Biomedical subjects
F R Hirsch
Publications and source records attributed to F R Hirsch.
Early death during chemotherapy in patients with small-cell lung cancer: derivation of a prognostic index for toxic death and progression.
Based on an increased frequency of early death (death within the first treatment cycle) in our two latest randomized trials of combination chemotherapy in small-cell lung cancer (SCLC), we wanted to identify patients at risk of early non-toxic death (ENTD) and early toxic death (ETD). Data were stored in a database and logistic regression analyses were performed to identify predictive factors for early death. During the first cycle, 118 out of 937 patients (12.6%) died. In 38 patients (4%), the cause of death was sepsis. Significant risk factors were age, performance status (PS), lactate dehydrogenase (LDH) and treatment with epipodophyllotoxins and platinum in the first cycle (EP). Risk factors for ENTD were age, PS and LDH. Extensive stage had a hazard ratio of 1.9 (P = 0.07). Risk factors for ETD were EP, PS and LDH, whereas age and stage were not. For EP, the hazard ratio was as high as 6.7 (P = 0.0001). We introduced a simple prognostic algorithm including performance status, LDH and age. Using a prognostic algorithm to exclude poor-risk patients from trials, we could minimize early death, improve long-term survival and increase the survival differences between different regimens. We suggest that other groups evaluate our algorithm and exclude poor prognosis patients from trials of dose intensification.
Outcome of combination chemotherapy in extensive stage small-cell lung cancer: any treatment related progress?
During the past two decades many different treatment regimens of combination chemotherapy have been applied in extensive stage small-cell lung cancer (SCLC). This study was carried out to identify whether these modifications have resulted in an improved overall survival for extensive stage during the past two decades. In total, 1111 patients with extensive stage SCLC were included in six consecutive randomised trials in our setting from 1973 until 1992. Of these, 526 patients treated in the early period (1973-1981) were compared with 585 patients treated in the late period (1981-1992) with respect to pretreatment prognostic factors, staging, treatment and outcome. No change in the distribution of prognostic factors was detected and the frequency of patients with extensive stage was equal in the two periods, and no difference in overall response rates and survival was observed (P = 0.49). Median survival in the two periods was 208 days and 215 days, respectively. No stage migration or treatment-related improved outcome was observed in extensive disease. We suggest restricting aggressive treatment to patients with favorable prognosis and long-term survival as a realistic aim.
Should maintenance chemotherapy be used to treat small cell lung cancer?
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Prevention and early detection of lung cancer-clinical aspects.
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Serum neuron specific enolase (S-NSE) reference interval evaluation by time-resolved immunofluorometry compared with a radioimmunoassay.
The serum neuron specific enolase (S-NSE; EC 4.2.1.11) reference interval was evaluated by DELFIA (Wallac) in 161 healthy blood donors and the method compared with the S-NSE RIA assay (Pharmacia). The DELFIA assay total analytical variation coefficient (CV%) was between 3.7% and 6.6%., the RIA CV% 7.6% to 13.1%. Late centrifugation (after hours) increased the variation as a result of contamination with blood cells. Log transformation into a gaussian distribution was selected by Box-Cox analysis and tested by two models: the gauss-distribution and the Refval transformation. The 95% reference intervals and corresponding 90% confidence intervals were: female 2.9-9.6 micrograms/l (2.6-3.2 and 8.5-10.7) micrograms/l and male 3.4-11.7 micrograms/l (3.0-3.8 and 10.2-13.2 micrograms/l). Mean values were significantly different (P < 0.001), female 5.3 (4.9-5.6), male 6.3 (5.8-6.7) micrograms/l. The serum NSE levels were analysed with both methods in a population of 110 patients. The results were significantly correlated (coefficient, 0.9896; r, 0.99; P < 0.0001-two tailed). For high S-NSE values (> 150.0 micrograms/l) differences between the methods exceeded the mean difference + 2S.D., while low concentrations were interconvertible. Maximal diagnostic efficacy was 0.91 for both assays, in DELFIA 17.2-23.9 micrograms/l and for RIA 17.2-21.9 micrograms/l. Identical sensitivity, specificity, discriminative power score, and likelihood ratio were found. The two methods are consequently interconvertible.
[Mammographic screening in the municipality of Copenhagen. Results of the first screening round].
The aim of the study was to evaluate the results from the prevalence round of the mammography screening programme in the Municipality of Copenhagen. All women who by 1 April 1991 were 50-69 years old, and who lived in the Municipality of Copenhagen, were during the period 1 April 1991-24 April 1993 offered a mammography. Those with suspect findings were recalled for further examination and possible biopsy. Women with breast cancer were offered treatment according to the standard national protocols (DBCCG). The participation rate was 71% (30,416/43,087). Among these 2043 (6.7%) were re-examined and 592 (1.9%) underwent surgical biopsy. Breast cancer was revealed in 359 (1.2%) women, of whom 88% had an invasive breast cancer. Prevalence of breast cancer increased significantly with increasing age. The positive predictive value for breast cancer among those re-examined was 18% and for those who had a surgical biopsy 61%. Among women with an invasive breast cancer 41% had a tumour of 10 mm or less, 80% had negative lymph node status and 56% had breast conserving surgery. During the following 12 months 14 women with a normal mammogram at the screening round developed breast cancer giving a sensitivity of 96%. It is concluded that the first mammography screening in Denmark showed the highest breast cancer prevalence published so far. A possible explanation could be a high sensitivity of the screening method, indicated by a relatively high frequency of small cancers. The screening programme was fully comparable with international standards.
[Treatment of primary breast cancer. Consequences of mammographic screening in the municipality of Copenhagen].
In order to analyse changes in the pattern of primary treatment of breast cancer after introduction of mammography screening in the Copenhagen municipal area every second year, retrospective analyses of data from the Danish Breast Cancer Cooperative Group were performed. Newly diagnosed patients with breast cancer of the age of 50-69 years from the Copenhagen municipal area (1040 patients) were compared to a similar group of patients from the rest of Denmark (7353 patients). Parameters such as tumour size, lymph node status, grade of anaplasia, frequency of breast preserving surgery and adjuvant treatment were analysed. Introduction of mammography screening resulted in almost a doubling of newly diagnosed patients with invasive breast cancer during the prevalence phase, and a significant increase in the number of patients with tumour size < or = 1 cm without metastases to the axillary nodes. The frequency of breast preserving surgery increased from 5 to 45% in the municipality of Copenhagen compared to 6 to 19% in the rest of the country. Ratio between low-risk versus high-risk patients increased from 1.0 before screening to 2.7 in the following prevalence phase and 2.5 in the first year of the subsequent incidence phase, while the ratio in the rest of Denmark was the same throughout the whole study period. It can be concluded that the introduction of mammography screening resulted in significant changes in the treatment pattern of patients with primary breast cancer.
[Male breast cancer. A review].
Male breast cancer is a rare disease, making up less than 1% of all breast cancers. A review of the literature does not disclose major differences between male and female breast cancer regarding etiological, prognostic or diagnostic features. In male breast cancer endocrine therapy is more widely used, but there are otherwise no differences in the therapeutic strategies used.
Superiority of cisplatin or carboplatin in combination with teniposide and vincristine in the induction chemotherapy of small-cell lung cancer. A randomized trial with 5 years follow up.
PURPOSE: The introduction of platinum compounds and epipodophyllotoxins in combination with vincristine as induction chemotherapy in small-cell lung cancer (SCLC) was investigated in order to: (1) compare the efficacy of cisplatin with that of carboplatin in combination with teniposide and vincristine as inducers of remission over three cycles; (2) compare the toxicity pattern of carboplatin and of cisplatin when given in combination regimens; and (3) compare a chemotherapeutic regimen consisting of three alternating combinations with that of regimens consisting of four alternating combinations. PATIENTS AND METHODS: From November 1985 to September 1991, 484 consecutive, previously untreated patients with SCLC, performance status 0-4, entered a three armed randomized trial with three cycles of cisplatin (arm I) or carboplatin (arm II) in combination with teniposide and vincristine alternating with three treatment blocks of cyclophosphamide, etoposide, lomustine and vincristine (block A), doxorubicin and vincristine (block B) and cisplatin, hexamethylmelamine and vindesine (block C) versus alternating treatment with block A, B and C (arm III). RESULTS: No difference in efficacy or toxicity was found between cisplatin and carboplatin at the present dosages. Induction chemotherapy with teniposide plus cisplatin or carboplatin did not result in higher complete response rates (objective response rates 63%, 72% and 65%, respectively) or in significantly greater toxicity, but overall survival was superior compared with the arm III (log-rank test, P = 0.02). The median survival difference was 7 weeks, and two year survival 15% versus 9%. The Cox regression analysis identified the arm III, poor performance status and elevated LDH as factors with statistically significant negative impact on survival. CONCLUSION: Cisplatin and carboplatin produced similar response and survival rates and similar toxicity. Induction with platinum and epipodophyllotoxins did not improve objective response rates, but significantly improved survival without increasing the toxicity.
Neuroendocrine characteristics in malignant lung tumors: implications for diagnosis, treatment, and prognosis.
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Therapy-related acute promyelocytic leukemia with t(15;17) (q22;q12) following chemotherapy with drugs targeting DNA topoisomerase II. A report of two cases and a review of the literature.
BACKGROUND: The development of therapy-related acute myeloid leukemia (t-AML) with balanced translocations to chromosome bands 11q23 and 21q22 has recently been significantly related to previous treatment with several cytostatic drugs poisoning DNA topoisomerase II. A similar association was suspected for other balanced chromosomal aberrations such as the t(15;17) characteristic of acute promyelocytic leukemia (APL). PATIENTS AND METHODS: Two cases of acute promyelocytic leukemia were observed following treatment for seminoma with etoposide, cisplatin, and bleomycin and treatment for breast cancer with 4-epi-doxorubicin and subsequent cyclophosphamide, methotrexate, and 5-fluorouracil followed by radiotherapy. Both cases presented a t(15;17) (q22;q12) and were examined for the characteristic chimeric rearrangement of the RAR alpha and PML genes observed in acute promyelocytic leukemia de-novo. RESULTS: In both cases the characteristic chimeric rearrangement was demonstrated. Case no. 2 in addition to the t(15;17) showed an inversion of the long arm of a chromosome no. 5 and a del(7)(q22) in all abnormal mitoses studied. Despite these findings the patient obtained a complete morphological and cytogenetic remission of the leukemia following treatment with all-trans-retinoic acid. CONCLUSIONS: Based on these two cases and a review of the literature it is concluded that the development of t-APL with the balanced translocation t(15;17) is related to previous treatment with cytostatic drugs targeting DNA topoisomerase II and that additional abnormalities of the long arms of chromosomes no. 5 and no. 7 do not interfere with the induction of remission with all-trans-retinoic acid.
[Neonatal cancer in Denmark 1943-1985].
In order to describe the incidence, distribution and prognosis of neonatal cancer, 76 cases (44 boys, 32 girls) of cancer in the first 28 days of life were identified in the Danish Cancer Registry within the period 1943-85. All cases were re-evaluated and the International Classification of Disease for Oncology (ICD-O) code was applied. The incidence is calculated to 2.38 (1.88-2.98) cases per 100,000 births. The most common tumour was neuroblastoma (26%) followed by leukaemias (16%), soft tissue sarcomas (14%) and brain tumours (11%). The five year survival rate was 25% (15.1-39.0) with the highest survival rate among soft tissue sarcomas (55%) and neuroblastomas (25%) and the lowest among leukaemias and brain tumours (0). Eighteen per cent of the cases were incidental findings. Two cases of secondary malignancy were identified.
Are pathologists biased by clinical information?: A blinded cross-over study of the histopathological diagnosis of mesothelial tumours versus pulmonary adenocarcinoma.
In a blinded cross-over design, we studied whether three pathologists were biased by clinical information when making histopathological diagnoses of adenocarcinoma of the lung and benign and malignant mesothelial tumours. Furthermore, the interobserver variation of these diagnoses was assessed. Forty-one cases of adenocarcinoma of the lung and mesothelial tumours were assessed by three pathologists in four rounds. In the first two rounds, slides stained by H&E and clinical information were available. Slides and information were matched so that a specific slide in one round was given clinical information suggesting adenocarcinoma and in the other round, the clinical information suggested mesothelial tumour. In the third and fourth rounds, a panel of immunohistochemical stains was added. The clinical information was matched in the same way as in the first and second rounds. Bias by clinical information was observed when the diagnoses were made on slides stained by H&E, while no bias could be demonstrated when immunohistochemical reactions were included. The reproducibility also improved significantly when these slides were available.
Differentiation of adenocarcinoma of the lung and malignant mesothelioma: predictive value and reproducibility of immunoreactive antibodies.
A panel of antibodies against keratins, epithelial membrane antigen (EMA), epithelial antigen (Ber-EP4), carcinoembryonic antigen (CEA), tumour-associated glycoprotein (B72.3), vimentin and LeuM1 was applied to sections of adenocarcinoma of the lung and malignant mesothelioma in a randomized design. The proportion of stained tumour cells within each section was estimated independently in five categories by three pathologists (no positive tumour cells, 1-10%, 11-33%, 34-66% and more than 67% positive tumour cells). The kappa values representing the chance corrected interobserver agreement for the different antibodies in such a five group assessment were between 0.38 and 0.72. In two group assessment the kappa values were between 0.53 and 0.94. Nosological sensitivity and nosological specificity were calculated for all antibodies, and diagnostic sensitivity and diagnostic specificity (predictive values) were calculated for the Ber-EP4, CEA, B72.3, LeuM1 and vimentin. The difference between nosological sensitivity and nosologic specificity and the clinically relevant predictive values of positive and negative tests were demonstrated. In respect of the reproducibility and the diagnostic power defined by the predictive values, we demonstrated that a panel of antibodies, including CEA, Ber-EP4 and B72.3 and, to a lesser degree, LeuM1 and vimentin is applicable for the histopathological distinction between adenocarcinoma of the lung and malignant mesotheliomas. Before introduction of new diagnostic tests, including new antibodies, the prevalence of the tested tumours should be estimated. Nosological sensitivity and nosological specificity should be converted to predictive values.
Interobserver variability in histopathologic subtyping and grading of pulmonary adenocarcinoma.
BACKGROUND: The classification of lung tumors by the World Health Organization (WHO 1981) describes subtyping of adenocarcinoma of the lung (ACL) into acinar adenocarcinoma and papillary adenocarcinoma, bronchioloalveolar carcinoma, and solid carcinoma with mucus formation. Acinar and papillary adenocarcinoma may be graded as well-, moderately, or poorly differentiated. This study evaluated the interobserver variability in the subtyping and grading of ACL according to the WHO classification. METHODS: Histologic specimens from 211 patients with disease of Stages IIIa-IV were classified in a blind manner by three panelists. All available paraffin-embedded tissue blocks, including metastatic tumors, were sampled, and new slides were made for the study. RESULTS: Twenty-two ACL tumors could not be assigned a subtype by Panelist 1, which left 189 tumors as the basis for additional evaluation. Overall agreement for the three panelists regarding subtypes was 41%. Nonchance agreement was evaluated by kappa statistics, which may vary between -1 in the event of agreement that is less than that expected by chance and /1 in the event of full agreement. The kappa value regarding subtypes was 0.18 (95% confidence limits, 0.14-0.23). Overall observed agreement regarding degree of differentiation was 43%, with a kappa value of 0.12 (95% confidence limits, 0.06-0.17). Histologic material was obtained by thoracotomy in a subgroup of 53 patients, and in this patient group unanimity among two or more panelists was 88% for subtyping and 100% for degree of differentiation. CONCLUSIONS: The degree of agreement in subtying and grading of ACL in Stages IIIa-IV is low, suggesting that more objective criteria is needed before a prognostic impact of such variables can be assessed. The quality and quantity of material available for subtyping obviously influence the results, which is reflected in a better agreement when histologic material is obtained by thoracotomy.
Monoclonal antibodies in the detection of bone marrow metastases in small cell lung cancer.
Using conventional examination (CE) of H&E stained slides from bone marrow aspirates, metastases can be detected in approximately 25% of patients with small cell lung cancer. We investigated a panel of monoclonal antibodies using immunohistochemistry in the diagnosis of bone marrow infiltration from SCLC and compared the results with CE. Seven monoclonal antibodies raised against epithelial antigens (CAM 5.2, MOV 15, NCCST 433, PE 35, LCA1/L38, HMFG 1 AND HMFG 2) were applied on bone marrow sections from three groups of patients (pts): (1) 19 pts in whom SCLC-metastases were detected by CE, (2) 44 pts with SCLC in whom metastases could not be detected by CE, and (3) 20 pts with non-malignant bone marrow diseases. All the antibodies except LCA1/L38 were positive in 60-90% of the slides with infiltrating tumour cells in group 1. No positive tumour cells were detected in group 2. A few plasma cells and megakaryocytes were slightly positive for MOV 15 and NCCST 433, but no other positive cells were detected in group 3. In conclusion, the monoclonal antibodies used in this study may be useful for diagnostic purposes when a suspicious looking infiltration is detected by CE. However, these antibodies could not detect metastatic tumour cells in the bone marrow sections from patients in whom CE did not reveal any tumour cells.
An immunohistochemical investigation of diagnostic biopsy material taken from short and long term survivors with small cell lung cancer.
An immunohistochemical study has been carried out on fibre optic-biopsy specimens from patients with small cell lung cancer (SCLC) who had either died within 3 months, or who had survived more than 2 years. Long term survivors (LTS) were identified from completed clinical trials at major UK centres and were matched for age and sex within the trial with short term survivors (STS). The panel of immunohistochemical markers included those previously reported to be associated with prognosis, and reagents representative of both neuroendocrine and epithelial differentiation. A preliminary screen of 17 antibodies identified 11 as consistently reactive on paraffin-embedded material using streptavadin-biotin immunoperoxidase. Of 186 identified patients, 110 biopsy samples were retrieved. Of these, 70 gave sufficient material for analysis. All sections were scored by three observers without knowledge of the prognosis. The analysis failed to identify any antigen whose expression was correlated with prognosis. We conclude that, in fibre-optic biopsy specimens, immunohistochemical analysis does not add prognostic information in SCLC.