Two randomised phase II trials of subcutaneous interleukin-2 and histamine dihydrochloride in patients with metastatic renal cell carcinoma.

Histamine inhibits formation and release of phagocyte-derived reactive oxygen species, and thereby protects natural killer and T cells against oxidative damage. Thus, the addition of histamine may potentially improve the efficacy of interleukin-2 (IL-2). Two randomised phase II trials of IL-2 with or without histamine dihydrochloride (HDC) in patients with metastatic renal cell carcinoma (mRCC) were run in parallel. A total of 41 patients were included in Manchester, UK and 63 in Aarhus, Denmark. The self-administered, outpatient regimen included IL-2 as a fixed dose, 18 MIU s.c. once daily, 5 days per week for 3 weeks followed by 2 weeks rest. Histamine dihydrochloride was added twice daily, 1.0 mg s.c., concomitantly with IL-2. A maximum of four cycles were given. The Danish study showed a statistically significant 1-year survival benefit (76 vs 47%, P = 0.03), a trend towards benefit in both median survival (18.3 vs 11.4 months, P = 0.07), time to PD (4.5 vs 2.2 months, P = 0.13) and clinical benefit (CR + PR + SD) (58 vs 37%, P = 0.10) in favour of IL-2/HDC, whereas the UK study was negative for all end points. Only three patients had grade 4 toxicity; however, two were fatal. A randomised phase III trial is warranted to clarify the potential role of adding histamine to IL-2 in mRCC.

A phase II study of outpatient subcutaneous histamine dihydrochloride, interleukin-2 and interferon-alpha in patients with metastatic melanoma.

BACKGROUND: Experimental data had suggested a synergistic effect of histamine with interleukin-2 (IL-2) and interferon-alpha (IFN-alpha). PATIENTS AND METHODS: Forty-one patients with metastatic melanoma received IL-2 9 MU subcutaneously (s.c.) twice daily on days 4-8 and 25-29, and once daily on days 11-15 and 32-36. IFN-alpha-2b was given as 5 MU s.c. on days 1-3 and then daily to day 43. Histamine 1 mg s.c. was administered twice daily, following IL-2 and IFN injections starting on day 4. Efficacy and toxicity were compared with those of 42 patients included on exactly the same criteria and receiving the same regimen but without histamine. RESULTS: Two patients achieved a partial response (PR) for an objective response rate of 5% [95% confidence interval (CI) 1% to 17%]. Median overall survival was 7.8 months (95% CI 6.4-9.1). In the control group, two complete responses and one PR were achieved. Median overall survival was 7.1 months (95% CI 5.4-8.9). CONCLUSIONS: This IL-2 and IFN regimen was well tolerated on an outpatient basis. However, the applied regimen cannot be recommended because of the low clinical efficacy. Histamine did not add efficacy or toxicity in combination with this moderate-dose schedule of IL-2 and IFN.

Subcutaneous interleukin-2 and interferon-alpha plus cisplatin with and without prophylactic cimetidine in patients with metastatic malignant melanoma: a phase II study.

A phase II study was performed to evaluate the efficacy of cisplatin combined with interleukin-2 and interferon-alpha2b administered subcutaneously to patients with metastatic malignant melanoma (MMM). Between April 1994 and January 1999, 87 patients with MMM and a WHO performance status of < or = 2 were entered into the study. The first 42 patients had prophylactic cimetidine; the other 45 patients did not. An overall response rate of 27% was achieved in the 82 patients evaluable for response. The median response duration was 7.0 months (range 4.4-29.0 months). The median survival for all patients was 10.1 months (range 0.4-64.9+ months). Toxicity was substantial but generally manageable and usually reversed on dose reduction or temporary interruption of treatment. Two patients (2%) died of treatment-related toxicity. No difference in response or survival was seen in the patients treated with or without cimetidine. In multivariate analysis, lactate dehydrogenase level (P < 0.001), number of metastatic sites (P = 0.014) and performance status (P = 0.035) was shown to be independent prognostic factors for survival. This high dose interleukin-2 subcutaneous regimen resulted in a small fraction of long-term survivors. The response and survival results were not superior to other studies using lower and less toxic interleukin-2 doses.

Detection of methanotrophs in groundwater by PCR.

Methanotrophic bacteria have significant potential for bioremediation, which would require methods for monitoring the presence and activity of these organisms in environmental samples. In this study, PCR was used to detect methanotrophic bacteria. Primers were designed on the basis of a partial sequence of pmoA, which encodes one of the proteins of the particulate methane monooxygenase. Specific amplification of a portion of pmoA was obtained with template DNA isolated from lab strains of methanotrophs. A pmoA product was also obtained by using DNA from groundwater. The identity of the PCR product was confirmed by sequencing or by amplification with a nested primer. Reverse transcriptase PCR detected pmoA mRNA.

Randomized study of initial versus late chest irradiation combined with chemotherapy in limited-stage small-cell lung cancer. Aarhus Lung Cancer Group.

PURPOSE: To evaluate if the timing of chest irradiation with respect to chemotherapy would influence survival and local and distant control in patients with limited-stage small-cell lung cancer (LSCLC). PATIENTS AND METHODS: From 1981 to 1989, 199 consecutive patients with LSCLC were randomly allocated to receive initial chest irradiation (ICI; n = 99) or late chest irradiation (LCI; n = 100) given 18 weeks delayed. Both groups received the same nine cycles of combination chemotherapy: three cycles of cisplatin and etoposide and six cycles of cyclophosphamide, doxorubicin, and vincristine. In the first part of the study, prophylactic cranial irradiation (PCI) was only given to patients randomized to ICI, but after inclusion of 42 patients in the LCI arm, the protocol was changed, so that all patients received PCI independent of the timing of the chest irradiation (CI). A total of 157 patients received PCI with a radiation dose of 25 Gy in 11 fractions. RESULTS: The timing of radiotherapy had no significant effect on the 2-year overall survival rate (20% after ICI v 19% after LCI, P = .4) or the 2-year in-field recurrence rate (72% after ICI v 68% after LCI, P = .2). Median survival durations were 10.5 (ICI) and 12.0 (LCI) months. Similarly, no difference in the 2-year incidence of CNS recurrences was found between the 2 arms in patients who received PCI (19% after ICI v 13% after LCI, P = .24). Bone marrow toxicity was acceptable, as 15% developed World Health Organization (WHO) grade 4 leukocytopenia and 4% grade 4 thrombocytopenia. Grade 4 leukocytopenia was more pronounced in the ICI group. There was no difference in the frequency and severity of other toxicities between the 2 groups. CONCLUSION: Timing of CI did not significantly influence the incidence of in-field recurrences, CNS recurrences, or overall survival.

Prophylactic cranial irradiation in limited stage small cell lung cancer: survival benefit in patients with favourable characteristics.

The value of prophylactic cranial irradiation (PCI) in the treatment of small cell lung cancer (SCLC) remains controversial. As part of a randomised study investigating the timing of chest irradiation (CI) with respect to combination chemotherapy, the effect of PCI was evaluated. Between 1981 and 1989, patients were randomised to initial chest irradiation ICI (99 patients) or 18 weeks delayed late chest irradiation LCI (100 patients). PCI was given to 157 patients. In the beginning, only ICI patients received PCI, but in October 1984 the strategy was changed so that all patients received PCI. Thus, the patients who did not receive PCI were randomly allocated. The PCI dose was 33 Gy/11 fractions (45 patients) and 25 Gy/11 fractions (112 patients). The 2-year CNS-recurrence rate (+/- standard error) was significantly lower in patients who received PCI, 16.3 +/- 4.1%, than in those who did not, 55.1 +/- 12.4% (p = 0.01). In contrast, the 2-year cause-specific survival was not significantly different, 24.9 +/- 3.6% and 16.9 +/- 6.2% (p = 0.31). The 2-year progression-free rates with or without PCI were 18.5 +/- 3.3% and 11.4 +/- 5.4%, respectively (p = 0.58). To test the hypothesis that a benefit from PCI would mainly be expected among the patients with the best prognosis, a multivariate regression analysis of prognostic factors was undertaken. Based on weight loss, performance status, serum sodium and age, the third of the patients with the best prognosis were identified. In that group of patients, the survival advantage from PCI was statistically significant, 35.5 +/- 7.2% versus 14.1 +/- 8.0%, P = 0.029. These results are currently being tested in a Danish multicentre trial where patients with a good prognosis are randomised either to receive PCI or not to receive PCI.

Spinal epidural hematomas.

During the period 1943-1985 six patients were operated for spinal epidural hematomas at the department of neurosurgery of the University Hospital of Arhus. It is essential to perform acute laminectomy in case of rapidly increasing neurological symptoms. In the case of slowly increasing symptoms operation may provide a good result even if it is performed a week after the onset of symptoms. It is important to watch patients with fracture/dislocations of the spine closely during the first weeks after a trauma. If they develop neurological symptoms the patients should immediately be transferred to the department of neurosurgery with a view of

Treatment of cervical disc disease using Cloward's technique. Part V. The effect of reoperations.

Among 1,106 patients with cervical disc disease in whom Cloward's operation had been performed over a fifteen-year period, 145 patients were reoperated upon with a new Cloward procedure. In the 1st year after the first operation 3/4 of the patients were operated upon on the previous level, whereas reoperations performed later mainly were done on new levels. The effect of the reoperation was poorer than the effect of the 1st operation. Early reoperations--which were due to: an initially unsatisfactory clinical course, postoperative complications or graft problems--had a poor result, but late reoperations--which were caused by relapses--showed a result corresponding to the first operation. The frequency of relapses leading to a 2nd Cloward operation was 8.8% in the first year falling to 0.2% in the following years of observation.

The significance of preoperative radiological examinations in patients treated with Cloward's operation.

During a fifteen-year period 1,106 patients with symptoms and signs of cervical disc disease underwent Cloward's operation. Plain x-rays were performed in 94%, but the severity and extension of degenerative changes had no prognostic value. In 91% of the patients myelography was performed and in recent years mainly metrizamide was used as it was found to be more accurate. The findings on the myelograms were correlated according to age, severity and number of affected disc levels, but were independent of the duration of symptoms. Patients with medullary symptoms were found more often than not to have an anterior indentation into the spinal canal whereas most patients with radicular symptoms had wide cervical root sleeves or lateral compression. The best outcome was found among patients with monosegmental symptoms and signs and one affected disc level on the myelogram underlining that the indication for surgery in cervical disc disease should be based on both clinical and radiological findings.

Treatment of cervical disc disease using Cloward's technique. The prognostic value of clinical preoperative data in 1,106 patients.

During a fifteen-year period 1,106 patients underwent Cloward's operation due to cervical disc disease. An analysis of the clinical features showed that the diseases had a very complex pattern of symptoms and signs. In young patients a syndrome of herniated disc predominated whereas a clinical picture of "cervical spondylosis" was found more often in the elderly. It was demonstrated that best results were obtained in young patients, patients with slight symptoms and patients with monoradicular symptoms. A short duration of symptoms is essential for a good outcome, and, on the basis of the data presented, operation is recommended 3 months after the onset of symptoms of cervical disc disease, if previous conservative treatment has failed.

Treatment of cervical disc disease using Cloward's technique. III. Evaluation of cervical spondylotic myelopathy in 138 cases.

Among 1,106 patients with cervical disc disease treated with Cloward's operation over a fifteen-year period, 138 patients had symptoms and signs of spinal cord involvement. The median symptom duration was one year. Nearly all had gait disturbances, 63% had spasticity of the lower extremities and 11% had various degrees of tetraplegia. Three months after surgery 78% of the patients were found to have some symptoms, but only 5% had no symptoms at all. At the time of the questionnaire (average 7.7 years postoperatively) 46% of the patients stated they were still affected by the operation. The duration of preoperative symptoms was of significance to the outcome, but age, sex, and severity of myelopathy were not. It was demonstrated that patients with medullary involvement had a higher annual mortality rate than patients with radicular symptoms, and that this rate depended on the severity of the spinal cord symptoms.

Treatment of cervical disc disease using Cloward's technique. I. General results, effect of different operative methods and complications in 1,106 patients.

During the period from April, 1965, to October, 1979, 1,106 patients with symptoms or signs of cervical disc disease were operated on using Cloward's technique. 94% of the patients alive filled in a questionnaire forwarded on October, 1980. The study revealed that 81% experienced an immediate effect of the operation, and 63% were in a better condition than preoperatively at the time of the questionnaire. It appeared that the effect of the operation 1 year postoperatively was independent of age and observation time, but the functional result and postoperative working capacity were very significantly better in young patients, but still independent of observation time. The result was independent of the number of primarily inserted grafts, cutting of the posterior spinal ligament or the finding of a free herniated disc. Use of calf bone grafts resulted in more reoperations. Primary complications were registered in 13% of the patients, reduced to 5% after 3 months. 3 patients developed a severe tetraplegia, and 6 patients died within 3 months of the operation.

Sudden death in mitral valve prolapse: associated accessory atrioventricular pathways.

Sudden death in patients with mitral valve prolapse is a rare complication with a possible arrhythmic mechanism. We made a detailed postmortem examination of the conduction system in three patients with MVP who died suddenly. One patient who died in cardiac failure had a normal conduction system. The two other patients with no cardiac symptoms prior to death had both accessory atrioventricular pathways. These findings suggest a higher incidence than hitherto known of accessory bypass tracts in patients with MVP who die suddenly, and support the presumption of an arrhythmic cause of death.