[Analysis of therapy-relevant receptors in bone marrow carcinosis : Comparison of pathological and clinical parameters]. / Untersuchung von therapierelevanten Rezeptoren bei Knochenmarkkarzinosen : Ein Vergleich pathologischer und klinischer Parameter.

BACKGROUND: Bone marrow carcinosis is a sign of advanced tumor stage with nonspecific clinical and hematological symptoms. Diagnosis is based on bone marrow biopsy and histopathology, but biopsies are not part of the standard work-up in oncological diseases and data on the correlation between clinical presentation and pathological findings are sparse. MATERIAL AND METHODS: In a retrospective single-center study, data from 20 tumor patients with bone marrow carcinosis were analyzed. Bone marrow biopsies were re-evaluated regarding quantity of tumor cells, fibrosis/necrosis, and bone changes. Immunohistochemistry of potential therapy-relevant receptors and PD-L1 was performed. RESULTS: The median age in these 20 patients (13 women, 7 men) was 65 years. The most frequent diagnoses were breast (n = 8) and lung cancer (n = 5). Anemia (94% of patients), thrombocytopenia (72%), and elevated LDH (83%) were frequent findings. The degree of bone marrow infiltration was highly variable and accounted for between 1 and 95% of biopsy space. Significant bone remodeling was present in 14/20 biopsies. No correlation could be found between histological and radiological findings. Treated patients showed some clinical and biochemical improvement, but the overall survival was poor (median 4.5 months, range < 0.5 to 21.5 months). DISCUSSION: Anemia and thrombocytopenia are frequently associated with bone marrow carcinosis, but are nonspecific. The extent of tumor cell infiltration and osteolytic/osteoblastic changes did not correlate with radiological findings. Therapy-relevant target factors should be evaluated, but therapeutic options are often limited and the prognosis is bad.

[Malignant atrophic papulosis (Köhlmeier-Degos disease). Failure to respond to interferon alpha-2a, pentoxifylline and aspirin]. / Maligne atrophische Papulose (Morbus Köhlmeier-Degos) Kein Ansprechen auf Interferon alpha-2a, Pentoxifyllin und Azetylsalizylsäure.

A 45 year old female patient presented with the cutaneous manifestations of malignant atrophic papulosis (Köhlmeier-Degos disease) for two years. The typical papules with central porcelain-white atrophy correspond histologically to wedge-shaped necrosis of the connective tissue due to thrombotic occlusion of small vessels in the corium. The pathogenesis of malignant atrophic papulosis and effective treatment modalities are unknown. A slow virus infection has been suggested by some authors. Therefore, we attempted an immune therapy with interferon alpha-2a over a period of 11 months, but failed to cause a significant effect on the appearance and progression of the skin lesions. Furthermore, we could not confirm the effectiveness of a recently reported treatment modality with pentoxifylline and aspirin administered to our patient over a period of 5 months.

Randomised comparison of CHOEP versus alternating hCHOP/IVEP for high-grade non-Hodgkin's lymphomas: treatment results and prognostic factor analysis in a multi-centre trial.

BACKGROUND: With CHOP, the standard protocol of recent decades, about 30% of long-term survival has been reported. A number of studies using more aggressive multidrug regimens or alternating chemotherapies have recently suggested higher CR rates and increased survival. In 1989 we reported similar results with a combined-modality treatment administering 6 cycles of CHOP supplemented with etoposide and an involved field irradiation for patients in PR or CR. PATIENTS AND METHODS: To confirm the efficacy of this approach, we initiated a prospective randomised trial comparing 4 cycles of CHOP-VP16 (CHOEP) with 4 cycles of two alternating regimens, 'hCHOP and IVEP'. One hundred seventy-five patients with high-grade non-Hodgkin's lymphomas stages II-IV were stratified for age, stage and LDH and randomised to receive either four cycles of cyclophosphamide, doxorubicin, vincristine, etoposide, prednisolone (CHOEP) in arm A or four cycles of chemotherapy with a dose-intensified CHOP (hCHOP) alternating with ifosfamide, etoposide, vindesine, prednisolone (IVEP) in arm B. After four cycles of chemotherapy an involved field irradiation with a total dose of 35 Gy was given to all patients demonstrated to be in complete or partial remission. RESULTS: Of the 185 randomised patients, 175 were eligible and 171 evaluable for response and survival. One hundred forty-six of the 171 patients (85%) achieved complete remission (CR) with 87% and 84% CRs in arms A and B, respectively. With a median follow-up of 36 months the estimated overall survival at 2 years is 66% and 73% for arms A and B, respectively. The percentage of all patients in first CR is estimated to be 59% and 55% at 2 years for arms A and B, respectively. None of the differences in CR rate, survival, or relapse-free survival are statistically significant. Multivariate analysis of subgroups incorporating the factors of sex, age, performance status, stage, B symptoms, bulky disease, LDH and histology revealed that only stage and LDH were factors which independently affected outcome. The estimated 2-year survival rate of patients with stages II, III and IV is predicted to be 84%, 62% and 52%, respectively. Patients with LDH > 250 U/l have an estimated survival of 52% at 2 years versus 84% for patients with LDH < or = 250 U/l. According to the newly proposed international score system, the 2-year survival was 81% for low-risk-, 64% for low intermediate risk-, 50% for high intermediate risk-, and 43% for high-risk patients. The toxicity in both arms was tolerable. Three patients died of treatment-related causes (2 in arm A, 1 in arm B). The main toxicity was haematological with 75% of patients suffering from grades 3 or 4 neutropenia at some point during treatment. CONCLUSIONS: We observed no superior benefit for alternating regimens, and conclude that both are effective treatment protocols for aggressive histologic-type malignant lymphomas. The results obtained with four cycles of poly-chemotherapy followed by an involved field irradiation are comparable to programs using more aggressive and/or prolonged chemotherapy.

Effect of clomipramine and lithium on fenfluramine-induced hormone release in major depression.

Prolactin (PRL) and cortisol responses to oral administration of d-1 fenfluramine hydrochloride (60 mg) and placebo were examined in patients with endogenous major depressive disorder on three separate occasions: prior to treatment with clomipramine (CMI), after 4 weeks of CMI administration (175-250) mg/day), and 3 weeks after addition of lithium (Li) carbonate (serum level 0.5-0.9 mmol) to the treatment regimen. CMI significantly increased baseline PRL levels which were further elevated following Li supplementation. PRL response to fenfluramine (minus elevated baseline PRL levels) but not to placebo, was significantly increased by CMI administration, reflected over the 6-hr time course examined and in peak minus baseline values. Following addition of Li, the degree of enhancement was diminished although the peak minus baseline value remained significant relative to the pretreatment response. Cortisol levels were not increased by fenfluramine and were not altered by CMI or CMI + Li administration. The effect of CMI extends previous observations regarding the action of antidepressant treatment on serotenergically mediated hormone release. Methodological considerations relevant to the effect of CMI + Li are discussed.

Enhanced serotonergic responsivity following electroconvulsive therapy in patients with major depression.

Prolactin release in response to fenfluramine hydrochloride (60 mg orally) and placebo was evaluated in 18 medication-free patients with RDC major depressive disorder, endogenous subtype, before and after a series of bilateral treatments with ECT. Before ECT, fenfluramine induced a twofold increase in plasma prolactin levels. This response was significantly enhanced after the ECT series, while baseline prolactin levels and response to the placebo challenge were not altered. There was no significant difference in plasma fenfluramine and norfenfluramine levels during the pre- and post-ECT challenges. These findings suggest that ECT enhances central serotonergic responsivity and extend to depressed patients pre-clinical observations regarding the effect of electroconvulsive shock on serotonergic function.

Effect of fenfluramine on mood: a double-blind placebo-controlled trial.

Depressed patients (n = 10), schizophrenics (n = 6), and normal control subjects was (n = 9) were administered fenfluramine hydrochloride (FF) (60 mg/os) or placebo in the context of a randomized, double-blind crossover trial. No effect of FF on mood or activation was detected over a 6-hr period. A previous report claiming acute antidepressant effects of FF in depressed subjects was not confirmed.

Sequential versus alternating chemotherapy for high grade non-Hodgkin's lymphomas: a randomized multicentre trial.

In a multicentre phase III trial 146 previously untreated patients with high grade non-Hodgkin's lymphomas stage II-IV were randomized to receive either four cycles of CHOEP (cyclophosphamide 750 mg/m2 iv d 1, doxorubicin 50 mg/m2 iv d 1, vincristine 2 mg iv d 1, etoposide 100 mg/m2 iv d 3-5, prednisolone 100 mg po d 1-5) (treatment arm A), or four cycles of chemotherapy with hCHOP (cyclophosphamide 1200 mg/m2 iv d 1, doxorubicin 40 mg/m2 iv d 1 + 2, vincristine 2 mg iv d 1, prednisolone 100 mg po d 1-5) alternating with IVEP (ifosfamide 1500 mg/m2 iv d 1-5, vindesine 3 mg/m2 iv d 1, etoposide 120 mg/m2 iv d 3-5, prednisolone 100 mg po d 1-5) (treatment arm B). After four cycles of chemotherapy an involved field irradiation with a total dose of 35 Gy was given to all patients in complete or partial remission without persisting extranodal disease. A complete response (CR) was seen in 124/146 patients (86 per cent) with 87 per cent CR in arm A versus 83 per cent CR in arm B. During a median follow-up of 17 months (range 2-40) 30 patients relapsed (16 patients arm A, 14 patients arm B). The overall survival at 40 months is projected to be 71 per cent versus 70 per cent for arm A and B, respectively. Disease-free survival is projected to be 68 per cent in arm A and 59 per cent in arm B at 40 months. So far, the differences in CR, survival and disease-free survival are not statistically significant.(ABSTRACT TRUNCATED AT 250 WORDS)

[Tumor markers, significance for clinical diagnosis]. / Tumormarker, Bedeutung für die klinische Diagnostik.

A wide variety of tumour markers has been described in bronchial carcinoma. Clinical studies have been most frequently conducted with the substances CEA, NSE, CK-BB and for the peptid hormones ACTH, calcitonin and ADH. The serum levels for CEA, NSE and CK-BB correlate to a certain extent with the stage of the tumour disease, the prognosis and the survival time. On the other hand, the peptid hormones have no clinical significance on account of their low sensitivity and specificity. Outside of clinical studies the determination of tumour markers in bronchial carcinoma is clinically irrelevant.

Sequential versus alternating chemotherapy for high-grade non-Hodgkin's lymphomas: preliminary results of a phase III multicentre trial.

In a multicentre phase III trial 105 previously untreated patients with high-grade non-Hodgkin's lymphomas stage II-IV were randomized to receive either 4 cycles of CHOEP (cyclophosphamide 750 mg/m2 i.v. day 1, doxorubicin 50 mg/m2 i.v. day 1, vincristine 2 mg i.v. day 1, etoposide 100 mg/m2 i.v. days 3-5, prednisolone 100 mg p.o. days 1-5) (treatment arm A), or 4 cycles of chemotherapy with hCHOP (cyclophosphamide 1,200 mg/m2 i.v. day 1, doxorubicin 40 mg/m2 i.v. days 1 + 2, vincristine 2 mg i.v. day 1, prednisolone 100 mg p.o. days 1-5) alternating with IVEP (ifosfamide 1,500 mg/m2 i.v. days 1-5, vindesine 3 mg/m2 i.v. day 1, etoposide 120 mg/m2 i.v. days 3-5, prednisolone 100 mg p.o. days 1-5) in treatment arm B. After 4 cycles of chemotherapy an involved field irradiation with a total dose of 35 Gy was given to all patients demonstrated to be in complete or partial remission without persisting extranodal disease. A complete response (CR) was seen in 86/105 patients (82%) with 88% CR in arm A vs. 76% CR in arm B. During a median follow-up of 11 months (range 2-31 months) 13 patients relapsed (6 patients arm A, 7 patients arm B). The overall survival at 30 months is projected to be 72% vs. 83% for arm A and B respectively. Disease-free survival is projected to be 78% in arm A and 45% in arm B at 28 months. So far, the differences in CR, survival and disease-free survival are not statistically significant.(ABSTRACT TRUNCATED AT 250 WORDS)

[Results of 2 multicenter therapy studies in inoperable non-small cell bronchial cancer]. / Ergebnisse zweier multizentrischer Therapiestudien beim inoperablen nichtkleinzelligen Bronchialkarzinom.

A total of 166 patients with non-small cell lung cancer (NSCLC) were included in two multicenter trials testing different treatment regimens. In study I, 116 patients received 4 cycles of aggressive polychemotherapy consisting of cis-platinum 100 mg/m2 (day 1), etoposide 100 mg/m2 (days 4-6), and vindesine 3 mg/m2 (day 1) (CEV); patients without distant metastases subsequently received chest irradiation with 50 Gy. In study II, 50 patients were treated with monochemotherapy consisting of etoposide 250 mg/m2 (days 1-3), and ifosfamide 5 g/m2 as 24-h infusion (day 29). While this program was repeated in responders with extensive disease (ED), patients with limited disease (LD) subsequently received chest irradiation with 50 Gy using 20 mg/m2 cis-platinum weekly as a radiosensitizer. Response rates (CR + PR) to chemotherapy were higher in study I than in study II, and were 26% (CR 3%) vs. 8% (CR 0%) for all patients, 18% (CR 0%) vs. 4% (CR 0%) for ED, and 45% (CR 11%) vs. 13% (CR 0%) for LD. The increase in response rates by radiotherapy was marginal in study I (CR + PR 47%, CR 18%), but remarkable in study II (CR + PR 42%, CR 29%). While median survival was slightly longer in study I than in study II for ED (7.7 vs. 6.6 months) and LD (14.4 vs. 12.0 months), the 2-year survival rate was in favor of study II (10% vs. 25%). Toxicity was clearly more pronounced in study I, including 3 lethal complications and 16 discontinuations of therapy due to side effects or refusal. Thus, while in ED the efficacy of both treatment regimens was very restricted, in LD radiotherapy with cis-platinum as a radiosensitizer achieved a relatively high 2-year survival rate which justifies further testing of this treatment strategy.

Prognostic value of pretreatment carcinoembryonic antigen, neuron-specific enolase, and creatine kinase-BB levels in sera of patients with small cell lung cancer.

Carcinoembryonic antigen (CEA), neuron-specific enolase (NSE), and the BB isoenzyme of creatine kinase (CK-BB) were evaluated before therapy in the sera of 195 patients with histologically confirmed small cell lung cancer (SCLC) in a prospective multicenter trial. Forty-four percent (84 of 193) of all patients had CEA levels higher than 5 ng/ml, 66% (111 of 168) had NSE levels higher than 12.5 ng/ml, and 32% (40 of 123) had CK-BB levels higher than 10 ng/ml. Clear pathologic levels were less frequently observed. Significantly higher pretreatment titers for CEA, NSE, and CK-BB were found in patients with bone marrow and/or liver metastases. The most elevated marker levels were observed in the group of nonresponding patients with bone marrow and/or liver metastases. Only a slight correlation between the pretreatment CEA level and survival time could be observed. Patients with pathologic NSE (greater than or equal to 30 ng/ml) levels and, in particular, those with pathologic CK-BB (greater than or equal to 25 ng/ml) levels had a significantly shorter median survival than those with normal or elevated levels. In addition, a positive linear correlation between pretreatment NSE and CK-BB (n = 116, r = 0.54) levels was found, but CEA levels did not correlate with other marker levels. From these data it is concluded that pretreatment CEA, NSE, and CK-BB levels are helpful in the clinical management of a subset of patients with SCLC, i.e., those with bone marrow and/or liver metastases.

Characterization of the state of differentiation of six newly established human non-small-cell lung cancer cell lines.

Six new non-small-cell lung cancer (NSCLC) cell lines were established directly from human tissue or indirectly via nude mouse xenografts in serum-supplemented media with success rates of 8% and 13%, respectively. They comprised one adenocarcinoma (ADLC-5M2), two squamous cell carcinomas (EPLC-32M1, EPLC-65H), two large cell carcinomas (LCLC-97TM1, LCLC-103H), and one malignant biphasic mesothelioma (MSTO-211H). All cell lines grew adherent to culture vessels with population doubling times (PDT) of 16-40 h, formed colonies in soft agarose with efficiencies of 0.1%-5.1%, and all grew in athymic nude mice. Xenograft histologies appeared as follows: (a) undifferentiated carcinomas with feeble resemblance to the original tumors in the case of adenocarcinomas and squamous cell carcinomas; (b) large cell carcinoma with high resemblance to the original tumor; (c) an undifferentiated tumor with predominance of large epithelial cells and few fibrous cells in the case of mesothelioma. Human chorionic gonadotropin (HCG) was found by radioimmunoassay and high-affinity binding sites for epidermal growth factor (EGF) by radio-receptor assay in 4/4 cell lines. A very low activity of L-DOPA decarboxylase (DDC) was detectable only in the adenocarcinoma cell line. All cell lines overexpressed the c-myc protooncogene, and no gene rearrangement or amplification was observed. Chromosome analysis revealed modal chromosome numbers of 70-73 in ADLC-5M2, EPLC-32M1, EPLC-65H, and MSTO-211H. Cell lines derived from large cell carcinoma had modal values of 65 and 170 and a wider chromosome distribution than all other cell lines. A NSCLC specific chromosomal aberration has been undetectable until now. These cell lines may aid in elucidating the biology of NSCLC and its interrelationship to other lung tumors.

Cisplatin/etoposide versus ifosfamide/etoposide combination chemotherapy in small-cell lung cancer: a multicenter German randomized trial.

A total of 144 patients with small-cell lung cancer (SCLC) were randomized to receive cisplatin/etoposide (PE) or ifosfamide/etoposide (IE) combination chemotherapy. PE consisted of cisplatin, 80 mg/m2, intravenously (IV) on day 1, and etoposide, 150 mg/m2, IV on days 3 through 5. IE consisted of ifosfamide, 1,500 mg/m2, IV on days 1 through 5, and etoposide, 120 mg/m2, IV on days 3 through 5. Six cycles were administered in 3-week intervals. Nonresponders were switched immediately to CAV, consisting of cyclophosphamide, 600 mg/m2, IV on days 1 and 2, Adriamycin (Adria Laboratories, Columbus, OH), 50 mg/m2, IV on day 1, and vincristine, 2 mg, IV on day 1. Patients obtaining complete remission (CR) received prophylactic cranial irradiation with 30 Gy. After completion of chemotherapy, patients with limited disease received chest irradiation with 45 Gy. No maintenance therapy was given to patients in CR. Minimum follow-up was 2 years. Of the 141 patients evaluable, the overall response rate was 65% in PE therapy and 68% in IE therapy. The CR rate was 32% v 20% for all patients, 50% v 24% for limited disease, and 22% v 18% for extensive disease, all in favor of PE therapy. Median survival for all patients was 11.6 months v 9.4 months, for limited disease 14.8 months v 11.0 months, and for extensive disease 8.9 months v 7.5 months, all preferring PE therapy. The 2-year survival rate was higher in PE therapy than in IE therapy for all patients (12% v 9%) and for limited disease (23% v 10%), but not for extensive disease (5% v 9%). Median progression-free survival was 7.5 months v 6.0 months for all patients, 12.2 months v 8.8 months for limited disease, and 5.9 months v 4.4 months for extensive disease, all in favor of PE. Relapse in the area of the primary tumor was found less often after PE than after IE therapy (25% v 38%). Response to second-line CAV was seen in 30% of patients with prior PE and 43% with prior IE therapy, but was usually short lasting, and only one patient achieved CR. Toxicity included three lethal complications. Nausea, vomiting, diarrhea, and skin lesions occurred more often after PE than after IE therapy. These results suggest that PE is superior to IE chemotherapy in limited-stage, but not in extensive-stage SCLC, and that CAV is cross-resistant to PE, as well as to IE in the majority of patients.

Alternating versus sequential chemotherapy in small cell lung cancer. A randomized German multicenter trial.

A total of 306 patients with small cell lung cancer (SCLC) were randomized to receive chemotherapy in a sequential or alternating mode. Sequential chemotherapy consisted of eight cycles of cyclophosphamide, Adriamycin (doxorubicin), and vincristine (CAV) and alternating chemotherapy consisted of three cycles (1, 3, 5) of etoposide, vindesine, and ifosfamide (EVI); three cycles (2, 4, 6) of cisplatin, Adriamycin, and vincristine (PAV); and two cycles (7, 8) of cyclophosphamide, methotrexate, and CCNU (CMC). Responsive patients received prophylactic cranial irradiation after three cycles and chest irradiation after eight cycles of chemotherapy. No maintenance therapy was applied to patients achieving complete remission. Minimum follow-up was 2 years. Of the 302 patients evaluable, overall response rate was 59% in the sequential arm and 70% in the alternating arm. Patients treated with CAV had a complete response rate of 21% in contrast to 36% for those receiving alternating therapy. The median survival for all patients was 9.8 versus 11.3 months, for limited disease 11.1 versus 13.4 months, and for extensive disease 8.9 versus 9.9 months, all in favor of the alternating treatment. Two-year survival rate for all patients was 6% versus 9%, for limited disease 11% versus 14%, and for extensive disease 3% versus 6%, all preferring the alternating treatment mode. Progression-free survival demonstrated a strong correlation to the extent of response irrespective of the treatment regimen applied. Toxicity included 11 lethal and 8 life-threatening complications with a higher frequency in the alternating treatment arm. These results suggest that alternating treatment of SCLC with different drug combinations is more effective than sequential application of CAV.

Establishment, growth properties, and morphological characteristics of permanent human small cell lung cancer cell lines.

Cell lines from SCLC were established with a success rate of 43% from different metastatic sites of treated and untreated patients. All 6 SCLC cell lines grew as floating cell aggregates without substrate adherence. The degree of aggregation ranged from very tight spheroids to very loose sheets and chains. This gross morphological property showed a striking correlation to the PDT, with short PDTs in loose growing cell lines and long PDTs in tight growing cell lines. Cell size and nuclear features, i.e., chromatin pattern and nucleolar prominence, also seemed to correlate with the PDT and gross morphology. All SCLC cell lines had dense core granules by electron microscopical examination. Several different serum-free and serum-supplemented growth media were tested for their feasibility in establishing and permanently growing SCLC. Serum-free SIT medium and SIT2.5 medium provided the best results in liquid culture. For semisolid SCLC cultivation, R 10 medium was superior to all other media tested. These cell lines are currently under intensive biochemical, molecular biological, and cytogenetical investigation in different laboratories and thus provide a tool for studying the biology of lung cancer.

Markers and characteristics of human SCLC cell lines. Neuroendocrine markers, classical tumor markers, and chromosomal characteristics of permanent human small cell lung cancer cell lines.

Permanent human small cell lung cancer (SCLC) cell lines established in our laboratory were investigated for their expression of the enzymatic neuroendocrine markers L-DOPA decarboxylase (DDC), neuron-specific enolase (NSE), and creatine kinase (CK), including its BB isoenzyme (CK-BB), the classical tumor markers carcinoembryonic antigen (CEA), the alpha and beta subunits of human chorionic gonadotropin (alpha-HCG, beta-HCG), and alpha-fetoprotein (alpha-FP), and their chromosomal characteristics. DDC activities were detectable in 5/6 SCLC cell lines and absent in non-SCLC. NSE levels ranged from 160 to 1422 ng/mg soluble protein and were less than 290 ng/mg soluble protein in non-SCLC. Activities of CK and levels of CK-BB clearly distinguished SCLC from non-SCLC with CK activities greater than 1000 munits/mg soluble protein and CK-BB levels greater than 3000 ng/mg soluble protein in SCLC and less than 300 munits/mg soluble protein and less than 2000 ng/mg soluble protein in non-SCLC. CEA was detectable in 5/6 SCLC cell lines but absent in non-SCLC, and its level seemed to correlate with those of DDC, NSE, and CK. One cell line, SCLC-16H, lost some of its neuroendocrine properties and CEA after 1 year of in vitro cultivation. Generally, marker levels were low in fast growing cell lines and high in slow growing cell lines. HCG alpha and beta subunit and alpha-FP were not detectable in SCLC cell lines. All SCLC cell lines examined had near diploid DNA indices and modal chromosome numbers. Double minute chromosomes and homogeneously staining regions were found in 2/5 and 4/5 SCLC cell lines respectively. With respect to chromosomal aberrations, we found a deletion of the short arm of at least one chromosome 3 in all SCLC cell lines (5/5). These data show that SCLC expresses neuroendocrine markers and CEA; CK is the most sensitive marker, and DDC and CEA are the most specific markers for SCLC in vitro; individual marker levels correlate with each other and the in vitro malignancy of SCLC; and SCLC cell lines have relatively uniform chromosomal characteristics. Our results suggest that patients whose tumors have high levels of DDC, NSE, CK-BB, and CEA have a better prognosis than those with low marker levels. This hypothesis could be proved by comparing pairs of patients that are matched for all known prognostic parameters, in particular tumor spread, for their serum and tumor marker levels with respect to the patients' outcome and prognosis.

Identification of cytoskeletal structures in hormone producing lung cancer cell cultures.

In order to investigate the intermediate filament protein content of hormone producing lung tumor cell cultures a panel of 16 different cytokeratin antisera were tested using immunocytochemical and biochemical techniques on lung carcinoma cell cultures from different origin. These included three cell cultures derived from small cell lung carcinoma, two large cell carcinoma cell cultures, and two cell cultures derived from squamous cell carcinomas. Flow cytometric analysis of the cell cultures demonstrated that all cell lines examined were aneuploid with DNA-indices ranging from 1.7 to 3.1 rimes the DNA-content of normal human lymphocytes. In both immunofluorescence and immunoperoxidase techniques six out of seven cell cultures reacted with most of the cytokeratin antisera used in a filamentous manner, while a large cell carcinoma cell culture did not react with any of the cytokeratin antisera used. None of the cell cultures examined reacted with the antibodies to neurofilament proteins, suggesting that none of these (neuro)hormone producing cell cultures were of neural origin. All cell cultures which were growing as adherent cell cultures did express vimentin. The cell culture that grew with cells floating in aggregates did not express this intermediate filament protein while a subline which did attach, expressed vimentin. This findings strongly indicates the relation between growth pattern in vitro (floating vs. adherent) and the expression of vimentin. No reaction was found with antisera to desmin and GFAP. The presence of cytokeratins and vimentin in most cell cultures could be confirmed using one- and two-dimensional gel electrophoresis. Cytokeratins 7, 8, 18 and 19 were most commonly present.

Two randomized trials for alternating polychemotherapy of small cell lung cancer.

Patients with small cell carcinoma of the lung (SCCL) were treated in two multicenter trials with different cytostatic drug regimens including ifosfamide. In the first randomized study, including 306 patients, alternating chemotherapy with VP 16, ifosfamide, vindesine (VPIV), adriamycin, cisplatinum, vincristine (APO), and cyclophosphamide, methotrexate, CCNU (CMCC) was compared against standard treatment with ACO (adriamycin, cyclophosphamide, vincristine). It was shown that the alternating therapy resulted in a higher response rate (88% vs 78%) and a longer median survival time (11 months vs 10 months). Regarding toxicity, VPIV was similar to ACO, whereas APO and CMCC had more side-effects, leading to an increase in the number of drop-outs. In the second randomized study 144 patients were treated either with ifosfamide/VP 16 (IVP) or with cisplatinum/VP 16 (PVP). In the case of no further response, no change, or progression the induction therapy was changed to ACO. Interim analyses show that both regimens have similar therapeutic effects; but higher toxicity was observed in patients treated with cis-platinum/VP 16 than in patients treated with ifosfamide/VP 16. According to the response rate in patients treated with ACO after first-line therapy there was less cross-resistance of IVP than of PVP to ACO.