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First proof to show that (-)-deprenyl/selegiline (DEP), the first selective inhibitor of MAO-B, later identified as the first β-phenylethylamine (PEA)-derived synthetic catecholaminergic activity enhancer (CAE) substance and (2R)-1-(1-benzofuran-2-yl)-N-propylpentane-2-amine (BPAP), the tryptamine-derived presently known most potent, selective, synthetic enhancer substance, are specific markers of unknown enhancer-sensitive brain regulations.Longevity study disclosing the operation of tumor-manifestation-suppressing (TMS) regulation in rat brain. Immonohistochemical identification of a fibromyxosarcoma in rats. Experiments with human medulloblastoma cell lines. Analysis of the mechanism of action of enhancer substances.Whereas 20/40 saline-treated rats manifested a fibromyxosarcoma, in groups of rats treated with 0.001mg/kg DEP: 15/40 rats; with 0.1mg/kg DEP: 11/40 rats (P0.01); with 0.0001mg/kg BPAP: 8/40 rats (P0.001); with 0.05mg/kg BPAP: 7/40 rats (P0.01) manifested the tumor. Experiments with human medulloblastoma cell lines, HTB-186 (Daoy); UW-228-2, showed that BPAP was devoid of direct cytotoxic effect on tumor cells, and did not alter the direct cytotoxic effectiveness of temozolomide, cisplatin, etoposide, or vincristine. Interaction with distinct sites on vesicular monoamine-transporter-2 (VMAT2) is the main mechanism of action of the enhancer substances which clarifies the highly characteristic bi-modal, bell-shaped concentration-effect curves of DEP and BPAP.Considering of the safeness of the enhancer substances and the finding that DEP and BPAP, specific markers of unknown enhancer sensitive brain regulations, detected the operation of an enhancer-sensitive TMS-regulation in rat brain, it seems reasonable to test in humans low dose DEP or BPAP treatment against the spreading of a malignant tumor.

The purpose of this study was to investigate whether detectable protein biomarker overexpression is a prerequisite for the presence of increased gene copy number or activating mutations and responsiveness to the epidermal growth factor receptor (EGFR) inhibitors gefitinib and erlotinib in patients with lung adenocarcinomas. EGFR status was prospectively analyzed in tumor biopsy samples by three methods: protein expression (n = 117) by standardized immunohistochemistry (IHC), gene copy number (n = 97) by fluorescent in situ hybridization (FISH), and mutation analysis by sequencing (n = 126). Fifty-nine percent of the samples were positive by IHC, 40% were positive by FISH, and 13.5% contained activating kinase domain mutations. Thirty-four percent of the FISH-positive and 27% of the mutant samples were also IHC-negative. All EGFR mutant patients had major clinical responses (five complete response and five partial response) to gefitinib or erlotinib treatment, although three of these tumors were IHC-negative and four were FISH-negative. In a retrospective analysis of samples from nine patients with excellent therapeutic responses (three complete response, five partial response, one stable disease) to erlotinib or gefitinib, mutations were identified in eight cases, but IHC was negative in four of these tumors. These results indicate that molecular diagnostic methods appear to be most important for the identification of lung adenocarcinoma patients who may benefit from EGFR inhibitor treatments.

The purpose of this phase I study was to evaluate the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), the recommended dose for phase II study, pharmacokinetics, and antitumor activity of TZT-1,027 (soblidotin) in patients with non-small cell lung cancer (NSCLC) when administered every 3-4 weeks.Eligible patients had the following characteristics: stage III/b or IV NSCLC that was refractory to conventional therapy or for which no standard therapy was available; Eastern Cooperative Oncology Group (ECOG) performance status (PS)or=2; adequate organ function; and ageor=20 and75 years. The patients were administered TZT-1,027 in escalating doses from 0.5 to 5.6 mg/m(2). Pharmacokinetic samples were collected during each treatment course.Forty-nine patients were enrolled. Three patients had DLTs, including neutropenia, neutropenia complicated by fever, myalgia, and neuropathic pain. The common toxicities included constipation, anorexia, alopecia, nausea, leukopenia, and neutropenia. One complete response and three partial responses were observed. The pharmacokinetic parameters (AUC and C (max)) of TZT-1,027 tended to increase linearly with dose.DLTs included neutropenia, neutropenia complicated by fever, myalgia, and neuropathic pain. The MTD was 4.8 mg/m(2). The recommended phase II study dose of TZT-1027 is 4.8 mg/m(2) administered every 3-4 weeks.

The occurrence of treatment-related second malignancy following Hodgkin's disease (HD) has now been recognized as a major problem. The purpose of this study was to review our experience with second malignancies in patients treated for Hodgkin's disease, comparing the results with the international literature data. Six hundred and sixty five patients with HD were treated in our department, between 1978 and 1996. Second neoplasm developed in 32 cases (4.8%). Seven secondary hematological malignancies were observed: four acute nonlymphocytic leukemias, two non-Hodgkin's lymphomas and one chronic myeloid leukemia. Among patients with second hematological malignancies, the mean age at diagnosis of HD was 44 years and the mean interval until the development of second malignancy was 6.1 years. Five patients received chemo- and radiotherapy and in two cases chemotherapy was used. Three of the seven patients are alive. Twenty-five patients have had solid tumors, affecting lung (5), breast (3), colon (3), stomach (2), urinary bladder (2), head-and-neck (1), thyroid gland (1), esophagus (1), liver (1), pancreas (1), furthermore, three sarcomas and two malignant melanomas were observed. Their mean age at the diagnosis of HD was 46 years and the mean period of latency was 8.3 years. Chemotherapy was applied to nine patients, 16 patients received both chemo- and radiotherapy. Eleven patients had solid tumors in the region irradiated earlier. Ten out of the 25 patients are alive, three patients' present state is unknown. Since alkylating agents increase the risk of leukemia and irradiation contributes mainly to other malignancies, future treatment protocols should attempt to reduce the most serious consequence of therapy without compromising the survival. It is necessary to investigate the impact of additional risk factors. Careful, lifelong observation is indicated for patients with HD, with special attention given to new clinical signs and symptoms.

BACKGROUND Successful chemotherapy for patients with soft tissue sarcoma (STS) has been limited by a lack of active drugs. The most effective single agents are doxorubicin, dacarbazine, and, more recently, ifosfamide. Previously the most widely used combination has been CYVADIC (cyclophosphamide, vincristine, doxorubicin, and dacarbazine). In one randomized trial, ifosfamide was superior to cyclophosphamide; two nonrandomized studies also reported favorable results. Etoposide monotherapy was successful in 8%; the effectiveness of cisplatin was 5–23%. In view of these findings, the authors treated STS patients with an etoposide, cisplatin, and ifosfamide (VIP) combination. METHODS The eligibility criteria included histologically confirmed, inoperable, metastatic or locally recurrent STS; a World Health Organization (WHO) performance status of 0–2; a maximum age of 75 years; and progressive, measurable disease. A total of 104 patients were treated from January 1990 to June 1997. The median age of the patients was 42.4 years. The patients were treated with a combination of etoposide (100mg/m2 for 5 days), ifosfamide (2000mg/m2 for 2 days), and cisplatin (20mg/m2 for 5 days) once a month via a peripheral vein. The treatment response and the toxicity were assessed according to WHO criteria. RESULTS Of 104 evaluable patients, 47 responded. The overall response rate was 46% (complete response: 10%; partial response: 36%). In 43 patients the disease remained stable (41%). Remission duration was 4.6 months. Toxicity was moderate. The main adverse events were alopecia (100%), nausea and vomiting (73%), and leukopenia (29%). CONCLUSIONS This new combination is promising for the treatment of patients with advanced STS. Cancer 2000;89:177–80. © 2000 American Cancer Society.

SUMMARY Twenty-five breast cancer patients previously not exposed to adriamycin, were treated with 30 mg/m2/day aclarubicin for four consecutive days. Out of the 19 evaluable cases 1 CR and 2 PR were observed giving an overall remission rate of 16%. No cardiotoxicity was observed. Myelotoxicity and hair loss were mild (WHO grades 1 and 2). Grade 2 and 3 nausea and vomiting occurred frequently.

In the last two decades cancer mortality dramatically increased in the majority of Central and Eastern European countries. In the period from 1992 to 1995, the Hungarian male population had the highest death rate (265.0 of 100,000) due to malignancies among 46 countries worldwide. Hungarian women ranked third in cancer death rate among these countries (138.0 of 100,000). Several factors might be responsible for these figures: a) increases in environmental carcinogenic risk factors, b) unfavourable lifestyle changes in the population especially related to high tobacco consumption and dangerous drinking habits, c) lack or insufficiency of cancer prevention procedures particularly in screening and early detection, d) delay in diagnosis, e) inadequate therapeutic patient management, f) shortage of manpower, and g) unsatisfactory financial support. Efforts have been made to overcome these difficulties by: a) detailed analysis of exogenous risk factors, b) review of lifestyle of the population, c) public education efforts for effective prevention, d) introduction of model screening programs, e) reorganisation of cancer diagnosis and treatment services, and f) design and establishment of a National Cancer Control Program.

A preterm female infant presented with intractable hypoglycaemia within 10 minutes of delivery. Normoglycaemia could be maintained only by the intravenous infusion of glucose at a rate of 20-22 mg/kg/min. Persistent hyperinsulinaemic hypoglycaemia of infancy was diagnosed from an inappropriately raised plasma insulin concentration (33 mU/l) at the time of hypoglycaemia (blood glucose < 0.5 mmol/l). Medical treatment with glucagon, somatostatin, and diazoxide led to only a modest reduction in the intravenous glucose requirement; a 95% pancreatectomy was performed and histological 'nesidioblastosis' confirmed. In vitro electrophysiological studies using patch clamp techniques on isolated pancreatic beta cells characterised the ionic basis for insulin secretion in nesidioblastosis. The beta cells were depolarised in low ambient glucose concentrations with persistently firing action potentials; these were blocked reversibly by the calcium channel blocking agent verapamil. Persistent postoperative hyperinsulinaemic hypoglycaemia was treated with oral nifedipine. This increased median blood glucose concentrations from 3.5 to 4.8 mmol/l and increased in duration the child's tolerance to fasting from 3 to 10.5 hours. These data allude to an abnormality in the ionic control of insulin release in nesidioblastosis and offer a new logical approach to treatment which requires further evaluation.

A boy aged 21 months who was being investigated for developmental delay and failure to thrive was found to have punctate epiphyseal calcification. He had no evidence of rhizomelic shortening of the limbs or cataracts. Investigation revealed defective plasmalogen synthesis due to isolated deficiency of dihydroxyacetonephosphate acyltransferase (DHAP-AT). The parents were consanguineous and a sister was similarly affected, suggesting autosomal recessive inheritance. Hitherto, recessively inherited isolated DHAP-AT deficiency has only been described in patients with a phenotype similar to that of rhizomelic chondrodysplasia punctata. This report indicates that the same biochemical disorder can be associated with a less severe phenotype.

One hundred and eleven previously untreated patients with extensive small cell lung cancer were included in a prospective randomized study with the aim to assess the efficacy and tolerance of high-dose epirubicin (120 mg/m2) in combination with either cyclophosphamide (800 mg/m2; arm 1) or cisplatin (60 mg/m2; arm 2). Ninety-six patients were evaluable for response and toxicity and additional 12 patients for toxicity only. The overall response rate (CR+PR) in arm 1 and 2 were 61.4 (27/44) and 67.3% (35/52), respectively. The mean duration of remission was 4.4 months (arm 1) and 4.9 months (arm 2). The mean survival time was 6.6 months in arm 1 and 7.7 months in arm 2. WHO grade 4 toxicity was encountered in 25.5 and 15.8% of patients in arm 1 and 2, respectively. One case of cardiotoxicity resulting in the patient's death was observed in arm 1. Both combinations showed considerable antitumor activity. Toxicity was acceptable.

Previous studies of the hyphenation of gas chromatographic separation and spectrophotometric detection in the ultraviolet wavelength range between 168 and 330 nm showed a high potential for applications where the analysis of complex samples is required. Within this paper the development of a state-of-the-art detection system for compounds in the vapour phase is described, offering an improved behaviour compared to previous systems: Dependent on the requirements of established detection systems hyphenated with gas chromatography, the main components of the system have to be designed for optimum performance and reliability of the spectrophotometric detector: A deuterium lamp as a broadband light source has been selected for improved stability in the measurements. A new-type absorption cell based on fiber-optics has been developed considering the dynamic necessary to compete with existing techniques. In addition, the influence of the volume of the cell on the chromatogram needs to be analyzed. Tests for determining the performance of the absorption cell in terms of chemical and thermal influences have been carried out. A new spectrophotometer with adequate spectral resolution in the wavelength range, offering improved stability and dynamic for an efficient use in this application was developed. Furthermore, the influence of each component on the performance, reliability and stability of the sensor system will be discussed. An overview and outlook over the potential applications in the environmental, scientific and medical field will be given.

Metastatic melanoma is one of the most aggressive forms of cutaneous cancers. While recent therapeutic advances have prolonged patient survival, prognosis remains dismal. Mer is a receptor tyrosine kinase with oncogenic properties that is often overexpressed or activated in various malignancies. Using both protein immunohistochemistry and microarray analyses, we demonstrate that Mer expression correlates with disease progression. Mer expression was highest in metastatic melanomas followed by primary melanomas whereas the lowest expression was observed in nevi. In addition, over 50% of melanoma cell lines overexpressed Mer compared to normal human melanocytes, however overexpression did not correlate with mutations in BRAF or RAS. Stimulation of melanoma cells with the Mer ligand Gas6 resulted in activation of several downstream signaling pathways including MAPK/ERK, PI3K/Akt, and Jak/STAT. Mer inhibition via shRNA reduced Mer-mediated downstream signaling, reduced colony formation by up to 59% (p Citation Format: Jennifer Schlegel, Maria Sambade, Susan Sather, Stergios Moschos, Aik-Choon Tan, Amanda Winges, Deborah DeRyckere, Craig C. Carson, Dimitri G. Trembath, John J. Tentler, Gail Eckhardt, Pei-Fen Kuan, Ronald L. Hamilton, Lyn M. Duncan, C. Ryan Miller, Nana Nikolaishvili-Feinberg, Bentley R. Midkiff, Xiaodong Wang, Jing Liu, Weihe Zhang, Chao Yang, Stephen V. Frye, H. Shelton Earp, Janiel Shields, Douglas K. Graham. Mer receptor tyrosine kinase is a novel therapeutic target in melanoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3037. doi:10.1158/1538-7445.AM2013-3037

BACKGROUND Interferon (IFN) treatment trials in multiple myeloma have yielded discordant results regarding response rates, maintenance duration, and survival times. Further randomized trials and global evaluations of available data are urgently needed for clarification. PATIENTS AND METHODS 256 patients participated in a randomized trial, 125 on IFN + VMCP, and 131 on VMCP alone. 100 patients were randomized to IFN maintenance (n = 46) or were untreated controls (n = 54). Global evaluations are based on 1,518 patients in induction and 924 in maintenance trials. RESULTS The induction trial demonstrated a significantly (p < 0.05) lower rate of progressive disease under IFN + VMCP (10.6%) than under VMCP (22.9%), but this benefit was limited to stage I or II patients. Median progression-free survival was longer in the IFN + VMCP arm (23.2 months vs. 15.8 months); median overall survival did not differ significantly (38.9 vs. 30.2 months). The IFN maintenance treatment trial showed significantly superior results in the IFN arm versus controls (median maintenance duration: 17.8 months and 8.2 months (p < 0.01), survival: 50.6 and 34.4 months (p < 0.05), respectively). Previous IFN treatment increased the benefits of IFN maintenance therapy. Adverse effects of IFN during induction were hematologic toxicity, fever, and infections, requiring dose reductions. Toxic effects of IFN maintenance treatment were mild. Global evaluations of randomized trials showed small but significant benefits of combined IFN induction therapy and significantly prolonged maintenance duration and survival under IFN maintenance. CONCLUSIONS Presently available data support the use of IFN maintenance treatment because it significantly prolongs maintenance duration and survival. IFN added to induction chemotherapy resulted in minor improvements at the expense of increased toxicity, highlighting the need for better induction regimens.

A 71-year-old male patient had been aware for 3 years of a slowly-growing nodule in his left breast that began to produce a discharge in the 3 months prior to his presentation. The discharge became progressively blood-stained. Nevertheless, he consulted a doctor only one week before admission. Physical examination revealed an ulcerated mass retracting the nipple (Fig. 1) and involving the entire glandular substance. Axillary lymph nodes were clinically enlarged. Mastectomy with axillary block dissection was performed. The tumour proved to be a ductal invasive carcinoma (Fig. 2) positive for oestrogen and progesterone receptor by radio-immunoassay determination. Twelve of eighteen lymph nodes examined contained tumour metastasis. The patient was given postoperative radiotherapy /50 Gy/ to the chest wall and regional lymph node areas and received adjuvant tamoxifen in the dosage of 20 mg daily for a period of 18 months. He died three years after postoperative radiotherapy. The cause of death was not related to tumour. No autopsy was done.

Between April 1986 and May 1989 a multicentre study was conducted to evaluate the efficacy of a 4-h intravenous infusion of 1000 mg/m2 5-fluorouracil (5-FU) followed by a 1-h infusion of 25 mg/m2 cisplatin (CDDP) given for 4 consecutive days every 4 weeks to patients with advanced squamous-cell carcinoma of the head and neck. A total of 189 consecutive patients entered the study, including 106 who had previously undergone chemotherapy and 83 who were chemotherapy-naive. Of the 165 evaluable patients, 96 (58%) responded to treatment, including 22 (13%) who achieved a complete remission (CR). In the group of previously untreated patients an objective response (CR+PR) was seen in 78% (CR, 14%) whereas in pretreated patients the response rate (CR+PR) was 40% (CR. 13%). The median survival period was 10 months. No significant difference in the duration of survival or of remission was found between the two groups in relation to previous therapy, tumour localisation, disease stage or performance status. Almost half of the patients (49%) experimenced leucopenia but it was severe in only 11% of cases. Anemia (mainly WHO grades 1–2) occurred in 38% of the patients. Nausea and vomiting were common (84%). Nephrotoxicity (23%) was mild and of short duration. Moderate hair loss was seen in 42% of the patients, and phlebitis occurred in 8%. A few cases of cardiotoxicity and neurotoxicity were observed. This regimen is well tolerated and can be given even on an outpatient basis. The resultant response rate and side effects appear to be similar to those previously reported for combination chemotherapy with CDDP and continuous 5-FU infusion.

Colorectal cancer (CRC) represents a major health burden and accounts for nearly 10% of all cancer-related deaths in the U.S. Among the many new pathways being exploited for cancer treatment is the insulin-like growth factor receptor (IGF1R) signaling pathway, which appears to be a robust target in CRC (e.g., hyperactivated in more than 50% of CRC patients). OSI-906 is a novel selective dual inhibitor IGF-1R and IR kinase activities. Despite advances in molecular predictive markers, a substantial proportion of patients selected for targeted therapy has nonresponsive tumors and require additional combination-based regimens. Unlike cytotoxic chemotherapeutic agents, most novel signal transduction modulators (STMs) induce only modest tumor regression, thus there is significant need for establishing functional pharmacodynamic (e.g., therapy response) endpoints for inhibition of signaling via particular pathways. In the present study we established noninvasive imaging-based endpoints for response to OSI-906 in CRC mouse models. Female nude mice were implanted with either of two human CRC cell lines (one sensitive and one resistant) or individual human surgical CRC explants (with unknown sensitivity). Metabolic changes (decreased glucose uptake and lactate production by FDG-PET and proton MRS, respectively) were apparent in OSI-906-sensitive xenografts as early as 2 days post-treatment when no changes in tumor size were yet detected. A significant decrease in tumor size and membrane choline-containing phospholipids by MRI and MRS, respectively, were seen after 27 days of treatment in OSI-906-sensitive xenografts. No changes in FDG-PET, MRS, or tumor progression were observed in OSI-906 resistant xenografts. Our data indicate that noninvasive functional imaging endpoints can provide early and sensitive markers for cytostatic action of IGF1R/IR inhibitors. This talk is also presented as Poster A14.

Starting in January 1984, 63 patients with resistant Hodgkin's disease received CEP as salvage-usually third-line-chemotherapy. Complete response (CR) was achieved in 3%, partial response (PR) in 51%. The median duration of remission (CR + PR) was greater than 15 months. Treatment was generally well tolerated. Our results confirm that CEP is an effective therapeutic regimen in resistant Hodgkin's disease.

The effect of toremifene treatment on the serum levels of sex steroids (estradiol, progesterone, testosterone), FSH, LH, prolactin, TSH, T3, T4 and SHBG was investigated. Basal prolactin level and the “prolactin reserve capacity” of the hypophysis was also studied by the TRH functional test. Steroid hormone receptors were detected in the patients where a tumor biopsy could be obtained. In a randomized trial patients were treated by 60 and 300 mg of toremifene per os, daily. Hormone levels were assayed prior to treatment and at the 2nd, 6th, 8th and 12th week of toremifene therapy. The hormonal effects of toremifene were the most marked at the 2nd and at the 8th week. Estradiol decreased continuously, SHBG increased slightly and the high initial value of basal prolactin level decreased. The TRH induced prolactin release was suppressed by toremifene after an 8-week period. No clinical response-related tendency was found.

The identification and quantification of compounds in the gas phase becomes of increasing interest in the context of environmental protection, as well as in the analytical field. In this respect, the high extinction coefficients of vapours and gases in the ultraviolet wavelength region allow a very sensitive measurement system. In addition, the increased performance of the components necessary for setting up a measurement system, such as fibres, light sources and detectors has been improved. In particular the light sources and detectors offer improved stability, and the deep UV performance and solarisation resistance of fused silica fibres allow have been significantly optimized in the past years. Therefore a compact and reliable detection system with high measuring accuracy is developed. Within this paper possible applications of the system under development and recent results will be discussed.

Following the recent introduction of AlGaN/GaN based ultraviolet Light Emitting Diodes (UV-LEDs) in the 250 nm to 350 nm wavelength region, a wide range of research activities have begun. For example, using the high levels of power of available UV-light, chemical reactions can be stimulated. However, when optical detection techniques are considered, light intensity and wavelength accuracy are more important to achieve low detection limits. Using LED-based light sources in the ultraviolet instead of the classical deuterium, xenon, mercury or metal halide sources is very attractive due to their high power conversion, relatively simple electronic driving circuitry and low power consumption. For both absorption and fluorescence detection, such LEDs and complete detection systems are powerful tools both traditional and new applications in the field and laboratory. In this work, the electrical and optical properties of these new UV-LEDs will be described. Further, the flexibility of using optical fibres for UV-light delivery will be discussed with respect to the available UV-wavelengths and UV-induced damage. To exemplify the potential of UV LEDs, a self correcting fibre optic detection system over the wavelength range 260 and 280 nm, based on such LEDs will be shown. Further, an overview discussing flexible optical fibre UV-light delivery systems will be given and applications for both will be considered.

3582 Background: Apomab, a fully human affinity-matured IgG1 monoclonal antibody, is a DR5 pro-apoptotic receptor agonist that triggers the extrinsic pathway of apoptosis. DR5 is expressed both on malignant and normal cells; however, pre-clinical data indicate that DR5 activation stimulates apoptosis predominantly in malignant cells. This first-in-human study assessed the safety, pharmacokinetics (PK) and any early evidence of anti-cancer efficacy of Apomab. Methods: Patients with advanced treatment-refractory solid tumors received Apomab IV on Day1 (cycle 1 = 28 days, cycles 2–8 = 14 days) at 1, 4, 10, 15, or 20 mg/kg (stage 1); with cohort expansion at 10 mg/kg or the MTD (if lower) every 14 days (stage 2). Tumor assessments were made after 2, 4 and 8 cycles. Therapy continued past 2 cycles as permitted by on-going evidence of benefit, until disease progression or unacceptable toxicity occurred. Results: 26 patients ECOG PS ≤1 have been enrolled and treated through 20 mg/kg. The 20 (8M, 12F) with confirmed data (up to 15mg/kg) received a median of 2 cycles (range 1–8). All dose levels have been tolerable (4 mg/kg are greater than those displaying activity in preclinical models. No HAHA responses have been seen to date. Conclusions: Apomab is well tolerated with a minor response seen in a colorectal cancer patient. Enrollment is continuing at 10mg/kg. Further safety and efficacy data will be presented. No significant financial relationships to disclose.

The development of imatinib resistance has become a significant therapeutic problem, in which the etiology appears to be multifactoral (Bcr-Abl mutation and/or overexpression, multidrug-resistance, protein overexpression, etc.) and poorly understood. As of today, there are no precise clinical criteria to predict the development of imatinib resistance in CML, other than relapse of the disease. However, there is evidence that the control of glucose-substrate flux is an important mechanism of the antiproliferative action of imatinib. Thus, imatinib-resistant gastrointestinal stromal (GIST) KIT-activated tumors reveal highly elevated glucose uptake in PET scans. Currently, there is no information about the changes in glucose cell metabolism during development of imatinib resistance in CML patients. We used nuclear magnetic resonance (NMR) spectroscopy and gas chromatography mass spectrometry (GC-MS) to assess 13C glucose uptake and metabolism (glycolysis, the TCA cycle, nucleic acid ribose synthesis) during imatinib treatment in cultured human CML cells with different sensitivity to imatinib. Our results demonstrate that imatinib-sensitive K562 and LAMA84 Bcr-Abl positive cells have decreased glucose uptake, decreased lactate production and improved oxidative TCA cycle upon imatinib treatment. The LAMA84-r (resistant to imatinib due to Bcr-Abl overexpression) and the K562-r (unknown mechanism of resistance) cells maintained high glycolytic metabolic phenotype with elevated glucose uptake and lactate production in the presence of imatinib (Figure 1). In addition, oxidative synthesis of RNA ribose from 13C-glucose via glucose-6-phosphate dehydrogenase was decreased and RNA synthesis via the non-oxidative transketolase pathway was increased in imatinib resistant cells. CML cells which exhibited an [oxidative/non-oxidative] flux ratio for nucleic acid ribose synthesis > 1, were sensitive to imatinib. The resistant K562-r and LAMA84-r exhibited the [oxidative/non-oxidative] flux ratio < 0.7. We correlated 13C glucose uptake and metabolism with intracellular expression and localization of GLUT-1 transporter protein in these cells. There was no difference in total protein load of GLUT-1 upon imatinib treatment between imatinib-sensitive and resistant cell lines. However, the changes in glucose uptake and metabolism were accompanied by intracellular trans-location of GLUT-1 from the plasma membrane to the cytoplasm in imatinib-sensitive treated cells, while GLUT-1 remained at the membrane surface in LAMA84-r and K562-r cells (Figure 1). In summary, elevated glucose uptake and non-oxidative glycolytic metabolic phenotype can be used as sensitive markers for imatinib resistance in Bcr-Abl positive cells with different origins of resistance. Figure 1: Figure 1:.

We previously reported that imatinib decreased glucose uptake in the BCR-ABL+ cells in a dose- and timedependent fashion by switching from glycolysis to Krebs cycle metabolism and improving the cell energy state. The goal of this study was to evaluate metabolic aspects of imatinib resistance in paired imatinib-sensitive and resistant clones of two CML cell lines, K562 and LAMA84. LAMA84-r cells are resistant due to BCR-ABL and P-glycoprotein overexpression, the mechanism of resistancy in K562-r cells is still unknown (may be implicating other tyrosine kinases). Resistant clones were grown in imatinib containing medium (K562-r: 5μM; LAMA84-r: 1μM). Sensitive cells were incubated with 1μM imatinib for 24h. [1-13C] glucose was added to all cells for the last 4h. Magnetic resonance spectroscopy (MRS) was performed on cell extracts to evaluate glucose metabolism (1H, 13C) and energy state (31P). In imatinib treated sensitive cells mitochondrial glucose metabolism was slightly improved (C4-glutamate signal increased to 137% and 114% vs. untreated K562-s and LAMA84-s). No significant changes in glycolysis rate or glucose uptake were seen. In resistant K562-r cells mitochondrial activity was significantly lower (C4-glutamate decreased to 47%, p

The therapy of primary liver cancer is still an unsolved problem. Until now, surgery has been the only therapeutic modality that can significantly increase the life‐span of patients in early stages of disease. Radiotherapy does not prolong the disease‐free interval. It is therefore important to explore possibilities of new therapeutic approaches, especially those of chemotherapy. Adequate trial data are available for methotrexate (MTX), 5‐fluorouracil (5‐FU), chloroethyl‐cyclohexyl‐nitrosourea (CCNU), methyl‐CCNU, hydroxyurea, cytosine arabinoside, dimethyltriazenoimidazole carboxamide, actinomycin D, mitomycin C, and adriamycin. These findings show that these substances when used as single agents are not very active in the treatment of primary liver cancer. Exceptions are MTX given intraarterially, adriamycin, 5‐FU, and their combination. Experimental agents are triethyleneglycol diglycidil ether, DL‐serine bis(2‐chloro‐propyl)carbamate ester, butyryloxyethylglioxal dithiosemicarbazone, cobaltiproto‐porp...

The therapeutic efficacy of the combination of epirubicin + dibromodulcitol was evaluated in 108 previously treated or untreated patients with advanced breast cancer. The overall response rate was 39.8%, complete remission 3.7% (mean duration 6.3 months) and partial remission 36.1% (mean duration 3.5 months). The response was rated in function of age, menopausal status, performance status and previous therapy. Toxicity (in case of 115 patients) was evaluated according to the WHO recommendation. The similar therapeutic effectiveness and less toxicity of the above drug combination compared to ADM + DBD regimen are demonstrated.

Aclacinomycin A (ACM) in a daily dose of 30 mg/m2 was infused over 1 h on 4 consecutive days to 50 patients. Myelotoxicity was acceptable, nausea and vomiting was frequent, hair loss was mi

Hormonal treatment of prostatic carcinoma may give rise to secondary hormone resistance that poses serious problems. Estramustine phosphate (Estracty, ® AB Leo, Helsingborg, Sweden) has been studied in 50 patiens with prostatic carcinoma that had developed secondary hormone resistance. The results of the clinical study were evaluated at the end of a fllow-up period ranging from 6 months to 2 years. A positive response has been noted in a large proportin of the patients: viz. shrinkage of the primary tumour, decrease in residual urine in nearly 50%, and subjective relief and improvement of the general condition in a still larger proportion. On the other hand, with the exception of one patient, the skeletal metastases remained unaffected. Secondary effects, if any, were rare. Estracyt recommends itself for hormone-resistant patients are still in a good general condition: on the other hand, it offers little benefit in the far-advanced state of the disease, i.e. with extreme cachexia.

The uptake of [ 3 H ]-dibromodulcitol ([ 3 H ]-DBD) into glioblastomas, white matter and cerebrospinal fluid was studied in 10 patients. Single-tissue samples were taken from different subjects at 4, 15 and 24 hr after [ 3 H ]-DBD administration. The level of 3 H -compounds in the central nervous system was similar after a single (400 mg/m 2 ), or 3 smaller daily oral doses of 150–180 mg/m 2 of [ 3 H ]-DBD. The distribution of radioactivity was uniform in the tumour, white matter and muscle. Between 3 and 15 hr after administration of DBD the concentration of radioactivity did not change significantly and was between 5 and 13 μg of DBD/ g tissue wet wt. At the same time the level in the cerebrospinal fluid (CSF) remained between 1 and 4 μg/ml . Meanwhile, the average concentration of radioactivity in the plasma fell from 11 to 3 μg/ml . The elimination half-life of the labelled compounds from the tissues was about 1 day as judged from the limited number of non-serial data obtained 4 and 24 hr after the last dose of repeated drug administration.

The results of combined irradiation and intravenous Vincristine therapy applied to 18 malignant glioma patients after operation and reoperation are reported. Histological examination of the first 15 tumours showed that 12 were glioblastomas and 3 malignant astrocytomas. Tumours removed by reoperation were glioblastomas.

Prednimustine (Stereocyt, Leo 1031) is a chlorambucil ester of prednisolone. Results from clinical trials confirm that prednimustine is active in malignant lymphomas. The efficacy of Stereocyt was evaluated in 25 patients, who were divided into three subgroups: 10 patients with refractory Hodgkin's disease and 7 with refractory non-Hodgkin lymphoma (NHL), while 8 patients received prednimustine as primary therapy for low-grade NHL. Totally 17 partial remissions were observed in all three groups of patients. Leukopenia and thrombopenia were induced in 3 patients, but were mild and reversible after withdrawal of the drug.

Earlier at this conference Professor Eckhardt had a paper on the chemical structure and pharmacological properties of the new Hungarian Vinca derivative F-Leurosine. My paper is concerned with results obtained by F-Leurosine treatment of the 3 main groups of malignant haematological disorders, such as leukaemias, lymphomas and multiple myeloma.

The idea that earlier diagnosis leads to better prognosis is appealingly simple. This chapter concerns the extension of that idea to the routine periodic screening of large populations of persons without symptoms. To convert this idea into an effective large-scale programme is a complex organisational undertaking, for which the expected benefit should be reasonably clearly known before it is embarked upon.

20% of malignant diseases in childhood; 17 new cases per year, per million of children less than 15 years of age (Manchester Register).

Chemotherapy is planned on the basis of observed differences between normal and tumour cells in response to antitumour agents used both singly and in combination. Part of the difference between normal and neoplastic cells can be explained by consideration of proliferative characteristics; however, it must be emphasized that cell kinetics cannot explain all the consequences of tumour cell exposure to a drug, since these are also dependent upon pharmacokinetics, biochemistry and tumour biology.

Central nervous system (CNS) tumours account for 2%–5% of all tumours in man. The incidence is higher among the white races than among Negroes. The sex ratio is about 1:1 for most histological types. An important male predominance is found in medulloblastomas. Meningiomas and acoustic neuromas predominate in adult females. CNS tumours occur at all ages. There is a peak incidence of glial tumours in childhood; they rank first among solid tumours before puberty. Certain mesenchymal tumours have a familial tendency. Phakomatoses are often associated with a higher frequency of different types of intracranial tumours. Lesions of other organs (retina, viscera) are often associated with haemangioblastoma.

The most essential role of Miacalcic (Calcitonin Sandoz), a 32-amino-acids peptide, is the preservation of osseal integrity. Based on this physiological fact it is assumed that this hormone may have a bone-regenerating effect in bone metastasis formation and sometimes in other malignancies. Though no considerable calcium incorporation could be revealed in our 58 patient treated with Miacalcic, a marked relief of pain was observed in 65.5% of the patients. For objectivation of the subjective pain sensation, the decrease in the quantity of other analgetics used daily, duration of pain and changes of its intensity were studied. These figures were 35.4% on the average, from 12.5-6 h and 23.6%, respectively. The pain-killing character of Miacalcic cannot be explained, but the following assumptions are made: (1) it partially inhibits the synthesis of algogenous peptides; (2) with its possibly cytostatic effect it inhibits the cell proliferation in loco and normalizes the internal pressure of the destroyed region, and (3) by conversion into beta-endorphin it exerts its effect centrally. Compared to the pain-killing effect, the simultaneous improvement of the quality of life seems to be even more essential. It has been proved earlier that a hormone physiologically present, when applied in a high dose, has an analgetic effect, i.e. by utilizing the endogenous substance of the organism, relief of pain can be achieved. We should like to point out that Miacalcic is the only analgetic agent capable of ensuring relief of pain with a simultaneous improvement of the quality of life. Accordingly, the application of Miacalcic in patients suffering from malignant tumours is highly recommended.