Molecular alterations of the IDH1 gene in AML: a Children's Oncology Group and Southwest Oncology Group study.

Recent whole-genome sequencing efforts led to the identification of IDH1(R132) mutations in acute myeloid leukemia (AML) patients. We studied the prevalence and clinical implications of IDH1 genomic alterations in pediatric and adult AML. Diagnostic DNA from 531 AML patients treated on Children's Oncology Group trial COG-AAML03P1 (N=257), and Southwest Oncology Group trials SWOG-9031, SWOG-9333 and SWOG-9500 (N=274), were tested for IDH1 mutations. Codon R132 mutations were absent in the pediatric cohort, but were found in 12 of 274 adult patients (4.4%, 95% CI 2.3-7.5). IDH1(R132) mutations occurred most commonly in patients with normal karyotype, and those with FLT3/ITD and NPMc mutations. Patients with IDH1(R132) mutations trended toward higher median diagnostic white blood cell counts (59.2 x 10(9) vs 29.1 x 10(9) per liter, P=0.19) than those without mutations, but the two groups did not differ significantly in age, bone marrow blast percentage, overall survival or relapse-free survival. Eleven patients (2.1%) harbored a novel V71I sequence alteration, which was found to be a germ-line polymorphism. IDH1 mutations were not detected in pediatric AML, and are uncommon in adult AML.

The effect of an individual's cytochrome CYP3A4 activity on docetaxel clearance.

Docetaxel is a chemotherapeutic agent effective in the treatment of various solid tumors. Patients given a standard dose of docetaxel exhibit wide interpatient variation in clearance (CL) and toxic effects. Docetaxel undergoes metabolism by cytochrome CYP3A4. Thus, interpatient variability in CYP3A4 activity may account in part for differences in toxicity and CL. Twenty-one heavily pretreated patients with metastatic sarcomas received docetaxel (100 mg/m2). Hepatic CYP3A4 activity in each patient was measured by the [14C-N-methyl]erythromycin breath test (ERMBT). Blood samples were taken at selected times over the next 24 h for pharmacokinetic analysis. Phenotypic expression of hepatic CYP3A4 activity measured by the ERMBT varied over 20-fold (administered 14C exhaled in 1 h: mean, 2.53%; range, 0.25-5.35%), which is similar to a normal control population. CL of docetaxel varied nearly 6-fold (mean, 21.0 liters/h/m2; range, 5.4-29.1 liters/h/m2). The ERMBT was the best predictor of CL when compared with serum alanine aminotransferase, albumin, alkaline phosphatase, or serum alpha-1-acidic glycoprotein. The natural log of ERMBT accounted for 67% of the interpatient variation in CL. Multivariate analysis showed that the natural log of ERMBT and albumin together accounted for 72% of the interpatient variation in CL. The greatest toxicity was seen in patients with the lowest ERMBT. Hepatic CYP3A4 activity is the strongest predictor of docetaxel CL and accounts for the majority of interpatient differences in CL. Patients with low CYP3A4 activity are at risk for having decreased CL and may thus experience increased toxicity from docetaxel. Those with high activity may be receiving a suboptimal dose. By measuring CYP3A4 activity, the ERMBT may be clinically useful in tailoring doses of CYP3A4 substrates, such as docetaxel, in certain individuals.

Phase II evaluation of cisplatin and etoposide followed by mitotane at disease progression in patients with locally advanced or metastatic adrenocortical carcinoma: a Southwest Oncology Group Study.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Splenic fluorodeoxyglucose uptake increased by granulocyte colony-stimulating factor therapy: PET imaging results.

UNLABELLED: Using PET, we investigated the change in 18F-fluorordeoxyglucose (FDG) uptake in the spleen after granulocyte colony-stimulating factor (G-CSF) treatment. METHODS: Forty-two FDG PET scans in 12 patients with locally advanced breast cancer who received G-CSF treatment were studied (12 baseline, 10 during G-CSF, 20 after G-CSF treatment). The PET images obtained at 50-60 and 60-70 min after intravenous FDG (370 MBq) injection were assessed visually and were compared with those before G-CSF treatment. For a semiquantitative index of FDG uptake, we determined the standardized uptake value calculated on the basis of predicted lean body mass (SUL) on these images, and we calculated the SUL ratios normalized to their baseline SUL values. RESULTS: During G-CSF treatment (n = 10), 9 scans (90%) showed increased splenic FDG uptake (3 slightly, 6 substantially). After G-CSF treatment (n = 20), 13 (65%) showed no change, 7 (35%) showed slightly increased uptake, but no case showed substantially increased FDG uptake in the spleen (P = 0.0003). Out of 30 PET scans obtained during and after G-CSF treatment, 16 (53%) showed increased FDG uptake in the spleen (10 slightly, 6 substantially), whereas 26 (87%) showed increased bone marrow FDG uptake (14 slightly, 12 substantially). The FDG uptake in other normal organs (liver, blood and lung) showed no change during or after G-CSF treatment. Similar to the change in the bone marrow, the SULs in the spleen significantly increased during G-CSF treatment (baseline, 1.50+/-0.31, versus during G-CSF, 2.69+/-0.84; P = 0.0004), then decreased after discontinuation of G-CSF (1.65+/-0.23). There was a significant correlation between the SUL ratios in the spleen and those in the bone marrow (r = 0.778, P < 0.0001), whereas there were no correlations between those in other organs and those in the bone marrow. CONCLUSION: Substantially increased FDG uptake was observed in the spleen during and after G-CSF treatment, although this change was less frequent and not as marked as the change observed in the bone marrow. The recognition and understanding of this phenomenon will be increasingly important when interpreting FDG PET images in cancer patients to avoid confusing this normal phenomenon with pathological splenic (tumor) involvement.

Randomized trial comparing cisplatin with cisplatin plus vinorelbine in the treatment of advanced non-small-cell lung cancer: a Southwest Oncology Group study.

PURPOSE: Cisplatin has played a major role in the treatment of non-small-cell lung cancer (NSCLC). This randomized trial was performed by the Southwest Oncology Group (SWOG) to determine whether the combination of vinorelbine and cisplatin has any advantage with regard to response rate, survival, and time to treatment failure over single-agent cisplatin in the treatment of patients with advanced NSCLC. METHODS: Between October 1993 and April 1995, 432 patients with advanced stage NSCLC were randomized to receive arm I (cisplatin 100 mg/m2 every 4 weeks) or arm II (cisplatin 100 mg/m2 every 4 weeks and vinorelbine 25 mg/m2 weekly). All patients were chemotherapy-naive, had performance status (PS) 0 or 1, and had adequate hematologic, renal, and hepatic function. RESULTS: Four hundred fifteen patients were eligible and assessable. On arm I (cisplatin), there was a 12% partial response rate. Arm II (cisplatin and vinorelbine) had a 26% response rate (2% complete responses and 24% partial responses, P = .0002). There was a statistically significant advantage with regard to progression-free survival (median, 2 v 4 months; P = .0001) and overall survival (median, 6 v 8 months; P = .0018) for the cisplatin and vinorelbine arm. One-year survival was 20% for cisplatin alone and 36% for the combination arm. There was more hematologic toxicity on arm II of the study (81% grades 3 and 4 granulocytopenia v 5% on arm I). Other toxicities, such as renal insufficiency, ototoxicity, and nausea and vomiting, and neuropathy were similar. CONCLUSION: The results of this study indicate that the combination of cisplatin and vinorelbine is a superior treatment when compared with single-agent cisplatin in the treatment of advanced NSCLC. Cisplatin and vinorelbine is the new standard for SWOG against which new therapies will be evaluated.

A Southwest Oncology Group and Cancer and Leukemia Group B phase II study of doxorubicin, dacarbazine, ifosfamide, and mesna in adults with advanced osteosarcoma, Ewing's sarcoma, and rhabdomyosarcoma.

BACKGROUND: 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. METHODS: This Phase II study evaluated doxorubicin, dacarbazine, ifosfamide, and mesna (MAID) in adults with inoperable or metastatic Ewing's sarcoma, rhabdomyosarcoma, or osteosarcoma. RESULTS: 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; P < 0.005). 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. CONCLUSIONS: 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.

Preclinical and clinical studies of bone marrow uptake of fluorine-1-fluorodeoxyglucose with or without granulocyte colony-stimulating factor during chemotherapy.

PURPOSE: To evaluate the effect of granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) on bone marrow glucose metabolism in rodents and in patients, as assessed by 2-[fluorine-18]-fluoro-2-deoxy-D-glucose (FDG) uptake measured directly or by positron-emission tomography (PET) scanning. MATERIALS AND METHODS: Groups of three rats received either daily saline, G-CSF, or GM-CSF injections for 7 days. After treatment, FDG was injected and F-18 activities in tissues measured 1 hour later. Twenty-two breast cancer patients treated with multiagent chemotherapy were sequentially studied with PET. Eleven patients received G-CSF therapy as an adjunct to chemotherapy, while 11 received chemotherapy only. The standardized uptake value-lean (SUL) of bone marrow FDG uptake was measured and compared. RESULTS: In rats, bone marrow F-18 activity was significantly higher in both CSF groups than in the saline group (G-CSF, 0.44 +/- 0.08; GM-CSF, 0.33 +/- 0.02; saline, 0.18 +/- 0.02% injected dose [ID]/g x kg; P < .05), but the other normal tissues had comparable biodistributions to controls. In breast cancer patients, the FDG uptake of bone marrow did not change with chemotherapy alone; however, marrow uptake was increased after treatment with G-CSF. The dose of G-CSF and duration of treatment were correlated with the extent of increase in FDG uptake. The SUL of bone marrow was as follows: baseline, 1.56 +/- 0.23; after one cycle, 3.13 +/- 1.40 (P < .01); after two cycles, 2.22 +/- 0.85 (P < .05); and after three cycles, 2.14 +/- 0.79 (P < .05), respectively. Although the FDG uptake of bone marrow declined after G-CSF treatment was completed, it was higher than the baseline level for up to 4 weeks postcompletion of G-CSF and the elevated marrow FDG uptake was sustained longer than the period of blood neutrophil count elevation. CONCLUSION: Substantial increases in bone marrow FDG uptake are rapidly induced by CSF treatments and should not be misinterpreted as diffuse bone marrow metastases.

13-cis-retinoic acid or all-trans-retinoic acid plus interferon-alpha in recurrent cervical cancer: a Southwest Oncology Group phase II randomized trial.

PURPOSE: Preclinical and clinical data support the study of retinoids and interferon-alpha (IFN-alpha) in advanced squamous cell carcinoma of the uterine cervix (SCC). This phase II randomized trial of the Southwest Oncology Group sought to estimate the response rate for IFN-alpha plus either 13-cis-retinoic acid (13cRA) or all-trans-retinoic acid (ATRA) in women with recurrent cervical SCC. PATIENTS AND METHODS: Eligibility for this trial required bidimensionally measurable locally recurrent or metastatic squamous or adenosquamous carcinoma of the uterine cervix; SWOG performance status of

The future of sarcoma treatment.

The last two decades have shown exciting and dramatic improvements in the management of osteogenic sarcoma, while progress in soft tissue sarcomas has lagged behind considerably. Osteogenic sarcoma treatment has been a model of multidisciplinary collaboration. Orthopedic surgeons working together with medical and pediatric oncologists have improved disease-free survival while improving limb salvage rates and limb function. In contrast, the care of soft tissue sarcoma remains fragmented among many disciplines and specialties. Medical and pediatric oncologists, radiation oncologists, and a myriad of surgical specialists are all involved in the care of soft tissue sarcomas, and significant treatment (usually surgical) often occurs before referral to a center. Significant variation in managment leads to considerable difficulty in assessing the effects of treatment on outcome. Improvement in soft tissue sarcoma management will occur only when physicians recognize the need to centralize care to appropriate physicians within referral centers where patients can be treated on standardized cooperative protocols.

Retention of esthetic veneers on primary stainless steel crowns.

The purpose of this study was to ascertain the amount of shearing force necessary to fracture, dislodge or deform the esthetic veneer facings of four commercially available veneered primary incisor stainless steel crowns. The four types tested were: Cheng Crowns, [Peter Cheng Orthodontic Laboratory]; Whiter Biter Crown II, [White Bite Inc.]; Kinder Krowns, [Mayclin Dental Studio, Inc]; and NuSmile Primary Crowns, [Orthodontic Technologies, Inc]. The crowns (#4 right central incisor) from each manufacturer were obtained with the facings attached. The crowns were soaked for ninety days and thermocycled at 4 degrees C and 55 degrees C for 500 45-second cycles. The crowns were cemented to standardized chromium cobalt metal dies. Each die was placed in to a custom holder on the Instron Universal testing machine. A force was applied at the incisal edge of the veneer at 148 degrees, (the primary interincisal angle), with a crosshead speed of 0.05 inches/minute until the veneer either fractured, dislodged or deformed. The mean force (Ibs) required +/- SD to produce failure, in descending order, was as follows: Cheng (107.8 +/- 17.3); NuSmile (100.2 +/- 18.2); KinderKrown (91.3 +/- 27.4)d Whiter Biter (81.5 +/- 21.7). To test the hypothesis of no difference among the four manufacturers, an analysis of variance was performed using PROC GLM. The resultant F statistic was 2.79 (p < 0.0543), indicating a marginally statistically significant difference in the response variable "pressure" among the four groups. A posthoc test was then performed to ascertain where these differences occurred. These results, using Turkey's studentized range test for pairwise comparisons, suggested that the only difference was between the Cheng and Whiter Biter manufacturers.

Effects of a physician communication intervention on patient care outcomes.

OBJECTIVE: To determine whether an intervention designed to improve patient-physician communication increases the frequency with which physicians elicit patients' concerns, changes other communication behaviors, and improves health care outcomes. DESIGN: Pretest-posttest design with random assignment of physicians to intervention or control groups. SETTING: General medicine clinics of a university-affiliated Veterans Affairs Hospital. PATIENTS/PARTICIPANTS: Forty-two physicians and 348 continuity care patients taking prescription medications for chronic medical conditions. INTERVENTIONS: Intervention group physicians received 4.5 hours of training on eliciting and responding to patients' concerns and requests, and their patients filled out the Patient Requests for Services Questionnaire prior to a subsequent clinic visit. Control group physicians received 4.5 hours of training in medical decision-making. MEASUREMENTS AND MAIN RESULTS: The frequency with which physicians elicited all of a patient's concerns increased in the intervention group as compared with the control group (p = .032). Patients perceptions of the amount of information received from the physician did increase significantly (p < .05), but the actual magnitude of change was small. A measure of patient satisfaction with the physicians was high at baseline and also showed no significant change after the intervention. Likewise, the intervention was not associated with changes in patient compliance with medications or appointments, nor were there any effects on outpatient utilization. CONCLUSIONS: A low-intensity intervention changed physician behavior but had no effect on patient outcomes such as satisfaction, compliance, or utilization. Interventions may need to focus on physicians and patients to have the greatest effect.

Phase I trial of Adozelesin using the treatment schedule of daily x5 every 3 weeks.

CC-1065 is a unique alkylating agent that preferentially binds in the minor groove of double-stranded DNA at adenine-thymine-rich sites. Although it has broad antitumor activity in preclinical models its development was discontinued because of deaths observed during preclinical toxicology studies. Adozelesin is a potent synthetic analog that was chosen for clinical development because it had a similar preclinical antitumor spectrum, but did not produce deaths similar to CC-1065 at therapeutic doses. Phase I evaluations using a variety of Adozelesin treatment schedules have been conducted. This report describes our experience using a multiple dose treatment schedule. Endpoints including antitumor response, maximum tolerated dose, dose limiting toxicity as well as other toxicities and the recommended Phase II starting dose were determined. Adozelesin was given as a 10 minute IV infusion for 5 consecutive days every 21 days or upon recovery from toxicity. The dose range evaluated was 6-30 mcg/m2/day. All patients had refractory solid tumors and had received prior cytotoxic treatment. Thirty-three patients (22 men: 11 women) were entered onto the study and 87 courses were initiated. Dose limiting toxicity was cumulative myelosuppression (leucopenia, thrombocytopenia). The maximum tolerated dose was 30 mcg/m2/day. The only other significant toxicity was an anaphylactoid syndrome that occurred in 2 patients. A partial response was observed in a patient with refractory soft tissue sarcoma. The recommended Phase II starting dose of Adozelesin using a 10 minute IV infusion for 5 consecutive days is 25 mcg/m2/day to be repeated every 4-6 weeks to allow recovery from myelotoxicity, based on our experience. Additional Phase I and II studies with Adozelesin are recommended.

Psychological distress in patients with gastroesophageal reflux disease.

BACKGROUND: Psychological factors play a role in a variety of gastrointestinal illnesses, including esophageal diseases. The role of psychological factors in gastroesophageal reflux disease (GERD) is not known. The purpose of this study was to determine if psychological distress is present in patients with reflux disease. METHODS: We performed psychological assessments in 51 patients with documented gastroesophageal reflux disease and in 43 age-matched controls using a battery of instruments. RESULTS: Patients with reflux differed from controls on scales of depression, somatization, anxiety, and intensity of reporting symptom distress. However, a secondary analysis revealed that it was a subset of reflux patients (30%) that accounted for the differences between the two groups. CONCLUSIONS: These results suggest that although most patients with GERD are psychologically similar to patients without GERD, a subset of psychologically distressed patients are more likely to be found among patients with GERD. They suffer from general psychological distress rather than a specific psychiatric disorder. This psychological factor could affect the clinical manifestations of reflux disease in these individuals. Recognition and management of psychological distress in this subgroup may aid in the management of reflux disease.

Systemic adjuvant chemotherapy for soft tissue sarcomas.

Adjuvant chemotherapy for soft tissue sarcoma remains investigational. Continued study of multidisciplinary treatment programs in high-grade sarcomas in formal clinical trials remains a priority. The National Cancer Institute is currently conducting a randomized trial of postoperative adjuvant doxorubicin and ifosfamide as compared with observation in high-grade sarcoma. The completion and outcome of this trial will contribute to this ongoing debate. Finally, a better understanding of the biology of soft tissue sarcoma that determines subsequent clinical course may serve as a foundation for further investigation.

Pharmacokinetics of 9-methoxy-N,N-dimethyl-5-nitropyrazolo [3,4, 5-kl]acridine-2(6H)-propanamine (PZA, PD 115934, NSC 366140) in mice: guidelines for early clinical trials1.

Pharmacokinetic studies that consisted of measuring the plasma drug profile, tissue drug distribution, and elimination in urine and feces were performed in female C57BL/6 x DBA/2 (hereafter called B6D2F1) and male B6D2F1A/2 and C57BL/6 x CH3 (hereafter called B6C3F1) mice following treatment with a 1-h i.v. infusion of the PZA, PD115934 (NSC 366140). This drug is the first of a new class of cytotoxic agents and was selected for clinical trials because of both its broad antitumor activity in vivo against murine solid tumors and human xenografts, and its in vivo toxicity profile that was predictable based on drug dose and schedule of administration. The pharmacokinetic results obtained here in mice have been used to facilitate the dose escalations during the Phase I trial and to determine pharmacokinetic drug exposure targets for its acute and sub-acute toxic effects. Plasma samples from three to four mice per time point were pooled, and then individual tissue samples from the same mice were collected at specified times following treatment. All samples were prepared using solid-phase extraction and assayed using high pressure liquid chromatography. The acute dose-limiting toxicity was neurological and occurred immediately after treatment at 300 mg/m2. The peak plasma level range at the acute maximum tolerated dose was 1040-1283 ng/ml. Thus, peak plasma levels <1000 ng/ml were the acute toxicity target. Variations in the area under the plasma drug concentration x the time curve were observed that did not appear to be related to sex or age. The previously defined subacute dose-limiting toxicity was myelosuppression that occurred at a maximum tolerated dose of 600 mg/m2 (300 mg/m2 x 2) in B6D2F1 females. Thus, the area under the plasma drug concentration x the time curve in B6D2F1 females at this dose (1048 microg/ml x min) was the area under the plasma drug concentration x the time curve target. Drug levels were detected at 60 min following treatment in all tissues examined with a plasma:tissue ratio as high as 1:500. The organs with the highest levels were kidney, pancreas, liver, lung, and brain. Fecal excretion was low (range, 0.04-0.20% of the dose administered) and was not clearly different between males and females. Urinary excretion was higher (range, 5-28% of the dose administered) and did show evidence of sex-related differences, with male urinary drug excretion being higher than female urinary drug excretion. The drug was >/=95% protein bound. Preliminary evidence for drug metabolism was found in urine and feces and will be further explored.