Symptomatic treatment versus combination chemotherapy for patients with extensive non-small cell lung cancer.

In a randomized clinical trial, 87 patients with inoperable, extensive non-small cell lung cancer (NSCLC) were randomized to receive either combination chemotherapy (cisplatin at 70 mg/m2 intravenously [i.v.] on day 1 and etoposide at 100 mg/m2 i.v. on day 1 and 200 mg/m2 orally on days 2 and 3) or symptomatic treatment. No statistically significant differences in survival time were found between the two treatment techniques. A major problem in the interpretation of the results was the use of semicurative radiation therapy (3000 to 4200 cGy) to the primary tumor and mediastinum, which was given with symptomatic intent. Three long-term survivors were seen in the latter group.

Phase I/II study of carboplatin and 5-fluorouracil in patients with advanced head and neck carcinoma.

59 patients with histological verified squamous cell carcinoma of the head and neck, 39 with primary disease and 20 with relapse were given carboplatin and 5-fluorouracil (5-FU) in escalated carboplatin doses. The starting dose with carboplatin was 200 mg/m2 and the dose was escalated to 300 mg/m2, 350 mg/m2, 400 mg/m2 and thereafter by 20 mg/m2 per step. All patients received a dose of 1000 mg/m2 5-FU as a continuous infusion for 5 days. The myelotoxicity was moderate. No patients had grade 4 haemoglobin toxicity, while 7 patients had grade 3 toxicity. 2 patients had grade 4 leucocyte toxicity and 1 patient had grade 3. 4 patients were observed with a grade 4 platelet toxicity. 2 early deaths occurred at a dose level of 420 mg/m2. 18 out of 39 patients in primary treatment responded while 2 out of 20 patients treated for relapse responded. On the basis of the present study the maximum tolerable dose for carboplatin in combination with 5-FU 1000 mg/m2 is between 350 and 400 mg/m2.

Primary irradiation, surgery or combined therapy in squamous cell carcinoma of the larynx. A comparison of treatment results from two centers.

We compared two groups of patients with squamous cell carcinoma of the larynx. Group 1 consisted of 483 patients treated from 1958 through 1978. Primary surgery was selected in 41% pre- or postoperative radiation therapy in 16% and primary radiation therapy in 43%. Group 2 consisted of 247 patients treated from 1978 through 1983. Primary surgery was selected in only 1.6%, pre- or postoperative radiation therapy in 23%, and primary radiation therapy, with surgery in reserve for residual or recurrent carcinoma, in 76%. Although the results were comparable for patients with early stage tumors in the two groups, significantly higher local-regional tumor control rates and corrected survival rates were recorded for patients with advanced tumors in group 2. More patients survived with a cancer-free functional larynx, the surgical salvage rates were higher, the complication rates and the death rates lower in group 2 compared to group 1.

Turnover and maturation kinetics in the hairless mouse epidermis. Continuous [3H]TdR labelling and mathematical model analyses.

Hairless mice were continuously labelled with 10 microCi of tritiated thymidine ([3H]TdR) every 4 h for 8 d, and the proportions of labelled basal and differentiating cells were recorded separately. The mitotic rate was measured by the stathmokinetic method and the cell cycle distributions were measured by flow cytometry of isolated basal cells at intervals during the labelling period. The mitotic rate of the [3H]TdR-injected animals did not deviate from control values during the first 5 d. Computer simulations of the data based on various mathematical models were made, and three main conclusions were obtained: (1) a large spread in transit times through the G1 phase was found, together with a very narrow distribution in maturation time of differentiating cells; (2) about 20% of the differentiating cells were estimated to leave the basal cell layer directly after mitosis. This is consistent with results obtained from different sets of data; and (3) during continuous labelling more than 90% of the cells are labelled during each passage through the S phase.

Retinopathy after low dose irradiation for an intracranial tumor of the frontal lobe. A case report.

A 32-year-old man underwent an operation for an oligodendroglioma of the left frontal lobe. Postoperatively he was irradiated to a target dose of 54 Gy. One year later he developed bilateral retinopathy quite similar to diabetic retinopathy. There were no clinical or biochemical signs of diabetes or hematological disease. The calculated maximum dose to the retina was 11 Gy. This is to our knowledge the lowest retinal dose of ionizing radiation reported to produce retinopathy.

DNA flow cytometric values in bladder carcinoma biopsies obtained from fresh and paraffin-embedded material.

DNA-histograms were obtained by flow cytometry (FCM) of nuclei prepared from fresh bladder carcinoma biopsies and from 100 micron sections of paraffin-embedded material from the same biopsies. Linear regression analysis of ploidy values from fresh material versus those from paraffin blocks showed excellent correlation (R2 = 0.957). Owing to the high background, the paraffin-embedded material was less suited for analysis of S-phase fraction. It is concluded that DNA FCM of nuclei obtained from paraffin-embedded bladder carcinoma biopsies yields reliable results concerning ploidy, but does not permit evaluation of the S-phase fraction.

A randomized study evaluating radiotherapy versus chemotherapy in patients with inoperable non-small cell lung cancer.

A combination of cisplatin (70 mg/m2 i.v. day one) and etoposide (100 mg/m2 i.v. day one, 200 mg/m2 orally days 2 and 3) repeated every third week to a maximum of 4 cycles were compared with high voltage radiotherapy, 42 Gy given in 15 fractions over a 3-week period to patients with inoperable non-small cell lung cancer (a shield was used in the posterior field to reduce the total spinal dose less than 40 Gy). One hundred and eighteen patients received radiotherapy; the median survival was 10.6 months compared to 10.5 months for the 116 chemotherapy patients (p = 0.81). The objective response rate (CR + PR) was 42% for the radiotherapy and 21% for the chemotherapy group (p = 0.009). At progression it was optional to cross over to the other treatment modality or to receive phase II chemotherapy. Thirty patients primarily treated with radiotherapy and 54 allocated to chemotherapy received second line antineoplastic treatment.

DNA flow cytometry in metastases and a recurrency of malignant melanomas. A comparison of results from fresh and paraffin embedded material.

Single cell suspensions from 16 biopsies from 15 patients with metastatic or recurrent malignant melanoma were prepared according to the method described by Vindeløv (1977) and the nuclear DNA content was measured by a laboratory-built flow cytometer. The DNA histograms thus obtained were compared with those obtained from suspensions of single nuclei from the same biopsies after formalin fixation and paraffin embedding, according to the method of Hedley et al. (1983). Linear regression analysis of ploidy values from fresh material compared with those from paraffin blocks showed a strong correlation (R2 = 0.85), while that of the S-phase fraction was somewhat weaker (R2 = 0.66). It is concluded that archival wax preparations of malignant melanoma cell populations are suitable for FCM analysis of ploidy, and to a lesser extent for analysis of fraction of cells in various cell cycle phases.

Toxicity, physical function and everyday activity reported by patients with inoperable non-small cell lung cancer in a randomized trial (chemotherapy versus radiotherapy).

In a randomized trial, patients with inoperable non-small cell lung cancer with limited disease were randomly given either radiotherapy (42 Gy) or combination chemotherapy with cisplatin, 70 mg/m2, and etoposide, 100 mg/m2, given every third week with a maximum of 4 cycles. The patients were asked to fill in a questionnaire concerning psychosocial well-being, medical and treatment related symptoms, physical function and everyday activity. Of the chemotherapy patients 61% reported nausea 5 weeks after their last chemotherapy session and 44% had spells of vomiting. Only 14% of the radiotherapy patients had nausea and 5% vomited 14 weeks after start of treatment. Of the radiotherapy patients 64% experienced dysphagia compared to 8% of the chemotherapy patients 6 weeks after the start of treatment.

Survival of large bowel carcinoma patients with different DNA ploidy.

One hundred patients operated for large bowel carcinoma were divided into a distinct aneuploid group of 63, and a near diploid one of 37. Flow cytometry was used for determination of the DNA ploidy pattern. All tumours in the aneuploid group contained one or more aneuploid cell populations. All patients were followed clinically from 3.5 to 7.8 years. The corrected 5 year survival was 64% and 49% for patients with near diploid and aneuploid tumours, respectively (not significant). Significant differences in corrected survival time were not observed for Dukes' stages A, B, and C patients pooled, nor for Dukes' stage D patients. However, for Dukes' stage C patients alone, there was a tendency (P = 0.10) for patients with near diploid tumours to show a better survival. A highly significant predominance of aneuploid tumours was seen in males, in contrast to an equal distribution of aneuploid and near diploid tumours in females. A slight predominance of aneuploid tumours in the left colon and rectum was seen. Both these findings indicate the influence of environmental factors (hormonal, anatomical, phenotypical) on the development of tumours with a particular DNA ploidy pattern.

Circulating secretory component in breast neoplasms.

The serum concentrations of IgAp and IgMr associated secretory component (SIgA and SIgM) of 98 patients with neoplasms of the breast were measured. Of the 56 patients with carcinomas, 11 had increased concentrations of circulating SIgM, which was almost twice as sensitive as SIgA as a marker for carcinoma. Concentrations of circulating SIgA and SIgM were independent of expression of secretory component, IgA, and carcinoembryonic antigen (CEA); histological tumour grade; and tumour cell DNA ploidy, whereas a weak correlation between SIgA and SIgM and circulating CEA was seen. The three patients who had liver metastases indicated had particularly high concentrations of circulating SIgA and SIgM, whereas no difference was generally seen between patients with malignancy and those with benign tumours.

Plasma CEA in large bowel carcinoma: which patients should be followed by regular postoperative measurements? Preliminary follow-up results in 100 patients with different tumor DNA-ploidy patterns.

In 100 patients with large bowel carcinomas, the tumors were divided into a distinctly aneuploid (AN) group (63) and a near diploid (ND) group (37) by flow cytometric (FCM) DNA quantitation of cell suspensions. Preoperative plasma CEA levels were determined in all patients. Thirty-eight patients with AN and 28 patients with ND tumors were operated on for cure and had normal plasma CEA levels postoperatively. These two groups had regular CEA plasma measurements as part of the clinical follow-up. In the AN group, 12 of 15 patients have had recurrence preceded by CEA elevation. In the ND group, however, only one of eight recurrences was preceded by a rise in CEA level; the one with elevation also had increased plasma CEA prior to operation. It thus seems that a low CEA output of ND tumors explains many of the "false-negative" CEA measurements in disseminated cases. It is concluded that, in addition to patients with an elevated preoperative plasma CEA level, all patients with aneuploid tumors should be subjected to repeated plasma CEA measurements as part of the follow-up program.

Changing aspects in the treatment of squamous cell carcinoma of the oral tongue.

Two groups of patients were compared. In group 1, consisting of 304 patients treated from 1958 to 1972 (minimum observation time of 5 years), the local and regional control rate was 35 per cent. In group 2, consisting of 126 patients treated 1978 to 1983 (median observation time of 58 months), the local and regional control rate was 60 per cent (p less than 0.0001). The local and regional control rates were improved for all stages, but the differences were significant only for stages T1N0, T2N0, T3N0 and TXN2,3. The actuarial survival rates also showed improvement in group 2 patients. The incidence of treatment failure, with regard to the neck alone or tongue and neck combined, decreased from 51 per cent to 27 per cent with the newer techniques. The greatest improvement was observed in patients with T1N0 and T2N0 tumors. There was also a decrease in the failure rates in patients with the more advanced tumors.

Comparison of two CEA assays in primary and recurrent large bowel carcinoma with different DNA ploidy pattern.

Pre-operative CEA levels were measured in 100 patients with large bowel carcinomas with different DNA ploidy pattern and serial post-operative determinations performed in the 64 who had been operated for cure. The follow-up period was 3 1/2-8 yr. All CEA measurements were performed consecutively with a RIA (Roche), and subsequently repeated in one batch with an EIA (Roche) based on a monoclonal antibody. Both assays showed a similar number of 'false-negative' CEA levels pre-operatively--varying from 69% in aneuploid (AN) Dukes' A to 8% in AN Dukes' D tumours, and from 75% in near diploid (ND) Dukes' A to 40% in ND Dukes' D tumours. The sensitivity for detecting recurrence in patients with tumours of either ploidy pattern was slightly better with EIA than with RIA. A difference between the AN and ND group was shown somewhat better with RIA, the sensitivity in the AN group being 79% and the median lead time 7 months compared to 13% and 2 months in the ND group. The corresponding figures with EIA were 71% and 7 months for the AN group and 63% and 1 1/2 months for the ND group. However, all but one of the patients with ND DNA pattern who showed recurrence-associated CEA elevation with EIA also had an elevated level pre-operatively. We conclude that all patients operated for cure should be followed by regular CEA measurements post-operatively if they had an elevated CEA level prior to operation.(ABSTRACT TRUNCATED AT 250 WORDS)

DNA flow cytometry in human bladder carcinoma.

The cell kinetic fractions (G0/G1; S; G2 + M) were evaluated by DNA flow cytometry (DNA FCM) in 102 biopsies from bladder carcinoma, previously untreated by cytotoxic therapy, and in 25 biopsies taken at least 3 months after prior treatment (chemotherapy, radiotherapy, surgery). Non-diploid DNA-stemlines were most often found in tumours of a high T category and of a high histopathological grade. Also the number of tumours with a fraction of cells in S-phase above 10% correlated with the clinical stage and histological grade. When the cytotoxic treatment preceded the actual biopsy by 3 months or more the distribution of stemline ploidies in the recurrent or residual tumours were similar to that seen in previously untreated patients. Furthermore, 4 of 5 individual muscle infiltrating bladder tumours treated with surgery, radiotherapy or systemic chemotherapy had the same stemline ploidy before and after treatment. The analysis of ploidy and cell kinetic parameters obtained from DNA FCM offers a possibility to evaluate the prognosis and the therapy effects in human bladder carcinoma.

DNA flow cytometry of cells obtained from old paraffin-embedded specimens. A comparison with results of scanning absorption cytometry (a methodological study).

Suspensions of single cell nuclei were obtained from 31 different samples of 7-9 years old paraffin-embedded bladder cancer biopsies. The DNA content of the ethidium-bromide-stained nuclei was analyzed by flow cytometry (FCM). The tumour stemline ploidy, as determined by FCM, was compared with that obtained by Feulgen scanning absorption cytometry (SACM) in imprints obtained from the same biopsy before it was fixed. Fifteen tumours that were diploid by FCM were also diploid by SACM. All of the 16 tumours with non-diploid DNA-stemlines by FCM were non-diploid by SACM, though minor differences between the ploidy values were occasionally seen when the results of the two methods were compared. The background activity due to cell debris was considerable and resulted in a mean variation coefficient (CV) of 5.1% for human spleen cells fixed and embedded before preparation for FCM in the same way as the tumour samples. In the tumour samples there was a large and unpredictable variation of the ratio between the DNA values of chicken erythrocytes (internal standard) and diploid cells. In some specimens this ratio would have resulted in incorrect evaluation of the FCM DNA histogram. The following method for evaluation of FCM histograms is therefore proposed: Single peak histograms obtained from paraffin embedded tissue should always be interpreted as representative for a diploid cell population. In FCM histograms from paraffin-embedded tissue with more than one peak, the first peak should be considered as representing diploid cells.

Evidence of mouse epidermal subpopulations with different cell cycle times.

In order to obtain information on the distribution of total cell cycle times in hairless mouse epidermis, basal cells were isolated and prepared for DNA flow cytometry at intervals after a pulse labeling with 50 microCi of thymidine. The DNA distributions were recorded, and cells were sorted from windows in the S, G2, and G1 phases of the cell cycle, collected on glass slides, and subjected to autoradiography. The proportions of labeled cells were scored in each fraction, and the percentage of labeled mitoses was determined in histologic sections from the same animals. Grain count distributions were recorded at selected time points over labeled cells in sorted fractions and over labeled mitoses. The movement of the labeled S-phase cohort was thus followed through all cell cycle phases. Peaks in labeled cells were observed at about 36 h in S phase, G2 phase, and mitosis, and high levels of labeled G2 cells and mitoses were seen at about 80 h. These results indicate the existence of one rapidly cycling subpopulation of keratinocytes with a cell cycle time slightly less than 30 h, in addition to keratinocytes with considerably longer cell cycle times. The first peak of labeled G2 cells reached only about 30%. This is consistent with earlier findings of about 30% G2 cells with a rapid traverse, and 70% with a considerably delayed traverse through G2 phase. The proportion of labeled G1 cells reached a value corresponding to twice the initial labeling index at 8 h after pulse labeling. This is consistent with previously obtained phase durations, indicating an unperturbed cell cycle traverse of labeled cells from S phase through G2 and mitosis.