Time dependent protection of amifostine from renal and hematopoietic cisplatin induced toxicity.

Efficacy of chemotherapy may be maximized and its toxicity can be minimized if drugs would be administered at specified daily times. The present study was aimed to examine if the protection of amifostine against cisplatin toxicity is time dependent. Amifostine is an organic thiophosphate that protects selectively normal tissues, but not tumors, against the cytotoxicity of DNA binding chemotherapeutic agents such as cisplatin. ICR male mice which were entrained to Light:Dark (L:D) 14:10 were injected (intrapritoneal bolus) for 5 consecutive days with either: cisplatin, cisplatin plus amifostine (administered 30 minutes prior to cisplatin). Injections were given at either 08:00, 13:00, 20:00 or 01:00. Five days later, on day 10, each set of mice was sacrificed (at the same hour corresponds to the injection hour), blood count, blood creatinine and blood urea nitrogen (BUN) were assayed. Cisplatin treated mice exhibited nephrotoxicity, as indicated by increased blood urea nitrogen values and by high blood urea nitrogen to creatinine ratios, as well as myelotoxicity that was indicated by low levels of hemoglobin and platelets. Co-administration of amifostine-cisplatin reversed both, the nephrotoxicity of cisplatin, and its myelosuppressive effects. For BUN, hemoglobin and platelets, maximal protections were observed at 08:00, (p <0.05, p <0.01 and p <0.01 respectively). For BUN/Cr ratio (p <0.05), maximal protections was observed at 13:00. These findings show that amifostine exhibits time dependent protection against cisplatin toxicity and thus it is recommended to use the protector when treatments are given during morning hours. The results also further validate the notion that chronochemotherapy is advantageous at least in reducing drug toxicity and thus should be integrated in the design of clinical protocols.

Fluorescence polarisation changes in lymphocyte cytoplasm as a diagnostic test for breast carcinoma.

Lymphocytic cytoplasm from individuals with malignant disease, and from those without, differ in such a way as to be diagnostic both of malignancy generally and of specific types of cancer. Mitogenic stimulation of lymphocytes by phytohaemagglutinin (PHA) and antigenic stimulation by encephalitogenic factor (EF) and certain specific tumour-associated antigens, provokes changes in the structure of the cytoplasmic matrix (SCM) which are detectable upon fluorescence polarisation. The degree of change is quantifiable both by calculating the polarisation ration (PR, polarisation before and after stimulation) and the relative ratio (RRSCM, the ratio between the polarisation obtained after exposure to EF [PEF] and to the polarisation measured after exposure to PHA [PPHA]). A new tumour-associated antigen specific for breast cancer, CaBr, was tested for its diagnostic efficacy in comparison with that of EF, by prospectively testing blood samples from 138 consecutive women with suspicious breast masses. The previously known discriminatory power (sensitivity 60.7% and specificity 90.7%) of the polarisation-derived RRSCM was reconfirmed. However, the RR'SCM (the new ratio using CaBr instead of EF), was significantly more sensitive (77.4%; P < 0.01) and specific (94.4%) than the RRSCM in detecting breast cancers. The polarisation changes in the cytoplasmic matrix after stimulation by CaBr alone suggest the best discriminatory power (sensitivity 90.5% and specificity 94.4%) between cancerous and non-cancerous patients.

A low-dose adrenocorticotropin test reveals impaired adrenal function in cancer patients receiving megestrol acetate therapy.

Megestrol acetate (MA) has glucocorticoid activity and can induce significant secondary adrenal suppression. We designed this study to determine the extent of adrenal insufficiency in cancer patients receiving MA by utilising a sensitive low-dose adrenocorticotropin (ACTH) stimulation test. Adrenal function was assessed by a low-dose (0.625 microg) ACTH (1-24) stimulation test in 30 patients receiving MA for metastatic cancer. 10 of the patients who failed this test underwent a standard (250 microg) test on another day. Adrenal function was also evaluated in 15 of the patients by measuring the excretion of free cortisol in 24-h urine samples. Peak serum cortisol levels following stimulation with low-dose (0.625 microg) ACTH (1-24) were <18 microg/dl in 16 of 30 (53%) patients, of whom 9 had a basal serum cortisol level of <5 microg/dl. Five of 16 poor responders to the low-dose test showed normal stimulation with the standard (250 microg) ACTH (1-24) test. Thus, adrenal insufficiency would fail to be detected by the standard high dose test in these patients. Patients who failed the low-dose ACTH (1-24) test had lower 24-h urinary free cortisol excretion (8.7+/-10.3 microg/24 h) than normal responders (35+/-12.7 microg/24 h). Impaired adrenal function is common in cancer patients receiving MA. The low-dose ACTH (1-24) test is apparently capable of revealing adrenal insufficiency undetected by the standard high-dose ACTH test. Patients receiving MA might have inadequate adrenal function during episodes of infection or after withdrawal of MA therapy and this may require prompt corticosteroid treatment.

Hepatic arterial chemotherapy in metastatic colorectal patients.

Hepatic metastases are a major cause of morbidity and mortality for patients with colorectal cancer (CRC). The rationale for hepatic arterial chemotherapy has both an anatomical and pharmacological basis. Several randomized clinical studies of fluoropyrimidine showed higher response rates in all trials when the drug was given as an hepatic arterial infusion (HAI) versus systemic administration. However, the studies did not accurately define survival for the following reasons: (1) some allowed a crossover; (2) some were too small; and (3) some used inadequate systemic chemotherapy. Patients who have failed to respond to previous systemic chemotherapy have an approximately 50% response rate with HAI treatment. Hepatic toxicity, especially biliary sclerosis, is the dose-limiting toxicity, occurring in 6% to 25% of patients. Adding dexamethasone to HAI fluoropyrimidine decreases the hepatobiliary toxicity. The therapeutic benefit of HAI in one study was also demonstrated by an increased time with normal quality of life. To truly define the role of regional therapy in patients with CRC confined to the liver, the current Cancer and Leukemia Group B (CALGB) study is randomizing patients to HAI versus systemic therapy without a crossover to demonstrate if HAI improves survival and/or quality of life in addition to response rates.

Time dependency of hematopoietic growth factor coupled to chronotoxicity of carboplatin.

A growing body of data suggests that cancer therapy may be improved and toxicity reduced by administration of antineoplastic agents and cytokines at carefully selected times of the day. The time-dependent effects of each of the drugs have been documented, but not their mutual time dependencies. In the present studies we sought to determine the best time for granulocyte colony-stimulating factor (G-CSF) administration after carboplatin treatment. Carboplatin was injected in different groups of ICR mice at four different circadian stages for 5 consecutive days. Mice were synchronized with an alternation of 12 h of light (from 6:00 a.m. to 6:00 p.m.) and 12 h of darkness. After the last injection, peripheral WBCs of three mice from each group were counted every 4 h over a 24-h period. Bone marrow toxicity was estimated with the mean 24-h WBC count. The most severe leukopenia occurred in the group injected at 3:00 p.m. - 9 h after light onset. The second set of experiments evaluated the time-dependent effect of G-CSF when singly injected or given after carboplatin injections for 5 days only at 3:00 p.m. G-CSF was injected into various groups on days 8 and 9 at the same four different circadian stages. On the 10th day after the first injection, peripheral WBCs of three mice from each group were counted every 4 h over a 24-h period. Time-dependent effects were observed when G-CSF was injected as a single agent. When G-CSF was given at various times to the group with the most severe carboplatin-induced leukopenia, peripheral WBC count recovery was monitored at all injection times; it reached its highest level (exceeding even that of the control) when G-CSF was injected at 3:00 a.m. Dosing times of both chemotherapy and growth factor are relevant for optimization of carboplatin's hematologic tolerability.

Bone scan and bone biopsy in the detection of skeletal metastases.

This study provides the first quantitative indication of the limits of sensitivity of a bone scan with technetium (99Tc-MDP) in detecting skeletal metastases and thereby also helps to explain the fact that bone scans may be negative when metastases are present in the bone marrow. Since 99Tc-MDP remains the least noxious and most widely used isotope for bone scanning, these results have direct clinical relevance in the evaluation of patients with solid tumors and possible metastatic spread.

The effect of chlorpromazine and haloperidol on DNA transcription.

The ability of human cells to repair DNA damage can be indirectly assessed by measuring transcriptional activity relating to active genes, a process referred to as RNA synthesis. This study was carried out to investigate the effects of chlorpromazine and haloperidol on the transcriptional activity of actively transcribed genes as an expression of DNA damage and repair. Three cultured human fibroblast lines were used: two were "normal" in previous RNA recovery testings and one was abnormally sensitive to UV irradiation. In the "normal" line, recovery of RNA synthesis occurred within 1 hour of UV after exposure to three concentrations of chlorpromazine (125, 250 and 500 ng/ml) and haloperidol (5, 10 and 20 ng/ml). Following treatment with the same concentrations of chlorpromazine and haloperidol, the UV-sensitive cell line showed markedly depressed recovery of RNA synthesis at 1 and 4 hours. Complete recovery was not reached even after 24 hours. Our results suggest that neuroleptics widely used in clinical practice adversely affect cell lines that are sensitive to DNA-damaging agents.

Strontium-89 (89Sr) analgesia for rare thymic carcinoid tumor with bony metastases.

The authors report the cases of two patients in whom strontium-89 (89Sr) was used to relieve diffuse metastatic bone pain. The type of cancer involved, thymic carcinoid tumor, is itself rare and the risk of its metastasizing to the bone is very low. Both patients showed a measure of response to treatment, suggesting that this analgesic method has value for some patients. The marked benefit of one patient for a total of 9 months was attributable to two 89Sr injections, whereas the other patient improved for only 5 weeks after one injection.

Clear cell chondrosarcoma of rib following repetitive low-impact trauma.

A case of clear cell chondrosarcoma of the rib in a 30-year-old man is described. The tumor developed at the site of repetitive low-impact trauma (on the arm of a wheelchair) over a period of 24 years. An association between chondrosarcoma and external trauma has not been previously reported. Chondrosarcoma has been described in previously irradiated bone and in Paget's disease. In both these examples there is an increase in new bone formation associated with necrosis of bone and increased resorption of bone, respectively. A possible mechanism in our case is increased new bone formation elicited by repeated microfractures of trabeculae of rib bone.

Kaposi's sarcoma on a lymphedematous arm after mastectomy.

Two patients with Kaposi's sarcoma developing in an area of lymphedematous arm postmastectomy are reported. The Kaposi's sarcoma occurred after latent periods of 26 and 7 years following radical and modified-radical mastectomy, respectively, in the edematous tissue of the ipsilateral arm. The cutaneous nodules were purple in color and ranged in size from a few millimeters to > 1 cm in diameter. The results of routine laboratory tests were all within normal limits. Human immunodeficiency virus (HIV) antibody and cytomegalovirus (CMV) antigen, using enzyme-linked immunosorbent assay (ELISA), were negative.

Phase II study of carboplatin and etoposide as salvage treatment for patients with metastatic breast cancer.

A phase II study of carboplatin and etoposide as salvage polychemotherapy in metastatic, infiltrating breast carcinoma was carried out with 25 multiply pretreated patients. Six of 25 patients (24%) had a partial response that lasted an average of 3.5 months; of the six responders, four had undergone either four or five previous chemotherapeutic treatments. Eight of 25 patients (32%) had stable disease, and 11 (44%) manifested disease progression. The median survival from time of entry to the salvage protocol was 8 months. There were treatment responses in lung, chest wall, liver, and skeleton. The most common side effects were leukopenia (68% of 25 patients), thrombocytopenia (56%), anemia (40%), fever (28%), and weakness (16%). Carboplatin combined with etoposide may be an effective and tolerable salvage regimen in advanced breast cancer.

Spontaneous regression of retroperitoneal metastases from a primary pure anaplastic seminoma: a case report.

Spontaneous regression of pure seminoma metastases is a rare phenomenon, with only a few cases reported to date. To the best of our knowledge, this is the first report of regression of anaplastic pure seminoma metastases located in the retroperitoneum. We present a 27-year-old man, a marihuana smoker, with metastatic pure anaplastic seminoma in the high retroperitoneal lymph nodes. After orchiectomy, his metastases regressed with no medication. Several mechanisms are suggested to explain this phenomenon, which still remains elusive.

CMF (cyclophosphamide, methotrexate, 5-fluorouracil) versus cnf (cyclophosphamide, mitoxantrone, 5-fluorouracil) as adjuvant chemotherapy for stage II lymph-node positive breast cancer: a phase III randomized multicenter study.

A multicenter phase III randomized study compared the efficacies of two adjuvant polychemotherapeutic regimens in 145 patients with stage II node-positive breast cancer. The standard chemotherapy combination, CMF (cyclophosphamide, methotrexate, 5-fluorouracil), was administered to 77 women. The experimental protocol, CNF (cyclophosphamide, mitoxantrone, 5-FU), in which mitoxantrone (Novantrone) replaced methotrexate, was given to 68 patients. Follow-up of the 145 patients by six participating hospitals showed no statistically significant difference (p = 0.6) between the two treatment regimens during a median follow-up of 4.5 years in terms of overall survival. There was, however, a significant advantage (p = 0.04) in the disease-free survival for those receiving mitoxantrone (mean survival 4.4 years for CNF versus 2.7 years for CMF). Toxic side effects associated with CNF (particularly alopecia and myelotoxicity) were relatively more frequent but acceptable and did not lead to dose reduction. In light of its association with improved disease-free survival in this study, larger studies should be undertaken on the role of mitoxantrone as adjuvant treatment in stage II breast cancer.

Small cell carcinoma of the gallbladder: clinical course and response to chemotherapy.

Small cell carcinoma of the gall bladder is a rare tumor. The neoplasm is highly lethal, metastasizes early, and may cause death shortly after diagnosis. An oat cell carcinoma of the gallbladder metastatic to the liver and adjacent lymph nodes is described in a 60-year-old male. Partial cholecystectomy was performed followed by aggressive chemotherapy with etoposide and cisplatinum. An 80% reduction in the size of the unexcised tumor was noted over a period of 6 months. The partial response and the relatively long survival of the patient suggest the use of the above protocol for these rare cases.

Primary spinal epidural non-Hodgkin's lymphoma. The contribution of nuclear magnetic resonance imaging, therapeutic approach and review of the literature.

Primary spinal epidural lymphoma (Stage I) is diagnosed predominantly late after a long prodromal phase of local back pain resulting in spinal cord compression. The use of CT and NMR images in the early stage of investigation and their analysis may help to diagnose these cases prior to the appearance of neurologic deficit. We report on 2 patients who presented with prolonged localized back pain with sudden symptoms of spinal cord compression. CAT scan and NMR imaging demonstrated the characteristic appearance of lymphoma. Decompressive laminectomy supported the diagnosis. Radiotherapy treatment to the region of the non-Hodgkin's lymphoma resulted in complete resolution. Thereafter, systemic chemotherapy with CHOP achieved a good response.

Extrapulmonary neoplasms among asbestos-exposed power plant workers.

Three cases of fatal extrapulmonary neoplasms among asbestos-exposed power plant workers are described. These cases add to the growing evidence for a causal relationship between asbestos exposures and extrapulmonary neoplasms.

Safety and efficacy of 188-rhenium-labeled antibody to melanin in patients with metastatic melanoma.

There is a need for effective "broad spectrum" therapies for metastatic melanoma which would be suitable for all patients. The objectives of Phase Ia/Ib studies were to evaluate the safety, pharmacokinetics, dosimetry, and antitumor activity of (188)Re-6D2, a 188-Rhenium-labeled antibody to melanin. Stage IIIC/IV metastatic melanoma (MM) patients who failed standard therapies were enrolled in both studies. In Phase Ia, 10 mCi (188)Re-6D2 were given while unlabeled antibody preload was escalated. In Phase Ib, the dose of (188)Re-6D2 was escalated to 54 mCi. SPECT/CT revealed (188)Re-6D2 uptake in melanoma metastases. The mean effective half-life of (188)Re-6D2 was 12.4 h. Transient HAMA was observed in 9 patients. Six patients met the RECIST criteria for stable disease at 6 weeks. Two patients had durable disease stabilization for 14 weeks and one for 22 weeks. Median overall survival was 13 months with no dose-limiting toxicities. The data demonstrate that (188)Re-6D2 was well tolerated, localized in melanoma metastases, and had antitumor activity, thus warranting its further investigation in patients with metastatic melanoma.

Endometrioid carcinoma of the ovary presenting as primary carcinoma of the breast. A case report and review of the literature.

A case is presented of endometrioid carcinoma of the ovary, metastasizing to the breast in a 63-year old woman. Differentiation of metastatic cancer to the breast for primary breast carcinoma and discovering the primary tumor site are rather important for treatment and prognosis. Lumpectomy, followed by panhysterectomy, was performed and six courses of cisplatinum and cyclophosphamide were given. No signs of recurrence or metastasis are apparent 16 months after the discovery of the breast lesion.