A phase I safety and pharmacologic study of a twice weekly dosing regimen of the oral taxane BMS-275183.

PURPOSE: BMS-275183, an orally administered C-4 methyl carbonate paclitaxel analogue, showed promising activity in a phase I trial investigating a weekly treatment regimen, but was associated with a relatively high incidence of neuropathic side effects. The current dose escalation phase I trial was initiated to investigate whether twice weekly administration of BMS-275183 would improve its safety and tolerability. Additionally, the pharmacokinetics and possible antitumor activity were studied. EXPERIMENTAL DESIGN: A cycle consisted of 4 weeks (i.e., eight twice weekly oral doses). The starting dose was 60 mg/m(2) and the dose was increased by 20 mg/m(2) increments. Cohorts consisted of three patients and were expanded to at least six patients when toxicity was encountered. Plasma pharmacokinetics were done on days 1 and 15. RESULTS: A total of 38 patients were enrolled. The maximum tolerated dose was 100 mg/m(2) twice weekly. Seventeen patients were treated at the maximum tolerated dose; 3 of 17 patients experienced a dose-limiting toxicity, consisting of a combination of neutropenia, neuropathy, and diarrhea. BMS-275183 seemed to have a considerably lower incidence of neuropathic side effects compared with the weekly treatment regimen. Confirmed partial responses were observed in two patients with non-small cell lung cancer, one patient with prostate cancer, and one patient with melanoma. In addition, a long-lasting prostate-specific antigen response was observed in a patient with prostate carcinoma with nonmeasurable disease. CONCLUSIONS: BMS-275183 is preferably given in a twice weekly regimen and has considerable antitumor activity. A phase II trial in non-small cell lung cancer using the twice weekly schedule has been initiated.     

Survivin and b7-h1 are collaborative predictors of survival and represent potential therapeutic targets for patients with renal cell carcinoma.

PURPOSE: Clear cell renal cell carcinoma (ccRCC) is an immunogenic tumor that can progress in the presence of an intact host immune system. We previously reported that survivin and B7-H1 are independently associated with disease progression and death when expressed by ccRCC tumors. Herein, we examine the clinical effect of ccRCC combined expression of both survivin and B7-H1. EXPERIMENTAL DESIGN: Specimens from 298 patients who underwent nephrectomy for ccRCC between 1990 and 1994 were immunohistochemically stained for survivin and B7-H1. Cancer-specific survival was estimated using the Kaplan-Meier method. Associations of both markers with ccRCC death were assessed using Cox proportional hazards regression models. RESULTS: At last follow-up, 94 patients died from ccRCC. Among the living patients, the median follow-up was 11.2 years (range, 0-15 years). There were 177 (59.4%) survivin(Low)/B7-H1(-), 51 (17.1%) survivin(Hi)/B7-H1(-), 29 (9.7%) survivin(Low)/B7-H1(+), and 41 (13.8%) survivin(Hi)/B7-H1(+) tumors. The 5-year cancer-specific survival rates for patients within each group were 89.3%, 59.7%, 70.0%, and 16.2%, respectively. Combined survivin(Hi)/B7-H1(+) expression was associated with ccRCC death univariately (risk ratio, 12.82; 95% confidence interval, 7.50-21.92; P < 0.001) and in multivariate analysis (risk ratio, 2.81; 95% confidence interval, 1.56-5.04; P < 0.001). Survivin(Hi)/B7-H1(+) tumors exhibited increased levels of infiltrating mononuclear cells and survivin-specific T cells compared with survivin(Low)/B7-H1(-) tumors. CONCLUSION: Patients with survivin(Hi)/B7-H1(+) ccRCC tumors are at increased risk of ccRCC death. Survivin(Hi)/B7-H1(+) tumors also harbor increased amounts of infiltrating mononuclear cells and survivin-specific T cells relative to survivin(Low)/B7-H1(-) tumors. Taken together, dual expression of survivin and B7-H1 can be used to predict ccRCC tumor aggressiveness.     

A potential to reduce pulmonary toxicity: the use of perfusion SPECT with IMRT for functional lung avoidance in radiotherapy of non-small cell lung cancer.

BACKGROUND AND PURPOSE: The study aimed to examine specific avoidance of functional lung (FL) defined by a single photon emission computerized tomography (SPECT) lung perfusion scan, using intensity modulated radiotherapy (IMRT) and three-dimensional conformal radiotherapy (3-DCRT) in patients with non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Patients with NSCLC underwent planning computerized tomography (CT) and lung perfusion SPECT scan in the treatment position using fiducial markers to allow co-registration in the treatment planning system. Radiotherapy (RT) volumes were delineated on the CT scan. FL was defined using co-registered SPECT images. Two inverse coplanar RT plans were generated for each patient: 4-field 3-DCRT and 5-field step-and-shoot IMRT. 3-DCRT plans were created using automated AutoPlan optimisation software, and IMRT plans were generated employing Pinnacle(3) treatment planning system (Philips Radiation Oncology Systems). All plans were prescribed to 64 Gy in 32 fractions using data for the 6 MV beam from an Elekta linear accelerator. The objectives for both plans were to minimize the volume of FL irradiated to 20 Gy (fV(20)) and dose variation within the planning target volume (PTV). A spinal cord dose was constrained to 46 Gy. Volume of PTV receiving 90% of the prescribed dose (PTV(90)), fV(20), and functional mean lung dose (fMLD) were recorded. The PTV(90)/fV(20) ratio was used to account for variations in both measures, where a higher value represented a better plan. RESULTS: Thirty-four RT plans of 17 patients with stage I-IIIB NSCLC suitable for radical RT were analysed. In 6 patients with stage I-II disease there was no improvement in PTV(90), fV(20), PTV/fV(20) ratio and fMLD using IMRT compared to 3-DCRT. In 11 patients with stage IIIA-B disease, the PTV was equally well covered with IMRT and 3-DCRT plans, with IMRT producing better PTV(90)/fV(20) ratio (mean ratio - 7.2 vs. 5.3, respectively, p=0.001) and reduced fMLD figures compared to 3-DCRT (mean value - 11.5 vs. 14.3 Gy, p=0.001). This was due to reduction in fV(20) while maintaining PTV coverage. CONCLUSION: The use of IMRT compared to 3-DCRT improves the avoidance of FL defined by perfusion SPECT scan in selected patients with locally advanced NSCLC. If the dose to FL is shown to be the primary determinant of lung toxicity, IMRT would allow for effective dose escalation by specific avoidance of FL.     

Phase I and pharmacokinetic study of 7-hydroxystaurosporine and carboplatin in advanced solid tumors.

PURPOSE: Based on preclinical data showing synergy between 7-hydroxystaurosporine (UCN-01) and platinum agents, a phase I trial of carboplatin with UCN-01 administered as a 3 h infusion in patients with advanced solid tumors was done. The primary goals of this trial were to evaluate the tolerability of this combination and the pharmacokinetics of UCN-01 when administered over 3 h and to compare the tolerability and pharmacokinetics with previously described schedules. Patients and Methods: Patients with advanced solid tumors, good performance status, normal organ function, and no potentially curative therapy were eligible for the trial. Carboplatin was escalated from an area under the curve (AUC) of 3 to an AUC of 5. UCN-01 was escalated from 50 to 90 mg/m(2). RESULTS: Twenty-three patients with advanced solid tumors (20 with prior platinum treatment) received a total of 60 cycles of therapy. Full doses of both agents (carboplatin AUC 5, UCN-01 90 mg/m(2) in cycle 1, 45 mg/m(2) in subsequent cycles) could be administered. The major toxicity noted was hypotension, which could be abrogated with the use of saline prehydration and posthydration. No responses were seen; however, seven patients were able to receive more than two courses of therapy. Of note, two of three patients with refractory, progressive small cell lung cancer were able to receive six cycles of therapy without evidence of progression. One patient experienced resolution of paraneoplastic syndrome of inappropriate antidiuretic hormone. The pharmacokinetic variables C(max) and t(1/2) of the 3 h infusion were essentially identical to those previously observed when UCN-01 was administered over 72 h. The average t(1/2) for cycle 1 was 506 +/- 301 h, and the mean C(max) for all dose levels was >30 micromol/L. The mean AUC over the dosing interval for each dose level ranged from approximately 6,000 to 9,000 micromol/L h. Thus, the AUC of UCN-01 after the 3 h infusion was lower than was observed after a 72 h infusion. CONCLUSION: The regimen of carboplatin and UCN-01 (administered as a 3 h infusion) was well tolerated. Further development of this combination, particularly in small cell lung cancer, is warranted.     

Complete atrioventricular block induced by rituximab in monotherapy in an aged patient with non-Hodgkin’s diffuse large B-cell lymphoma

Rituximab is a treatment option to non-Hodg kin's diffuse large B-cell lymphoma (NHDLBCL) in advanced stage and comorbility. It is known the cardiotoxicity effect of this drug, but there is no previous report describing a complete atrioventricular block (CAVB) secundary to treatment with Rituximab. We present an elderly woman treated with monotherapy with Rituximab who experienced a CAVB after administration of the fifth dose of this drug.     

Quantitative detection of molecular markers ProEx C (minichromosome maintenance protein 2 and topoisomerase IIa) and MIB‐1 in liquid‐based cervical squamous cell cytology

BACKGROUND.

In this study, the authors conducted a comparative quantitative evaluation of the proliferation markers ProEx C (an aberrant S‐phase induction marker, human papillomavirus E6‐E7 correlated) and MIB‐1 in squamous intraepithelial lesions (SIL) to identify a biomolecular profile informative for the diagnosis of high‐grade SIL/cervical intraepithelial neoplasia 3 or greater that was complementary to the morphologic Papanicolaou (Pap) test (“biomolecular Pap test”).

METHODS.

After the cytologic diagnosis, reflex immunocytochemistry was carried out on 76 unstained SurePath cell samples (20 routine samples that were negative for intraepithelial lesion or malignancy and 56 positive samples that were selected with matching histology). Both a morphometric analysis with a software imaging analysis system and a quantitative analysis of atypical squamous clusters were performed.

RESULTS.

The quantitative evaluation revealed an excellent, direct correlation between the 2 markers, although ProEx C was more selective and more informative for the progression of low‐ and moderate‐grade lesions, because it only revealed cells in aberrant S‐phase cell cycle. The quantitative morphometric analysis revealed the increased presence of atypical, positive clusters and the percentage of positive cells within, both paralleling the severity of the lesions. The threshold of a 3% ProEx C‐positive nuclear area was useful for splitting lesions into groups with a low risk or high risk of progression.

CONCLUSIONS.

Both ProEx C and MIB‐1 were valid proliferation markers in cytologic preparations, and nuclear positivity was quantified successfully by using computer‐assisted analysis. The analysis of atypical clusters may be a valuable tool in the diagnosis of SIL. The presence of atypical clusters and their positivity for proliferation markers are good first‐glance indicators of lesion grade. Cancer (Cancer Cytopathol) 2008. © 2008 American Cancer Society.     

High-frequency oscillatory ventilation and partial liquid ventilation after acute lung injury in premature lambs with respiratory distress syndrome

OBJECTIVE: Conventional mechanical ventilatory support (CV) contributes to lung injury in premature lambs with respiratory distress syndrome, a disease that is characterized by progressive deterioration of gas exchange and increased lung inflammation. Lung recruitment strategies, such as high-frequency oscillatory ventilation (HFOV) and partial liquid ventilation (PLV), improve gas exchange and attenuate lung inflammation when instituted immediately after birth. However, whether these recruitment strategies are effective as rescue treatment after established lung injury is unknown. To determine the separate and combined effects of HFOV and PLV when initiated after the establishment of acute lung injury in severe respiratory distress syndrome, we studied the effects of these strategies on gas exchange and histologic signs of acute lung injury in premature lambs. DESIGN: Animals were intubated, treated with surfactant and ventilated with 1.00 FIO2 for 4 hrs. After 2 hrs, animals were either continued on CV (controls) or treated with one of three strategies: HFOV; CV + PLV; or HFOV + PLV. The response to low-dose inhaled nitric oxide (5 ppm) was measured in each group at the end of the study. SETTING: An animal laboratory affiliated with University of Colorado School of Medicine. SUBJECTS: A total of 20 premature lambs at 115-118 days of gestation (term = 147 days). MEASUREMENTS AND MAIN RESULTS: In comparison with control animals, each of the rescue therapies improved PaO2 after 1 hr of treatment. The HFOV and HFOV + PLV groups had higher PaO2 than CV + PLV or CV alone (p < .05). Mean airway pressure (Paw) was lower in the PLV groups during CV or HFOV compared with their controls (p < .05). Inhaled NO improved PaO2 in all groups; however, the increase in PaO2 was greatest in the HFOV + PLV group (p < .05). Histologic examination and myeloperoxidase assay were not different between groups. CONCLUSION: We conclude that each lung recruitment strategy improved oxygenation in premature lambs with established lung injury.