Subchronic toxicity evaluation of glucosamine and glucosamine in combination with chondroitin sulfate in obese Zucker rats.

D-glucosamine is a widely consumed dietary supplement used to promote joint health and treat osteoarthritis. It also stimulates intracellular hexosamine flux and increases transforming growth factor ß1 (TGFß1) mRNA expression and insulin resistance in animal studies. The effects of D-glucosamine exposure were investigated in obese Zucker rats. Male (leprfa/leprfa) Zucker rats were exposed to 30, 120, 300 and 600 mg D-glucosamine HCl per kg/day either alone or with chondroitin sulfate (24, 96, 240 and 480 mg/kg/day respectively) for 90 days. After 4 weeks exposure, these doses produced CmaxD-glucosamine concentrations of up to 24 µM in tail vein serum concurrent with a transient 30% increase in blood glucose concentration in the 600 mg/kg/day dose group. D-Glucosamine did not significantly alter body weight, blood glucose or serum insulin levels at any dose tested after 13 weeks exposure, but did increase urinary TGFß1 concentrations. The Zucker rats developed nephropathy and scrotal sores that were related to their hyperglycemia and obesity, and D-glucosamine exposure exacerbated these conditions to a small extent. The incidence of pulmonary osseous metaplasia was increased in rats exposed to D-glucosamine and a single incidence of adrenal osseous metaplasia was noted in one animal exposed to 600/480 mg D-glucosamine HCl/chondroitin sulfate. These lesions may have been treatment related. These studies suggest that the risk of adverse effects of oral D-glucosamine is small compared to that of hyperglycemia in these animals, but the potential for TGFß1-mediated pathologies, such as osseous metaplasia and renal nephropathy may be increased.

Comparison of endpoints relevant to toxicity assessments in 3 generations of CD-1 mice fed irradiated natural and purified ingredient diets with varying soy protein and isoflavone contents.

Diet is an important variable in toxicology. There are mixed reports on the impact of soy components on energy utilization, fat deposition, and reproductive parameters. Three generations of CD-1 mice were fed irradiated natural ingredient diets with varying levels of soy (NIH-41, 5K96, or 5008/5001), purified irradiated AIN-93 diet, or the AIN-93 formulation modified with ethanol-washed soy protein concentrate (SPC) or SPC with isoflavones (SPC-IF). NIH-41 was the control for pairwise comparisons. Minimal differences were observed among natural ingredient diet groups. F0 males fed AIN-93, SPC, and SPC-IF diets had elevated glucose levels and lower insulin levels compared with the NIH-41 group. In both sexes of the F1 and F2 generations, the SPC and SPC-IF groups had lower body weight gains than the NIH-41 controls and the AIN-93 group had an increased percent body fat at postnatal day 21. AIN-93 F1 pups had higher baseline glucose than NIH-41 controls, but diet did not significantly affect breeding performance or responses to glucose or uterotrophic challenges. Reduced testes weight and sperm in the AIN-93 group may be related to low thiamine levels. Our observations underline the importance of careful selection, manufacturing procedures, and nutritional characterization of diets used in toxicological studies.

Toxicity evaluation of bisphenol A administered by gavage to Sprague Dawley rats from gestation day 6 through postnatal day 90.

Bisphenol A (BPA) is a high production volume industrial chemical to which there is widespread human oral exposure. Guideline studies used to set regulatory limits detected adverse effects only at doses well above human exposures and established a no-observed-adverse-effect level (NOAEL) of 5 mg/kg body weight (bw)/day. However, many reported animal studies link BPA to potentially adverse effects on multiple organ systems at doses below the NOAEL. The primary goals of the subchronic study reported here were to identify adverse effects induced by orally (gavage) administered BPA below the NOAEL, to characterize the dose response for such effects and to determine doses for a subsequent chronic study. Sprague Dawley rat dams were dosed daily from gestation day 6 until the start of labor, and their pups were directly dosed from day 1 after birth to termination. The primary focus was on seven equally spaced BPA doses (2.5-2700 µg/kg bw/day). Also included were a naïve control, two doses of ethinyl estradiol (EE2) to demonstrate the estrogen responsiveness of the animal model, and two high BPA doses (100,000 and 300,000 µg/kg bw/day) expected from guideline studies to produce adverse effects. Clear adverse effects of BPA, including depressed gestational and postnatal body weight gain, effects on the ovary (increased cystic follicles, depleted corpora lutea, and antral follicles), and serum hormones (increased serum estradiol and prolactin and decreased progesterone), were observed only at the two high doses of BPA. BPA-induced effects partially overlapped those induced by EE2, consistent with the known weak estrogenic activity of BPA.

Effect of tonsillar fossa closure on postoperative pain and bleeding risk after tonsillectomy.

OBJECTIVE: To determine if closing the tonsil fossa after tonsillectomy leads to less pain and bleeding. STUDY DESIGN: Interventional, Randomized, Single Blind, Active Control, Single Group Assignment, Safety/Efficacy Study. FOLLOW-UP: 2 months. METHODS: Generalized Estimating Equations (GEE) analyzed effects of tonsillar pillar closure, surgeon experience and interaction on outcomes. SETTING: Primarily academic tertiary care referral center, institutional practice, primarily children, both ambulatory and hospitalized care. SUBJECTS: 763 subjects (age 8-264 months) undergoing tonsillectomy. EXCLUSIONS: suspected malignancy or active peritonsillar abscess. At the discretion of the attending surgeon, patients undergoing tonsillectomy during the 4 year study period were offered participation. A computer selected the side closed. 131 subjects withdrew (complete lack of follow-up information) after the first 72 h. INTERVENTION: 3-0 chromic sutures on tapered needles to close one tonsillar fossa. The subject was not told which side was closed. MAIN OUTCOME MEASURES: postoperative bleeding (at any time) and pain reported was sought on days 1, 7, 14, 21, and 28. RESULTS: Closure of the tonsillar fossa did not change the risk of bleeding. Closing the tonsillar fossa had a 40% increase in the odds ratio of postoperative pain. In the tonsillar fossa sides left open, greater surgeon experience decreased the risk of bleeding. In closed sides, enriched surgeon experience increased the risk of bleeding (p<.0.05). CONCLUSIONS: Suture closure of the tonsillar fossa after tonsillectomy does not reduce the risk of bleeding. Additionally, closing the tonsillar fossa increased postoperative pain. LEVEL OF EVIDENCE: 1b (individual randomized controlled trial).

Differential Secondary Reconstitution of In Vivo-Selected Human SCID-Repopulating Cells in NOD/SCID versus NOD/SCID/γ chain Mice.

Humanized bone-marrow xenograft models that can monitor the long-term impact of gene-therapy strategies will help facilitate evaluation of clinical utility. The ability of the murine bone-marrow microenvironment in NOD/SCID versus NOD/SCID/γ chain(null) mice to support long-term engraftment of MGMT(P140K)-transduced human-hematopoietic cells following alkylator-mediated in vivo selection was investigated. Mice were transplanted with MGMT(P140K)-transduced CD34(+) cells and transduced cells selected in vivo. At 4 months after transplantation, levels of human-cell engraftment, and MGMT(P140K)-transduced cells in the bone marrow of NOD/SCID versus NSG mice varied slightly in vehicle- and drug-treated mice. In secondary transplants, although equal numbers of MGMT(P140K)-transduced human cells were transplanted, engraftment was significantly higher in NOD/SCID/γ chain(null) mice compared to NOD/SCID mice at 2 months after transplantation. These data indicate that reconstitution of NOD/SCID/γ chain(null) mice with human-hematopoietic cells represents a more promising model in which to test for genotoxicity and efficacy of strategies that focus on manipulation of long-term repopulating cells of human origin.

Developmental toxicity of Citrus aurantium in rats.

BACKGROUND: Ephedra was commonly used in herbal products marketed for weight loss until safety concerns forced its removal from products. Even before the ban, manufacturers had begun to replace ephedra with other compounds, including Citrus aurantium, or bitter orange. The major component in the bitter orange extract is synephrine which is chemically similar to ephedrine. The purpose of this study was to determine if relatively pure synephrine or synephrine present as a constituent of a bitter orange extract produced developmental toxicity in rats. METHOD: Sprague-Dawley rats were dosed daily by gavage with one of several different doses of synephrine from one of two different extracts. Caffeine was added to some doses. Animals were sacrificed on GD 21, and fetuses were examined for the presence of various developmental toxic endpoints. RESULTS AND CONCLUSION: At doses up to 100 mg synephrine/kg body weight, there were no adverse effects on embryolethality, fetal weight, or incidences of gross, visceral, or skeletal abnormalities. There was a decrease in maternal weight at 50 mg synephrine/kg body weight when given as the 6% synephrine extract with 25 mg caffeine/kg body weight; there was also a decrease in maternal weight in the caffeine only group. This decrease in body weight may have been due to decreased food consumption which was also observed in these two groups. Overall, doses of up to 100 mg synephrine/kg body weight did not produce developmental toxicity in Sprague-Dawley rats.

Humanized bone marrow mouse model as a preclinical tool to assess therapy-mediated hematotoxicity.

PURPOSE: Preclinical in vivo studies can help guide the selection of agents and regimens for clinical testing. However, one of the challenges in screening anticancer therapies is the assessment of off-target human toxicity. There is a need for in vivo models that can simulate efficacy and toxicities of promising therapeutic regimens. For example, hematopoietic cells of human origin are particularly sensitive to a variety of chemotherapeutic regimens, but in vivo models to assess potential toxicities have not been developed. In this study, a xenograft model containing humanized bone marrow is utilized as an in vivo assay to monitor hematotoxicity. EXPERIMENTAL DESIGN: A proof-of-concept, temozolomide-based regimen was developed that inhibits tumor xenograft growth. This regimen was selected for testing because it has been previously shown to cause myelosuppression in mice and humans. The dose-intensive regimen was administered to NOD.Cg-Prkdc(scid)IL2rg(tm1Wjl)/Sz (NOD/SCID/γchain(null)), reconstituted with human hematopoietic cells, and the impact of treatment on human hematopoiesis was evaluated. RESULTS: The dose-intensive regimen resulted in significant decreases in growth of human glioblastoma xenografts. When this regimen was administered to mice containing humanized bone marrow, flow cytometric analyses indicated that the human bone marrow cells were significantly more sensitive to treatment than the murine bone marrow cells and that the regimen was highly toxic to human-derived hematopoietic cells of all lineages (progenitor, lymphoid, and myeloid). CONCLUSIONS: The humanized bone marrow xenograft model described has the potential to be used as a platform for monitoring the impact of anticancer therapies on human hematopoiesis and could lead to subsequent refinement of therapies prior to clinical evaluation.

Prediction of postoperative recurrence-free survival in non-small cell lung cancer by using an internationally validated gene expression model.

PURPOSE: This study was performed to discover prognostic genomic markers associated with postoperative outcome of stage I to III non-small cell lung cancer (NSCLC) that are reproducible between geographically distant and demographically distinct patient populations. EXPERIMENTAL DESIGN: American patients (n = 27) were stratified on the basis of recurrence and microarray profiling of their tumors was performed to derive a training set of 44 genes. A larger Korean patient validation cohort (n = 138) was also stratified by recurrence and screened for these genes. Four reproducible genes were identified and used to construct genomic and clinicogenomic Cox models for both cohorts. RESULTS: Four genomic markers, DBN1 (drebrin 1), CACNB3 (calcium channel beta 3), FLAD1 (PP591; flavin adenine dinucleotide synthetase), and CCND2 (cyclin D2), exhibited highly significant differential expression in recurrent tumors in the training set (P < 0.001). In the validation set, DBN1, FLAD1 (PP591), and CACNB3 were significant by Cox univariate analysis (P ≤ 0.035), whereas only DBN1 was significant by multivariate analysis. Genomic and clinicogenomic models for recurrence-free survival (RFS) were equally effective for risk stratification of stage I to II or I to III patients (all models P < 0.0001). For stage I to II or I to III patients, 5-year RFS of the low- and high-risk patients was approximately 70% versus 30% for both models. The genomic model for overall survival of stage I to III patients was improved by addition of pT and pN stage (P < 0.0013 vs. 0.010). CONCLUSION: A 4-gene prognostic model incorporating the multivariate marker DBN1 exhibits potential clinical utility for risk stratification of stage I to III NSCLC patients.

Independent influence of dietary protein on markers of kidney function and disease in obesity.

Obesity is associated with glomerular hyperfiltration and increased urinary protein excretion, as well as structural and functional changes that lead to kidney disease and failure. Dietary protein mimics obesity's effects on the glomerular filtration rate (GFR) and proteinuria and, in certain circumstances, may have the potential to adversely affect kidney function. Here we tested the hypothesis that dietary protein independently explains elevations in the GFR and proteinuria found in obese persons with a normal serum creatinine. Seventeen patients were randomized in a double-blind, crossover fashion for 1-week periods to high (140 g/day) and low (50 g/day) protein diets with a 1-week washout interval separating these periods. High protein consumption was associated with a very modest but significant increase in the GFR of 5 ± 6 ml/min. Hence, while dietary protein does modulate kidney parameters, it is unlikely to fully account for the elevations in GFR and proteinuria found in obesity.

Utility of fecal lactoferrin in identifying Crohn disease activity in children.

OBJECTIVES: Fecal lactoferrin (FL) is a noninvasive biomarker that is elevated in Crohn disease (CD) compared to irritable bowel syndrome. The purpose of this study was to evaluate FL in identifying children with active versus inactive CD. PATIENTS AND METHODS: Fresh stool samples were collected from children with CD scheduled for endoscopy or a clinic visit, and from new outpatients who were scheduled for colonoscopy. FL was determined using a polyclonal antibody-based enzyme-linked immunosorbent assay. Physical global assessment, endoscopic findings, erythrocyte sedimentation rate (ESR), and the Pediatric CD Activity Index (PCDAI) were recorded for patients with CD. The PCDAI scores symptoms, laboratory parameters, physical examination, and extraintestinal manifestations. A score of ≤10 is inactive disease, 11 to 30 is mild active, and ≤31 is moderate to severe active. RESULTS: Of 101 study patients (4- to 20-year-old, 66 boys), 31 had active CD, 23 had inactive CD, and 37 had noninflammatory bowel disease (non-IBD) conditions. Four patients with ulcerative colitis and 6 patients with polyposis were excluded from analysis. FL was significantly elevated in CD versus non-IBD (P < 0.001) and in active versus inactive CD (P < 0.001). The PCDAI and ESR were higher in active CD than in inactive CD (both P < 0.001). Using an FL cutoff of 7.25 µg/g, FL has 100% sensitivity and 100% negative predictive value in detecting active CD. Using an FL cutoff level of 60 µg/g, FL had 84% sensitivity, 74% specificity, 81% positive predictive value, and 77% negative predictive value for detecting active CD. CONCLUSIONS: FL is a promising biomarker of active CD and may be more practical to use when it is not feasible to obtain all of the necessary clinical information for the PCDAI.

Implementation of routine access to herpes simplex virus type 2 antibody testing in a public health sexually transmitted disease clinic.

BACKGROUND: Testing for herpes simplex virus type 2 (HSV-2) antibody is not common in clinical practice. Client characteristics associated with HSV-2 rapid antibody test uptake and test positivity were analyzed in clients attending an urban sexually transmitted disease clinic. METHODS: This optional test was available for $30. The HerpeSelect Express assay was performed on serum. Demographic and behavioral characteristics were compared between clients who requested testing and those who did not and between those who were HSV-2 antibody positive and negative. RESULTS: In 4 months, 3498 individuals attended the clinic and 443 (12.7%) opted for HSV-2 testing. Clients who were black, younger, or female were less likely to request testing. Recent sexual behavior and self-reported sexual orientation were not associated with uptake of testing. Of the 442 clients with results available, 109 were positive for HSV-2 antibody (24.7%). Women were significantly (P <0.001) more likely to test positive; 42 of 111 (38.4%) versus only 67 of 331 (20.2%) men. A positive HSV-2 antibody test was also associated with increasing age and black race. There was an association with the number of partners in the last 30 days, but no association with the number of partners in the last year. Of the 109 clients who had a positive HSV-2 antibody test, 71 (64.5%) accepted a prescription for suppressive acyclovir therapy. CONCLUSIONS: Uptake of testing was modest in this population, especially among the highest risk individuals, possibly due to the cost of the test. Improved education regarding HSV-2 and subsidized testing may be needed in the populations that have the highest prevalence in order to encourage testing.

Variation in polyp detection rates at screening colonoscopy.

BACKGROUND: Variation in polyp detection among endoscopists has been used to justify the need for establishing quality standards for colonoscopy performance. OBJECTIVE: To measure variation in polyp detection rates (PDRs) among endoscopists who perform screening colonoscopy and to identify associated factors. DESIGN: Cross-sectional analysis of summary-level data. SETTING: Endoscopy practices in central Indiana. SUBJECTS: Twenty-five endoscopists and their patients. MAIN OUTCOME MEASUREMENTS: Mean procedure time (MPT); proportions of patients with any polyp, any adenoma, any polyp > or =1.0 cm, and multiple adenomas; and variation in PDRs and identification of outliers. Multiple linear regression analysis identified factors that accounted for the variation in PDRs. RESULTS: A total of 2664 screening colonoscopies (1108 women and 1556 men) were performed. The mean patient age was 59 years; the mean proportion of women was 42%; the MPT was 17.1 minutes. Adenoma detection rates ranged from 7% to 44% (P < .001) and from 0% to 13% for large polyps, which was not statistically significant (P = .07). For all polyp categories, only 1 to 3 high outlier endoscopists (ie, higher than mean PDRs) were identified. Models that included the number of procedures, mean age, percentage of women, and MPT accounted for 36% to 56% of the variation in PDRs. In all models, only MPT was significantly associated with PDRs. LIMITATIONS: Whether each endoscopist's cohort was at comparable risk for colorectal neoplasia was uncertain. In comparison with individual-level data, analysis of summary-level data is limited. CONCLUSIONS: PDRs vary widely among endoscopists, although only a few (high) outliers were identified. Variation in PDRs was associated only with MPT. Further research is needed to determine the clinical importance of and reasons for this variation.

Effect of screening colonoscopy on colorectal cancer incidence and mortality.

BACKGROUND & AIMS: Colonoscopy is used widely for colorectal cancer (CRC) screening; however, its long-term impact on the incidence and mortality of CRC is not known. METHODS: We assessed CRC incidence and mortality in a group of asymptomatic average-risk patients who underwent screening colonoscopy between 1989 and 1993 at a university hospital. By using standardized incidence ratios and standardized mortality ratios, we compared our observed CRC rates with expected rates from the Surveillance, Epidemiology, and End Results (SEER) data. RESULTS: The cohort comprised 715 patients (mean age, 61 +/- 6.5 y; 59% male; 95% Caucasian) with 10,492 patient-years of follow-up. There were 12 cases of CRC: 5 found at baseline and 7 found after a median follow-up period of 8 years (range, 3-16 y). When the first 2 years of follow-up were excluded, there were 7 incident cases of CRC (95% confidence interval [CI], 2-13) over 9075 person-years of follow-up. The expected number based on SEER data was 21. The incidence rate was 0.77 cases per 1000 person-years, and the standardized incidence ratio was 0.33 (95% CI, 0.10-0.62), consistent with a relative risk reduction in CRC incidence of 67%. Three patients died from CRC (95% CI, 0-9). The expected number of deaths based on SEER data was 9. The mortality rate was 0.29 per 1000 person-years, and the standardized mortality ratio was 0.35 (95% CI, 0.0-1.06), consistent with a relative reduction in CRC death of 65%. CONCLUSIONS: In this average-risk cohort, CRC incidence and mortality were reduced after screening colonoscopy. These results provide additional evidence for the effectiveness of colonoscopy as a primary CRC screening modality.

Acceptability to Latino parents of sexually transmitted infection vaccination.

OBJECTIVE: To evaluate the acceptability to Latino parents of having their adolescent children vaccinated against sexually transmitted infections, and to identify potential demographic correlates of acceptability. METHODS: We applied established methodology to a sample of 119 Latino parents who accompanied their children (51% female, aged 12-17 years) to medical appointments. The parents used computer-based questionnaires to rate 9 hypothetical vaccine scenarios. The scenarios had 4 dimensions: mode of transmission (sexually transmitted or not sexually transmitted), severity of infection (curable, chronic, or fatal), vaccine efficacy (50%, 70%, or 90%), and availability of behavioral methods for prevention (available or not available). Willingness by parents to vaccinate their adolescents under each vaccine scenario was assessed on a scale (range, 0-100). Conjoint analysis was used to determine the relative contribution of each dimension to the ratings. RESULTS: The study sample consisted of predominantly Mexican immigrant parents, 94% of whom chose to complete the Spanish version of the computerized interview. The mean value of the parents' willingness to accept vaccination for their adolescent children was exceptionally high. For example, the mean score of the Latino parents for the 6 sexually transmitted infection (STI) vaccine scenarios (score 86.2; SD 21.1) was far higher than the mean score in previous studies (81.3, SD 21.1). Conjoint analysis revealed that the dimensions of vaccine efficacy and severity of infection were equal in terms of their influence on vaccine ratings for the Latino parents. The next most influential dimension on vaccine ratings was the availability of behavioral prevention, followed by the sexual transmissibility of the infection. CONCLUSIONS: Our sample of predominantly Mexican parents was accepting of the concept of STI vaccination for their adolescent children. Important issues for parents include vaccine efficacy and severity of infection, followed by vaccines for infections that had no method of behavioral prevention available. Overall, there is little difference in the relative preference of a STI versus non-STI vaccine for their adolescent children.

Survival of elderly persons undergoing colonoscopy: implications for colorectal cancer screening and surveillance.

BACKGROUND: In the elderly, the increased prevalence of colorectal neoplasia and the protective effect of colonoscopy may be offset by advancing age and comorbidity. OBJECTIVE: To describe and quantify the endoscopic findings, survival, and predictors of mortality of elderly persons after colonoscopy. DESIGN, SETTING, AND PATIENTS: Retrospective cohort study of persons aged>or=75 years who underwent colonoscopy in 1999 and 2000 at a U.S. Veterans Affairs facility and urban county hospital. MAIN OUTCOME MEASURES: Advanced neoplasms were defined as colorectal cancer (CRC), polyp with high-grade dysplasia, villous histologic features, or tubular adenoma>or=1 cm. Comorbidity was measured with the Charlson comorbidity index. Subjects were followed until death or study closure. RESULTS: Of 469 eligible subjects, 65 were excluded and 404 were included in the study. Fifty-nine of 404 (15%) had an advanced neoplasm, including 8 (2%) with CRC. There were 167 deaths (41%); the mean overall survival was 4.1+/-0.1 years (median 5.95 years). A symptomatic indication for colonoscopy was not predictive of death. Mortality was predicted by age (hazard ratio 1.16 for each year increase beyond age 75 years, 95% CI 1.07-1.3, P=.0003) and Charlson score (hazard ratio 8.3 for each point increase, 95% CI 1.4-48.5, P=.02). The median survival of patients aged 75 to 79 years was >5 years if the Charlson score was or=80 years, the median survival was <5 years regardless of Charlson score. LIMITATIONS: Retrospective design. CONCLUSIONS: In this cohort of elders, age and comorbidity were predictors of death. The protective effect of younger age lessens as comorbidity increases. These findings may have important implications for CRC screening and surveillance in elders.

The relationship between the extent of surgical margin positivity and prostate specific antigen recurrence in radical prostatectomy specimens.

The presence of positive surgical margins is a negative prognostic indicator in patients undergoing prostatectomy for prostate cancer; whether the extent of the positive margins affects the clinical outcome with regards to prostate-specific antigen (PSA) recurrence remains uncertain. We evaluated the linear extent of margin positivity as a prognostic indicator in a series of radical prostatectomy specimens. One hundred seventy-four consecutive margin-positive prostatectomy specimens were evaluated. The linear extent of margin positivity was measured with an ocular micrometer and ranged from 0.05 to 75.0 mm (mean, 8.94; median, 5.0). The linear extent of margin positivity was associated with tumor volume (P = .03) but was not associated with patients' age at surgery, preoperative PSA level, prostate weight, pathologic stage, Gleason score, extraprostatic extension, seminal vesicle invasion, perineural invasion, high-grade prostatic intraepithelial neoplasia, or PSA recurrence. In the full model multiple Cox regression, significant predictors for PSA recurrence were Gleason score (P = .001) and preoperative PSA (P = .01); extent of margin positivity was not predictive of PSA recurrence (hazard ratio, 1.00; 95% confidence interval, 0.98-1.02; P = .97) nor was tumor volume a significant factor when adjusted for other covariates (P = .27). Preoperative PSA, tumor stage, and Gleason score remained significant prognostic factors in evaluating the likelihood of PSA recurrence in patients with positive surgical margins; the extent of margin positivity, however, is not a prognostic factor for PSA recurrence and should, therefore, not necessarily be included in the final report for radical prostatectomy specimens.

Final report of toxicity and efficacy of a phase II study of oral cyclophosphamide, thalidomide, and prednisone for patients with relapsed or refractory multiple myeloma: A Hoosier Oncology Group Trial, HEM01-21.

Thalidomide has direct antimyeloma and immunomodulatory effects. In addition, both thalidomide and metronomic chemotherapy inhibit angiogenesis. The synergy of such a combination may decrease toxicity while maintaining efficacy. The Hoosier Oncology Group conducted a phase II trial of oral cyclophosphamide (50 mg b.i.d. for 21 days), thalidomide (200 mg/day), and prednisone (50 mg q.o.d.) (CTP) per 28-day course in patients with relapsed multiple myeloma (MM). Of the 37 patients enrolled, 16 had prior stem cell transplantation. The median follow-up time was 25.3 months (95% confidence interval [CI] 23.2-27.7). Of 35 patients treated, 22 patients (62.9%) responded: 7 (20.0%) complete responses, 2 (5.7%) near-complete responses, and 13 (37.1%) partial responses. Eight patients (22.9%) had stable disease, and three (8.6%) had disease progression. Two patients withdrew from the study early due to reasons unrelated to progression or toxicity and were treated as nonresponders. The median time to best response and time to progression were 3.6 months (95% CI 2.8-10.9) and 13.2 months (95% CI 9.4-21.0), respectively. The median number of treatment cycles was seven (range 1-12 cycles). Grade III to IV toxicities included leukopenia (42.9%; febrile neutropenia, 11.4%), hyperglycemia (20%), sensory neuropathy (11.4%), thromboses (8%), and motor neuropathy (5.7%). No patient withdrew from the study due to toxicity. The efficacy and low toxicity of the CTP regimen support the future development of such an approach in MM.

Phase II study of cisplatin plus epirubicin salvage chemotherapy in refractory germ cell tumors.

PURPOSE: Initial cisplatin (CIS) combination chemotherapy will cure 70% of patients with disseminated testicular cancer. This phase II clinical trial evaluated the combination of CIS plus epirubicin (CIS-EPI) in patients with metastatic germ cell tumors (GCT) not amenable to cure with standard salvage therapy. PATIENTS AND METHODS: Between March 2001 and August 2005, 30 patients with GCT, who had received at least one previous CIS-based regimen, were enrolled. All patients were males, with median age 36 (range, 24 to 45 years). Twenty-one patients (70%) had experienced late relapses (> 2 years). Patients received EPI 90 mg/m2 on day 1 and CIS 20 mg/m2 on days 1 to 5 every 3 weeks for maximum of four cycles. RESULTS: Nineteen (63%) of 30 patients received all four cycles. Toxicity was primarily hematologic: grade 3/4 neutropenia, four patients (one neutropenic fever); two patients had grade 3 thrombocytopenia, and five patients had grade 3/4 anemia. Nonhematologic toxicity was grade 3 acute renal failure in two patients; grade 3 electrolyte wasting in two patients; grade 3 nausea/vomiting in eight patients; grade 3 elevation of aminotransferases in one patient; and grade 3 diarrhea in one patient. There were no occurrences of severe mucositis, cardiotoxicity, or treatment-related deaths. Nine patients achieved a complete remission; seven of these patients remain without evidence of disease at 25+, 27+, 29+, 44+, 45+, 46+, and 48+ months. One patient remains alive with stable pulmonary nodules at 28+ months. CONCLUSION: CIS-EPI is an active regimen in metastatic GCT, with an acceptable toxicity profile. This regimen offers potential for long-term disease-free survival in this population.

Weekly bortezomib/methylprednisolone is effective and well tolerated in relapsed multiple myeloma.

BACKGROUND: The standard schedule of bortezomib requires frequent infusions and is often associated with dose-dependent, adverse effects such as sensory neuropathy and thrombocytopenia. Because of the known additive effect between bortezomib and glucocorticoid, we explored weekly bortezomib/methylprednisolone in patients with relapsed multiple myeloma. PATIENTS AND METHODS: Twenty-nine patients were treated at Indiana University with bortezomib (1.3 mg/m2) and methylprednisolone (500-2000 mg) intravenously on days 1, 8, and 15 of 28-day cycles. Response was evaluated using the Blade criteria. Twenty-one patients (70%) had previous stem cell transplantation, and 13 were in third relapse or higher. RESULTS: A response was observed in 18 patients (62%): 1 (3%) complete response, 1 (3%) near complete response, and 16 (55%) partial responses. Six (21%) had stable disease, and 5 (17%) had disease progression. The median time to progression, which was defined from the beginning of therapy until progression, was 6.6 months (95% confidence interval, 6.4-9.2 months). The median number of treatment cycles was 6 (range, 2-12 cycles). The median overall survival was 20.2 months (lower 95% confidence interval, 13.1 months). The most common toxicities were fatigue and gastrointestinal disturbances. Grade >or= 3 adverse effects included neuropathy (2 grade 3), gastrointestinal side effects (1 grade 3), and congestive heart failure (1 grade 3). CONCLUSION: The weekly bortezomib/methylprednisolone regimen was well tolerated and yielded a response rate comparable with the standard schedule of bortezomib alone. Our data support further investigation of this regimen in larger patient cohorts.