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Patients:Soft tissue sarcomas are uncommon malignancies with few therapeutic options for recurrent or metastatic disease. Dolastatin-10 (Dol-10) is a pentapeptide anti-microtubule agent that binds to tubulin sites distinct from vinca alkaloids. Based on the novel mechanism of action, limited activity of other anti-microtubular agents, and anti-neoplastic activity in pre-clinical screening of Dol-10, this multi-institutional phase II study was conducted to determine the objective response rate of Dol-10 in recurrent or metastatic soft tissue sarcomas that had not been treated with chemotherapy outside of the adjuvant setting. Methods: Dol-10 was given intravenously at a dose of 400 μg/m2 and repeated every 21 days. Toxicities were assessed using the Common Toxicity Criteria (version 2.0). Radiographic studies and tumor measurements were repeated every two cycles to assess response [Miller AB, et al. Cancer 1981; 47(1): 207]. Results: Dol-10 was associated with hematological toxicity and with some vascular toxicities. There was no significant gastrointestinal, hepatic or renal toxicity. There was one death on study due to respiratory failure. There were no objective responses in 12 patients treated with Dol-10. Discussion: Based on this phase II trial, further study of Dol-10 on this schedule is not recommended in advanced or metastatic soft tissue sarcomas.

Patients:Soft tissue sarcomas are uncommon malignancies with few therapeutic options for recurrent or metastatic disease. Dolastatin-10 (Dol-10) is a pentapeptide anti-microtubule agent that binds to tubulin sites distinct from vinca alkaloids. Based on the novel mechanism of action, limited activity of other anti-microtubular agents, and anti-neoplastic activity in pre-clinical screening of Dol-10, this multi-institutional phase II study was conducted to determine the objective response rate of Dol-10 in recurrent or metastatic soft tissue sarcomas that had not been treated with chemotherapy outside of the adjuvant setting.Methods:Dol-10 was given intravenously at a dose of 400 μg/m2and repeated every 21 days. Toxicities were assessed using the Common Toxicity Criteria (version 2.0). Radiographic studies and tumor measurements were repeated every two cycles to assess response [Miller AB, et al.Cancer1981; 47(1): 207].Results:Dol-10 was associated with hematological toxicity and with some vascular toxicities. There was no significant gastrointestinal, hepatic or renal toxicity. There was one death on study due to respiratory failure. There were no objective responses in 12 patients treated with Dol-10.Discussion:Based on this phase II trial, further study of Dol-10 on this schedule is not recommended in advanced or metastatic soft tissue sarcomas.

A previous Southwest Oncology Group study demonstrated a 30% response rate with the combination of cisplatin and mitotane in the treatment of patients with metastatic adrenocortical carcinoma. Several case reports suggested that the combination of etoposide and cisplatin may be an active regimen in this disease. Because of these reports of potential activity, the authors conducted a Phase II trial evaluating the combination of etoposide and cisplatin. Due to the lack of data regarding the objective response rates to mitotane, the authors planned to evaluate the response rate to mitotane after disease progression on etoposide and cisplatin in patients with no prior mitotane therapy.Patients with advanced, unresectable, or metastatic adrenocortical carcinoma with objectively measurable disease or biochemical abnormalities received cisplatin, 50 mg/m(2), intravenously on Days 1 and 2, and etoposide, 100 mg/m(2), on Days 1, 2, and 3. Cycles were repeated every 21 days. At the time of disease progression, patients who had not previously received mitotane received 1000 mg orally 4 times a day along with cortisone acetate and fludrocortisone acetate.Of the 47 patients entered onto the study, 45 were eligible. Nine patients had received mitotane previously and 36 had not. Objective responses were noted in 11% of patients (5 of 45 patients) (95% confidence interval, 3.7-24%). The median survival was 10 months. The most common toxic effects were hematologic, gastrointestinal, and neurologic. Only 16 patients with no prior mitotane therapy went on to receive mitotane at the time of disease progression. An objective response was noted in 13% of patients (2 of 16 patients). The most common toxic effects were edema and gastrointestinal effects.The current study demonstrates that the combination of cisplatin and etoposide has minimal activity in advanced and metastatic adrenocortical carcinoma and other treatment strategies are warranted.

Appropriate adjuvant chemotherapy for resected head and neck cancer patients has yet to be defined. Multiple trials have noted trends toward improved disease-free survival and local control. The Southwest Oncology Group undertook a feasibility trial of postoperative cisplatin and radiotherapy followed by three cycles of cisplatin and 5-fluorouracil.Patients with resected stage III or IV head and neck cancer received cisplatin, 100 mg/m2, on days 1, 22, and 43 of radiotherapy. This therapy was followed by three cycles of cisplatin, 100 mg/m2 or last tolerated dose, and 5-fluorouracil, 1000 mg/m2, on days 1 to 4 every 21 days.Seventy-two patients from 22 institutions were registered; 68 were evaluable. Sixty-eight patients received radiotherapy. Only 25 of 68 patients (36.7%) were able to complete all six cycles of chemotherapy. Forty-three of 68 patients (63%) completed all three cycles with radiotherapy. Toxicities were tolerable. One toxic death occurred.It is not feasible to deliver six cycles of chemotherapy postoperatively in the sequence described. Compliance issues need further exploration to define effective adjuvant chemotherapy for head and neck patients.

This phase II multi-institutional trial of the Southwest Oncology Group was designed to evaluate the efficacy and toxicity of docetaxel in chemotherapy-naive patients with extensive-stage small cell lung cancer.Forty-seven patients with extensive-stage small cell lung cancer were entered onto the study. Treatment consisted of docetaxel, 100 mg/m2, as a 1-hour intravenous infusion repeated every 21 days, with protocol-specified dose reductions for toxicity.Forty-three patients were eligible. A total of 158 cycles of docetaxel were administered (median, three cycles; range, one to nine). Ten patients (23%) (95% confidence interval, 12% to 39%) achieved partial responses. The median progression-free and overall survivals were 3 and 9 months, respectively. Therapy was generally well tolerated. Grade 4 neutropenia occurred in 58% of patients. Febrile neutropenia developed in five patients (12%), and infection was documented in 14% of patients. There was one treatment-related death caused by pneumonia in a patient who had developed bilateral pneumothoraces. Other toxicities (grade 3/4) included malaise, fatigue, and lethargy (21%); nausea (19%); stomatitis (14%); edema (9%); and sensory neuropathy (9%).Docetaxel, at a dose of 100 mg/m2, is an active agent in the treatment of small cell lung cancer. Reversible neutropenia is the most common toxicity associated with this treatment. The overall survival (9 months) with this agent is comparable to that reported with other new chemotherapeutic agents in small cell lung cancer and warrants additional evaluation of docetaxel in combination therapy.

Interferon alfa has modest but definite activity in the treatment of metastatic melanoma and is the only agent currently available for adjuvant therapy of high-risk resected disease. A variety of retinoic acid derivatives have been shown to be synergistic with interferon alfa in vitro and in vivo, with nonoverlapping toxicities. If promising combinations of interferon alfa and retinoids could be developed for melanoma patients, they would have clinical relevance for the treatment of advanced as well as localized disease.To determine the efficacy and toxicity of a combination of interferon alfa-2a and all-trans-retinoic acid in patients with measurable metastatic melanoma, the South-west Oncology Group conducted a phase II clinical trial.Fifty-seven patients with measurable metastatic melanoma (American Joint Committee on Cancer stage IV) were entered; five patients were unevaluable. Treatment consisted of oral all-trans-retinoic acid (37.5 to 75 mg/m2 orally twice daily for 21 days followed by 7 days' rest) plus subcutaneously administered interferon alfa-2a (6 MU/m2 three times a week).Two complete and three partial responses were observed among 52 evaluable patients, for an objective response rate of 10% (95% confidence interval 3% to 21%). Responses were seen only in patients with pulmonary, nodal, or subcutaneous metastases, and lasted from 4 to 23+ months. Median survival for the 52 patients was 8 months. Side effects were tolerable but significant, with one case of grade IV anemia and 92% of patients experiencing at least grade II toxicity. Flu-like symptoms were the most commonly reported side effects. There was one case of grade III hyperlipidemia.The combination of recombinant human interferon alfa-2a with all-trans-retinoic acid did not result in a greater percentage of objective responses or a longer overall survival than that associated with interferon alfa alone. This combination cannot be recommended for further evaluation in melanoma in either the advanced disease or the adjuvant settings.

Hereditary hemochromatosis, a common autosomal recessive trait caused by mutations in the HLA-H gene, is often diagnosed by the pathologist at the time of histologic examination. Unfortunately, histologic parameters alone do not differentiate between hereditary hemochromatosis and other causes of iron overload. We performed a retrospective study to determine the frequency of familial hemochromatosis in patients diagnosed with he mochromatosis by abnormal liver histology.DNA was isolated from paraffin-embedded tissue sections from 15 patients and used in a polymerase chain reaction-based assay in which we tested for the C282Y and H63D mutations. We found that in this group of patients, 5 (33%) were homozygous for the common C282Y genetic mutation, 3 (20%) were heterozygous, and 7 (47%) were normal.Our study shows that the molecular assay is the gold standard for the diagnosis of hereditary hemochromatosis. The case study also illustrates that a definitive diagnosis of familial hemochromatosis has significant counseling implications allowing for accurate family studies.

Ewing's sarcomas, osteosarcomas, and rhabdomyosarcomas are significantly more responsive to chemotherapy than other sarcomas. Adjuvant chemotherapy is used routinely based on data from randomized trials. Although a percentage of children with locally advanced or metastatic tumors remain curable, few data exist regarding the tumor's natural history or response and survival in adults.This Phase II study evaluated doxorubicin, dacarbazine, ifosfamide, and mesna (MAID) in adults with inoperable or metastatic Ewing's sarcoma, rhabdomyosarcoma, or osteosarcoma.Between 1987-1991, 81 patients were entered; 69 patients were eligible. One patient died of neutropenic infection. Ten patients (14%) responded completely and 34 patients (49%) had a complete or partial response. Response rates were significantly higher for patients with Ewing's sarcoma and rhabdomyosarcoma than for those with osteosarcoma (77%, 64%, and 26%, respectively; P0.005). Although there were no significant differences in progression free survival by histology, survival for patients with Ewing's sarcoma was significantly longer than for patients with osteosarcoma (P = 0.004.) At the time of last follow-up, 7 patients (10%) were alive without progression: 3 with Ewing's sarcoma, 1 with osteosarcoma, and 3 with rhabdomyosarcoma.MAID chemotherapy is an active regimen in adults with advanced or metastatic Ewing's sarcoma and rhabdomyosarcoma. Although there was no direct comparison with a doxorubicin and cisplatin-based regimen, the response rate and survival in patients with osteosarcoma suggest that doxorubicin and cisplatin-based chemotherapy would remain the accepted initial chemotherapy regimen. For patients with rhabdomyosarcoma and Ewing's sarcoma, 10-20% of patients remained disease free at 5 years.

Interest in high-dose cytarabine (HDAC) for both induction and postremission therapy for acute myeloid leukemia (AML) prompted the Southwest Oncology Group (SWOG) to initiate a randomized trial comparing HDAC with standard-dose cytarabine (SDAC) for remission induction of previously untreated AML and to compare high-dose treatment versus conventional doses for consolidation therapy. Patients less than 65 years of age with de novo or secondary AML were randomized for induction between SDAC 200 mg/ m2/d for 7 days by continuous infusion or HDAC at 2 g/ m2 intravenously every 12 hours for 12 doses; both groups received daunorubicin (DNR) at 45 mg/m2/d intravenously for 3 days. Complete responders to SDAC were randomized to receive either two additional courses of SDAC plus DNR or one course of HDAC plus DNR. Complete responders to HDAC were nonrandomly assigned to receive one additional course of HDAC plus DNR. Of patients randomized between SDAC (n = 493) and HDAC (n = 172) induction, 361 achieved complete remission (CR). The CR rate was slightly poorer with HDAC: 55% versus 58% with SDAC for patients aged less than 50, and 45% (HDAC) versus 53% (SDAC) for patients aged 50 to 64 (age-adjusted one-tailed P = .96). With a median follow-up time of 51 months, survival was not significantly better with HDAC (P = .41); the estimated survival rate at 4 years was 32% (HDAC) versus 22% (SDAC) for those aged less than 50, and 13% (HDAC) versus 11% (SDAC) for those aged 50 to 64. However, relapse-free survival was somewhat better following HDAC Induction (P = .049): 33% (HDAC) versus 21% (SDAC) at 4 years for those aged less than 50, and 21% (HDAC) versus 9% (SDAC) for those aged 50 to 64. Induction with HDAC was associated with a significantly increased risk of fatal (P = .0033) and neurologic (P.0001) toxicity. Among patients who achieved CR with SDAC, survival and disease-free survival (DFS) following consolidation randomization were not significantly better with HDAC compared with SDAC (P = .77 and .46, respectively). Patients who received both HDAC induction and consolidation had the best postremission outcomes; however, the proportion of CR patients who did not go on to protocol consolidation therapy was more than twice as high after HDAC induction compared with SDAC. Induction therapy with HDAC plus DNR was associated with greater toxicity than SDAC plus DNR, but with no improvement in CR rate or survival. Following CR induction with SDAC, consolidation with HDAC increased toxicity but not survival or DFS. In a nonrandomized comparison, patients who received both HDAC induction and consolidation had superior survival and DFS compared with those who received SDAC induction with either SDAC or HDAC consolidation.

The characteristics of PBSC mobilized with GM-CSF, which has been shown to augment monocyte/macrophage (Mo/Mx) antitumor and accessory activities, were evaluated. Patients with metastatic cancers were treated with GM-CSF at 5 micrograms/kg sc, days 1 to 7; leukaphereses were performed on days 6 and 7. A mean of 3.3 x 10(10) mononuclear cells were collected, 59% of which were lymphoid and 32%, monocytoid. Spontaneous Mo/Mx tumor cell cytotoxicity was not detectable in the leukapheresis product, either before or after cryopreservation; Mo/Mx tumor cell cytotoxicity, however, was inducible in vitro with IFN-gamma. Likewise, spontaneous lymphocyte cytotoxicity was not detectable in the leukapheresis product; lymphokine-activated killer cell activity was inducible in vitro with IL-2. Whereas lymphoproliferative responses to tetanus toxoid of cryopreserved PBSC were less than that of freshly collected PBSC, the capacity of Mo/Mx from cryopreserved PBSC to function as accessory cells in the lymphoproliferative response was maintained. These results indicate that significant numbers of immune cells can be mobilized with GM-CSF alone. Cryopreserved, GM-CSF-mobilized PBSC do not demonstrate spontaneous antitumor cytolytic activity; however, accessory activity is present and antitumor cytolytic activity mediated by both monocytoid and lymphoid cells is inducible.

The objectives of this Phase II trial of paclitaxel were to estimate the response rate and to define the toxicities of paclitaxel administered with recombinant granulocyte-colony stimulating factor in patients with advanced soft tissue sarcomas.Patients were eligible if they had a histologic diagnosis of unresectable, recurrent or metastatic soft tissue sarcoma and had had no prior chemotherapy or radiotherapy. Paclitaxel at 250 mg/m2 was given by continuous intravenous infusion over 24 hours every 21 days. Doses were modified in subsequent courses based on nadir counts. Granulocyte-colony stimulating factor was given at 5 micrograms/kg subcutaneously days 3-18.Forty-eight patients were treated; 1 patient had a complete response and 5 had partial responses for an overall response rate of 12.5% (95% confidence interval, 4.7%-25.3%). Thirty-eight of the 48 patients experienced grade 4 toxicities, with most of these life-threatening toxicities being hematologic. No deaths were attributed to therapy.At the tested dose and schedule paclitaxel has antitumor activity approximating that of decarbazine in soft tissue sarcomas. Whether paclitaxel would be more effective administered in a longer infusion or with a chemosensitizer remains to be tested in this group of heterogeneous neoplasms.

Carboplatin (CBDCA) is an active agent in the treatment of acute leukemia and is associated with limited extramedullary toxicity. Simultaneous phase II trials were conducted by the Southwest Oncology Group in adult patients with relapsed or refractory acute myeloid leukemia (AML). CBDCA was given as a continuous infusion at a dose of 300 mg/m2 daily for 5 days. Three (8%) of the 37 eligible patients in the relapsed group achieved complete remissions (CRs) lasting 3, 4, and 26 months. Entry of patients was stopped early in the refractory group due to slow accrual and in the relapsed group due to low CR rate. For both groups combined, the CR rate was 3/45 or 7% (95% confidence interval 3-18%). There were 12 fatal toxicities. Four patients died of intracerebral hemorrhage, three of infection, and five of hepatic and/or renal failure. Nonhematologic grade 4 toxicity included diarrhea in three patients, hyperbilirubinemia in four, and mucositis and renal toxicity in one each. These results suggest that CBDCA should not be considered for treatment of relapsed or refractory AML patients with prior high-dose therapy.

Between February 1982 and December 1986, the Southwest Oncology Group conducted a prospective study in patients with newly diagnosed acute myeloid leukemia (AML) with two objectives: to evaluate the role of allogeneic marrow transplantation for patients in first remission, and to evaluate the role of low-dose monthly maintenance therapy in those patients not transplanted in first remission. Among 522 evaluable patients, 295 (57%) achieved complete remission (CR), including 70% of patients age 49 or less. Twenty-four patients (15%) age 49 or less in CR were not HLA-typed, mostly because of financial constraints. HLA-identical donors were found for 39% of patients, of whom two-thirds were transplanted in first CR. The 5-year disease-free survival among those transplanted in first CR, those with donors not transplanted in first CR, and those less than age 50 without donors was 41, 42, and 29%, respectively (P = 0.60). A total of 150 eligible patients were randomized to receive late intensification alone or late intensification plus monthly maintenance. In multivariate analyses, treatment with maintenance was associated with prolonged disease-free survival (P = 0.028), but not improved overall survival (P = 0.27). Factors associated with improved overall survival included younger age, lower white blood count (WBC) at diagnosis, having leukemia of M3 morphology, and being of white race. In this study, a diagnosis of M3 AML was particularly favorable, with disease-free and overall survivals of 75 and 56%, respectively, at 7 years.

The sodium salt of pyrazine-2-diazohydroxide (PZDH; NSC 361456) was identified as an active congener of the antitumor lead pyridine-2-diazotate with enhanced chemical stability under physiological conditions. In a phase I trial of PZDH administered as a single i.v. bolus injection, 19 patients with refractory solid tumors received 44 courses of therapy at dose levels ranging from 50 to 350 mg/m2. No objective responses to PZDH were noted. Myelosuppression characterized by prolonged, delayed onset leukopenia and thrombocytopenia was the dose limiting toxicity. A maximum tolerated dose of 350 mg/m2 was identified for this treatment schedule. Nonhematological toxicity was limited to severe nausea and vomiting, experienced by all patients treated at the lower doses, although reasonably well controlled when antiemetics were given prior to chemotherapy. The plasma pharmacokinetics of PZDH was evaluated following a single course of therapy in 16 patients. Drug levels were monitored using a specific capillary gas chromatographic assay with a 1-ng/ml lower limit of quantitation. In patients treated with doses greater than 50 mg/m2, the concentration of PZDH in plasma declined in a distinctly triexponential manner and remained above 1.5 ng/ml for at least 8 h. However, the initial decay phase, characterized by a harmonic mean half-life of 3.9 +/- 3.5 (SD) min (range, 2.2-6.3 min), was the primary determinant of drug disposition, as indicated by its 85.5-93.1% contribution to the area under the plasma concentration-time profiles from time zero to infinity. The harmonic mean terminal half-life increased with escalations in dose from 2.7 +/- 0.8 h (n = 2) at 100 mg/m2 to 8.5 +/- 3.0 h at 350 mg/m2 (n = 6). Total plasma drug clearance was very similar in patients treated with doses of 50-250 mg/m2, exhibiting a mean value of 42.5 +/- 7.8 liters/h/m2 (n = 10); however, it was significantly lower at the 350 mg/m2 dose level, 27.2 +/- 6.6 liters/h/m2 (n = 6; P0.002), denoting a departure from linear pharmacokinetic behavior. The rather low steady state apparent volume of distribution, which ranged from 6.0 +/- 1.5 (50 mg/m2, n = 2) to 12.7 +/- 8.0 (350 mg/m2, n = 6) liters/m2, was indicative of limited distribution of the drug into body tissue. The absence of objective antitumor effects should not discourage continued evaluation of PZDH against solid tumors selected for probable sensitivity as indicated by preclinical testing. A dose of 250 mg/m2 on a single i.v. bolus schedule is recommended for these phase II trials.

The Southwest Oncology Group (SWOG) performed a phase II trial of a combination of ifosfamide/mesna/cisplatin in patients with metastatic soft-tissue sarcoma who had previously received one chemotherapeutic regimen. A total of 39 patients were registered in the study, including 7 treated during a limited-institution pilot phase; 38 patients were fully eligible and evaluable. During the pilot phase, patients were treated with 2.5 g/m2 ifosfamide daily on days 1-3, 2.5 g/m2 mesna daily on days 1-4, and 100 mg/m2 cisplatin on days 2 and 9. Due to excessive myelosuppression, the day-9 cisplatin dose was dropped when the study was opened groupwide, and the subsequent 32 patients were treated at 3- to 4-week intervals with 2.5 g/m2 ifosfamide daily on days 1-3, 2.5 g/m2 mesna daily on days 1-4, and 100 mg/m2 cisplatin on day 2. Myelosuppression was severe, with granulocytopenia (0.5 x 10(9)/l) being observed in 26 of 38 patients. Three cases of National Cancer Institute grade 3 or 4 nephrotoxicity (serum creatinine,3 times the normal value) and three cases of grade 3 or 4 central nervous system toxicity were reported. Overall, three complete and five partial responses were achieved, for a major response rate of 21%. The median survival of all patients was 11 months. We conclude that ifosfamide-based chemotherapy can produce objective responses in previously treated patients with metastatic soft-tissue sarcoma but that cisplatin increases the toxicity of therapy. Phase II trials of new agents are needed to identify drugs with clinical activity in the treatment of soft-tissue sarcomas.

Malignant mesothelioma is a highly treatment-resistant neoplasm. This study represents an attempt to define an effective form of systemic therapy.Twenty-six patients with unresectable diffuse malignant mesothelioma were enrolled in Southwest Oncology Group (SWOG) study 8731 and treated with ifosfamide, 2 g/m2 intravenously for 4 days, and mesna 2 g/m2 intravenously for 5 days, every 3 weeks. Patients were either previously untreated with chemotherapy or had at most one prior systemic treatment.Two patients, or 8% (95% confidence interval, 1-25%), achieved partial response, with response durations of 4 and 6 months. One additional patient met criteria for tumor size reduction but not duration criteria. Thirteen (50%) patients had stable disease of 4 months' median duration (range, 1-13 months). The median survival of the entire group was 6.5 months. The dose-limiting toxicity was granulocytopenia (11 patients,or = 250/microliters).Ifosfamide/mesna has modest activity in malignant mesothelioma. It could be tested using alternate dosage schedules and in combination with other agents in treating this highly resistant neoplasm.

Between August 1978 and September 1982, 642 patients with newly diagnosed acute myelogenous leukemia (AML) were entered onto a Southwest Oncology Group Study which addressed four questions. (i) What is the comparative utility of rubidazone versus adriamycin in remission induction? (ii) What is the role of prophylactic intrathecal therapy in AML? (iii) Does late intensification affect treatment outcome? (iv) Does maintenance with levamisole affect disease-free survival or overall survival? Among 611 evaluable patients, 329 (54%) achieved complete remission. There was no difference in the remission rate between those patients receiving rubidazone (54%) and those receiving adriamycin (54%) as part of the induction regimen. Prophylactic intrathecal therapy with cytosine arabinoside had no effect on the incidence of central nervous system disease or survival. After nine months of complete remission, patients were randomized between late intensification with POMP (mercaptopurine + vincristine + methotrexate + prednisone) or continued maintenance with OAP (vincristine + cytosine arabinoside + prednisone). T patients randomized to late intensification had better survival and disease-free survival, compared to those randomized to receive no late intensification (p = 0.027 and 0.030, respectively). At twelve months of remission, surviving patients were randomized to receive levamisole or no further treatment. There was no evidence that levamisole affected survival or disease-free survival.

Acidic fibroblast growth factor (aFGF), also known as heparin-binding growth factor 1, is a mitogen for a variety of mesoderm- and neuroectoderm-derived cells. Several different aFGF mRNA species resulting from alternative splicing have been reported. These results suggest that the gene structure and regulatory mechanism for gene expression of aFGF are complex. As a first step toward understanding aFGF gene structure, we have isolated nine overlapping genomic DNA clones spanning 54 kbp and determined the complete DNA sequences of all three coding exons. Comparison of the nucleotide sequences between the human and bovine DNA showed that the sequence similarity extended 2400 bp downstream from the coding region. Cloning of the aFGF gene allowed us to characterize this locus in acute nonlymphocytic leukemia (ANLL) patients. A fraction of ANLL patients (10-20%) have a deletion in the long arm of chromosome 5, whose distal breakpoint overlaps the aFGF locus. Therefore, a prospective cohort of eight ANLL patients was screened using three different repetitive sequence-free probes derived from the aFGF locus. Using beta-globin gene as a normalization probe for hybridizing band intensities, we conclude that there is no allelic loss or gross rearrangement within the 40 kbp stretch of the aFGF gene locus in ANLL patients with or without 5q- deletion. Consistent with this observation, the aFGF mRNA was not detected in the mononuclear cells derived from either an ANLL patient or a normal individual as judged by the reverse transcription and polymerase chain reaction. We also identified a DNA fragment, 10.7 kbp upstream from the first coding exon of human aFGF, whose sequence is conserved in both the primate and rodent genomes. Further characterization of this fragment is likely to provide insight into the significance of this high degree of conservation.

Between August 1984 and January 1987, the Southwest Oncology Group (SWOG) registered 46 patients with metastatic sarcomas on SWOG 8465, a Phase II trial of high-dose cisplatin in patients with metastatic soft tissue sarcoma. Six patients were ineligible for the following reasons: poor performance status (two patients); ineligible diagnosis (three patients, two with Ewing's sarcoma of bone and one with metastatic chondrosarcoma); and evaluable but nonmeasurable disease (one patient with bone-only disease). Of the 40 fully evaluable patients, 34 had received prior chemotherapy; treatment was with cisplatin (40 mg/m2/d for 5 consecutive days). Cisplatin was mixed in 250 ml of 3% NaCl and hydrated with a normal saline solution at a rate of 250 ml/h, beginning 12 hours before the first dose of cisplatin was specified. The second treatment was given 3 weeks after the first, with all subsequent treatments given every 4 weeks. After three cycles of treatment, responding patients were treated at a cisplatin dose of 20 mg/m2/d for 5 consecutive days. Leukopenia was of Grade 3 or 4 in seven patients, whereas thrombopenia was of Grade 3 or 4 in eight patients. More severe myelosuppression was produced in patients who had received prior radiotherapy. A single case of reversible Grade 4 nephrotoxicity was produced; neurotoxicity was observed in 11 cases, but was of Grade 3 in only 2 cases. Of the 40 evaluable cases, six showed partial responses or no responses, for a major response rate of 15%. High-dose cisplatin has minor activity and major toxicity in the treatment of metastatic soft tissue sarcomas, and should be considered investigational.

The rates of polymerization and depolymerization of identical concentrated deoxygenated hemoglobin S (HbS) solutions following a rapid temperature change were examined by several methods. Two of these methods measured viscosity changes in either gently agitated (AGT) or nonagitated (NAGT) samples. The third method utilized a change in turbidity at 735 nm (SDT). By all three methods, a delay period, during which no observable change was detected, followed the temperature change. Gelation, as determined in nonagitated samples by a viscosity- based technique, occurred before or coincided with gelation as determined spectrophotometrically. The slope of the concentration dependence of the delay time is significantly decreased by agitation. Similar monitoring of the depolymerization reaction indicated the persistence of increased viscosity after observation of a marked decrease in turbidity.

Adriamycin and daunomycin produce dose-related cardiac toxicity that may be related to oxygen radicals. Addition of these compounds to human erythrocyte suspensions resulted in stimulation of hexose monophosphate shunt activity that was markedly impaired in the absence of oxyhemoglobin. Evidence for generation of hydrogen peroxide by these compounds was provided by oxidation of reduced glutathione, by 14C- formate oxidation, and by the catalase-aminotriazole trapping technique. These experiments indicate that Adriamycin and daunomycin interact with oxyhemoglobin to generate reactive oxygen metabolites. A similar interaction with oxymyoglobin may occur in the heart and produce oxygen radicals that injure cardiac myocytes.

A deficiency of adenosine deaminase, an enzyme important in purine nucleoside catabolism, is associated with a severe combined immunodeficiency disease in children. Inhibition of this enzyme in vitro and in vivo results in an impairment in lymphoblast proliferation. We have investigated the pharmacologic inhibition of this enzyme by 2′-deoxycoformycin in 15 patients with hematologic malignancies. Biochemical consequences of the administration of this agent were closely monitored in erythrocytes, nucleated peripheral blood and bone marrow cells, serum, and urine. A marked rise in erythrocyte dATP was accompanied by a depletion of ATP in those patients exhibiting toxicity. Most patients excreted large amounts of deoxyadenosine but not adenosine in the urine. Serum deoxyadenosine rose in patients demonstrating a marked decrease in cell mass. The biochemical disturbances and clinical toxicity, including hepatic, renal, and conjunctival abnormalities, were usually reversible. Central nervous system toxicity, which potentially was the most serious consequence, was associated with high erythrocyte dATP/ATP ratios and high levels of cerebrospinal fluid deoxyadenosine. In patients with lymphoma and leukemia, objective responses were observed but were short- lived. Patients with chronic lymphocytic leukemia receiving weekly low doses of the drug demonstrated minimal toxicity and some efficacy. The chemotherapeutic potential o 2′-deoxycoformycin, as either a single agent or in combination with Ara-A, merits further exploration.

Peripheral blood mononuclear cells (PBMC) from 18 untreated patients with non-Hodgkin's lymphoma (NHL) were studied to characterize the cellular mechanisms contributing to impaired in vitro lymphocyte responses after stimulation by the mitogen conconavalin A (Con-A). In vitro reactivity was quantitated by the 3H-thymidine incorporation in response to an optimal dose of Con-A. All patients demonstrated impaired in vitro reactivities compared to normal controls. These in vitro impairments were partially reversible since patient's cells precultured in media alone for 3 days demonstrated enhanced Con-A responses. In greater than half of the patients, the hyporeactive PBMC suppressed the enhanced reactivities of autologous precultured PBMC when assayed in cocultures. Suppressor activity was detected mainly in those untreated patients presenting with either constitutional symptoms or diffuse histology and in general was not marked compared to the severity of impairments. Adherent monocytes were shown to participate in the suppression of autologous lymphocyte reactivity but only appeared partially responsible for the in vitro impairments. In those patients lacking detectable suppressive activity, preculturing also enhanced Con-A reactivities and was compatible with the presence of a reversible, inhibitory mechanism differing from active suppression. Many patients' hyporeactive PBMC, however, failed to demonstrate normal responses after preculturing. This failure could not be directly attributed to aberrant regulatory populations, but rather appeared to possibly represent an additional intrinsic impairment of potentially reactive populations.

Vasoactive intestinal polypeptide (VIP) was found to be a potent stimulator of lymphocyte adenylate cyclase activity. VIP-induced activation of adenylate cyclase was specific for lymphocytes among peripheral blood cells; i.e., VIP did not stimulate the adenylate cyclase activity of neutrophils, monocytes, or platelets. The VIP-induced activation of lymphocyte adenylate cyclase was time, temperature, and concentration dependent. VIP and the GTP analog, Gpp(NH)p, acted synergistically to stimulate lymphocyte adenylate cyclase; stimulation by VIP and PGE1 was additive; and VIP activation was antagonized by somatostatin. VIP-mediated activation of lymphocyte adenylate cyclase was observed in normal human T cells, B cells obtained from a patient with chronic lymphocytic leukemia, and a human T cell culture line. The Raji human B cell culture line did possess adenylate cyclase activity, but this activity was not stimulated by VIP. These results suggest that lymphocytes possess functional receptors for VIP and that this peptide may play a role in modulation of lymphocyte function.

Oxygen equilibrium was determined on hemoglobin of individuals both heterozygous and homozygous for hemoglobin E. The whole blood oxyhemoglobin dissociation curve of AE blood was identical to that of normal AA blood. E hemoglobin, isolated by diethylaminoethyl Sephadex and carboxymethyl cellulose column chromatography, had oxygen affinity, heme-heme interaction, and Bohr effect identical to those of hemoglobin A prepared from the same column. Furthermore, the two hemoglobins had equal reactivity with 2,3-diphosphoglycerate. Phosphate-free hemolysates of blood from E and A homozygotes also had identical oxygen saturation curves. These results do not confirm earlier reports that hemoglobin E has an abnormally low oxygen affinity.

SUMMARY The ferrokinetic data of patients with primary polycythaemia are those of patients with depleted iron stores. Differences in iron kinetics between polycythaemia vera and secondary polycythaemia are related to the variation in the quantity of iron stores and do not appear to be inherent to the type of polycythaemia. If ferrokinetic studies are to be used to evaluate or classify polycythaemia, storage iron must be assessed.

Sixty-three patients with Hodgkin's disease (HD) or non-Hodgkin's lymphoma (NHL) were studied to analyze the mechanisms responsible for impaired in vitro lymphocyte reactivities to the mitogen concanavalin A. Lymphocytes from 43 of the 52 untreated patients acquired enhanced in vitro responsiveness after preculturing in media alone for 3 days. However, 38 of the untreated patients failed to achieve entirely normal lymphocyte responses after preculturing . Suppressor cells were detected in 25 patients, but the intensity of suppression was much less than expected when compared with the severity of in vitro impairments. Suppressor activity did correlate with certain clinical characteristics in NHL, whereas no correlation was observed for HD. In contrast to the untreated patients, successfully treated patients demonstrated either normal responses or profound, irreversible impairments. The data indicate that several mechanisms which usually coexist can contribute to the impaired in vitro lymphocyte responses in untreated HD and NHL, and that a single, irreversible type of mechanism explains the impaired reactivities in successfully treated patients.

Vasoactive intestinal polypeptide (VIP) was found to be a potent stimulator of lymphocyte adenylate cyclase activity. VIP-induced activation of adenylate cyclase was specific for lymphocytes among peripheral blood cells; i.e., VIP did not stimulate the adenylate cyclase activity of neutrophils, monocytes, or platelets. The VIP-induced activation of lymphocyte adenylate cyclase was time, temperature, and concentration dependent. VIP and the GTP analog, Gpp(NH)p, acted synergistically to stimulate lymphocyte adenylate cyclase; stimulation by VIP and PGE1 was additive; and VIP activation was antagonized by somatostatin. VIP-mediated activation of lymphocyte adenylate cyclase was observed in normal human T cells, B cells obtained from a patient with chronic lymphocytic leukemia, and a human T cell culture line. The Raji human B cell culture line did possess adenylate cyclase activity, but this activity was not stimulated by VIP. These results suggest that lymphocytes possess functional receptors for VIP and that this peptide may play a role in modulation of lymphocyte function.

Two groups of non-anemic dogs, one with normal tissue iron stores and one with decreased tissue iron stores, underwent a surgical construction of two equal segments of duodenum and jejunum. A solution of 0.1 mg ferrous sulfate and 1 mg ascorbic acid was injected into the lumen of each segment. The solution for the duodenal segment contained 30 muc of iron59, for the jejunum segment 60 muc of iron55. The solutions were left in the segments for 2 1/2 hours before washout. On the 14th postoperative day, iron59 and iron55 radioactivity per ml/RBC was measured, and iron uptake by segments determined in two ways. Bone marrow, liver, and spleen were histologically assessed of iron stores. In dogs with normal iron stores, percent iron retained was slightly higher in jejunum that duodenum. In dogs with decreased iron stores percent retention was always higher in duodenum; in this group iron retained was about four times higher than in dogs with normal iron stores. This indicates that mucosal uptake of iron from lumen and mucosal transfer of iron from plasma vary inversely with body iron stores, but compared to mucosal uptake, mucosal transfer is more restricted to duodenum, more affected by body iron stores, more limited, and more crucial to regulation of iron absorption.

Thirty-five fully evaluable patients with advanced multiple myeloma, refractory to standard chemotherapeutic agents, were entered into a phase II trial with mitoxantrone at a starting dose of 12 mg/m2 iv every 3 weeks. There was one (3%) partial response (lasting 2 1/2 months) in a patient who had received treatment with five different agents, including doxorubicin (total dose, 150 mg/m2). Four additional patients (11%) showed objective evidence of clinical improvement, lasting 4-7 months. Mitoxantrone was well-tolerated with no drug-induced deaths and only moderate to severe leukopenia as the dose-limiting toxicity in the majority of patients. Although mitoxantrone had a low level of activity in this heavily pretreated patient population, consideration should be given to future trials incorporating mitoxantrone into a new drug combination.

Cytembena is a nonmyelosuppressive drug that has received phase I--II trials in this country and is presently being used as a chemotherapeutic agent in Europe. Sterile abscesses at the site of im injection and "autonomic storm" after iv bolus represent the most frequent dose-limiting toxic effects, and intermittent schedules reflect reports of prolonged plasma levels of drug. This report of excellent oral absorption and a short half-life suggests that alternative routes and schedules of administration should be evaluated. The dose-limiting toxic effects observed after frequent oral administration were transient proteinuria and increased creatinine levels.

The purpose of this study was to document early structural changes in the human heart after the initial administration of doxorubicin. Endomyocardial biopsies were performed at baseline and at 4 and 24 hours after doxorubicin administration to 13 patients. Morphometric analysis of electron micrographs (x 31,200) quantitated mitochondrial and tubular sizes (sarcoplasmic reticulum and T tubules). The mitochondrial size increased from 0.25 +/- 0.01 mu 2 (mean +/- SE) at baseline to 0.27 +/- 0.03 mu 2 (not significant [NS]) at 4 hours and 0.30 +/- 0.03 mu 2 (NS) at 24 hours. The tubular size increased from 2.24 +/- 0.13 x 10(4) nm2 at baseline to 2.60 +/- 0.26 x 10(4) nm2 (P less than 0.05) at 4 hours and 2.46 +/- 0.29 x 10(4) nm2 (NS) at 24 hours. Micrographs analyzed for nuclear changes showed nucleolar contraction and segregation of granular and fibrillar components. These changes were noted in five of ten patients at 4 hours and in eight of 13 patients at 24 hours. Serial echocardiographic and systolic time interval determinations of left ventricular function demonstrated a significant improvement at both 4 and 24 hours. In conclusion, doxorubicin has its most significant effect on tubular structures. Left ventricular function improved during this time despite these findings.

Doxorubicin induced acute as well as chronic myocardial morphologic alterations. Twenty patients with normal cardiovascular function were randomized to 2 groups based on age and dose of doxorubicin. Group I received placebo 1 hour before doxorubicin administration; group II received acetylcysteine (N-acetyl-L-cysteine) (Nac) 1 hour before doxorubicin. Endomyocardial biopsies were performed at base line at 4 and 24 hours after doxorubicin administration. Biopsy tissue was viewed by electron microscopy, and stereoscopic techniques were used to determine tubular and mitochondrial area. The change of the tubular area was similar in the 2 groups, was maximum at 4 hours, and was proportionately spread throughout the cell. The mitochondrial swelling was also similar in the 2 groups and proportionate throughout the cell but was maximum at 24 hours. This study demonstrated that the acute doxorubicin-induced damage was diffuse and not prevented by Nac.

Filterability and morphology of cyanate-treated sickle cells were compared to those of untreated cells at equal oxygen saturations to determine whether carbamylation inhibited sickling by an effect other than by its alteration of the oxygen dissociation curve. Morphology of treated and untreated cells was not significantly different at all levels of oxygen saturation examined. Filterability, on the other hand, was improved significantly by carbamylation. This latter finding indicates that carbamylation enhances deformability of sickle cells by a mechanism(s) in addition to its effect on red cell oxygen saturation. This mechanism(s) may account for the clinical benefit of cyanate therapy with doses which do not significantly affect the oxygen dissociation curve.

Carbamylation of red cells with sodium cyanate has been suggested as a potential treatment for sickle cell disease. Because carbamylation of red cells increases their oxygen affinity, the present study was done to determine whether cyanate administration caused impaired tissue oxygenation. Rats given i.p. (250 mg/kg/wk) or oral (625 mg/kg/wk) cyanate were found to have significantly reduced skin bubble oxygen tensions compared to controls. These reduced oxygen tensions were associated with significantly increased blood oxygen affinity. Treated animals developed greater red cell masses than controls, but these increases were not sufficient to compensate for increased blood oxygen affinity. These findings need to be considered when cyanate is used for treatment of sickle cell disease.

In this Southwest Oncology Group (SWOG) study, 216 adults with acute leukemia were treated with ten-day chemotherapy consisting of vincristine sulfate (Oncovin), cytarabine (ara-C) (100 mg per square meter of body area per day by 24-hour infusion), and prednisone (ten-day OAP). The results were compared with those of a previous SWOG study in which cytarabine (200 mg per square meter of body area per day) was given for five days (five-day OAP). Patients entering complete remission (CR) were given three consolidation courses of five-day OAP and randomized to maintenance chemotherapy alone (32 patients) or combined with BCG vaccine (24 patients). For 160 previously untreated patients with acute myelogenous leukemia, there was no difference in remission rates (53% vs 43%) or median survival times (48 vs 47 weeks) between ten-day and five-day OAP. The difference in duration of CR (74 vs 54 weeks, respectively) between the two maintenance arms was not statistically significant. However, 14% of evaluable patients with acute myelogenous leukemia and 26% of those achieving CR were alive and in remission more than five years.

The total lymphocyte, T, B, and null cell content of peripheral blood from 32 healthy individuals and 30 patients with non-Hodgkin's lymphoma was determined. The patients had a significant reduction of B cells (complement receptor and membrane immunoglobulin positive cells) and a significant reduction in T cells. Correlation of patients' characteristics with lymphocyte abnormalities demonstrated several findings. Patients with advanced disease (III and IV) had significantly lower total lymphocyte and T cells than patients with localized disease (I and II) or normal controls. Patients with hypogammaglobulinemia had lower total lymphocyte and T cells than patients with normal gamma globulin status or normal controls. Patients with diffuse histology and B symptoms had lower total lymphocyte and T cells than normal controls. Discriminant analysis of lymphocyte populations categorized patients by disease extent and gamma globulin status with 70 and 68% accuracy, respectively.

Peripheral blood BFU-E are primitive erythroid progenitor cells that have been reported to exhibit an absolute dependence on T-cells for proliferation in the plasma clot system. The study reported here was undertaken to define the differential effects of TS and TH lymphocytes on proliferation of BFU-E. We investigated the effect of unfractionated T-cells, TS, and TH on in vitro growth of peripheral blood BFU-E. Cell populations were negatively selected by treatment with murine monoclonal antibodies (OKT-3, OKT-4, OKT-8) and C'. Our experiments suggest that proliferation of peripheral blood BFU-E exhibits an absolute requirement for T-cells. The capacity to enhance growth of BFU-E is approximately equal between normal unfractionated T-cells and TS and TH cells. The data suggest that the TH and TS cells defined by the OKT antibodies are not critical in the modulation of erythroid proliferation.

VIP is a 28 amino acid peptide found in highest concentration in central and peripheral nervous tissue. This study measured VIP in pure populations of peripheral blood cells to determine the presence or absence of VIP in noninnervated tissues. Cell populations were purified by Ficoll-hypaque gradient centrifugation followed by dextran sedimentation or differential adherence to culture plates. Platelets were purified by differential centrifugation. VIP was isolated by acid-ethanol extraction and quantified by radioimmunoassay. A mean value of 1.1 +/- 0.6 ng of VIP per 10(8) cells was extracted from PMNs. This peptide appears to be a specific marker for PMNs, since it was not measurable in pure populations of lymphocytes, monocytes, erythrocytes, or platelets. Mononuclear cells obtained from five patients with AML and seven patients with CML contained measurable VIP, whereas mononuclear cells from nine of 10 patients with AMML and from five patients with ALL contained very low or unmeasurable levels of VIP. Thus, although the role of VIP in normal PMN function is unknown, measurement of VIP in leukemic cells may aid in the differential diagnosis of acute leukemias.

Three hundred and ninety-eight patients with disseminated solid tumors other than breast cancer, were treated with a combination chemotherapy protocol utilizing cyclophosphamide, vincristine sulfate, methotrexate, 5-fluorouracil, and prednisone. Three hundred and eighty were evaluable (95.5%). Partial or complete tumor regressions were noted in 73 of 380 (19%) evaluable patients. Response to therapy was associated with a prolongation and survival. The largest tumor categories were lung, ovary, and gastrointestinal. The proportion of complete plus partial responses in evaluable lung cancer patients was 40/236 (17%), compared to 20/44 (45%) for ovarian cancer patients and 6/39 (15%) for gastrointestinal tumors. Of the patients who could be evaluated for toxicity, 47% had minimal or no toxicity, 51% had moderate to severe toxicity, and 2% had life threatening toxicity. Virtually all patients were treated and managed as outpatients.