[Biomarker screening for early detection of cancer]. / Sinn und Unsinn von Tumormarkern in der Krebsfrüherkennung.

The question of when a certain concentration of a serum biomarker turns into a tumor marker, i. e. an objectively verifiable criterion for tumor diagnosis, leads to the analysis of the specificity (a measure of the proportion of correctly identified healthy individuals), sensitivity (a measure of the proportion of correctly recognized cancer patients), and precision (positive predictive value). Or in short: a tumor marker is specific if no healthy individual has one. This constitutes the problem: The serum concentrations of biomarkers of cancer patients and healthy subjects overlap. Healthy individuals occasionally have "tumor markers" and cancer patients in turn sometimes express inconspicuous biomarkers.

[Evaluation of the therapeutic benefit of 41.8 degrees C whole body hyperthermia plus ifosfamide, carboplatin and etoposide (ICE) for patients with malignant pleural mesothelioma using the Modified Brunner-Score (MBS)]. / Bewertung des therapeutischen Gewinns von Patienten mit Pleuramesotheliom unter Therapie mit 41,8 degrees C Ganzkörperhyperthermie plus Ifosfamid, Carboplatin und Etoposid (ICE) anhand des Modifizierten Brunner-Score (MBS).

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.

A Systemic Hyperthermia Oncologic Working Group trial. Ifosfamide, carboplatin, and etoposide combined with 41.8 degrees C whole-body hyperthermia for metastatic soft tissue sarcoma.

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.

Ifosfamide, carboplatin and etoposide combined with 41.8 degrees C whole body hyperthermia for malignant pleural mesothelioma.

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.

[Aromatase inhibitors of the 3rd generation. What can the "pill against breast cancer" really do?]. / Aromatasehemmer der dritten Generation. Was kann die "Pille gegen Brustkrebs" wirklich?

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.

Hyperthermia and mafosfamide in a human-derived malignant pleural mesothelioma cell line.

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.

Ureteric and pulmonary endometriosis.

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.

Modulation of VP-16 cytotoxicity by carboplatin and 41.8 degrees C hyperthermia.

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.

A preclinical model for experimental chemotherapy of human head and neck cancer.

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.

A pilot study of whole body hyperthermia and carboplatin in platinum-resistant ovarian cancer.

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.

Local hyperthermia, radiation, and chemotherapy in recurrent breast cancer is feasible and effective except for inflammatory disease.

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.

Advanced non-seminomatous germ cell cancer of the testis with brain metastases: feasibility of additional brain irradiation and whole body hyperthermia plus chemotherapy.

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.

An animal model for anaplastic large cell lymphoma in the immunocompetent syngeneic C57Bl/6 mouse.

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.

[Chemotherapy in combination with whole-body hyperthermia in advanced malignant pleural mesothelioma]. / Chemotherapie in Kombination mit Ganzkörperhyperthermie bei fortgeschrittenem malignem Pleuramesotheliom.

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.

Nephrotoxicity of ifosfamide, carboplatin and etoposide (ICE) alone or combined with extracorporeal or radiant-heat-induced whole-body hyperthermia.

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.

Coexistence of factor V Leiden and primary antiphospholipid syndrome: a patient with recurrent myocardial infarctions and thrombocytopenia.

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.

[New immunotherapeutic approaches for the treatment of anaplastic large cell lymphoma in a mouse model]. / Neue immuntherapeutische Ansätze des grosszelligen anaplastischen Lymphoms in einem Maus-Modell.

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.