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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 main advantage of transaxillary robotic-assisted thyroid surgery (TRAT) is the avoidance of a scar on the neck. As TRAT is still rarely performed in Germany, there are not yet any German reports on acceptance, operation times and complications.In a pilot study all patients with an indication for hemithyroidectomy without preoperative evidence of malignancies or previous neck surgery and a lobe size 30 ml, a body mass index (BMI) 30 and age 18 years were offered transaxillary robotic-assisted hemithyroidectomy (TRAHT) after a detailed explanation of this operation. The acceptance of this new technique, the operation time, complications and patient satisfaction were prospectively recorded and analyzed.Between January 2013 and October 2014 a total of 65 patients were offered the option of a TRAHT and 21 (32%) patients opted for this surgical technique. None of these 21 operations had to be converted and there were no intraoperative complications. The median operation time was 190 min (range 106-300 min) with a significant learning curve (first 5 TRAHT 219 min and last 5 TRAHT 163 min), 10 (48%) patients had a postoperative slight transient skin dysesthesia in the area of the access route, 4 (19%) patients had a transient recurrent laryngeal nerve palsy and 2 patients (9%) had a transient upper brachial plexus palsy. After the first 21 TRAHT operations, 2 Dunhill operations for Grave's disease were also performed via a single axillary incision. The operation times were 320 min and 260 min without complications and 21 out of the 23 patients (91%) were highly satisfied with the cosmetic result and would choose TRAT again.The TRAT procedure still has low acceptance by German patients but patient satisfaction after surgery is high due to the cosmetic result. The extended operation time, new complications (e.g. transient plexus palsy) and a potentially increased rate of transient recurrent laryngeal nerve palsy must be critically considered.

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.

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.

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.

Type 2 diabetes mellitus is a common late-onset disease with a strong genetic component. It is characterized by insulin resistance which results from alterations in insulin signal transduction. The G protein beta 3 subunit 825T allele was recently found to be associated with hypertension and obesity which makes it a sensible candidate gene for type 2 diabetes.In a case-control study on 320 male patients and 962 male healthy controls we investigated the association of two candidate genes with diabetes, i.e. (i) the GNB3 825T allele, associated with a G protein beta 3 subunit splice variant and enhanced intracellular signal transduction, and (ii) the insulin receptor substrate-1 (IRS-1) 972Arg variant, which encodes a protein variant associated with cellular insulin resistance.The GNB3 825T allele and the IRS-1 972Arg variant were significantly associated with diabetes (odds ratios for either variant 1.4 1.8). Odds ratios were 3 4 in males carrying both alleles.The results document an association of a hypertension susceptibility gene with type 2 diabetes which may partially explain the frequent coexistence of both disorders.

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.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/m(2) for 5 days), ifosfamide (2000 mg/m(2) for 2 days), and cisplatin (20mg/m(2) for 5 days) once a month via a peripheral vein. The treatment response and the toxicity were assessed according to WHO criteria.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%).This new combination is promising for the treatment of patients with advanced STS.

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 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) detail 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) reorganization of cancer diagnosis and treatment services, and f) design and establishment of a National Cancer Control Program.

In recent years numerous molecular biological discoveries enlightened the various steps of the neoplastic transformation. Based on new targets, this development made it possible to synthetize new tumour inhibitory substances. Among them taxanes capable to block depolymerization of tubulin--which is an essential molecule in cell division--play an important role. Docetaxel (Taxotere) belongs to this group and is an active drug in the treatment of breast cancer. Moreover, platinum-resistant tumours may also respond to the therapy. It is important to note that even visceral (hepatic) metastases may express chemosensitivity. Results of combination chemotherapy seem to be also promising. The antitumour effect of Taxotere in NSCLC and other malignant neoplasms in under investigation. The toxicity of Taxotere may be successfully reduced by premedication of steroids. The necessary protective measures render the Taxotere therapy safe and of being perspectivistic.

Taxol is a novel cytostatic agent which inhibits the depolymerisation of microtubulin. The stabilization of this important substance leads to cellular arrest and consecutively apoptosis. Accordingly, taxol is capable to influence neoplastic growth in several malignancies. At present the following standard regimen is recommended: 175 mg/m2 taxol in a 3-hour i. v. infusion following corticosteroid + diphenhydramine + cimetidine premedication. Its antitumour activity has been proved especially in advanced ovarian and breast cancer. Encouraging results have been reported in various bronchial, testicular malignancies, lymphomas and leukemias. Clinical investigations in several other malignancies are ongoing.

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.

Those research trends which are currently in the focus of interest of various research groups are summarized. The main tendency is to look for new molecular targets and to synthesize new antitumour drugs. Moreover, new research concepts emerge out of which differentiation induction, inhibition of MDR and study of apoptosis seem to be promising. Among clinical approaches megachemotherapy, neoadjuvant treatment and progress in supportive therapy are the main research directions. Last but not least, quality of life issues of the cancer patient are of particular importance.

One hundred ninety patients with germ cell line testicular tumours were treated according to the modified Einhorn scheme. The response rate was 67.9%. The most favourable results were found in the embryonal histologic type (RR = 76.9%) in the biological markers (beta-HCG and AFP) negative (RR = 97.4%) and in the minimal pulmonary extent group (RR = 94.1%). The authors treated 112 patients with including these VPB-resistant germ cell testicular tumour and those with recurrence after this treatment. The patients' mean age was 28.8 (limits 19 to 44) years. Patients were given Vepeside (100 mg/m in infusion for days 1-5), Adriablastin (40 mg/m in infusion on day 1) and Cisplatin (20 mg/m in infusion) for day 1-5. The treatment resulted in CR with 18 patients (16.1%) and PR with 42 (37.5%) (RR = 53.6%). The best results were obtained with the seminoma patients who were marker-negative and had small-volume metastasis. CR developed in 4 of 7 seminoma patients (57%) and in 7 of 25 marker-negative individuals (28%), and PR developed in 11 patients (44%) (RR = 72%). Out of 12 patients with small volume metastatis four (33%) showed CR and five revealed PR (41.7%), their RR turned out to be 74.6%. The average remission period was 37 (range 4-70) months in CR but merely 6.1 (range 2-38) months in PR. It can be stated that fairly good results can be achieved with second-line VpAP treatment in case of resistance developed to primary VPB therapy or subsequent relapse. The efficacy of combined chemotherapy of Vepesed+Holoxan +/- Adriablastin as third-choice was studied in advanced testicular cancer patients refractory to, or recurrent after, first- and second-line cytostatic therapy. Between September 1981 and January 1988 49 evaluable patients were treated with Vepesid (VP-16213--100 mg/m2 days 1-5), Holoxan (40 ml/kg days 1-5), hydration, urine-alkylation + Uromitexan +/- Adriablastin (40 mg/m day 1). The single dose of Uromitexan was 20% of the daily dose of Holoxan, and the patients received it i.v. just prior to Holoxan administration (h 0), the 4 and 8 h later. Two patients got into CR and 10 to PR. The rate of remission was 24.5%. The most severe side effect was leukopenia. The elevation of BUN and se. creatinine was transient and mild. In those cases where Holoxan was not included in the first- or second-line regimens, when combined with Vepesid and Adriablastin as third-choice therapy one could achieve further improvement. In case of CR the prolongation of life is also noteworthy. The first-, second- and third-line therapy plus salvage RLA and/or pulmonary metastasectomy achieved long-term survival only in one quarter of the patients.

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.

Attenuated (nonpathogenic) avian viruses have been used as a form of nonspecific immunological treatment for advanced human cancer. For this study, we used Newcastle disease virus (NDV) vaccine MTH-68/N in an open phase II/B, placebo-controlled (26 patients), multicenter clinical trial for the treatment of 33 patients with advanced cancers. NDV (4000 U/day) or placebo was administered by inhalation twice weekly. During the 6-month trial, the size and presence of primary tumors and metastases were objectively monitored at five institutions by radiologists unaware of the type of treatment that was given. Regression of tumor(s) and/or metastases were observed in eight cases treated with virus (vs. none in the placebo group; p0.01). Ten additional patients treated with NDV had no further progression of their tumor sizes, whereas tumor stabilization was noted in only two control patients. Objective, favorable responses (regressions plus stabilization) to virus therapy thus occurred in a total of 18 patients (55%) compared to 2 patients in the placebo group (8%; p0.01). Two cases of complete remission were noted in the group treated with NDV. Patients receiving virus therapy had a higher rate of survival at 1 to 2 years. Of 33 patients receiving virus vaccine, 22 survived 1 year, compared to only 4 of 26 patients in the control group (p0.02). After 2 years, all seven survivors in the study were in the virus therapy group. There were no 2-year survivors in the control group (p0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

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.

In a combined phase I-II study the hormonal effects of Toremifene were investigated in 15-15 patients at two dose levels: 60 mg and 300 mg per os, daily. Serum estradiol, progesterone, testosterone, follicle-stimulating hormone, luteinizing hormone, prolactin, human growth hormone were monitored by radioimmunoassay and sexual hormone binding globulin by immunoradiometric assay prior to treatment and at the 2nd, 8th and 12th weeks. The influence of Toremifene upon the hypothalamo-hypophyseal axis was also controlled by a tirotropin releasing hormone functional test using 400 micrograms tirotropin releasing hormone injection iv. Estradiol, progesterone, follicle-stimulating hormone, luteinizing hormone and prolactin decreased proving the antiestrogenic activity of the drug. Sexual hormone binding globulin significantly (p less than 0.002) increased by week 12 at both doses, probably due to a direct effect of Toremifene upon the liver. The increase in sexual hormone binding globulin suggests the partial estrogenic effect of the drug. The tirotropin releasing hormone induced prolactin release was also suppressed. On the basis of hormonal changes and the clinical response of patients 60 mg of Toremifene proved to be as effective as 300 mg.

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 authors have developed a specific, sensitive, simple and economic method for the detection of occult colorectal bleeding. The new technique consists of the traditional guaiac type reaction and an immunochemical test which as a second-phase test using dried filter paper discs serves to eliminate or reduce the false-positive reactions, decreasing the necessity of further invasive diagnostic measures. They report on their experience obtained with the screening of a rural population of 3,346 persons; a positive colour reaction was observed in 546 individuals (16.3%) who were not on diet. In the second-phase immunochemical examination, however, this number decreased to 54 (1.6%). In this group of patients, who did have blood in their stools, 5 colorectal carcinomas (9.25%), each in the early Duke stage A, could be detected. The overall detection rate of carcinoma, polyp and colitis ulcerosa, likewise a precancerous state, was 40.73%. The results obtained so far suggest that this combined screening method represents an easier, cheaper and a more rapid diagnostic method for the detection of early colorectal carcinomas and precancerous states compared to the conventional ones. In mass screening the treatment and transportation of the test specimens are simple and hygienic.

Between December 1979 and July 1986, 190 patients with nonseminomatous germ-cell testicular tumors were treated according to the modified Einhorn scheme. The response rate was 67.89%. The most favorable results were found in the embryonal histologic type (RR = 76.9%), in the biological marker (AFP, HCG) negative (RR = 97.43%) and in the minimal pulmonary extent group (RR = 94.12%).

The objective of this trial was to define the antitumor activity and toxicity of etoposide for second-line treatment of patients with bulky ovarian carcinoma. Between February 1, 1986 and November 1, 1988 we recruited 82 patients. Out of them 77 (93.9%) were evaluable for toxicity and 71 (86.6%) for response. Patient characteristics are as follows: median age 57 years (range 15-75), median performance status: WHO 1, prior chemotherapy with more than 3 drugs 24 patients, with previous cisplatin 63 patients, with previous adriamycin 47 patients, with previous irradiation plus chemotherapy 17 patients. The following treatment schedule was applied: each patient started with 150 mg/m2 of etoposide administered i.v. on days 1-3. If this first cycle was well tolerated the dosage was escalated to 200 mg/m2 days 1-3. This higher dosage was then repeated at 4-week intervals. For evaluation of response the WHO criteria were used. One patient (1.4%) achieved complete remission and 5 (7.0%) partial remission. In 48 patients (67.6%) minor response or stabilisation of the disease were observed. Seventeen patients (24%) showed no response. The median duration of remission was 5.5 months (range 2-20). The median duration of stabilisation was 3 months (range 2-24). The median survival time was 10 months with a range of 2-30 months. The myelotoxic side-effects are as follows: WBC less than 2,000 was recorded in 6 patients and greater than 1,000 in 2 patients. Thrombocytopaenia with platelet count less than 50,000 occurred in 1 patient. 26 patients had anaemia WHO grades 2 and 3. Non-haematological toxicity consisted of nausea and vomiting (WHO grade 2:20 patients and grade 3:2 patients), alopecia (WHO grades 2-3:14 and 24 patients, respectively). Though the remission rate in this trial was low, the 10-month median survival with an acceptable quality of life can be taken as a fairly good salvage therapy result.

The purpose of the study was to investigate the antitumour activity and toxicity of high dose (120 mg m-2) single agent epirubicin therapy in untreated extensive small cell lung cancer patients. Out of 80 patients entered, 71 were evaluable for both antitumour activity and toxicity, 4 only for toxicity and 5 were lost for follow-up. The drug possessed a high antitumour activity, the overall response rate was 47.9% (34/71) with 4 complete remissions (CR) and 30 partial remissions (PR). The median remission duration was 3.5 months. Particular drug activity was observed in the primary tumours, lymph nodes and pleural metastases. Toxicity (leukopenia, anaemia, vomiting, reversible rhythmic cardiac disorder, stomatitis) was mild, alopecia was registered less than in adriamycin medication. One fatal congestive heart failure occurred. The actual mean survival time calculated on the basis of the data gained from 64 patients was 7.0 months (range 2-22). The high antitumour activity and no increase in toxicity justify the incorporation of high dose epirubicin into combination therapy.

Dianhydrogalactitol (DAG), labelled with 3H, was administered in single intravenous or oral doses to six patients (three in each group) with cancer. Kinetic parameters were calculated for the unchanged DAG and its biotransformation products. Elimination of the drug by metabolism and excretion was described by a catenary model. In order to elucidate the role of DAG as a mediator of the alkylating action of the cytostatic drug dibromodulcitol (DBD), the pharmacokinetic parameters of DAG and DBD were compared. The mean residence time for pharmacologically active molecules in the body was six times shorter for DAG (1.9 hr) than for DBD (11.4 hr). Alkylating action and metabolic degradation proceeded about 8-9 times faster for DAG than for DBD. The process of DBD alkylation implies a slow solvolytic conversion of the parent drug into the more reactive bromoepoxide and DAG. The preformed DAG would be rapidly consumed by intracellular alkylation and degradation, while unchanged DBD could form a depot in the cells and exert its cytostatic activity through the epoxides released in situ by solvolytic activation. Thus DBD entering the cells in unchanged form may have a more important role in its therapeutic effects than had been assumed earlier.

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...

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.

Lycurim [1,4-di(2'-methanesulfonyloxyethylamino)-1,4-dideoxymesoerythri tol dimethane sulfonate] is rapidly hydrolyzed in aqueous media to inactive products according to a second-order reaction. The respective rate constants are: k1 = 9.82 X 10(-2) and k2 = 1.76 X 10(-2) mumol/ml/min. The concentrations of the parent compound and alkylating intermediate(s) were measured by chemical trapping with N,N-diethyldithiocarbamic acid (DDTC). The rate of this reaction is substantially higher: k1 = 2.61 X 10(-1) and K2 = 4.76 X 10(-2) mumol/ml/min. By using 35S-labeled DDTC, alkylating compounds in concentrations as low as 0.04 microgram/ml could be detected in spiked plasma samples. After intracavitary application of 60 mg Lycurim no alkylating activity could be demonstrated in the plasma of patients at any time point.

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.

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.

The 5-year survival of patients with malignant testicular tumors rose during the past 25 years from 10-25% depending on stage to 55-100% after radical castration performed from high inguinal opening, retroperitoneal lymphadenectomy, ultra-tension irradiation and adjuvant chemotherapy. It is stressed that patients diagnosed at stage T1-2, N0-2, M0 may even recover perfectly upon complex therapy. Three to five-year long or even longer survival may be reached with 50% of the patients at the stage T1-3, N1-3, M1. Patients at stage T4, N3-4, M1 die because of the recurrence of the tumor and/or the complication of the adjuvant treatment within 1-3 years and even the interdisciplinary work which is very effective in other stages fails to change this at the present time.

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.

After having succeeded in imaging the prostate with 131I-Estracyt in our former experiments we tried to use the same method for scanning gynecological tumors. In about fifty per cent of the patients (34 cases) there was a convenient accumulation of the labeled estrogen, first of all the adenoid tumors, myomas of uteri and carcinomas can take up this radiopharmacon. Though the number of cases is rather low it is to be concluded that tumors of hormonal dependence can be scanned using estrogen hormon. Further investigations are in progress.

Advanced recurrent squamous cell head and neck cancer patients were prospectively randomized to receive or not receive dibromodulcitol 10 mg/kg PO weekly for 8 consecutive weeks in addition to bleomycin chemotherapy. Patients initially entered in the study received bleomycin 15 mu/m2 three times weekly for 8 weeks. This was later changed to 15 mu/m2 twice weekly for 8 weeks because of unacceptable stomatitis. Most patients had relapsed following surgery and/or radiotherapy, but none had received prior chemotherapy. A2 : 1 randomization in favor of the dibromodulcitol-containing therapy was used. There were 12 partial responses in the 44 evaluable patients receiving the combination (27%), and 4 partial responses in the 18 patients receiving single-agent bleomycin chemotherapy (22%). This difference was not statistically significant. Response durations were also relatively short for both therapies. Within the limitations of this study, we were unable to demonstrate that patient benefit resulted from the addition of dibromodulcitol to bleomycin chemotherapy for this patient population.