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Purpose. To study the long-term neurotoxicity of chemotherapy in adolescents and young adults treated for bone and soft tissue sarcomas.Patients and Methods. Thirty-six adolescents and young adults (median age 17 years) were examined following chemotherapy for bone and soft tissue sarcomas. Twenty-nine (29/36) had received cisplatin (median 400 mg/m(2)), 15/36 ifosfamide (median 20 g/m(2)), and 12/36 vincristine (median 16 mg). Neurotoxicity was assessed at a median of 8 months (range, 1-54 months) after completion of chemotherapy by clinical examination, nerve conduction studies, audiograms and autonomic function tests. The same nerve conduction studies were carried out in 20 normal volunteers to define normal ranges in this age group.Results. Sixteen patients (44%) had a significant reduction in deep tendon reflexes, and this clinical parameter correlated well with abnormalities detected in nerve conduction studies. Vibration perception threshold (VPT) was raised in 20/36 patients (55%) and this was the most sensitive single test in the assessment of neuropathy. There was a significant correlation between VPT and cumulative cisplatin dose received in mg/m(-2) (r=0.607, p<0.01). Ten of 29 patients (35%) had abnormal nerve conduction studies with a pattern characteristic of sensory axonal neuropathy. No patient complained of auditory symptoms, but minor high tone hearing loss was detected by audiograms in 5/28 patients who had received cisplatin. No patients had symptoms of autonomic neuropathy, but autonomic function tests showed minor abnormalities in 4/22 patients tested, and all had received cisplatin.Conclusions. This study demonstrates significant, although asymptomatic, long-term neurotoxicity of cisplatin in adolescents and young adults receiving chemotherapy for bone and soft tissue sarcomas. Follow-up studies are planned to assess whether these neurological deficits improve with time.

Tumour-secreted vascular endothelial growth factor (VEGF) exerts a number of effects which are important in tumour pathology, including stimulation of angiogenesis and permeabilisation of tumour-associated vasculature. In this study we have examined the possibility that VEGF may also play an autocrine role in tumour growth. Using reverse-transcriptase polymerase chain reaction (RT-PCR), the expression of VEGF was found in 15/15 human tumour cell lines examined, while the VEGF receptor KDR was detected only in three melanoma cell lines (MeWo and A375, both wild type and metastatic variant). Exogenously added VEGF (10ng/ml) was able to stimulate up to 40% increased proliferation of A375 M melanoma cells following a 48-h period of quiescence, suggesting that VEGF may indeed play a role in autocrine, as well as paracrine, stimulation of melanoma growth.

The protein binding of etoposide was studied in vivo in 36 cancer patients receiving etoposide therapy. Free etoposide was separated from plasma using an ultrafiltration method and the etoposide concentrations (free and total) were measured by high-performance liquid chromatography (HPLC). Considerable interpatient variation in the protein binding of etoposide was observed. The protein binding of etoposide varied from 80% to 97% (mean, 93%). Univariate analysis showed a significant inverse correlation between the free fraction of etoposide and serum albumin (r = 0.74), daily dose (r = 0.37) and age (r = -0.34). Multivariate analysis demonstrated that serum albumin and age were independent predictors of the etoposide free fraction. Serum bilirubin showed no correlation with etoposide protein binding. There is wide variation in etoposide protein binding in cancer patients, which is mostly dependent on serum albumin concentration.

Background: The hematopoietic growth factor P-100 is a monocyte-colony stimulating factor purified from human urine and has been reported to reduce neutropenia following chemotherapy. In this study the effect and toxicity of P-100 was evaluated in 26 patients receiving intensive chemotherapy for SCLC., Study Design: Chemotherapy consisted of four 28 day cycles of carboplatin (C) 600 mg/m2 i.v. on day 1 of cycle 1 + 2 and 300 mg/m2 i.v. on day 1 of cycle 3 + 4 and etoposide (E) 120 mg/m2 i.v. on day 1-3 of each cycle. Patients were randomised to receive P-100 for ten days following chemotherapy during either the first or second cycle. 12 Patients received P-100 with the first and 12 with the second cycle. For each group cycles with P-100 were compared to cycles without P-100., Results: P-100 was well tolerated but no significant differences between cycles with and without P-100 were seen in the administered chemotherapy dose, depth and duration of neutropenia, number of blood or platelet transfusions, WHO grade 3-4 infection or requirement for intravenous antibiotics. Of 24 evaluable patients 14 (58.3%) achieved CR and 4 (16.6%) PR. Patients achieving CR received radiotherapy. The median time to progression was 169 days (range 38-995+ days) and the median survival time was 305 days (range 42-1052+ days). Three patients are alive after 2 years (11.5%), 2 without relapse (7.7%). Alopecia, nausea and vomiting occurred in all patients but no treatment related deaths occurred., Conclusion: In this study P-100 did not significantly influence the myelotoxicity associated with carboplatin-etoposide chemotherapy in the treatment of SCLC.

Background: Malignant fibrous histiocytoma of bone (MFHB) is a rare tumour with a 3 year survival of 30%-40% when treated with surgery alone. A small number of patients have previously been treated with pre-operative chemotherapy and responses observed. The aim of the present study was to further determine the response of MFHB to pre-operative chemotherapy., Patients and Methods: A non-randomised study of 18 patients with MFHB. Twelve had localised disease and 6 had pulmonary metastases. In 14 patients pre-operative treatment consisted of methotrexate 8 g/m2 on day 1, ifosfamide 3 g/m2 and doxorubicin 60 mg/m2 on day 10. This regimen was given twice and twice post-operatively. A further 4 patients received cisplatin 100 mg/m2 on day 1 and doxorubicin 25 mg/m2 on days 1, 2, 3. Three cycles were given pre- and post-operatively., Results: 15 patients had surgery after chemotherapy. Tumour necrosis was present in all resection specimens and ranged from 50%-100%. 7/15 had > 90% necrosis. Disease free survival is 82% for those patients with a greater than 2 year follow-up., Conclusion: This study confirms previous reports that MFHB is a chemosensitive tumour. In view of its rarity collaborative trials are needed to establish the optimum drug treatment including drug selection dose and duration.

A weekly, intensive chemotherapy regimen has been used to treat 70 patients with small-cell lung cancer (SCLC). Forty-five patients had limited disease (LD) and 25 extensive disease (ED) with good prognostic features. The regimen consisted of cisplatin 50 mg/m2 intravenously (IV) day 1 and etoposide 75 mg/m2 IV days 1 and 2, alternating weekly with ifosfamide 2 g/m2 IV day 8 and doxorubicin 25 mg/m2 IV day 8, for a total of 12 weeks. Dose modifications were made according to defined hematologic criteria. Responding patients with limited disease subsequently received mediastinal radiotherapy. Overall response to chemotherapy was 91% with a complete response (CR) rate of 50%. Forty-five patients with limited disease (LD) achieved an overall response rate of 91% with a CR rate of 51%, and 25 patients with extensive disease (ED) achieved an overall response rate of 92% with a CR rate of 48%. Median survival for the whole group was 54 weeks (LD, 58 weeks; ED, 42 weeks). Hematologic toxicity was predictable, without the wide fluctuations in WBC count seen in conventional 3-weekly regimens. In all, one quarter of treatment courses were delayed, most frequently because of leukopenia. Dose reductions were required in 63% of cases. The average delivered dose intensity was calculated and shown to be 73% of projected. Nonhematologic toxicity was mild with nausea and vomiting being the most common. This weekly schedule of chemotherapy has proved to be active and well tolerated and is currently being compared with conventional 3-weekly chemotherapy in a randomized study.

We report on two patients with non-Hodgkin's lymphoma (NHL) who developed reversible, short-lived neurological deficit following intrathecal (i.t.) chemotherapy. One patient received i.t. methotrexate for treatment of meningeal disease, and the other received i.t. methotrexate with cytosine arabinoside (ara-C) and hydrocortisone as central nervous system (CNS) prophylaxis. Although transient paresis following i.t. chemotherapy has previously been reported, it has been attributed to the preservatives contained in the diluents. Our two patients, however, received preservative-free solutions.

Mouse monoclonal antibodies reacting with human mammary gland constituents have been generated and characterized in an attempt to raise breast- or breast-cancer-specific antisera. The immunogens used in these studies included fractionated human milk fat globule membrane, the human breast cancer cell line MCF7 and a crude membrane preparation derived from an axillary nodal metastasis from a patient with breast cancer. Of the antibodies obtained, 8 were characterized and found to bind to different structures in the normal breast. The antibody LICR-LON-LC28 recognizes secretory component and binds strongly to normal resting and lactating breast, but only focally to a minority of breast carcinomas. The antibodies LICR-LON-14.1 and 32.2 react strongly with the lactating breast and recognize kappa- and beta-casein, respectively. Caseins are not produced by breast tumors. The antibodies LICR-LON-TW19.5, H10A and 39.8 all react with carbohydrate epitopes and bind heterogeneously to normal resting breast luminal epithelium and cellular subsets of breast carcinomas. LICR-LON-59.2 and 19.2 react with normal breast myoepithelial cells and the basement membrane, respectively. LICR-LON-59.2 is unusual as a myoepithelial marker in that it stains cells in the majority of breast carcinomas. LICR-LON-19.2 shows extensive reactivity to tumor cell lines in culture but has no reactivity with carcinoma cells from breast biopsies.

Chemotherapy with mitomycin C, ifosfamide and cisplatin (MIC) is reported to produce responses of 56% and 69% in inoperable non-small-cell lung cancer (NSCLC). We evaluated the regimen in 45 similar patients who received up to six courses of 6 mg/m2 mitomycin C, 3 g/m2 ifosfamide, and 50 mg/m2 cisplatin every 3 weeks. In all, 18 patients had limited disease (LD) and 27 had extensive disease (ED). A total of 18 patients responded (40%), 9/18 with LD and 9/27 with ED; there were 4 complete responders. The median duration of response was 25 weeks, and median survival was 32 weeks (range, 2-96 weeks). Toxicity was moderate. Nausea and vomiting were controlled with i.v. dexamethasone and high-dose metoclopramide. Other toxicities included myelosuppression and alopecia. This study confirms that MIC is one of the most active regimens for treatment of NSCLC, with acceptable toxicity.

Thirty-nine patients with Hodgkin's disease (HD) with little or no clinical evidence of abdominal disease were investigated by abdominal CT scanning. The results were compared with those of bipedal lymphography and laparotomy and splenectomy. In the assessment of para-aortic lymph nodes, CT scanning and lymphography were of equal efficacy in determining the presence or absence of disease (87 and 79% respectively). Although CT scan could occasionally demonstrate disease in nodes in areas other than the retroperitoneum, its value was limited by its inability to detect involvement of nodes which were not significantly enlarged. CT assessment of splenic HD was unreliable, focal deposits being detected in only one of the 11 spleens involved. In this selected group of patients, CT scan had little advantage over lymphography in the description of disease extent. However, CT scan would appear to be the investigation of choice in patients with suspected abdominal relapse because of the more frequent presence of disease in sites not seen on lymphography. When treatment decisions are dependent on accurate knowledge of distribution of disease, CT scanning cannot yet effectively replace staging laparotomy and splenectomy as the means of achieving this information.

Adriamycin and mitomycin C in combination have been tested in the treatment of advanced breast cancer. In an initial pilot study 11 heavily pretreated patients received mitomycin C alone and 2 (18%) achieved partial responses. Subsequently, 27 patients who had not received prior chemotherapy for advanced breast cancer were treated with adriamycin 40 mg/m2 + mitomycin C 10 mg/m2 i.v. every 3 weeks. Six (22%) achieved complete and 10 (37%) achieved partial responses, giving an objective regression frequency of 59%. The median duration of response was 37 weeks (range 8-55+ weeks).

One hundred and twenty-five patients with progressive advanced carcinoma of the breast were treated with norethisterone acetate 20 mg tds orally after prior hormonal treatment or chemotherapy. Ninety-nine patients are evaluable for response. Sixteen patients (16%) achieved a partial response (median duration 4.5 months), 26 (26%) had stable disease (median duration 3 months) and 57 (58%) developed progressive disease on treatment. Patients who responded to norethisterone acetate had more often responded to prior hormonal or ablative treatment (56% vs 25%) and had received less prior treatment than those who did not respond (p less than 0.05). There was no statistically significant correlation between response and age, menopausal status, disease-free interval, stage at diagnosis, or distribution of disease. Side effects led to cessation of therapy in nine patients (9%).

The purpose of this study was to establish the time course and magnitude of changes in 1,25-dihydroxy-vitamin D receptor activity in rat mammary gland during pregnancy and lactation and to correlate these changes with casein production and alkaline phosphatase activity. Marked increases in both 1,25-dihydroxyvitamin D3 receptor and alkaline phosphatase activities were seen towards the end of pregnancy but the time course of these changes was not synchronous. Receptor activity was first detectable at 11 days of pregnancy with a marked rise in receptor levels at 3 days post-partum. Changes in alkaline phosphatase activity more closely correlated with casein production and peak activity was observed at the time of parturition. We conclude that 1,25-dihydroxyvitamin D3 receptor content increases during pregnancy and lactation and may be involved in maintaining milk calcium concentration.

Temporary but considerable increase in spasticity following myelography using metrizamide at 300 mgs I/ml concentration occurred in 4 patients. In 3 of the patients the diagnosis is uncertain, but it is likely to be some form of degenerative disease involving motor pathways in two of them; the fourth case has cervical spondylotic myelopathy. The spasticity might be related to the anticholinesterase activity of metrizamide or to competitive inhibition of endogenous glucose metabolism by the deoxyglucose component of the metrizamide molecule.

Eighteen cases of adult T-cell lymphoma have been studied with respect to clinical presentation, response to treatment, histology, enzyme histochemistry, immunocytochemistry, and gene rearrangement. Seven cases (39 per cent) presented at extra-nodal sites, and the age range was from 18 to 79. Treatment was with combination chemotherapy in most cases, and 11 of the 18 patients died within the three year follow-up period. The lymphomas were classified morphologically into six types; T-lymphoblastic lymphoma (TLL), angioimmunoblastic lymphadenopathy (AIL)-like T-cell lymphoma, T-zone lymphoma, pleomorphic mixed medium and large cell T-cell lymphoma (PMMLC), pleomorphic large cell T-cell lymphoma (PLC), and monomorphic large cell T-cell lymphoma (MLC). Enzyme histochemistry was found to be of limited value in the identification of T-cell lymphomas. Immunocytochemistry showed a degree of correlation between the immunological profile and morphology, with cases in the PLC and MLC groups showing limited expression of T-cell antigens. Re-arrangement of the beta chain of the T-cell receptor gene was detected in 12 of the 14 cases studied, and all showed germ-line immunoglobulin genes. The study emphasizes the varied morphological and clinical appearances of adult T-cell lymphoma.

In 141 postmenopausal node-positive patients with primary breast cancer, routine biochemical markers (alkaline phosphatase, gamma-glutamyl transpeptidase, carcinoembryonic antigen), and chest x-ray, in combination with history and clinical examination, have been performed at 3 monthly intervals for at least 2 years. Sixty one patients relapsed at a median time of 14 months. The recurrence was detected at routine follow-up in 40 (66%) patients. Of these 40 patients, 26 (65%) presented with symptoms, 11 (28%) were asymptomatic but were found to have relapsed on clinical examination, and only 3 (8%) had their relapse diagnosed on the basis of an abnormal chest x-ray. The remaining 21 patients presented early with symptoms. Therefore symptoms and clinical examination accounted for the detection of relapse in 58 of the 61 (95%) patients. Of the patients who had relapsed, 49% (30 of 61) had one or more abnormal markers/chest x-rays prior to relapse, rising to 79% (48 of 61) at the time of relapse. Of 80 patients with no evidence of recurrence, 36% (29) had no marker abnormality recorded, whereas in 64% (51) one or more abnormalities were found. These results suggest that history and examination are the important procedures in follow-up, and that abnormal markers are not always due to metastatic disease and may be misleading.

Since 1980, 75 patients with small-cell lung cancer (SCLC) have been entered into four consecutive studies of high-dose chemotherapy using autologous bone marrow transplantation (ABMT) to assist haematological recovery. In the first study, 25 patients were treated with cyclophosphamide (160-200 mg/kg) as the sole chemotherapy; in the second (26 patients), the cycle of high-dose cyclophosphamide (with or without 800-1,200 mg/m2 etoposide) was repeated as induction treatment. In the first study, response was high [14 complete responses (CR), 7 partial responses (PR)] but was not increased by repeating the cycle (15 CR, 8 PR), and survival was slightly worse in the second trial. In the third study, 15 patients were treated with doxorubicin, vincristine and etoposide for two cycles and then with 200 mg/kg cyclophosphamide. Although high-dose cyclophosphamide increased the complete response rate, the additional responses were short-lived. In the final study, an attempt was made to increase the initial CR rate by combination chemotherapy using carboplatin (400-600 mg/m2), etoposide (120 mg/m2 x 4) and either high-dose cyclophosphamide (40 mg/kg x 4) or melphalan (140 mg/m2). Although all nine patients responded, none underwent a CR. The long-term survival (up to 7 years) does not appear to be different from that in comparably selected cases treated with conventional chemotherapy.

Two monoclonal antibodies, LICR-LON-32.2 (32.2) and LICR-LON-14.1 (14.1), are described which react with human casein. 32.2 reacts with human beta-casein and 14.1 with human kappa-casein. 32.2 also reacts with rat band 2 casein and bovine beta-casein, but 14.1 appears to be specific for human kappa-casein. These monoclonal antibodies do not cross-react with other milk proteins.

The immunohistochemical analysis of human beta- and kappa-caseins in the human breast, benign breast disease, and breast carcinomas is reported. The monoclonal antibodies LICR-LON-32.2 and LICR-LON-14.1 which react with human beta- and kappa-casein, respectively (Earl, H. M., and McIlhinney, R. A. J. Mol. Immunol., 22: 981-991, 1985) were used for these studies. Human beta- and kappa-caseins were detected in lactating human breast tissue, lactational foci in the resting breast, and heterogeneously in the 16th-week pregnant breast, but not in normal breast tissue. In benign breast disease occasional epithelial cells were demonstrated to synthesize beta- and kappa-caseins, but this finding did not appear to correlate with the hormonal status or previous obstetric histories of the patients. However, similar studies in 45 breast carcinomas with a wide range of estrogen receptor content, demonstrated no detectable beta- or kappa-casein. These results demonstrate that the caseins, which are biochemical markers of mammary gland differentiated function, and have been previously put forward as markers of breast cancer, were not synthesized in the 45 human breast carcinomas studied here, even in tumors with high levels of estrogen receptor protein.