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Purpose: To determine the feasibility and safety of multiple sequential courses of high-dose chemotherapy and peripheral-blood progenitor cells (PBPCs) administered in a multicenter setting to patients with small-cell lung cancer., Patients and Methods: Sixty-nine patients (limited disease, n = 30; extensive disease, n = 39) treated at 15 European centers were scheduled to receive three courses of high-dose chemotherapy with ifosfamide 10 g/m(2), carboplatin 1200 mg/m(2), and etoposide 1200 mg/m(2) (ICE) divided over 4 days at 28-day intervals. PBPCs were harvested before treatment and mobilized with epirubicin 150 mg/m(2) administered via an intravenous bolus divided over 2 days and filgrastim 5 microg/kg/d administered subcutaneously., Results: The performed leukaphereses (one to five per patient) yielded a median of 16.6 x 10(6)/kg (range, 1.0 to 96.6 x 10(6)/kg) CD34(+) cells, which was sufficient for three reinfusions. Fifty patients (72%) completed the treatment according to schedule. Nine patients completed two courses, and six patients completed one course of treatment. The increase in dose-intensity was 290% that of a standard ICE regimen. The median duration of myelosuppression was similar between courses, namely 4 days (range, 1 to 12 days) for leukocytes less than 0.5 x 10(9)/L and 4 days (range, 0 to 22 days) for thrombocytes less than 20 x 10(9)/L. Febrile neutropenia developed in 66% of courses, severe diarrhea in 14%, mucositis in 10%, and nausea and vomiting in 21% of courses. There were six cases of toxic death (9%), most of which occurred in the first year of accrual and thus were attributable to the learning curve. The antitumor effect of the regimen was reflected in an 86% remission rate (95% confidence interval [CI], 74% to 93%), with 51% of patients achieving a complete response (95% CI, 38% to 63%). Median overall survival was 18 months for patients with limited disease and 11 months for patients with extensive disease., Conclusion: This multiple sequential high-dose ICE regimen could be safely administered on a multicenter basis to patients with small-cell lung cancer. The dose-intensity could be increased to 290% that of standard ICE regimen. The benefit of this approach is currently being tested in a randomized trial that aims to double the long-term rate of survival for patients with small-cell lung cancer.

Recent reports have suggested that the immunodetection of tumor cells in bone marrow of small-cell lung cancer (SCLC) patients is by far more effective than traditional cytohistological methods and that this may be clinically relevant. This study aimed to evaluate whether the level of detection of tumor cells in bone marrow is affected by different immunostaining methods. Using two anti-NCAM monoclonal antibodies (MAbs), we compared four different "sandwich" methods on cytospin preparations of the N592 human SCLC cell line and of bone marrow aspirates from 37 SCLC patients. Our data indicate that the combination of the alkaline phosphatase-anti-alkaline phosphatase and streptavidin-biotin-alkaline phosphatase complex methods provides the best results in terms of sensitivity and specificity, and of intensity of immunoreaction and absence of staining background. Moreover, bone marrow micrometastases detected by this method were prognostically relevant and identified, among patients with apparently limited disease according to conventional staging procedures, a subgroup with shorter survival. We suggest that the choice of a sensitive immunostaining technique may significantly increase the detection rate of SCLC cells in bone marrow, mirroring the biological aggressiveness of the disease.

The analysis of benzene in urine of the general population or of exposed workers can be performed with different methods using the 'purge and trap' or 'solid-phase microextraction' techniques in combination with gas chromatographic analysis and photoionisation or mass spectrometric detection. The published results, however, are deeply conflicting. Differences in sample preparation by different research groups and our own preliminary observations prompted us to investigate pre-analytical and analytical factors potentially capable of modifying the urinary benzene quantification results. Benzene concentrations were measured in 20 urine samples in relation to different conditioning conditions (at 24, 40 and 80 degrees C) and at basic or acid pH. Urinary protein concentrations were measured in the same samples. Urine heating at 80 degrees C yields benzene concentrations on average five times higher than at 24 degrees C. On acidification of urine, the benzene released increases up to 28-fold in comparison to that obtained at uncorrected 'physiological' pH. Despite a widely scattered data distribution, a statistically significant linear correlation was found between 'heat-released' and 'acid-labile' benzene values. There was no correlation between total urinary proteins present in 'physiological' concentrations (between 12 and 110 mg/l) and the different kinds of benzene in urine. Our results could perhaps be explained if it is supposed that part of the benzene in urine is absorbed onto sediment, or bound to specific proteins, or derived from parent molecules and is released with pH modification or heat administration. Our observations may also help to explain why the urinary benzene concentrations reported by different investigators vary considerably even when environmental levels are comparable.

Background: The combination of gemcitabine and cisplatin has proven effective in the treatment of advanced non-small-cell lung cancer (NSCLC). However, the optimal schedule for administration of the two drugs has not yet been determined. In this study we evaluated the activity and toxicity of a weekly gemcitabine and cisplatin schedule., Patients and Methods: Thirty-six untreated patients with stage IIIB IV NSCLC entered the study. Treatment consisted of gemcitabine 1000 mg/m2 i.v. and cisplatin 35 mg/m2 i.v., both given weekly on day 1,8, and 15, followed by one week of rest., Results: Ninety-seven courses (273 weekly administrations) were delivered. The median dose-intensity was 612 mg/m2 per week for gemcitabine (82%) and 21 mg/m2 per week for cisplatin (80%). All 36 of the patients were evaluable for toxicity, and 30 for response. Partial remissions were observed in 12 patients, for an overall response rate of 40% (95% confidence interval (95% CI): 22.5%-57.5%). Most of the partial remissions were seen in IIIB patients (54% of the stage IIIB and 22% of the stage IV patients responded). According to the intent-to-treat principle, the response rate was 33.3% (12 of 36 patients). The median response duration was 9.9 months (range 4-23) and the median survival time 11.8 months (range 1-24). World Health Organization (WHO) grade 3-4 myelotoxicity was: thrombocytopenia in nine patients (25%), neutropenia in six (16.6%) and anemia in six (16.6%); there was very little additional major toxicity., Conclusions: This regimen appears to be active and to have a favourable toxicity profile.

Background: Immunocytochemistry has been proven able to identify tumor cells in bone marrow aspirate (BMA) of patients with SCLC. However, few data exist about the clinical significance of the procedure., Patients and Methods: 108 BMA taken from 60 patients were incubated with the MoAb MLuC1 (cluster 6) and stained by the APAAP (alkaline phosphatase-antialkaline phosphatase) method. The serum levels of LDH, TPA, NSE and CEA were also studied in relation to bone marrow involvement by means of discriminant analysis., Results: Immunocytochemistry of the aspirate with MLuC1 detected positive cells in 23 patients (38%) (38 of 108 samples) vs. 13% of the conventional biopsies studied without MLuC1 (P < 0.001). With respect to bone marrow positivity, three groups of patients were identified: those with no positive cells in the aspirate and negative biopsy (group A); those with less than 10 positive cells in the aspirate and negative biopsy (group B); and those with more than 10 positive cells or clumps in the aspirate or positive biopsy (group C). Group C patients had poorer median survivals than those in the other two groups (5.5 vs. 11 months, respectively, P = 0.01). Discriminant analysis showed that the four serum markers were poor discriminators of the degree of bone marrow involvement, with only 55% of grouped cases being correctly classified., Conclusions: These results show that detection of bone marrow involvement i) can be improved by the use of MLuC1 ii) is not predictable by conventional tumor markers, and iii) is related to poor outcome.

Background: Studies of chemotherapy for patients with small cell lung carcinoma (SCLC) have shown that teniposide (T) may have higher activity than etoposide (E). In this randomized, controlled Phase III study, the authors compared cyclophosphamide, doxorubicin, and vincristine (CAV) with E and CAV with T as induction treatments for patients with SCLC. A second objective of the study was to study patients who had achieved complete response (CR). They were considered for a second randomization to maintenance therapy, in which they would receive either recombinant interferon-alpha (rIFN-alpha) or no treatment., Methods: From June 1990 to December 1995, 140 untreated SCLC patients were enrolled in this study. Patients were stratified by either limited disease (LD) or extensive disease (ED) and randomized to one of two treatment arms. The schedules for both arms included cyclophosphamide 1000 mg/m2 administered intravenously (i.v.), doxorubicin 50 mg/m2 i.v., and vincristine 2 mg i.v. on Day 1. Arm A (CAV-E) involved the addition of E 100 mg/m2 i.v. on Days 2, 3, and 4; Arm B (CAV-T) involved the addition of T 60 mg/m2 i.v. on Days 2, 3, and 4. Courses were repeated every 3 weeks. After 3 courses, patients with LD received chest radiotherapy and 2 additional consolidation courses, whereas patients with ED received 5 consecutive courses only. Patients with CR were considered for the second randomization, which consisted of either maintenance therapy with intramuscular (i.m.) rIFN-alpha-2b, 3 M.U., once a day for 9 months (IFN-alpha arm) or no therapy (control arm)., Results: At 5 years from start-up (3-year median observation time and 90% death rate), the study was closed. Results were as follows: 140 patients (71 in Arm A and 69 in Arm B) were eligible for survival analysis; 131 were evaluable for response and toxicity (66 in Arm A and 65 in Arm B), whereas 9 were not (6 early deaths and 3 with protocol violations). Among evaluable patients, 68 showed LD (35 assigned to Arm A and 33 to Arm B); the responses to treatment were 28.5% (10/35) CR and 51% (18/35) partial response (PR) to CAV-E, and 39% (13/33) CR and 39% PR (13/33) to CAV-T. Sixty-three patients showed ED (31 assigned to Arm A and 32 to Arm B); their responses were 22.5% (7/31) CR and 52% (16/31) PR to CAV-E, and 12.5% (4/32) CR and 50% (16/32) PR to CAV-T. Drug-related toxicity was WHO Grade 3-4 myelosuppression in 20% of 292 CAV-E courses and in 27% of 252 CAV-T courses. There were 6 toxic deaths, 1 in Arm A and 5 in Arm B (chi-square = 2.86); 2 patients in Arm A discontinued therapy due to persistent leukopenia and thrombocytopenia. No other remarkable toxicities were observed. Actuarial median survival (MS) was 13.7 months (range, 1.0-62.5 months) for patients with LD receiving CAV-E (Arm A) and 15.2 months (range, 0.5-68.2 months) for those receiving CAV-T (Arm B) (chi-square = 0.89); in patients with ED it was 10.5 months (range, 0.6-30.4 months) and 8.2 months (range, 0.2-24.8 months), respectively (chi-square = 3.42). Overall, MS was 12 months (range, 0.6-62.5 months) in Arm A and 10 months (range, 0.2-68.2 months) in Arm B (chi-square = 0.059). Thirty-nine patients with CR (27.8%) were candidates for the second randomization. Among them, 26 patients (18.5%) complied with the program and were randomized as follows: 14 were assigned to the IFN-alpha arm and 12 to the control arm. Starting from the second randomization, median time to progression was 12 months (range, 3-51 months) for patients in the IFN-alpha arm versus 7 months (range, 1-59 months) for patients in the control arm (chi-square = 0.12). MS was 15 months (range, 5-52.3 months) versus 9 months (range, 2-60.5 months) (chi-square = 0.13)., Conclusions: This study did not show a wide difference in activity and toxicity between CAV-E and CAV-T. The number of patients who entered the second randomization was too small to reach the second study endpoint.

Cell-surface high-affinity monomeric 67-kD laminin receptors have been proposed to promote the invasion and metastasis of a variety of tumours, but there are, as yet, no data regarding the expression of these molecules in pancreatic endocrine tumours (PETs). The prognosis of these very rare tumours is problematic and the only irrefutable evidence of their malignancy still continues to be the occurrence of local invasion and metastases. In this retrospective investigation, 34 functioning and 48 non-functioning sporadic PETs were evaluated for the expression of the MLuC5 monoclonal antibody, which specifically recognizes the 67-kD laminin receptors. Laminin receptors were found in 42/82 cases (51 per cent) and their expression was associated with metastatic disease (P < 0.001), high proliferative activity expressed by a Ki-67 index above 5.0 per cent (P < 0.001), absence of progesterone receptors (P = 0.013), immunoreactivity for hormones other than insulin (P < 0.001), a tumour diameter more than 3.0 cm (P = 0.001), and a fatal clinical outcome (P < 0.001). Laminin receptors were also expressed by most metastatic foci and all intravascular emboli of tumour cells. Positivity for laminin receptors was associated with shorter survival in functioning (P = 0.026) and non-functioning (P = 0.042) tumours, as well as in the whole series of pancreatic endocrine tumours (P < 0.001). On multivariate analysis, laminin receptor expression was not an independent prognostic factor, while a Ki-67 index above 5.0 per cent was the most powerful predictor of survival. However, the association of laminin receptor expression and Ki-67 index could identify a group of malignant PETs with low proliferative activity characterized by an intermediate prognosis. In conclusion, these data suggest that monomeric laminin receptors may play a role in the invasion and metastasis of PETs and that their expression may be an additional prognostic factor, along with proliferative activity.

Background: Since PLHN are rare, prognostic factors and the therapeutic strategy have not yet been clearly assessed., Patients and Methods: Seventy-one patients with PLHN (44 stage I, 27 stage II; 54 with high-grade histology) received the following treatments: 5 radical surgery, 21 radiotherapy, 43 combined treatment (mainly chemotherapy plus radiotherapy) [CT] and 1 was not treated., Results: Disease-related survival (DRS) and disease-free survival (DFS) were 84% and 69% at 5 years and 70% and 56% at 10 years. CT provided significantly better DRS and DFS than radiotherapy alone (92% and 81% vs 70% and 43% respectively), though the group receiving the CT included most of the patients with high-grade histology (37) and stage II (20). Outcome was not influenced by stage and site of involvement (Waldeyer's ring vs non-Waldeyer's ring). Multivariate analysis showed that favourable prognostic factors were age for DRS, high-grade histology and CT for DFS., Conclusions: Patients receiving the CT fared significantly better, though most of them had high-grade histology and stage II.

Primary cardiac sarcomas constitute a rare entity that have been uniformly associated with poor long-term survival. A case of left atrial leiomyosarcoma involving the interatrial septum and the right atrial free wall and presenting with syncope and atrial fibrillation, is described. Two extensive surgical excisions followed by adjuvant radiation and chemotherapy improved survival with a good quality of life. This approach of combined surgical, medical and radiation therapy may offer better longterm outcome, since our patient is the longest survivor thus far reported.

Prediction for malignancy of pancreatic endocrine tumors (PET) is often a formidable challenge for the pathologist. The authors evaluated the role of the proliferative activity and progesterone receptor protein (PgRP) in predicting prognosis and survival of PET. Twenty-three functioning (FT) and 31 nonfunctioning tumors (NFT) were evaluated for mitotic activity and immunostaining for Ki-67 antigen, proliferating cell nuclear antigen (PCNA), and progesterone receptor protein (PgRP) on paraffin sections. The results were expressed as a percentage (index) of immunoreactive or mitosing cells. All 54 cases showed immunostaining for Ki-67 and PCNA, and valuable mitotic index, whereas only a fraction of tumors (25 of 54 cases) exhibited PgRP expression. Ki-67 and PCNA indexes correlated strongly between themselves and to mitotic index, whereas an inverse relationship was observed between cell proliferation and PgRP status in both FT and NFT. Although univariate analysis showed that Ki-67, PCNA, mitotic and PgRP indexes, stage, immunoreactivity for hormones other than insulin, diameter, and nonfunctioning type of tumor were statistically correlated to survival, Cox's regression method let only Ki-67 index emerge as an independent predictor of survival using a cutoff value of 5% in both FT and NFT.

We reviewed 45 cases of Waldeyer's ring lymphomas (25 stage IE, 20 IIE): 73% had high-grade histology according to Kiel's classification. Fourteen patients received radiotherapy alone and 31 chemotherapy, combined with radiotherapy in 28. Complete remission rate was 95% and relapse rate 32%. At 8 years overall disease-related survival (DRS) and event-free survival (EFS) were 69% and 57% respectively. Combined treatment provided both significantly better DRS (82% vs 42%) and EFS (76% vs 25%) than radiotherapy alone. Most of the patients with high-grade histology (26/33) received the combined treatment and this subgroup achieved a long-term EFS of 78%. Both DRS and EFS were also significantly longer in patients under 60. At multivariate analysis favorable prognostic factors were lower age for DRS and combined treatment for EFS.

Among 18 patients with primary extragonadal germ cell tumors (8 seminoma and 10 non- seminoma), the disease involved the mediastinum (7), the retroperitoneum (8), multiple lymph nodal sites (2) and the pinealis gland (1). Seventeen patients received cisplatin-based chemotherapy as part of the initial treatment. Fifteen patients (83%) achieved complete remission (6 seminoma and 9 non-seminoma): 12 of them are relapse-free after a median follow-up of 82 months (range 13-138). Five-year overall survival was 65%. No statistically significant survival difference was found between mediastinal and retroperitoneal tumors or patients with seminoma and nonseminoma.

Background: Immunocytochemistry has often been used to identify tumor cells in bone marrow aspirate (BMA) of SCLC patients in order to improve the results of conventional histomorphology. However, whether the detection of bone marrow microlocalisation at diagnosis had implications for prognosis has not been clear., Patients and Methods: Eighty-four slides (44 patients) and 66 bone marrow biopsies (from 42/44 patients) were evaluated. Cytospins of BMA were incubated with the monoclonal antibody (MAb) NCC-LU-243, recognising the cluster 1 antigen (NCAM) and then stained by the APAAP (alkaline phosphatase-anti-alkaline phosphatase) method. The relationship among BMA and PS (performance status), NSE (neuron-specific enolase), stage, survival was also studied., Results: 33/84 (39%) BMA were positive for NCAM, compared with 8/66 (12%) bone marrow biopsies (p = 0.009), (17/44 and 6/42 patients, respectively). Moreover, BMA was positive for NCAM in 6/19 patients with limited disease. The presence of positive BMA did not correlate with PS, NSE or stage, but patients with positive BMA had shorter survivals than those with negative BMA (median survival: 7 and 12 months, respectively, p = 0.007)., Conclusions: Bone marrow involvement detected by immunocytochemistry appears to be related to survival but not to parameters of tumor burden (NSE, stage), suggesting that this technique might help to select patients with better prognoses for new therapeutic strategies.

It has been suggested that the oxidative modification of low-density lipoprotein (LDL) plays a major role in atherogenesis. We evaluated the oxidative resistance to copper-induced oxidative changes of LDL derived from patients affected by type IIa hyperlipoproteinemia compared with healthy subjects and faced the question of the importance of the antioxidants and polyunsaturated fatty acids (PUFAs) contained in LDL in determining its variability. LDL isolated from the plasmas of 25 subjects affected by familial hypercholesterolemia and 15 control subjects was oxidatively modified with Cu2+ in vitro, and the differences in LDL susceptibilities (lag and propagation phases) to lipid peroxidation were studied by measuring the changes in fluorescence intensity. LDL alpha-tocopherol and PUFAs were also measured. The lag phase was significantly lower and the propagation phase significantly higher in the type IIa patients than in control subjects (p < 0.01). The linoleic and arachidonic acids, expressed as percentage of total LDL fatty acids, were significantly higher in type IIa patients than in the control subjects (p < 0.01). There was a positive significant correlation between the LDL cholesterol and the linoleic and arachidonic acids as percentage of total LDL fatty acids (p < 0.01). Both linoleic and arachidonic acids turned out to be negatively correlated with the lag phase and positively with the propagation phase (p < 0.01). The concentration of LDL alpha-tocopherol was similar in the two groups. Therefore, type IIa patients have a greater susceptibility to LDL oxidation than control subjects. This may be due to a relative higher concentration of linoleic and arachidonic acids in LDL derived from patients with familial hypercholesterolemia.

We have used immunocytochemistry to identify tumor cells in bone-marrow aspirates of 40 untreated patients with small cell lung cancer and we compared the results with conventional histomorphology. The monoclonal antibodies (MAbs) used were NCC-LU-243 and NCC-LU-246 (both cluster 1). For each MAb 76 slides were evaluated. Sixty bone-marrow biopsies were also obtained from these patients. The positivity rate between the 2 MAbs was not statistically different (46% for NCC-LU-246 and 43% for NCC-LU-243). Bone-marrow biopsies detected tumor localization in 8/60 specimens (13%), significantly less than immunocytochemistry with anti-NCAM MAbs (p = 0.003). Moreover, bone-marrow aspirates were positive for cluster 1 antigen in 6/16 patients with limited disease at diagnosis. The results confirm that NCC-LU-243 and NCC-LU-246 have equivalent ability to identify bone-marrow involvement; immunocytochemistry appears to be better suited for this purpose than conventional bone-marrow biopsy; a non-negligible proportion of patients with "limited disease" might be understaged; the clinical value of detecting bone marrow involvement by immunocytochemistry is still unclear.

In this phase III, double-random study, we compared CAV-E to CAV-T combination as induction treatment (1st randomization) for SCLC. Subsequently, patients achieving a complete response (CR) were randomized again (2nd randomization) to receive maintenance treatment with alpha-IFN or no treatment. From June 1990 to June 1992, 75 untreated patients were enrolled in this trial. After stratification according to limited disease (LD) or extensive disease (ED), patients were randomized to receive the following treatment: cyclophosphamide 1000 mg/m2, adriamycin 50 mg/m2, vincristine 2 mg, day 1 i.v., plus etoposide (E) 100 mg/m2 (CAV-E: arm-A) or teniposide (T) 60 mg/m2 on day 2, 3, 4 i.v., every 3 weeks (CAV-T: arm-B). LD patients after 3 cycles of treatment received chest radiotherapy and 2 further cycles, whereas ED patients received 5 consecutive cycles. Patients who achieved a CR entered the 2nd randomization receiving a-IFN (3 x 10(6) I.U., i.m. daily x 9 months) or no treatment. A second-line treatment with carboplatin 300 mg/m2 plus E (if T was initially used) or T (if E was initially used) was also scheduled for patients achieving less than CR to induction treatment. Preliminary results are as follows: 75 patients were randomized, 72 were eligible for survival (arm-A = 37 and arm-B = 35) and 60 were fully evaluable for response (arm-A = 34 and arm-B = 26). In patients with LD the overall response rate was 79% (CR 21%) in arm-A vs 92% (CR 50%) in arm-B. In patients with ED, the overall response rate was 80% (CR 33%) in arm-A vs 84% (CR 7%) in arm-B. At a mean observation time of about 1 year (range 1-25 months), median survival of LD patients was 15 months in arm-A and 13 months in arm-B (Chi-square = 1.55; p > 0.05); in ED patients survival was 10.8 months and 8 months respectively (Chi-square = 2.88; p > 0.05). Cumulative survival probability was identical (12 months) in all patients of both arms. Toxicity was mainly haematologic and gastrointestinal: WHO grade 3-4 myelosuppression and vomiting were observed in 20% and 11% respectively, of cycles delivered in arm-A, compared to 19% and 8%, respectively, of cycles in arm-B. Two septic deaths occurred with CAV-T, while 1 patient discontinued treatment due to persistent myelosuppression with CAV-E. After the first and second-line treatment 20 patients showed a CR.(ABSTRACT TRUNCATED AT 400 WORDS)

Urinary drug metabolites were measured in 21 patients receiving ifosfamide by continuous infusion over 3 days. Mean values for the proportion of drug excreted as parent compound, 2-dechloroethylifosfamide (2-DC), 3-dechloroethylifosfamide (3-DC), carboxyifosfamide (CX) and ifosforamide mustard (IPM) were 19, 6, 10, 7 and 8% of dose respectively. The proportion of urinary drug products in the form of ifosfamide fell considerably over the course of the 3 days. This was mirrored by an increase in the proportion of 2-DC, 3-DC and CX. The proportion in the form of IPM, however, remained unchanged. With successive cycles the amount of 2-DC and IPM increased by about 10% per course. A very wide variation in the amount of each metabolite was reproducibly seen between patients, but no evidence for a genetic polymorphism was found. Urinary dechloroethyl metabolites correlated positively with each other and negatively with CX. Although autoinduction increases 'activation' of ifosfamide when given over 3 days, our evidence suggests that competing metabolic pathways prevent an increase in the amount of active metabolite formed.

We have used immunocytochemistry to identify tumor cells in bone-marrow aspirates of patients with small-cell lung cancer and we have compared the results with conventional histomorphology. The monoclonal antibodies (MAbs) used were NCC-LU-243 and NCC-LU-246 (cluster 1) and MLuC1 (cluster 6); 108 slides (52 patients) incubated with NCC-LU-246, 106 (51 patients) with NCC-LU-243 and 69 with MLuC1 (36 patients) were evaluated. Bone-marrow biopsies (83) were also obtained from 50 of these patients; 48/108 bone marrow aspirates were positive for cluster-1 antigen and 22/69 were positive for MLuC1. Immunocytochemistry with anti-NCAM MAbs detected bone-marrow localization in 38/83 bone-marrow aspirates compared with 9/83 bone-marrow biopsies, while MLuC1 was positive in 18/60 and bone-marrow biopsies in 6/60. Moreover, bone-marrow aspirates were positive for cluster-1 antigen in 7/17 patients with limited disease at diagnosis. Patients with positive bone-marrow biopsies had significantly shorter survival. No differences were found between patients with positive and those with negative marrow aspirates.

Regression of cardiovascular structural changes is a main goal of antihypertensive treatment. Two recent meta-analyses of relatively small noncomparative studies have suggested that angiotensin-converting enzyme (ACE) inhibitors may be more effective than other classes of drugs in inducing regression of left ventricular hypertrophy (LVH). The effect of different antihypertensive drugs on arteriolar structural changes has not yet been properly investigated. The aim of this study was to evaluate the effect of 6 months of treatment with amlodipine (5-10 mg o.d.) or enalapril (10-20 mg o.d.) on blood pressure (BP) (ambulatory monitoring), heart rate (HR), LV mass and function (M-mode echo, two-dimensionally guided), forearm minimal vascular resistance (min VR = BP/max blood flow-venous occlusion plethysmography, taken as an index of vascular structural changes) in 24 hypertensive patients in a comparative single-blind, randomized study, with blind reading of echocardiograms and plethysmographic tracings. After 6 months of treatment with amlodipine 5-10 mg o.d., significant reductions in LV mass index (p = 0.004) and forearm min VR (p = 0.02) were observed. Before and during treatment, LV systolic function, both at rest and during stress (handgrip test), evaluated by fractional shortening as related to end-systolic stress, was in every case within 95% confidence limits calculated in normal subjects. Similar results were observed with enalapril. No significant differences were observed for Doppler indices of diastolic filling after 6 months of treatment with either drug. These results indicate that a significant regression of structural changes in the heart and in the small resistance vessels can be observed after long-term treatment with amlodipine in essential hypertensive patients.(ABSTRACT TRUNCATED AT 250 WORDS)

We describe 53 patients with primary gastric non-Hodgkin's lymphoma (38 stage IE,15 stage IIE) treated with surgery as a primary procedure. According to the Working Formulation, 13 cases had low, 21 had intermediate and 19 had high grade malignancy. 34 patients considered at high risk received postoperative polychemotherapy. The overall 10-year disease-related survival is 91%. Median follow-up is 52 months. 7 patients relapsed (13%). The 10-year disease-free survival rate of the 19 patients initially treated with surgery is 60%, as compared with 92% in the patients who also received chemotherapy (P = 0.004). However, overall survival did not differ between the two groups, since two-thirds of the patients who relapsed after surgery alone were rescued with chemotherapy. Stage, age, sex and histology did not correlate with survival. In our experience, surgery was an adequate first step procedure; the addition of chemotherapy significantly reduced relapses and increased the disease-free survival rate in patients with unfavourable prognostic factors.

The neural cell adhesion molecule (NCAM) is a tumour-related antigen found on the surface of small-cell lung cancer (SCLC). NCAM exists in several molecular forms, including a soluble isoform. We have measured serum levels of NCAM using an enzyme immunoassay with 2 antibodies, NCC-LU-246 and NCC-LU-243, that react with different epitopes on the NCAM molecule. NCAM activity from 83 patients with active SCLC, either pre-treatment, progressing or in relapse was significantly higher than in 70 patients on follow-up. Overall, 40% of patients with active SCLC and 7% patients on follow-up had serum levels of NCAM > 2SD above controls; 61% of patients with relapsed SCLC had elevated levels of NCAM. Pre-treatment NCAM levels were significantly higher in 35 patients with "extensive" disease than in 19 patients with "limited" disease. Serum NCAM activity was also significantly higher in patients with tumour infiltration of the bone marrow. This difference could not be explained solely by the presence of "extensive" disease. Serum NSE levels in these patients were correlated with NCAM activity. The presence of raised serum NCAM in active disease and in patients in relapse suggests that this antigen could be used as a target for antibody-directed therapy of micrometastases.

Fifty-seven patients with primary gastric non-Hodgkin's lymphoma are here reported. All our patients were treated with surgery as first step procedure. Thirty-six were treated in addition with chemotherapy (four of them with radiotherapy also). Thirty-eight were stage IE and nineteen IIE. According to the Working Formulation, 12 cases were classified as low, 25 intermediate and 20 high malignancy. 55 patients achieved a complete remission (96%) and only 6 relapsed (11%). The 10-year disease-related survival is 89%. Patients treated with combined surgery and chemotherapy were mainly a high risk group (high grade histologic subtype, stage IIE, incomplete resection). Nevertheless the survival of this group was similar to the group initially treated with surgery alone (p = 0.17) in which such unfavorable prognostic factors were not present. Stage, presence of residual tumor after surgery, sex and age did not statistically correlate with survival. Furthermore, there was not statistical difference among the various histological subgroups (p = 0.16). We stress the importance of cooperation among surgeons and oncologists in order to plan an appropriate treatment.

From January 1987 to December 1990, 26/105 previously untreated patients affected by small cell lung cancer (SCLC), not suitable for intensive SCLC treatment since 19 of them were older than 70 years and 7 suffered from severe chronic diseases, received induction therapy consisting of teniposide alone, 60 mg/m2 on days 1-5, every 3 weeks until disease progression. After a minimum of two courses, 24 patients were evaluable for response: 13 with limited disease (LD) and 11 with extensive disease (ED) (2 patients were unevaluable: 1 early death and 1 protocol violation). Response rate, by disease stage, was: in the 13 LD, 1 complete response (CR), 8 partial responses (PR), 2 minor responses and 2 failures; in the 11 ED, 1 CR, 4 PR and 6 failures. The overall response rate was 58% (14/24) (95% confidence limits = 38-78%), comprising 8% CR and 50% PR. Median duration of response was 7 months (range 2-32). Median overall duration of survival was 9 months (range 1.5-36+). Toxicity was haematological WHO grade III in 13% of courses delivered, whereas no further important side-effects were recorded, excluding alopecia, which was common. Teniposide used alone appeared a safe and effective palliative treatment for poor-risk patients; the major limitation was the low CR rate.

Three different methods, morphologic, immunocytochemic, and fluorescence activated cell sorter (FC) analysis, were compared with respect to their efficiency in detecting breast cancer cells in bone marrow. In the first series of experiments, the three techniques were compared using bone marrow cells artificially mixed with a known amount of breast cancer cells, whereas in a second series bone marrow from breast cancer patients with bone metastases were used. The following results were obtained: When mixtures of the first series were analyzed, FC analysis detected from 1% to 10% of breast cancer cells in bone marrow (0.2% was a border line value), the morphologic method detected from 0.05% to 10%, and the immunocytochemic method, which was clearly superior, detected breast cancer cells in all mixtures (from 0.00025% to 10%). It was noted that, with both the morphologic and immunocytochemic methods, the percentage of breast cancer cells detected was 2 to 360 times higher than the percentage of added cells, and enrichment was inversely proportional to the percentage of added cells. This result could be a result of different separation of cells during centrifugation due to the different density of breast cancer cells. The superiority of the immunocytochemic method was confirmed in the second series of experiments.

A case of primitive lymphoma of the uterine cervix is discussed. After two years of vaginal post-coital bleeding, the echography showed the presence of a supraisthmic mass. The patient underwent a total hysterectomy with bilateral salpingo-oophorectomy. The histology was consistent with a B-cell non-Hodgkin's lymphoma (NHL), follicular centre derived. The patient was staged as IIE and treated with six cycles of chemotherapy (CHOP), achieving a complete remission. The paper stresses the value of histology in the diagnosis of lymphoma of the uterine cervix and the effectiveness of the treatment, and reviews the relevant literature.

Ethylene oxide was tested in environmental air and in the alveolar air of 10 workers employed in a hospital sterilizer unit at hourly intervals during the work shift. Alveolar ethylene oxide concentrations (Ca) were correlated with environmental concentration (Ci) in all the workers studied (r = 0.89-0.99). The ratio between alveolar and environmental concentration (Ca/Ci) given by the slope of the regression line obtained for all the data collected was 0.24. This means that the alveolar retention of ethylene oxide, expressed as 1 - (Ca/Ci), corresponded, on average, to about 75% of the environmental concentration.

The clinical records of 66 consecutive episodes of Gram-negative bacteremia occurring in 60 patients with hematologic malignancies during a 66-month period were reviewed to assess the major prognostic factors. The bacteremia-related mortality was 53%. Overall, Pseudomonas aeruginosa (54%) and Escherichia coli (24%) were the predominant isolates (fatality rate 78 and 31% respectively). The majority of patients (58/66) were granulocytopenic (PMN less than 1000/microliters). Among the 18 patients whose circulating granulocytes increased by one log10 or to above 1000/mmc during therapy, the fatality rate was 39%, as opposed to 70% in the 40 patients without such an increase. Pneumonia-associated bacteremia (56%) had a high fatality rate (73%) compared to isolated bacteremias (27%). Septic shock and inappropriate antibiotic therapy accounted for the highest mortality. Our data suggest that Pseudomonas etiology, persistent neutropenia, associated pneumonia, septic shock and inappropriate antibiotic therapy account for a bad prognosis in Gram-negative bacteremia in hematologic malignancies.

The metabolism of steroid hormones has been investigated in 10 workers exposed to lead and in 10 non-exposed subjects to determine whether lead interferes with the first or second phase reactions of steroid hormone biotransformation, or both. In the exposed workers blood lead concentrations (PbB) ranged from 45 to 69 micrograms/100 ml; in the controls PbB was less than 25 micrograms/100 ml. No statistical differences were found for the total amount of the urinary hormone metabolites, but a drop of about 50% was observed for the sulphated portion. It is suggested that lead interferes with the mechanisms of sulphoconjugation through an effect on the cytosol enzymes sulphotransferase and sulphokinase.

Occupational exposure to ethylene oxide (ETO) was studied in ten workers employed in a hospital sterilizer unit by testing environmental air, alveolar air and blood during and at the end of the workshift. Alveolar (Ca) and blood (Cb) ETO concentrations were correlated with each other (r = 0.744, n = 36, P less than 0.001) and both with the environmental (Ci) concentrations (r = 0.947, n = 144, P less than 0.001; r = 0.827, n = 36, P less than 0.001). The alveolar retention of ETO (1-Ca/Ci) was equal to 75-80% of the inhaled ETO. In comparison with a blood/air partition coefficient equal in vitro to 90 (SD = 20), the mean Cb/Ca ratio found in the exposed workers was equal to 12-17. During work the blood ETO concentration was, on average, three times the environmental ETO concentration.

Benzene, toluene, cumene and styrene were measured in the breath and blood of two groups of individuals. The first group included individuals belonging to a hospital staff, the second group included chemical workers who were not exposed to the abovementioned chemicals. The chemical workers were examined in plant infirmaries on the morning before the start of the workshift, and the hospital staff in the hospital infirmaries. One environmental air sample was taken in the infirmaries for each individual at the moment of the biological samplings. The environmental concentrations of benzene and styrene were significantly higher in the infirmaries of the chemical plant than in the infirmaries of the hospital. On the other hand, the environmental concentrations of toluene and cumene were not significantly different in the plant infirmaries and in the hospital infirmaries. In the hospital staff the alveolar concentrations of benzene, toluene and styrene were significantly lower than those in the chemical workers. In the hospital staff the blood concentrations of benzene, toluene and styrene were not significantly different from those in the chemical workers. Only the blood cumene concentration was significantly higher in the chemical workers. In hospital staff, smokers showed alveolar and blood concentrations of benzene and toluene that were significantly higher than those measured in the non smoker hospital staff. With reference to chemical workers, only alveolar benzene concentration was significantly higher in smokers than in non smokers.(ABSTRACT TRUNCATED AT 250 WORDS)

Benzene exposure of chemical workers was studied, during the entire workshift, by continuous monitoring of workplace benzene concentration, and 16 hours after the end of the workshift by the measurement of alveolar and blood benzene concentrations and excretion of urinary phenol. Exposure of hospital staff was studied by measuring benzene concentrations in the alveolar and blood samples collected during the hospital workshift. Instantaneous environmental air samples were also collected, at the moment of the biological sampling, for all the subjects tested. A group of 34 chemical workers showed an eight hour exposure to benzene, as a geometric mean, of 1.12 micrograms/l which corresponded, 16 hours after the end of the workshift, to a geometric mean benzene concentration of 70 ng/l in the alveolar air and 597 ng/l in the blood. Another group of 27 chemical workers (group A) turned out to be exposed to an indeterminable eight hour exposure to benzene that corresponded, the morning after, to a geometric mean benzene concentration of 28 ng/l in the alveolar air and 256 ng/l in the blood. The group of hospital staff (group B) had a benzene concentration of 14 ng/l in the alveolar air and 269 ng/l in the blood. Instantaneous environmental samples showed that in the infirmaries the geometric mean benzene concentration was 58 ng/l during the examination of the 34 chemical workers, 36 ng/l during the examination of the 27 chemical workers (group A), and 5 ng/l during the examination of the 19 subjects of the hospital staff (group B). Statistical analysis showed that the alveolar and blood benzene concentrations in the 34 workers exposed to 1.12 microgram/l of benzene differed significantly from those in groups A and B. It was found, moreover, that the alveolar and blood benzene concentrations were higher in the smokers in groups A and B but not in the smokers in the group of 34 chemical workers. The slope of the linear correlation between the alveolar and the instantaneous environmental benzene concentrations suggested a benzene alveolar retention of about 55%. Blood and alveolar benzene concentrations showed a highly significant correlation and the blood/air partition coefficient, obtained from the slope of the regression line, was 7.4. In the group of the 34 chemical workers no correlation was found between the TWA benzene exposure and the urinary phenol excretion.

Benzene was measured in blood and alveolar air of 168 men, aged 20-58 years, subdivided into four groups: blood donors, hospital staff, chemical workers occupationally exposed to benzene, and chemical workers not occupationally exposed to benzene. The group of exposed workers was employed in work places with a mean environmental exposure to benzene of 1.62 mg/M3 (8 hr TWA). Non-exposed workers were employed elsewhere in the same plant, with an environmental exposure to benzene lower than 0.1 mg/M3. Blood and alveolar air samples were collected in the morning, before the start of the work shift for the chemical workers. The group of exposed workers was found to be significantly different from the other three groups, both for blood and alveolar benzene concentrations. The mean blood benzene concentration was 789 ng/l in the exposed workers, 307 ng/l in the non-exposed workers, 332 ng/l in the hospital staff, and 196 ng/l in the blood donors. Apart from the exposed workers, blood benzene concentration was significantly higher in smokers than in non-smokers. The mean alveolar benzene concentration was 92 ng/l in the exposed workers, 42 ng/l in the non-exposed workers, 22 ng/l in the hospital staff, and 11 ng/l in the blood donors. Alveolar benzene concentration was significantly higher in smokers than in non-smokers in the groups of the hospital staff and non-exposed workers, but not in the blood donors and exposed workers. In the three groups without occupational exposure considered altogether, the alveolar benzene concentration correlated significantly with environmental benzene concentration measured at the moment of the individual examinations, both in the smokers (r = .636; p less than .001) and non-smokers (r = .628; p less than .001). In the same three groups and in the exposed workers, alveolar benzene concentration showed a significant correlation with the blood benzene concentration.

Passive intestinal permeability was measured in 15 adult patients with atopic eczema. Values in the patients did not differ significantly from those in 12 healthy control subjects. These results suggest that altered intestinal permeability is not important in the pathogenesis of atopic eczema in adults.