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A phase II study of mitoxantrone, an anthraquinone derivative with structural similarities to adriamycin, has been carried out in 34 patients with advanced breast carcinoma and other malignancies. The first 20 patients were treated with a starting dose of 12 mg/m2 by IV infusion repeated every 3 weeks; this was escalated to 14 mg/m2 in the subsequent 14 patients. Of the 29 patients with advanced breast carcinoma, 8 achieved a partial response and two further patients achieved a mixed response. There were no complete responses. Of the eight responding patients, five had received no prior chemotherapy. Response duration ranged from 3 1/2 months to 10+ months. No responses were seen in the other five patients, three whom had small cell carcinoma of the lung, and one colonic carcinoma. Neutropenia was the most frequently seen toxicity but was usually mild and transient; WBC fell to less than 2,000/mm3 in eight patients and to less than 1,000/mm3 in only two. Otherwise, the drug was well tolerated; nausea occurred in 35% of patients and vomiting in 21%; severe alopecia requiring a wig was never seen. Mitoxantrone appears to be a well-tolerated and clinically active agent against advanced breast carcinoma.

A phase-II study of vindesine was carried out in 23 patients with histologically proven advanced breast carcinoma. Toxicity was assessed in a further 24 patients with several different tumour tupes. Treatment was given in a starting dose of 3 mg/m2 weekly by IV bolus, increasing by 1 mg weekly as toxicity allowed. The response rate in 21 evaluable patients with breast carcinoma was 29%. In 47 patients evaluable for toxicity, leukopaenia occurred in 45% and was doserelated; thrombocytopaenia was rare (4%); neurotoxicity occurred in 40%; constipation in 17%, alopoecia in 46% and an influenza-like syndrome in 21%. It was concluded that vindesine was a clinically active agent in breast carcinoma, with a spectrum of toxicity lying between those of vincristine and vinblastine.

CNS relapse after PCI may reflect either suboptimal radiation dose schedules or reseeding from other sites of active disease. A retrospective study has been undertaken to investigate these alternative mechanisms of treatment failure. Between August 1981 and December 1983, 30 patients with SCLC treated by induction chemotherapy, followed by high-dose cyclophosphamide (7 Gm/m 2 ), were selected for PCI on the basis of clinical, radiological, and bronchoscopic CR. Pretreatment CT brain scans were normal in all patients, and 20 Gy mid-plane dose in 5 daily fractions were delivered by lateral fields to whole brain using megavoltage X rays and localizing check films. Progressive focal neurological signs of cranial metastases developed in 730(2386) patients 3–11 months after PCI, confirmed on CT scanning in 4 patients. Relapse at other sites, predominantly the thorax, occurred in all seven patients at intervals of 1–6 months prior to CNS relapse. Published clinical data of tumor volume doubling times in SCLC predict longer CNS relapse-free intervals after PCI than those observed in our patients if reseeding was responsible for relapse. This suggests that incomplete eradication of intracranial disease is the main cause of CNS relapse after PCI. Higher equivalent radiation doses may improve the results of PCI.

The site of action of aminoglutethimide (AG) has been investigated. An initial study was performed on 10 postmenopausal patients with advanced breast cancer who had taken 1000 mg AG per day and 20 mg hydrocortisone (HC) twice daily (b.d.) for greater than 3 months. There was a 15.5 +/- 5.6 s.e.-fold rise in 17-OH progesterone and a 4.9 +/- 0.9 s.e.-fold rise in 4 delta androstenedione but no rise in cortisol or oestrone 30 min after short Synacthen tests. These results suggested that peripheral aromatisation was a more important site of AG action than adrenal desmolase, and that adrenal 11 beta hydroxylase was inhibited. Since aromatase is more sensitive than desmolase to AG in vitro, lower doses of AG alone (i.e. without HC) were assessed for endocrine effects in 13 further post-menopausal women with advanced breast cancer. All of these patients tolerated 125 mg AG b.d., but 3 could not tolerate the conventional maximum dose. Oestrone levels on 125 mg AG b.d. were suppressed below pretreatment levels and were not significantly different from those on 500 mg AG b.d. alone, or with the addition of HC. Oestradiol levels were suppressed to a similar extent. Dehydroepiandrosterone sulphate (DHA-S) levels were not suppressed by AG alone, but fell on addition of HC. The endocrine results show low dose AG alone is an effective and well tolerated inhibitor of the peripheral production of oestrogens in postmenopausal patients. Therapeutic trials are now possible. DHA-S is not a marker of AG effect.

42 patients with metastatic breast carcinoma were treated with aminoglutethimide, which inhibits adrenal steroid hormone synthesis. Treatment was stopped in 2 patients before response could be assessed; of the other 40, 15 (37·5%) had an objective response, 1 (2·5%) showed a response in bone but not in soft tissue, and 4 (10%) had complete or very great relief of metastatic bone pain but no radiological evidence of improvement. 19 (53%) of 36 patients with bone metastases responded to treatment (15 had X-ray evidence and 4 had pain relief), as did 5 (45%) of 11 patients with soft tissue metastases, 2 (25%) of 8 with malignant marrow infiltration, 1 (14%) of 7 with lung metastases, and none of 13 with liver metastases. Response was commonest in patients who had previously responded to other forms of endocrine therapy. Sideeffects, usually mild and transient, occurred in a few patients; the most important were an initial period of somnolence in 9 patients and a rash in 5.

Aminoglutethimide in combination with hydrocortisone provides an effective therapy in postmenopausal advanced breast cancer patients, with response rates of 37.5-50‰ having been found. Treatment with aminoglutethimide of only four premenopausal breast cancer patients has been reported inwhich two patients responded. The clinical and endocrine effects of 1000 mg aminoglutethimide daily and 20 mg hydrocortisone twice daily were studied in 18 premenopausal patients with breast cancer. Eight patients developed menstrual abnormalities, but there were no objective tumor responses in the 14 patients with assessable disease. Adrenal suppression was produced in all patients, with dehydroepiandrosterone sulfate levels suppressed to 20‰ of baseline values. Estrone and estradiol levels were not suppressed into the postmenopausal range. However, the therapeutic regime resulted in suppression of estrogen peaks after Pergonal administration, thus demonstrating a partial block of ovarian estrogen synthesis. (J Clin Endoc...

Eighty-one postmenopausal women with advanced breast cancer were studied for the effects of treatment with aminoglutethimide (AG) plus hydrocortisone on peripheral hormones and response to therapy. There were 40 responders (R) and 41 non-responders (NR) at 3 months from the start of treatment. Plasma oestrone concentrations were higher in non-responders at 1 and 2 months after starting AG (Means: NR 106 +/- 50, R 84 +/- 26 pmol l-1, P less than 0.05; highest value NR 121 +/- 51, R 99 +/- 24 pmol l-1, P less than 0.05). High oestrone levels were correlated with bulky liver secondaries, but not with age, tumour-free interval, time from last menstrual period, time from relapse to start of AG or body weight. Non-responders had higher mean prolactin levels on treatment (prolactin less than 500 mIUl-1 in 14/40 NR, 2/35 R, P less than 0.01). High oestrone or prolactin levels were present in 28/41 NR and 6/40 R (P less than 0.001). Dehydroepiandrosterone sulphate suppression did not differ between R and NR. The differences in peripheral endocrine environment in non-responding patients suggest that oestrogen metabolism may differ in non-responding patients and that sub-groups could be selected for rational endocrine therapy.

Summary The use of the epipodophyllotoxin VP 16-213 is described in twenty patients with acute myelogenous leukaemia resistant to other chemotherapy. The drug was usually given in 5-day courses of 50 mg/m2 daily and occasionally in 24-hr infusions of 250 mg/m2, on the basis of its phase-activity. Complete remission was achieved in only two patients: in one of these, remission was maintained with VP 16-213 for 8 months, and in the other for 10 weeks. A partial response was achieved in one other patient. Seventeen patients showed no response. No responses or remissions were achieved when the drug was used in a 24-hr infusion. Side effects were minimal, and the degree of marrow depression much less than for most other agents known to be active in acute myelogenous leukaemia. It was of interest that remission was achieved in one patient without the customary period of marrow hypoplasia. It is suggested that, although VP 16-213 appears to have minimal activity in the dosage used here, improvement might be sought by increasing the dosage, by scheduling the drug in a different way, or by using it in a combination chemotherapy regime.

Thirteen patients with small cell carcinoma of the bronchus that had become resistant to conventional chemotherapy were given 4′-(9-acridinylamino) methanesulphon-m-anisidide (mAMSA) at a dose of 90 or 120 mg/m2 at 3-week intervals. Twenty percent of the courses at 90 mg/m2 produced marked myelosuppression. No responses were observed. Median survival from the start of treatment with mAMSA was 5 weeks.

Although it is true that some Kveim-Siltzbach test suspension may for reasons unknown behave in a totally nonspecific way and so be useless in the confirmation of active sarcoidosis, the experience with the Edinburgh spleen has shown that it is also true that a preparation can be made which acts specifically in the sarcoid context and fulfils all the Siltzbach criteria. The active principle probably resides in the membrane components of sarcoid tissue cells.

cis-Diammine-1,1-cyclobutane dicarboxylate platinum II (CBDCA, JM8), an analogue of cisplatin showing reduced toxicity in preclinical studies, was evaluated in 60 patients. Doses were given initially every 3 weeks and escalated from 20 to 520 mg/m2. Following this, doses were given every 4 weeks and escalated from 300 to 500 mg/m2. The dose-limiting toxicity, thrombocytopoenia, occurred in four-fifths of patients treated at 520 mg/m2, with the nadir occurring 3 weeks after treatment. Leucopoenia and anaemia also occurred but were less severe. Vomiting occurred in all patients receiving over 120 mg/m2 but seldom persisted beyond 24 h. Serial measurements of 51Cr-EDTA clearances, urinary N-acetylglucosaminidase, urinary leucine aminopeptidase, and beta 2-microglobulin did not reveal significant evidence of nephrotoxicity. Detriment to the audiogram has not been seen in the first 13 patients studied. Pharmacological studies showed that most of the dose of platinum was excreted in the urine, and that impairment of renal function may be associated with drug retention and an increased risk of myelosuppression. The previous therapy and age of the patient also affected the tolerance of the drug. Clinical responses were seen in patients with ovarian carcinoma receiving greater than 120 mg/m2. A further dose escalation was performed on a 4-week schedule in patients under 65 with good renal function. The maximum dose it was possible to administer repeatedly without incurring myelosuppression was in the range 400-500 mg/m2. JM8 is not significantly nephrotoxic and is less emetic than cisplatin. It has antitumour activity in man and deserves wider evaluation, along with the other analogues under study in various centres, as an alternative to cisplatin.

Since its introduction in the early 1970’s cisplatin has become established as one of the major cytotoxic drugs used in the treatment of cancer. Of particular note are its application in combination therapy to the treatment of testicular cancer (1) and in the treatment of ovarian cancer (2). The majority of patients with testicular teratoma are probably cured of their disease. Cisplatin is probably the most active single agent in the treatment of ovarian cancer producing an overall response rate in excess of 50% and a complete response rate of 20–30% (2). In our hands a group of 27 patients treated with high dose cisplatin for stage III ovarian carcinoma and followed for a minimum of 3 years had an actuarial survival of 35% at 3 and 4 years (3).

Seventeen patients with malignant mesothelioma were treated in a phase II study with carboplatin, a cisplatin analogue without significant nephrotoxicity or neurotoxicity. The drug was given in a dose of 300-400 mg/m2 by i.v. infusion, repeating at 28-day intervals. One patient achieved a complete clinical and radiological remission of 15 months' duration, and a second patient achieved a partial response of 11 months' duration (overall response rate 12%; overall response rate in previously untreated patients 20%). Four other previously untreated patients achieved symptomatic relief. Treatment was well tolerated without severe side-effects. Carboplatin, like most other cytotoxic drugs, is active only in a small minority of patients with mesothelioma, but its ability to achieve occasional good responses and frequent symptomatic relief, combined with low toxicity, may justify a short therapeutic trial in patients whose tumour is symptomatic.

Eleven patients with advanced adenocarcinoma of lung and six patients with large cell anaplastic carcinoma of lung were treated with combination chemotherapy using cyclophosphamide 1 g/m2 i. v., adriamycin 30 mg/m2 and 5-FU 500 mg/m2 i. v. on days 1 and 8, of a 28 day cycle. In neither group did any patient achieve a complete remission; 1 patient achieved a partial response in each group, and the rest showed no evidence of response. The duration of survival of the responding patients in each group was not significantly longer than those of the non-responders. Toxicity and side effects were considerable in all patients. This study demonstrates that these tumour types are refractory to this form of intensive combination chemotherapy. A literature review suggests that other forms of combination chemotherapy are usually equally ineffective.

In 8 patients receiving intravenous isophosphamide 2 g/m2 at 2-week intervals for advanced bronchogenic carcinoma the protective effect of 2-mercaptoethane sulphonate sodium (mesnum) against isophosphamide-induced urothelial toxicity was tested in a single-blind crossover trial. With isophosphamide alone, 7 of the 8 patients developed either haematuria or symptoms of bladder irritation; when mesnum was given in addition, only 1 patient had microhaematuria and frequency, and this was in association with a urinary-tract infection. 5 patients then received fifteen courses of isophosphamide in increasing doses of 4 to 8 g/m2 i.v. with mesnum. In contrast to previous experience with isophosphamide at this high dosage, frank haematuria was never seen, microhaematuria was seen after only three courses, and mild dysuria after only one course. Pharmacokinetic studies showed that mesnum did not interfere with the metabolism of isophosphoramide or its active anti-tumour metabolite, isophosphoramide mustard. Mesnum therefore enhances the therapeutic ratio of isophosphamide and may thereby increase its clinical efficacy.

Fifty-nine children with Hodgkin's disease were seen over a 34-year period. Compared with Hodgkin's disease in adults, there was an increased male incidence, especially in the younger children. This was associated with an increased male incidence of lymphocyte-predominant histology. Forty-six patients underwent lymphography as part of their staging, and 13 had staging laparotomies. The 5-year survival for the entire group was 85%, with a median survival of 10 years. Response to radiotherapy in children with Stages I-IIIA disease was: 12 children treated with involved-field radiotherapy after inadequate clinical staging had a 3-year remission rate of 13%, and a median length of remission of 18 months; 24 children treated with extended-field radiotherapy after adequate clinical staging, including lymphography, had a 3-year remission rate of 72%, and a median duration of remission not yet reached; 3 children treated with elective local radiotherapy for Stage IA disease after intensive clinical staging remain in complete remission for periods of up to 34 months. Eight out of 10 children with Stages IIIB-IV disease, treated with combination chemotherapy, achieved complete remission with a 3-year remission rate of 70%; 7 children treated with combination chemotherapy following relapse after radiotherapy all achieved complete remission with a 3-year complete remission rate of 66%. Thirteen children underwent laparotomy and splenectomy as a staging procedure. Five were found to have intra-abdominal disease, including 4 with splenic involvement. These results show that there is no place for involved-field radiotherapy after inadequate clinical staging, in the management of childhood Hodgkin's disease. Extended-field radiotherapy after adequate staging, and combination chemotherapy, produce results which are as good as those for adults, but the benefits of these treatments and of staging laparotomy must be balanced against the possible complications when they are used in children. These problems are discussed and a scheme of management is proposed.

Suppression of plasma 6-keto-prostaglandin F 1α and 13,14-dihydro-15-keto-prostaglandin F 2α by aminoglutethimide in advanced breast cancer

Serum prolactin concentrations were measured in 135 postmenopausal patients with advanced breast cancer prior to their treatment with one of 3 endocrine therapies: aminoglutethimide (AG), tamoxifen (T) + AG, or T + AG + danazol. The mean level of prolactin was higher, and there were more individuals with levels of prolactin greater than or equal to 500 mIUl-1, in the group of patients who did not respond to treatment. Of the patients whose disease progressed, those with prolactin levels greater than or equal to 500 mIUl-1 had a significantly shorter survival. It appears that high prolactin levels indicate a poor prognosis to endocrine therapy and the probability of a shorter than average survival time.

Overall survival of patients with primary breast cancer has not improved in the past ten years, despite increasing use of multiple-drug chemotherapy for treatment of metastases. Furthermore, there has been no improvement in survival from first metastasis, and survival may even have been shortened in some patients given chemotherapy. Chemotherapy probably does prolong survival in some patients, and further studies should be undertaken to identify these patients in advance.

Publisher Summary This chapter discusses techniques for sensing combustible gases and vapors. One of the problems concerning the safe operation of aircraft is the prevention of fires and explosions arising from the presence of inflammable gases and vapors. Mixtures of combustible gases or vapors with air are only capable of propagating flame over certain composition ranges, and the terminals of these ranges are known as limits of inflammability. As the characteristic property of the mixture that determines whether it is inflammable is the composition, it is customary to express these limits as the concentration of combustible in the mixture. The earliest device for sensing the presence of inflammable gases was the Davy safety lamp designed for use in coal mines. Of the various systems considered, the most promising appears to be that employing a heated catalytic filament arranged in a normally balanced bridge circuit. The main disadvantage of such a system is that the circuit must be manually balanced at fairly frequent intervals with uncontaminated air in the sensing cell, and its response to gas of known concentration must be checked at less frequent intervals.

Abstract #13 Background: BIG 1-98 compares letrozole (Let), tamoxifen (Tam) and sequences of Let and Tam as adjuvant endocrine therapy for postmenopausal women with receptor-positive breast cancer. Initial results (published in 2005) demonstrated the superiority of Let over Tam in significantly prolonging disease-free survival (DFS) and reducing the risk of relapse in distant sites. Following these results, investigators were informed of the treatment allocation for patients randomized to Tam alone, and about one third of these patients opted to receive Let. The three Let-containing treatments remained blinded. We now evaluate Let and Tam given in sequence compared with Let alone and update the comparison of Let alone and Tam alone. Methods: 6182 patients were randomized to the 4-arm option (entry Sep99-May03) [Tam x 5 years (Tam), Let x 5 (Let), Tam x 2→Let x 3 (Tam→Let), or Let x 2→Tam x 3 (Let→Tam)]. Another 1828 patients were randomized to the 2-arm option (Tam vs. Let; entry Mar98-Mar00). The primary endpoint was DFS (time from randomization to first occurrence of invasive breast cancer recurrence, invasive contralateral breast cancer, second non-breast malignancy, or death from any cause). The presentation will focus on the clinically-relevant comparisons evaluating Tam→Let vs. Let and Let→Tam vs. Let, assessed from the time of randomization. Acknowledging multiple comparisons, the hazard ratios are presented with 99% confidence intervals (CIs). Results: The median follow-up time is 71 months. Hazard ratios comparing treatments from time of initial randomization in terms of DFS, overall survival, and time to distant recurrence are displayed below. With this long term follow-up, adverse events for Let and Tam are consistent with the known safety profile of both agents. A protocol-specified update of the previously-reported comparison of Let x 5 vs. Tam x 5 (i.e., the monotherapy arms, including patients in both the 2-arm and 4-arm options; N=4922) suggests improved survival for patients treated with Let (HR=0.87, 95% CI=0.75-1.02, p=0.08, 76 months median follow-up). In this comparison, about a quarter of the patients in the Tam arm crossed over to Let after 3-5 years of Tam. Conclusion: The sequential treatments did not improve DFS compared with Let alone. Trends support initial use of Let in patients at higher risk of relapse. Patients commenced on Let can be switched to Tam if required. Updated results of the monotherapy comparison suggest superior overall survival with Let compared with Tam. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 13.

Eastern Papua straddles a minor plate boundary between the India plate to the south and the Solomon Sea plate to the north (Johnson & Molnar, 1972). This boundary is defined by a zone of weak, shallow, seismicity (Denham, 1969) and is clearly not particularly active at the present time. Nevertheless there is ample geological evidence for intense tectonic activity and volcanism at various times during the Cenozoic.

explained. The explanatiom is given in terms of the frequency of bubble shedding and the instability of two-phase flow. A physical explanation of the form of the equation is that bubbles break away from the surface as soon as the buoyancy forces are greater tham the surface temsion forces holding them on; and that burm-out occurs when the buoyant acceleration of the bubbles away from the surface is no longer great enough to keep the bubbles clear of their successors. (N.W.R.)