several patients with pancreatic cancer responded to therapy (1). Trofosfamide (TROFO) is an orally taken oxazaphosphorine prodrug. Metabolic products of TROFO include ifosfamide (IFO) and cyclophosphamide (CYCLO). In clinical pilot studies with TROFO against refractory malignancies mild toxicity was reported., Patients and Methods: Since virtually all patients with advanced pancreatic cancer are symtomatic, we designed and conducted a prospective phase II trial to evaluate the activity of single agent therapy with TROFO given orally continuously (three times 50 mg daily), and to assess the toxicity, duration of remission, and overall survival of the treated patients., Results: 16 patients were enrolled onto the study. In one patient a PR has been observed; the mayor response rate was 6%. The mayor toxicity was bone marrow toxicity with granulocytopenia (WHO grade II) and anemia (WHO grade II) in virtually all patients., Conclusion: Single agent therapy with TROFO in patients with pancreatic cancer is safe and well tolerated; however, it shows low clinical activity. more...

Whole Body Hyperthermia (WBH) enhancement of chemotherapy and/or radiation without a concomitant increase in myelosuppression has been documented in clinical trials. We propose that the biological basis for this phenomena relates in part to the previously reported induction of peripheral cytokines by WBH, that is, granulocyte colony stimulating factor (G-CSF), interleukin (IL)-1 beta, IL-6, IL-8, tumor necrosis factor-alpha (TNF-alpha), and the regulatory cytokine IL-10. To further explain this myeloprotection and the additional clinical observation that WBH promotes early engraftment of bone marrow (when used as part of an allogenic bone marrow transplant preconditioning regimen) we developed a hypothesis: WBH increases peripheral IL-1 beta, IL-6, and TNF-alpha resulting in a secondary induction of IL-3 and granulocyte macrophage colony stimulating factor (GM-CSF) in the bone marrow, for which supportive data also exists. Taken collectively, these data provide an increased understanding of the biological sequelae of fever, as well as a testable unifying hypothesis, for future antineoplastic treatment strategies. more...

Rationalization in clinical care has reached its limits. Facing the need of further reducing health care costs it is relevant to reflect which diagnostic and therapeutic procedures are justified considering the public economic interests. A prioritized list of covered medical care requires a consensus of physicians, insurance companies and patients organizations on the basis of evidence-based medicine. more...

Previous in vitro studies of sarcoma and normal cell lines exposed to 41.8 degrees C (x 60 min) demonstrated selective increased expression of members of the heat shock protein (HSP) family 70 on the cell surface of the sarcoma cells only. One implication of these data relates to the clinical application of targeting a stress-inducible, tumor-specific immune response. We therefore elected to measure immune response parameters (i.e., serum antibodies against HSP70i, 60, and 27) in six patients with sarcoma using a Western blot technique. These study patients received one to four successive 41.8 degrees C whole-body hyperthermia (WBH) x 60-min treatments (given every 3 weeks). We also tested the serum of 10 untreated healthy control subjects for the same parameters. In all patients, baseline HSP antibody levels were detectable; in no case did WBH result in an increase in HSP antibodies. The serum of one patient with sarcoma demonstrated a strong nonfluctuating reaction against HSP27 before and after WBH that had no obvious correlation; this was not observed in the sera of the control subjects. This study suggests that WBH does not induce a B-cell response to HSP family 70 antigens; these data, however, do not exclude the possibility of NK cell activation due to HSP antigen presentation. more...

The palliative treatment of malignant stenoses of the upper gastrointestinal tract by self-expanding metal stents is a novel procedure with effective relief of dysphagia in most patients. There is little follow-up information with respect to the factors influencing clinical outcome and survival rates. Survival rates of 40 consecutive patients treated with 53 mesh stents were analyzed with regard to their degree of dysphagia (grades 0-3), quality of life (Karnofsky score), and the effect of additional radiation and chemotherapy. Following stent placement dysphagia improved in 36 of 40 patients. Endoscopic reinterventions for worsening of dysphagia were necessary in 23 patients during a median follow-up period of 74 days (range 51-149). There was a trend towards superior survival time in younger patients (<60 years) with high Karnofsky score ( 70). Patients receiving concurrent radiation and chemotherapy (n=12) experienced prolonged survival (median 318 days after diagnosis, 225 days after stent) compared with patients of equal tumour staging, but without additional therapy (n=17; median 157 days after diagnosis, p<0.001; 138 days after stent, p<0.05). The combination of endoscopic stenting with additional radiation and chemotherapy was associated with improved survival. A randomized trial is warranted. more...

Recent studies have shown that recombinant human erythropoietin (rHuEPO) is effective in correcting anaemia in about 50% of tumour patients. Predictive parameters for the response to rHuEPO still need to be established. In the present prospective study, rHuEPO therapy was scheduled in 22 patients with solid tumours for 12 weeks (3x10,000 U rHuEPO/week s.c.). If response was not achieved within 4 weeks, the dose was increased to 3x20,000 U rHuEPO/week. All patients received combined chemotherapy (ifosfamide, carboplatin, etoposide) before and during rHuEPO therapy. 10 of the 22 patients responded to rHuEPO and did no longer need blood transfusions. In 8 of the 10 responders and in 2 of the 12 non-responders serum creatinine concentration was increased before rHuEPO therapy was started. In addition, the endogenous serum EPO concentrations were significantly lower in the responders versus the non-responders. We conclude that rHuEPO is primarily effective in patients with chemotherapy-induced renal impairment. The rate of the response to rHuEPO is high when the baseline serum EPO level is <75 U/l and the serum creatinine concentration is greater than normal (or the estimated creatinine clearance <60 ml/min). more...

The antiphospholipid syndrome (APS) is an autoimmune thrombophilic disorder in which thromboembolism and thrombocytopenia occur. The antiphospholipid antibodies in these patients may cause acquired activated protein C resistance, whereas hereditary activated protein C resistance results from a common single point mutation in coagulation factor V (factor VLeiden). In a family of 11 members with 4 normal subjects, autoimmune thrombocytopenia was documented in 6 patients. Three out of these were found to have thrombocytopenia associated with primary APS. In addition, these 3 subjects were also heterozygous for the factor VLeiden. Only in this group of individuals did life threatening thromboembolic complications occur, while other thrombocytopenic family members showed no thrombotic manifestations. Genetic studies revealed no linkage between APS and HLA class II alleles. Taken together, we present a family with autoimmune thrombocytopenia, which is associated with primary APS in at least 50% of thrombocytopenic individuals. The coexistence of both APS and factor VLeiden in thrombocytopenic subjects, led to an increased number of thrombotic events, suggesting a critical role of combined acquired and hereditary activated protein C resistance in the development of thrombosis in this family. Since no association between APS and specific HLA groups was found, other underlying risk factors for the development of APS must be considered. more...

It was previously postulated on the basis of clinical data that the cardiovascular sequelae of extracorporeal whole-body hyperthermia (e-WBH), i.e., hypotension (which requires catecholamine support) results in unique nephrotoxicity in combination with select chemotherapeutic agents. In an attempt to explain this phenomenon, we mimicked e-WBH physiological conditions in a rat model. Animals were treated with and without ifosfamide (IFO) and/or carboplatin (CBDCA) at 37 degrees C or 41.5-41.8 degrees C, with blood pressure monitoring and catecholamine support comparable to the clinical setting. Ex vivo post-treatment data (24 h) from artificially perfused kidneys (i.e., histology, urine volume, perfusion rate, glomerular filtration rate, and the reabsorption of sodium, glucose, and water) demonstrated unique toxicity including proximal tubular necrosis for the combination of WBH and IFO, for WBH and CBDCA and for WBH and IFO plus CBDCA, but not for IFO and CBDCA without WBH. These data, considered together with results derived from a subsequent clinical trial and the laboratory work of others were consistent with the hypothesis. more...

It has previously been reported by the authors that the induction of a series of cytokines by 41.8 degrees C Whole Body Hyperthermia (WBH), i.e., interleukin (IL)-1 beta, IL-6, IL-8, IL-10, tumour necrosis factor alpha, and granulocyte colony stimulating factor (G-CSF). As cytokine levels are known to fluctuate as a function of time, i.e. circadian rhythm, the influence of circadian time structure on specific haemotopoetic growth factors is studied, i.e. granulocyte macrophage colony stimulating factor (GM-CSF), G-CSF and IL-3. Samples derived from four cancer patients undergoing extracorporeal WBH resulted in the following observations: G-CSF is induced by WBH, but unaffected by circadian rhythm, IL-3 fluctuates with circadian rhythm, but is unaffected by WBH. Specifically, a biphasic temporal pattern of IL-3 (i.e. with a peak at 2:00 and 5:00 a.m. and a nadir concentration at 5:00 p.m.) was found by analysis of variance. GM-CSF was below the lower detection limit pre and post WBH. The data show the importance of measuring cytokines as a function of time to circumvent conflicting results in the inter-relationship of 'true' cytokine induction and circadian rhythm. The implications of the differential induction of G-CSF, GM-CSF, and IL-3 for myeloprotection after WBH are discussed. more...

Whole Body Hyperthermia (WBH) has been shown to have physiological effects on myeloid and megakaryocytic haematopoietic tissue via both cytokine induction, as well as hormonal changes. In order to extend this knowledge base to the erythroid cells, endogenous erythropoietin (EPO) levels were studied in 17 cancer patients receiving 41.8 degrees C WBH and/or chemotherapy, as well as in 53 anaemic and non-anaemic control patients. Pre-treatment EPO levels showed a 'blunted' EPO response in cancer patients compared to the control patients. Post-treatment data demonstrated a significant chemotherapy induced increase in EPO levels with a peak at 36 to 48 hours (independent of changes in haemoglobin) and 10 to 13 days post chemotherapy (simultaneously with a drop in haemoglobin levels). The early change in EPO levels was not influenced by the addition of 41.8 degrees C (x 60 min) WBH to the same chemotherapy regimen, i.e., ifosfamide, carboplatin, and etoposide. Taken collectively, our data show that endogenous EPO levels in cancer patients can be effected by chemotherapy (independent of changes in haemoglobin). This EPO response to chemotherapy is not impacted on by 41.8 degrees C WBH. A relevant secondary conclusion can also be derived from this investigation, i.e., caution should be exercised as to the use of EPO levels during chemotherapy as predictors of exogenous EPO efficacy. more...

Preclinical studies are consistent with the concept that 41.8 degrees C whole body hyperthermia (WBH) can enhance the therapeutic index of specific chemotherapeutic agents. These laboratory investigations resulted in 2 phase I clinical studies, which also support this hypothesis. These trials were extended to 2 sequential phase II investigations of WBH plus ifosfamide, carboplatin and etoposide (ICE) for refractory sarcoma patients. The first study (involving 12 patients) using extra-corporeal WBH was prematurely closed to adopt a less toxic WBH technology, i.e., the radiant heat Aquatherm. To date, 12 patients have been accrued to the Aquatherm trial. Projections regarding reduced morbidity were correct. The response rate for ICE/WBH is currently 63%. The review to follow will summarize the results of these trials, as well as the laboratory and clinical data which serve to explicate the dramatic clinical results observed to date. more...

The relation between the number of platelets in blood and the concentrations of immunoreactive thrombopoietin (TPO), interleukin 6 and interleukin 11 (IL-6, IL-11) was studied in the sera of 32 normal subjects, of 29 untreated tumour patients and of 6 tumour patients following chemotherapy with ifosfamide, carboplatin and etoposide (ICE). Platelet counts, TPO and IL-6 concentrations were higher than normal in blood of tumour patients before chemotherapy. However, no statistical relation existed between these variables. Following chemotherapy, the number of circulating platelets decreased reaching a nadir at d 10-13, while the serum concentration of TPO increased concomitantly. Circulating IL-6 did not increase during chemotherapy-induced thrombocytopenia. IL-11 was not detectable in any serum. Thus, the reactive thrombocytosis in tumour patients could be related to elevated TPO and IL-6 levels. In contrast to circulating TPO, however, neither serum IL-6 nor IL-11 levels increase significantly in thrombocytopenia following myelosuppressive. chemotherapy. more...

The combination of ionizing irradiation and local hyperthermia therapy has been demonstrated to be efficacious in a variety of localized neoplasms. One of the most consistent conclusions from this experience, however, is the finding that large tumor size is a significant negative prognosticator for attaining complete tumor regression. During the past decade investigators have begun to look at the possibility of adding chemotherapy to thermo-radiotherapy in order to improve the efficacy of treatment in patients with large tumors. This review article summarizes the recent clinical experience with such triple modality therapy. more...

Preclinical data is consistent with the concept that the timing of chemotherapy during radiant heat-whole body hyperthermia (WBH) should affect therapeutic index. In order to test this hypothesis, a controlled clinical investigation was initiated. Patients received carboplatin (CBDCA) on an early or late schedule with respect to achieving target temperature (i.e. 41.8 degrees C) in alternating treatment cycles. The first cycle was randomized between patients regarding the early or late schedule for two planned sets per patient (i.e. four cycles). Ifosfamide, etoposide and granulocyte colony stimulating factor were delivered during all cycles with a standardized schedule. A total of 53 cycles involving 17 patients were analyzed. Detailed toxicity evaluation (i.e. delay in therapy secondary to thrombocytopenia, need for platelet transfusions, and days of hospitalization) taken collectively demonstrated a statistically and clinically significant advantage to delivering CBDCA 10 min after target temperature, during the plateau phase of WBH. more...

Background: Internal quality control of medical performance in the interest of patient safety is not a new idea. In fact it has been implemented in varying degrees since the beginnings of medicine., Actual Situation and Methods: Ever since hospitals are compelled by law to apply methods of quality assurance and external quality control, the question arises as to whether this law can achieve a concrete increase in quality of patient care or whether it rather serves to support economically motivated goals of health care policies, in the sense of an increase in efficiency of performance by physicians. Seen in the light of the overall situation of hospital care, the attempt to create mandatory quality standards is problematical. A reduction of hospital beds and a decrease in the average length of hospital stay contrasts the growing number of treated patients. This presents a problem which must be compensated for, despite cutbacks in budget and personnel. Methods of quality analysis are of the implicit as well as of the explicit type. Implicit methods are based on retrospective data analysis lacking previously set standards of comparison. These methods harbor the danger of viewer-dependent subjectivity (restricted reliability). Explicit methods are based upon comparison to previously defined standards. These methods are more objective, but often fail to give consideration to individual situations (restricted validity). The infrastructure necessary in order to sensibly apply quality control in the hospitals is not yet present in Germany. The software required in order to record and analyse data is still in a stage of development in many places., Conclusion: It is of importance not to leave external quality control to politicians and economists unfamiliar with the subject matter, but rather that quality control is implemented by experts in the medical field. more...

Purpose: To study the effect of hyperthermia on the cytotoxicity of glucose isophosphoramide mustard (D-19575), a derivative of ifosfamide, which does not require activation and preclinically demonstrates less nephrotoxicity and myelosuppression than ifosfamide., Methods: In vitro studies (using a crystal violet cell survival assay) of the interaction of hyperthermia with D-19575, as well as the activated form of ifosfamide (4-hydroperoxy-ifosfamide, D-18851), were performed using L929 and OVCAR-3 cell lines held at various temperatures (i.e. 37 degrees C (control), 40.5 degrees C, 41.8 degrees C, 42.5 degrees C, and 43 degrees C) for 65 min., Results: The following thermal enhancement ratios (TER) were demonstrated: D-19575 in L929 1.2, 2.0 and 2.3 at 40.5, 41.8 and 42.5 degrees C, respectively; for D-18851 in L929 1.7 at 41.8 degrees C; for D-19575 in OVCAR-3 2.1, 3.2 and 3.3 at 40.5, 41.8 and 42.5 degrees C, respectively; for D-18851 in OVCAR-3 4.6 at 41.8 degrees C., Conclusion: The significant observed increase in cytotoxicity of D-19575 caused by hyperthermia taken together with its known preclinical toxicity profile, encourage its further preclinical and ultimately clinical testing, including its use with whole body and regional hyperthermia. more...

Tumor size is a significant prognostic variable for attaining complete regression (CR) with local hyperthermia (HT) and radiation therapy (RT). The addition of weekly chemotherapy was evaluated to improve the efficacy of thermoradiotherapy in poor-prognosis lesions (i.e. > or = 7 cm2 or > or = 14 cm3) which have an expected CR rate of approximately 30 +/- 8%. Patients were entered into a two-arm phase-II study: arm 1 = breast cancer (10 patients), ifosfamide (1.5 g/m2) + epirubicin (20 mg/m2) + HT + RT; arm 2 = sarcoma (7 patients) and head and neck cancer (9 patients), cisplatin (40 mg/m2) + HT + RT. Therapy encompassing 106 triple-modality sessions was generally well tolerated for both arms; 2 instances of grade-3 and 1 of grade-4 (arm 2) local toxicity (WHO criteria) were observed. There were 4 instances of grade-3 myelosuppression (arm 1). The CR rates for arms 1 and 2 were 70 and 19%, respectively, suggesting that the combination of ifosfamide/epirubicin/HT/RT deserves further investigation in the context of localized breast cancer. more...

Two earlier studies resulted in the design of a phase II trial of 41.8 degrees C (x 60 min) extracorporeal whole body hyperthermia (WBH) with ICE, i.e. ifosfamide (5 g/m2), carboplatin (300 mg/m2), and etoposide given with WBH, as well as, day 2 and 3 post-WBH (100 mg/m2) for adult patients with refractory sarcoma. 12 patients entered this trial; all were evaluable. 8 patients had a history of prior chemotherapy associated with disease progression. Following WBH/ICE, 7 partial remissions were observed (58%); 3 patients experienced disease stabilisation; the aforementioned 10 patients each received four cycles of therapy. 2 patients exhibited progressive disease. Episodes of WHO graded (grade 3; grade 4) toxicity observed included: anaemia (2;2); leucopenia (5;7); thrombocytopenia (1;6); renal (0;1). Other toxicities (grade 1 and 2) included: anasarca, diarrhoea, ventricular arrhythmias, pressure sores, and perioral herpes simplex. more...

The potential for 41.8 degrees C whole body hyperthermia (WBH) to enhance ionizing irradiation and cytotoxic chemotherapy without a commensurate increase in normal tissue toxicity is currently receiving renewed clinical interest. Additionally, WBH may have other biological sequela which may be clinically exploited. In this paper, data are summarized revealing the ability of WBH to induce elevated plasma levels of granulocyte-colony stimulating factor (G-CSF), interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-10 (IL-10), and tumor necrosis factor-alpha (TNF-alpha) within hours of WBH. Data regarding TNF-alpha shows induction in only a proportion of patients. No induction of C-reactive protein (CRP) or the following cytokines was observed: granulocyte macrophage-colony stimulating factor (GM-CSF), interferon-gamma (IFN-gamma), interleukin-1 alpha (IL-1 alpha), interleukin-2 (IL-2), interleukin-4 (IL-4), interleukin-7 (IL-7), interleukin-11 (IL-11), interleukin-12 (IL-12), macrophage-colony stimulating factor (M-CSF), and macrophage inflammatory protein-1 alpha (MIP-1 alpha). Data regarding interleukin-3 (IL-3) and transforming growth factor-beta 1 (TGF-beta 1) were variable and inconclusive. The implications of these results to past and future clinical trials are discussed. more...

The purpose of this study was to evaluate the pharmacokinetics, biological interactions, and toxicities of ifosfamide and carboplatin combined with 41.8 degrees C whole-body hyperthermia (WBH) for 1 h in a pilot clinical study. Nineteen patients with refractory sarcoma or malignant teratoma were treated. To obtain baseline pharmacokinetic data for ifosfamide, the first chemotherapy course was given without WBH in six patients. This enabled comparison of systemic toxicity and pharmacokinetics of the drug combination with and without WBH (+/- WBH). All other patients received three thermochemotherapy treatments every 3 weeks. Ifosfamide was escalated from 5 to 10 g/m2 with a fixed carboplatin dose of 480 mg/m2. WBH was induced by extracorporally heated blood (in a hemodialysis apparatus) with general anesthesia. The drugs were given at target temperature. A total of 49 thermochemotherapy treatments was administered. The use of the hemodialysis device resulted in an approximate one-third reduction of blood concentrations of 4-hydroxyifosfamide, one activated intermediate metabolite of ifosfamide and carboplatin, but in an increase of chloroacetaldehyde, the other main ifosfamide metabolite. The WBC counts and the platelet nadirs (up to WBH grade 4) were not significantly different +/- WBH. Of 19 evaluable patients, 7 partial remissions, 8 disease stabilizations (average duration, 3 months), and 4 patients with progressive disease were observed. There was no WBH-related mortality. Toxicities observed included mild (anasarca, diarrhea, pressure sores, and perioral herpes simplex) and severe (reversible neuropathy, cardiopulmonary distress, and severe renal dysfunction). No hepatic or central nervous system toxicity occurred. Nephropathy was the dose-limiting toxicity. In conclusion, ifosfamide and carboplatin can be administered with extracorporally induced WBH with acceptable toxicity. Results obtained are consistent with continued evaluation of this combined modality approach. more...