Warfarin treatment of mice bearing autochthonous tumors: effect on spontaneous metastases.

Long-term oral administration of sodium warfarin significantly reduced the incidence of spontaneous metastases in the lungs from 83 percent in controls to 8 percent in treated C57/BL/6N mice. The size and weight of primary tumors in mice treated with warfarin were less than in control mice. Length of survival was unaffected.

Drug treatments for metastasis of the Lewis lung carcinoma: lack of correlation between inhibition of lung metastasis and survival.

The abilities of the Eli Lilly compounds LY150310, LY189332, and LY135305 to inhibit spontaneous metastasis and to increase animal survival were evaluated. These compounds represent widely varied structures and were evaluated because they have been found to inhibit thromboxane synthetase, cyclooxygenase, and thrombin activation, respectively. These biochemical processes have been proposed in the literature as targets for antimetastatic drugs. The purpose of this investigation was twofold: (a) to compare the antimetastatic activities of the Eli Lilly compounds to those of the reference antimetastatic compounds nafazatrom and RA233, and (b) to examine the correlation between inhibition of spontaneous lung metastasis and survival. Spontaneous metastasis of the Lewis lung carcinoma was used to evaluate the antimetastatic activity of the compounds. In this model 5 x 10(5) tumor cells were implanted into the gastrocnemius muscle, the primary tumor was resected on Day 14, and metastatic lung lesions were counted on Day 25. Compounds were administered every 12 h on Days 5 through 19. Nafazatrom, LY150310, LY189332, and LY135305 were found to inhibit spontaneous lung metastasis in a dose-dependent manner. The ED50 values for the respective inhibitions with these compounds were 50, 0.5, 2, and 0.35 mg/kg/day; the respective therapeutic indexes (LD50/ED50) were 7, 180, 255, and 511. To evaluate the effect of nafazatrom, LY150310, LY189332, and LY135305 on animal survival, the compounds were given at maximally antimetastatic doses of 200, 60, 20, and 6 mg/kg/day, respectively. Two dosing schedules were used: (a) on Days 5 through 19 and (b) on Day 5 until death. Neither the median survival times nor the numbers of long-term survivors were significantly changed with any of the compounds at any dosing schedule. RA233, given to a maximally tolerated dose of 200 mg/kg/day on Day 5 until death, did not inhibit lung metastasis and did not increase median survival time. Postmortem examination of animals dosed with nafazatrom, LY150310, LY189332, and LY135305 showed complete inhibition in lung lesions and the appearance of lesions in the liver, kidney, spleen, and brain. The results of this investigation show that the effect a compound has on the number of metastatic lesions in a target organ may not be predictive of its effect on survival. To successfully translate laboratory data into the clinic, survival should be considered as a predictor of a compound's potential clinical utility.

Early metastatic cancer of unknown primary origin at presentation. A clinical study of 302 consecutive autopsied patients.

We studied 302 consecutive autopsied patients who presented with carcinoma of unknown primary origin. The most frequent metastatic sites were the nodes, lung, and bone. The primary site was identified while patients were alive in 27% and at autopsy in 57%; the site remained unidentified in 16%. The pancreas (26.5%), lung (17.2%), kidney (4.6%), and colorectum (3.6%) were the most frequent primary sites, but the reliability of diagnostic tests used in the search for this site was disappointing. Survival was identical in patients whose primary site was discovered while alive, at autopsy, or remained unknown. The number of metastases at presentation was the major prognostic factor. Analysis of autopsy data demonstrated that patients with carcinoma of unknown primary origin pursue a different course than expected when the primary site is the first manifestation of the disease. On the basis of these results and the results of other modern series, we suggest an approach consisting of a limited initial workup but with greater emphasis on modern histochemistry studies and immunohistopathologic and other kinetic and morphologic parameters to understand the patient tumor characteristics better and base the clinical management on an individual basis.

Morbidity of emergency operations in patients with metastatic cancer receiving chemotherapy.

During a 5-year period, 21 patients with metastatic cancer receiving chemotherapy for periods ranging from 2 months to 5 years have required emergency abdominal operations. Symptoms in 15 indicated perforated viscus, whereas six developed massive, unremitting hemorrhage. All were operated upon with the sole intent of correcting the life-threatening problem, and every attempt was made to maintain or normalize physiologic parameters postoperatively. Despite this, 51 major complications occurred in 19 patients, and 17 died in the immediate postoperative period, 11 following multiple systems failure. Two died within 1 month of transfer to another hospital nearer home. A single patient lived 5 months at a nursing facility. The only survivor is living in a complete state of remission 9 months after discharge. No distinguishing features that might preoperatively predict which patient might survive emergency operation were found. The monetary cost of returning the sole survivor to society was over $500,000, discounting the emotional expenditure required of patients, families, and hospital staff. The dilemma the surgeon faces in making therapeutic decisions regarding such patients requires careful weighing of realities and the willingness to assume responsibility for the best possible choice in order to free the patient and family from agonizing deliberations.

Metastatic patterns in soft-tissue sarcomas.

In 242 patients with recurrent soft-tissue sarcomas, the most common sites of initial recurrence were the primary site in 47.5% of patients and the lungs in 38% of patients. Further recurrences in the course of the disease concerned the lungs, bones, liver, and brain. Total survival and survival after recurrence were influenced by the histologic type, which also affected the site of recurrence. In the management of local recurrence, a five-year disease-free survival rate of 38% was achieved with surgical treatment, while radiation or chemotherapy alone was ineffective. Local recurrences resulted in significantly higher survival rates than those involving other organs. The disease-free interval was a significant prognostic indicator of subsequent survival in the whole group of patients and among those with local recurrence.

Metastatic choroidal melanoma.

We studied the metastatic pattern of 41 patients initially referred with a primary choroidal melanoma who later developed widespread disease. In the order of frequency, the most common sites of metastatic involvement were the liver (56%), subcutaneous tissue (36.5%), and bone (7%). Whereas the median interval between enucleation and the onset of metastatic disease was approximately four years, in rare cases, metastases were diagnosed concurrently with a primary choroidal melanoma. Since patients with choroidal melanomas usually survive less than one year after the development of widespread disease, a metastatic examination should be done in all patients with pigmented choroidal tumors both before and after ocular therapy. From the data obtained in this and other studies on metastatic melanoma, a reasonable basic metastatic examination for choroidal melanoma patients should include a serum lactic dehydrogenase, a serum alkaline phosphatase, a routine chest X-ray, and a general physical examination.

Role of endocrine function tests in the evaluation of transsphenoidal hypophysectomy for advanced breast cancer.

Forty-three women underwent transsphenoidal hypophysectomy for metastatic breast cancer. Endocrine tests (luteinizing hormone, follicle-stimulating hormone, thyrotropin, prolactin and growth hormone) were done in 28 patients to evaluate the completeness of the procedure. Response of the metastatic breast cancer and duration of survival after hypophysectomy were determined and statistically compared with the posthypophysectomy hormone levels. Only one patient had an endocrinologically complete hypophysectomy, but the objective remission rate (32 percent) is comparable to the 30 to 40 percent objective remission rate reported in other studies that claim to have achieved complete hypophysectomy. No statistically significant associations were found between the levels of the hormones measured and the type of response (objective, subjective or none) to hypophysectomy. However, objective responders survived longer than nonresponders (p = 0.01). When analyzing the associations of the various hormone levels with the duration of survival after hypophysectomy, a positive correlation (p less than 0.05) of peak thyrotropin levels with duration of survival was found. Our data indicate that the clinical benefit advanced breast cancer patients received from an endocrinologically incomplete hypophysectomy is probably as great as that received from an endocrinologically complete hypophysectomy. It appears that a nonspecific disturbance of the hormonal milieu may adversely affect the growth of breast cancer. More studies are needed to elucidate the nature of the endocrine disturbance produced by hypophysectomy and its effects on hormone-sensitive tumors.

Evaluation of the role of surgery in 130 patients with neuroblastoma.

The role of surgery for children with neuroblastoma was evaluated by using a recently proposed TNM staging system. One-hundred thirty patients were retrospectively assigned a TNM clinical stage (CS) preoperatively and a pathologic stage (PS) postoperatively. Patients with CS 4 were separated into CS 4A and CS 4B according to their age and pattern of metastases. Patient survival was analyzed according to CS, age, location of primary, and PS. Actuarial survival of patients was as follows: CS 1, 100%; CS 2, 82%; CS 3, 63%; CS 4A, 50%; and CS 4B, 5%. For all stages, patients younger than 1 year old survived longer than those older than 1 year (72% v 32%). Prognosis for CS 1 was the same regardless of age. For CS 2 and CS 3, patients younger than 1 year old lived longer. CS 4A had better survival than CS 4B. Survival by site was 100% for cervical, 62% for mediastinal, 45% for pelvic, and 36% for retroperitoneal primaries. The role of surgery was evaluated by analyzing survival according to the postoperative PS. PS 1-2-3 A were regarded as satisfactory resections since all macroscopic tumor was removed. PS 3B as a debulking procedure, and PS 3C as an unresectable lesion which was biopsied. Patients with nonmetastatic disease (CS 1-3) with PS 1 and PS 2 disease had a 100% survival rate; PS 3A, 93%; PS 3B, 58%; and PS 3C, 21%. This proves the value of total resection in nonmetastatic disease. The role of surgery could also be proven in metastatic disease.(ABSTRACT TRUNCATED AT 250 WORDS)

[The efficacy of radiohypophysectomy with yttrium 90 in metastatic breast cancer (author's transl)]. / Erfahrungen mit der Hypophysenausschaltung mit Yttrium 90 beim metastasierenden Mammakarzinom an der II. Chirurgischen Universitätsklinik.

Radiohypophysectomy in 176 women with metastatic breast cancer, treated over the past 20 years, did not prolong life, but relieved pain in almost half of the patients. This procedure can be carried out quickly and without risk even in severly debilitated patients.

[Surgery of 19 bilateral simultaneous pulmonary metastases]. / A propos du traitement chirurgical de 19 métastases pulmonaires bilatérales et simultanées.

19 patients with bilateral simultaneous pulmonary metastases were operated on between 1954 and april 1976 at the Marie-Lannelongue surgical centre. Sarcomas were twice as common as carcinomas. In 10 cases the thoracotomy was only unilateral, either because thoracotomy was not attempted on the other side owing to the diffuse nature of the lesions (8 cases) or because prior chemotherapy had permitted complete reduction of the metastases on the opposite side (2 cases). This thoracotomy remained exploratory in 47 p. cent of cases, radical removal of all the tumour nodules was possible in 53 p. cent of cases (10 patients). Peripheral resections of the lesions were the rule. But in 4 cases, lobectomy was carried out on one side. 7 of the 9 bilateral operations were performed during the same stage. There were no operative deaths. The late results are encouraging considering the number of sarcomas in which the prognosis is usually poor. Bilateral lesions are thus not an absolute contra-indication, provided one remains within reasonable anatomical and functional limits, in the fields of well-conducted anti-cancer strategy.