Phase I/IIa trial of the mammalian target of rapamycin inhibitor ridaforolimus (AP23573; MK-8669) administered orally in patients with refractory or advanced malignancies and sarcoma.

BACKGROUND: Ridaforolimus is an inhibitor of mTOR with evidence of antitumor activity in an I.V. formulation. This multicenter, open-label, 3 + 3 design nonrandomized, dose-escalation, phase I/IIa trial was conducted to determine the safety, pharmacokinetic (PK) and pharmacodynamic parameters, maximum tolerated dose, and antitumor activity of oral ridaforolimus. PATIENTS AND METHODS: Patients with metastatic or unresectable solid tumors refractory to therapy were eligible. Seven different continuous and intermittent dosing regimens were examined. RESULTS: One hundred and forty-seven patients were enrolled in this study among which 85 were patients with sarcoma. Stomatitis was the most common DLT observed. The dosing regimen, 40 mg QD × 5 days/week, provided the best combination of cumulative dose, dose density, and cumulative exposure, and was the recommended dosing regimen for subsequent clinical development. PK was nonlinear, with less than proportional increases in day-1 blood AUC0-∞ and Cmax, particularly with doses >40 mg. The terminal half-life estimate of ridaforolimus (QD × 5 40 mg) was 42.0 h, and the mean half-life ∼30-60 h. The clinical benefit rate, (complete response, partial response, or stable disease for ≥4 months was 24.5% for all patients and 27.1% for patients with sarcoma. CONCLUSION: Oral ridaforolimus had an acceptable safety profile and exhibited antitumor activity in patients with sarcoma and other malignancies. ClinicalTrials.gov Identifier NCT00112372.

PIPELINEs: Creating Comparable Clinical Knowledge Efficiently by Linking Trial Platforms.

Adaptive, seamless, multisponsor, multitherapy clinical trial designs executed as large scale platforms, could create superior evidence more efficiently than single-sponsor, single-drug trials. These trial PIPELINEs also could diminish barriers to trial participation, increase the representation of real-world populations, and create systematic evidence development for learning throughout a therapeutic life cycle, to continually refine its use. Comparable evidence could arise from multiarm design, shared comparator arms, and standardized endpoints-aiding sponsors in demonstrating the distinct value of their innovative medicines; facilitating providers and patients in selecting the most appropriate treatments; assisting regulators in efficacy and safety determinations; helping payers make coverage and reimbursement decisions; and spurring scientists with translational insights. Reduced trial times and costs could enable more indications, reduced development cycle times, and improved system financial sustainability. Challenges to overcome range from statistical to operational to collaborative governance and data exchange.

Measurement of estrogen and progesterone receptors in human breast tumors: enzyme immunoassay versus binding assay.

To determine whether we could replace our current binding assay (BA) method for measurement of estrogen receptors (ERs) and progesterone receptors (PRs) with the recently developed enzyme immunoassay (EIA) method, we compared simultaneous measurements of ERs and PRs in frozen breast tumor samples by both methods. A value of greater than or equal to 10 fmol/mg cytosol protein was defined as positive. There was agreement between the BA and EIA on whether the sample was positive or negative in 75 of 91 (82%) samples measured for ERs and in 74 of 93 (80%) for PRs. When the threshold value for a positive assay was redefined as greater than or equal to 20 fmol/mg protein, there was agreement in 85 of 91 (93%) samples for ERs and 85 of 93 (91%) for PRs. The numerical value for ERs by EIA was not consistently greater or less than ERs by BA, but the difference between the EIA and BA measurement increased as the size of the measurement increased. We did not see an excess of premenopausal patients whose ERs by BA were negative and whose ERs by EIA were positive. Although we performed a linear regression analysis and determined the Pearson correlation coefficient to compare the BA and EIA as reported by others, we show that this analysis may be misleading when the objective is to demonstrate similarities between these methods. Our study shows that the EIA can be confidently used in place of the BA. However, a threshold value for a positive EIA should be confirmed clinically in future studies.

Randomized placebo-controlled study of recombinant human interleukin-11 to prevent chemotherapy-induced thrombocytopenia in patients with breast cancer receiving dose-intensive cyclophosphamide and doxorubicin.

PURPOSE: Thrombocytopenia may compromise cancer treatment, causing chemotherapy dose reductions, schedule alterations, or the need for platelet transfusions. We evaluated the efficacy and safety of recombinant human interleukin-11 (rhIL-11; Neumega, Genetics Institute, Inc, Cambridge, MA), a novel thrombopoietic growth factor, in reducing the need for platelet transfusions in patients who undergo dose-intensive chemotherapy. PATIENTS AND METHODS: Women with advanced breast cancer received cyclophosphamide (3,200 mg/m2) and doxorubicin (75 mg/m2) plus granulocyte colony-stimulating factor (G-CSF; 5 microg/kg/d). Patients were randomized to blinded treatment with placebo or 50 microg/kg/d rhIL-11 subcutaneously for 10 or 17 days after the first two chemotherapy cycles. RESULTS: Seventy-seven patients were randomized and constitute the intent-to-treat (ITT) population. Sixty-seven patients (the assessable subgroup) either completed both cycles without a major protocol violation (n = 62) or received a platelet transfusion before treatment was discontinued after the first cycle. In the ITT population, rhIL-11 significantly decreased the requirement for platelet transfusions; 27 of 40 (68%) patients who received rhIL-11 did not require transfusions, compared with 15 of 37 (41%) in the placebo group (P = .04). Treatment with rhIL-11 significantly reduced the total number of platelet transfusions required in the assessable subgroup (P = .03) and the time to platelet recovery to more than 50,000/microL in the second cycle (P = .01). Most adverse events associated with rhIL-11 were reversible, mild to moderate in severity, and likely related to fluid retention. CONCLUSION: rhIL-11 is safe and effective in reducing treatment-associated thrombocytopenia and the need for platelet transfusions in patients who undergo dose-intensive chemotherapy, and thus may permit chemotherapy to be administered as planned at intended doses and thereby maximize the potential for a successful outcome.

Ventilation scintigraphy with submicronic radioaerosol as an adjunct in the diagnosis of congenital lobar emphysema.

When clinical examination and routine chest x-ray do not adequately explain neonatal respiratory distress, lung scintigraphy using a submicronic aerosol particle may be most helpful. Three cases illustrating this point are presented. Discussion centers around the diagnosis of an atypical case of congenital lobar emphysema (CLE), and differentiating between CLE, foreign body aspiration and compensatory hyperinflation in neonates with respiratory distress. Conservative and surgical treatment options for CLE are also illustrated.

Mechanism and amelioration of recombinant human interleukin-11 (rhIL-11)-induced anemia in healthy subjects.

Recombinant human interleukin-11 (rhIL-11), or Neumega rhIL-11 Growth Factor, is a recombinant cytokine that stimulates megakaryocytopoiesis, increases platelet production, and also has shown anti-inflammatory and immune-modulating activity. Mild, reversible anemia was the most common adverse event observed in clinical studies and was demonstrated to be related to hemodilution. The purpose of this study was to examine the renal mechanisms of the rhIL-11-induced volume retention and devise a possible therapeutic intervention to ameliorate this effect. Eighteen healthy volunteers (9 male and 9 female) on a controlled sodium (180 mEq/day) and potassium (120 mEq/day) diet were randomized to one of six treatment sequences in a three-period crossover design. Each subject received 25 micrograms/kg IL-11 s.c. once daily, 25 micrograms/kg IL-11 s.c. once daily + Maxzide-25 twice daily, or placebo for 7 days in a crossover design. There was a 14-day washout period between treatment periods. Renal clearance parameters indicated that mean sodium excretion was decreased compared to placebo within 8 hours after dosing with rhIL-11, with these results reaching statistical significance 8 to 16 hours postdose (p < 0.01). The cumulative sodium excretion (mEq +/- SD) over the 7-day treatment period for each respective treatment group was the following: rhIL-11 = 833 +/- 154, rhIL-11 + Maxzide-25 twice daily = 1114 +/- 178, and placebo = 982 +/- 193 (p < 0.01). Hemoglobin concentration and hematocrit values, used as indicators of hemodilution, decreased in the rhIL-11-treated group as compared to the baseline and placebo groups (p < 0.01). Concurrent dosing with Maxzide-25 twice daily reduced the rhIL-11-associated hemodilution by about 50%.

Dedifferentiated chondrosarcoma with features of telangiectatic osteosarcoma.

We describe a 44-year-old female with a known history of a solitary osteochondroma of the scapula followed on X-ray for five years. She then presented with a rapidly growing lump. Imaging studies confirmed the presence of an aggressive looking lesion. Excision was performed and pathology showed a dedifferentiated chondrosarcoma with features of a telangiectatic osteosarcoma.

Identifying predictive variables for long-term weight change after participation in a weight loss program.

OBJECTIVE AND DESIGN: To determine if there was an association between weight change and 31 independent variables among obese persons 2 years after a weight loss program. Data were obtained from subjects' records and from questionnaires administered at enrollment and after a 2-year follow-up. SETTING: The 8-week weight control program was taught by registered dietitians and developed by the staff at the Sid Richardson Institute for Preventive Medicine, Houston, Tex. SUBJECTS/SAMPLES: Of the 1,460 subjects who attended at least one of eight classes, 509 subjects (123 men and 386 women) responded to the mailed follow-up questionnaire. MAIN OUTCOME MEASURES: Associations between weight change and the 31 independent variables were assessed. Heights and weights were measured by the dietitians during treatment. Two-year follow-up weights were self-reported. STATISTICAL ANALYSES PERFORMED: Analysis of variance was used for 16 of the independent variables. For the remaining variables we performed a test of the null hypothesis that the correlation coefficient was 0 based on the test of the regression coefficient between the independent and dependent variable. A stepwise regression process was used to determine the best combination of variables predictive of weight change. RESULTS: Of the 31 independent variables, 16 were significantly predictive of weight change. The adjusted R2 for the entire group of 16 variables was .379. Thus, 37.9% of the variance was explained by the joint efforts of the 16 variables. Eight variables with an adjusted R2 of .371 (accounting for 37.1% of the variance) were most important: feeling in control of eating habits, percentage over ideal body weight at enrollment, percentage of weight lost during the 8-week treatment, frequency of weight measurement, increase in physical activity, frequency of eating in response to emotions, number of pounds gained before subject resumed diet, and occupation. APPLICATION/CONCLUSION: The predictive variables for weight change may be useful to professionals who treat obese clients and may improve success rates of long-term weight loss.

Long-term follow-up of weight status of subjects in a behavioral weight control program.

Few studies have examined the long-term effectiveness of behavioral weight control programs. Interpretation of the results from these studies has been limited due to small sample size, use of only one sex, and the number of evaluation parameters. A 2-year follow-up study was designed to assess the effectiveness of a behavioral weight control program on 123 obese male and 386 obese female subjects. Body weights were measured by dietitians at baseline and after an 8-week treatment program. Two-year follow-up weights were self-reported from a mailed questionnaire. The subjects' mean weight at baseline was 185.6 +/- 43.4 lb (no. = 509). Their mean percent over ideal body weight at baseline was 29.7%. Following an 8-week treatment period, mean weight was 176.4 +/- 41.3 lb (no. = 509), yielding a mean weight loss of 9.2 +/- 6.4 lb. Weight change after the 8-week treatment period ranged from a loss of 37 lb to a gain of 5 lb. The 2-year follow-up study showed that mean weight of the 498 subjects was 179.8 +/- 42.9 lb, yielding a mean weight loss of 5.8 +/- 15.5 lb. Weight change ranged from a loss of 71 lb to a gain of 47 lb. After 2 years, 325 subjects (65.3%) were still below their baseline weights, 182 subjects (36.6% of the entire study group) had maintained or enhanced the weight loss achieved during treatment, and 80 subjects (16.1%) weighed at least 10% less than their baseline weight.(ABSTRACT TRUNCATED AT 250 WORDS)

Statistical methods that distinguish between attributes of assessment: prolongation of life versus quality of life.

The authors propose a method to generate information relevant to the decision tree that adds additional perspective to the characterization of health quality during survival. Their approach uses survival data to distinguish two attributes of utility: prolongation of life and quality of life (QOL). Health-state transition probabilities correspond to the prolongation of life and are modeled in a discrete-time transient semi-Markov process. Quality-of-life-state transition probabilities are derived from the assumptions of a simple recurrent Markov process. They reflect events within the health-state sojourn time that differentiate perceptions of pain and suffering over a short fixed time period. Outcomes for these two dimensions of utility are highly relevant to the assessment of medical technology that might prolong life at the cost of increased pain and suffering, implying a reduced QOL. The methods are demonstrated on a subset of follow-up data from the Beta-Blocker Heart Attack Trial (BHAT).

Transient thalamic changes on MRI in a child with hypernatremia.

Severe hypernatremia has been associated with a wide variety of central nervous system lesions. Neurologic sequelae are the usual outcome in those cases in which a lesion has been documented neuroradiologically. The authors report a 7-month-old male with severe hypernatremia who developed obtundation after correction of the electrolyte imbalance. Magnetic resonance imaging revealed bilateral thalamic signal changes that resolved on follow-up study, in accordance with complete clinical recovery. To the authors' knowledge, bilateral thalamic signal changes are previously unreported findings associated with hypernatremia. Pertinent literature and the clinical course of the authors' patient are the basis for questioning currently recommended guidelines for the rate of correction of hypernatremia.

Apophysial joint degeneration, disc degeneration, and sagittal curve of the cervical spine. Can they be measured reliably on radiographs?

STUDY DESIGN: Interexaminer reliability study. OBJECTIVES: To determine the reliability of grading apophysial joint and disc degenerative changes and the reliability of measuring sagittal curves on lateral cervical spine radiographs. SUMMARY OF BACKGROUND DATA: Several authors have proposed that the presented of degenerative changes and the absence of lordosis in the cervical spine are indicators of poor recovery from neck injuries caused by motor vehicle collisions. The validity of those conclusions is questionable because the reliability of the methods used in their studies to measure the presence of degenerative changes and the absence of lordosis has not been determined. METHODS: Kellgren's classification system for apophysial joint and disc degeneration, as well as the pattern and magnitude of the sagittal curve on 30 lateral cervical spine radiographs were assessed independently by three examiners. RESULTS: Moderate reliability was demonstrated for classifying apophysial joint degeneration with an intraclass correlation coefficient of 0.45 (95% confidence interval, 0.09-0.71). Classifying degenerative disc disease had substantial reliability, with an intraclass correlation coefficient of 0.71 (95% confidence interval, 0.23-0.88). Measuring the magnitude of the sagittal curve from C2 to C7 had excellent interexaminer agreement, with an intraclass correlation coefficient of 0.96 (95% confidence interval, 0.88-0.98) and an interexaminer error of 8.3 degrees. CONCLUSIONS: The classification system for degenerative disc disease proposed by Kellgren et al and the method of measurement of sagittal curves from C2 to C7 demonstrated an acceptable level of reliability and can be used in outcomes research.

Upper extremity physical factors affecting tennis serve velocity.

Forty tournament-level tennis players with expert serve technique volunteered to have their serve evaluated to determine relationships between anthropometric data, extremity strength, and functional serve velocity. All players underwent a complete physical examination, a video taped serve analysis, a radar measurement of serve velocity, and a series of upper extremity strength measurements. Statistical analysis was performed to determine which factors were related to serve velocity. Statistically significant relationships were found between serve velocity and several flexibility measurements including increased dominant wrist flexion (P < 0.05), increased dominant shoulder flexion (P < 0.05), and increased dominant shoulder internal rotation at 0 degrees of abduction (P < 0.05). Several strength measurements were also related to serve velocity including elbow extension torque production (P < 0.01) and the ratios of internal to external rotational torque production for both low- and high-speed measurements (P < 0.01 concentrically and P < 0.05 eccentrically). These findings relate strength and flexibility to serve velocity, suggesting that it may be possible to increase a tennis player's serve velocity through specifically directed muscular strengthening or stretching regimens. However, prospective studies must be undertaken to demonstrate these possibilities.

Value of three-dimensional gradient-echo magnetic resonance cholangiography in diagnosing choledocholithiasis.

OBJECTIVE: To evaluate the role of magnetic resonance cholangiography (MRC) in patients with suspected choledocholithiasis. PATIENTS AND METHODS: Twenty-six consecutive patients with suspected choledocholithiasis (11 men and 15 women ranging in age from 25 to 81 years) underwent three-dimensional gradient-echo MRC; each patient also underwent endoscopic retrograde cholangiography or operative cholangiography. Each set of images for each patient was reviewed independently by a radiologist who was unaware of the results of the other type of imaging. RESULTS: Diagnostic-quality MRC images were obtained for 17 of the patients. Of these, 13 had stones in the common bile duct, as confirmed by another imaging method, and MRC indicated the presence of these stones in all 13 patients. In the other four patients bile duct obstruction was due to either acute pancreatitis (in three) or cholangiocarcinoma (in one). For seven of the nine nondiagnostic-quality MRC studies, the bile duct was not obstructed, so there was no bile stasis and the MRC images could not be obtained. Motion artifacts due to inability to hold the breath were the limiting factors in the other two patients. CONCLUSION: Although MRC has some limitations, this new noninvasive technique may be used as a screening test in selected patients with suspected choledocholithiasis.

Hepatocellular adenomatosis associated with hereditary haemochromatosis.

A young healthy man presented with abdominal pain following an accidental fall. Imaging studies and laparoscopy revealed multiple yellowish well-defined hepatic lesions. Liver biopsies showed hepatic adenomas and iron overload. Laboratory investigation confirmed a diagnosis of hereditary haemochromatosis. To our knowledge this represents the first report of an association of hepatic adenomatosis and primary haemochromatosis.

Postoperative computed tomography scan study of the pterygomaxillary separation during the Le Fort I osteotomy using a micro-oscillating saw.

PURPOSE: The objective of the study was to evaluate the type of pterygomaxillary separation that occurs with use of a micro-oscillating saw. PATIENTS AND METHODS: Sixteen patients underwent a postoperative computed tomography scan. RESULTS: Ideal or near-ideal separations occurred on 26 of 32 sides (81%), while low-level fractures occurred in 6 of 32 sides (19%). No high-level fractures of the pterygoid plates, or fractures extending to the base of the skull or orbit, were seen. There was a striking difference in the number of ideal separations on the right-hand side (94%), compared with the left-hand side (50%), probably because of the greater difficulty of a right-handed surgeon positioning the saw blade correctly on the left side without bending the thin flexible saw blade backward. CONCLUSION: In view of the high percentage of ideal pterygomaxillary separations achieved using a micro-oscillating saw, and the absence of high-level pterygoid plate fractures extending to the base of the skull, this technique is recommended for the pterygomaxillary dysjunction.

Levator claviculae muscle discovered during physical examination for cervical lymphadenopathy.

During a routine physical examination of an adult female with a history of breast cancer and cervical lymphadenopathy, a mass was noted in the right supraclavicular region. The mass was unilateral and easily palpable along the superior border near the median aspect of the clavicle. Plain film radiography, performed to determine whether the mass represented an enlarged jugulo-omohyoid lymph node, revealed an elongated opaque mass in this region. Computed tomographic (CT) and magnetic resonance (MR) images were subsequently obtained. Sequential axial CT scans revealed a cylindrical mass that appeared to be independent of contiguous muscles, including the sternocleidomastoid, anterior, and middle scalene muscles. This mass attached inferiorly to the clavicle and superiorly to the transverse process of the sixth cervical vertebra. Sagittal, coronal, and axial MR scans confirmed the presence of a well-defined superficial mass. It is concluded that the mass represents a levator claviculae (cleidocervical) muscle. This observation underscores the importance of understanding soft tissue variants that may be encountered during a routine physical examination.

Skeletal metastases in colorectal carcinomas: a Saskatchewan profile.

PURPOSE: Colorectal cancer is the third leading cause of cancer-related deaths in the world. Death is usually attributed to progress of the disease with recurrence and metastases. Skeletal metastases in primary colorectal cancer is an uncommon event. When such an event occurs, it is usually a late manifestation of the disease. In our study this phenomenon is analyzed in a population-based database. METHODS: This report is a 25-year retrospective review that covers patients with skeletal metastases secondary to colorectal carcinomas registered at The Saskatchewan Cancer Foundation from 1970 to 1995. The latter is the sole registration agency of all cancers in the one million population base of the province of Saskatchewan. RESULTS: A total of 5,352 cases of primary colorectal carcinomas were seen between 1970 and 1995. Of these, 355 had skeletal metastases. The incidence of osseous metastases in our institution is 6.6 percent. Among the latter, 60 cases (16.9 percent) had skeletal metastases only, whereas 295 cases (83.1 percent) had skeletal metastases in combination with lung, liver or brain metastases. This is in keeping with the fact that solitary skeletal metastases from a primary colonic carcinoma is a rare event, with an incidence of 1.1 percent in our institution. The disease-free interval from the time of diagnosis of the cancer to the onset of skeletal metastases ranged from 10 days to 5,309 days. Thirty-eight percent of the cases with skeletal metastases only were alive at the end of five years in comparison with 16 percent of the cases with skeletal and other metastases. However, there was no significant difference in the ten-year survival curves from the onset of osseous metastases in the two groups. The majority were diagnosed by a bone scan or plain radiography or both. Most cases in our institution received a multimodal treatment consisting of radiotherapy in conjunction with palliative surgery or chemotherapy or both. Radiotherapy was, however, the most effective therapy for painful skeletal metastases. CONCLUSION: Skeletal metastasis is a rare event in primary colorectal carcinomas. Among these cases there is an emerging trend of a different clinical-biological behavior pattern between patients who develop solitary skeletal metastases vs. patients with skeletal and other organ metastases.

Cementless total knee arthroplasty in obese patients. A comparison with a matched control group.

The heaviest 45 patients (50 knees) who underwent cementless total knee arthroplasty were compared with a matched control group of 45 total knee arthroplasty patients (50 knees) with respect to clinical and radiographic data. Surgery was performed over a 10-year period (1980-1989) and follow-up evaluation averaged 7 years (range, 2-11 years). The control group consisted of nonobese patients matched to the obese group with respect to age, sex, diagnosis, preoperative deformity, and length of follow-up evaluation. Clinical evaluation was made using the Knee Society rating scale as well as an analysis of multiple other clinical parameters. Radiographically, each patient was evaluated with long-standing anteroposterior views, lateral and patellar views, and spot fluoroscopic views of the involved knee. This evaluation included an analysis of lucencies, bead shedding, and prosthetic alignment. The final average clinical score in the obese group was 88 points with four revisions, and that for the control group was 91 points with two revisions. There were no significant differences in the combined percentage of good and excellent results between the two groups. On the basis of the results of this study, it is believed that weight as a factor by itself should not compromise the early (7-year average follow-up period) results of total knee arthroplasty.

Outpatient treatment of febrile episodes in low-risk neutropenic patients with cancer.

BACKGROUND: Hospitalization and intravenous (IV) broad-spectrum antibiotics are the standard of care for all febrile neutropenic patients with cancer. Recent work suggests that a low-risk population exists who might benefit from an alternate approach. METHODS: A prospective randomized clinical trial was performed comparing oral ciprofloxacin 750 mg plus clindamycin 600 mg every 8 hours with IV aztreonam 2 g plus clindamycin 600 mg every 8 hours for the empiric outpatient treatment of febrile episodes in low-risk neutropenic patients with cancer. RESULTS: The oral regimen cured 35 of 40 episodes (88% response rate), whereas the IV regimen cured 41 of 43 episodes (95% response rate, P = 0.19). Although the cost of the oral regimen was significantly less than that of the IV regimen (P < 0.0001), it was associated with significant renal toxicity (P < 0.05), which led to early termination of the study. Overall, combining its safety and efficacy, the IV regimen was superior (P = 0.03). CONCLUSIONS: This prospective study suggested that outpatient antibiotic therapy for febrile episodes in low-risk neutropenic patients with cancer is safe and effective. Better oral regimens are needed.