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.

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.

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.

Incidence and risk factors for lymphoma in a single-center inflammatory bowel disease population.

AIMS: Previous studies on the risk of lymphoma in inflammatory bowel disease (IBD) have yielded conflicting results. We aim to determine the incidence and risk factors for lymphoma in a large IBD population. METHODS: Patients with lymphoma were identified from a single-center IBD database. The standardized incidence ratio (SIR) of lymphoma was estimated using data from the Surveillance, Epidemiology and End Results (SEER) registry. Risk factors for lymphoma were determined by comparing cases with a matched IBD control group. RESULTS: Eleven lymphomas were identified among 3,585 IBD patients during an average of 8.4 years of observation. Three patients were excluded. In the remaining eight, median age at diagnosis was 47 years and mean IBD duration was 20 years (range 7.5-45 years). The SIR for lymphoma was 1.6 [95% confidence interval (CI) 0.6-3.0], and for non-Hodgkin lymphoma (NHL), 1.5 (0.3-2.8). Three lymphoma patients (38%) received prior immunomodulators and two (25%) received biologics, versus 57% and 39% in the control group, respectively (P = 0.4). No correlation was seen with tobacco exposure, disease duration, use, or dose or duration of immunosuppressive therapy. CONCLUSIONS: In this IBD cohort, risk of lymphoma was not increased compared with the general population. Risk of lymphoma was not associated with any demographic or therapy-related factors.

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.

Provider recommendations for colorectal cancer screening in elderly veterans.

BACKGROUND: Decisions regarding colorectal cancer (CRC) screening in the elderly depend on providers' assessment of likelihood of benefit partly based on patient comorbidity and past screening history. We aimed to describe providers' experiences and practice patterns regarding screening for CRC in elderly patients in the VA system. METHODS AND PARTICIPANTS: A survey was sent to VA primary care providers who had previously participated in the CanCORS-sponsored Share Thoughts on Care study and at a VA medical center. The surveys consisted of clinical vignettes that varied by patient age (75, 80, or 85 years), comorbidity, and past CRC screening history. MAIN RESULTS: Completed questionnaires were received from 183 of 351 providers (52%). Ninety-five percent of providers would recommend screening for a healthy 75 year old compared to 66% and 39% for a healthy 80 and 85 year old, respectively (p-values < 0.0001). Providers were more likely to recommend screening for a 75 year old with moderate CHF versus severe CHF [61% versus 15%, OR 9.0 (95% CI 5.8-14.0), p < 0.0001] and more likely to recommend screening for an 80 year old with prior colonoscopy within the preceding 10 years, versus 5 years [42% versus 23%, OR 2.6 (95% CI 1.9-3.5), p < 0.0001]. A substantial minority of respondents (range 15-21%) reported they would screen a 75 year old with an active malignancy, severe CHF, or severe COPD. Provider demographic characteristics were not significantly associated with the probability of a screening recommendation. CONCLUSIONS: VA providers incorporate patient age, comorbidity, and past CRC screening history into CRC screening recommendations for elderly veterans; however, substantial proportions of these recommendations are inappropriate.

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.

Gefitinib plus celecoxib in chemotherapy-naïve patients with stage IIIB/IV non-small cell lung cancer: a phase II study from the Hoosier Oncology Group.

BACKGROUND: Gefitinib, an inhibitor of the epidermal growth factor receptor (EGFR) pathway, has single agent activity in non-small cell lung cancer (NSCLC). Preclinical studies demonstrate significant interactions between the EGFR and cyclooxygenase 2 (COX-2) pathways and that simultaneous inhibition may have benefits over EGFR inhibitors alone. ELIGIBILITY CRITERIA: chemotherapy-naive, stage IIIb (with pleural effusion) or IV NSCLC, Eastern Cooperative Oncology Group Performance Status (PS) 0-1. Patients were treated with gefitinib 250 mg po daily plus celecoxib 400 mg po every 12 hours. Cycles consisted of 21-day treatment and continued until unacceptable toxicity or progression of disease. The primary objective was to evaluate the overall response rate; secondary objectives included estimation of progression free survival, overall survival, and to assess the toxicity of this regimen. RESULTS: From January 2004 to November 2004, 31 patients were enrolled: male/female 13/18; median age 70 years (range, 19-93); 68% had adenocarcinoma; Eastern Cooperative Oncology Group PS 0/1 13/18; stage IIIb/IV 2/29. Two patients died of interstitial lung disease due to treatment. There were three additional deaths during treatment that were not considered treatment related. Two additional patients discontinued treatment due to adverse events (elevated liver enzymes). Select grade 3/4 toxicities included: pneumonitis (3%), hepatic (7%), diarrhea (7%), and skin (3%). Response rate was 16% (95% CI, 5-34%), median progression free survival and overall survival were 3.2 (95% CI, 2.7-5.7 months) and 7.0 months (95% CI, 3.7-14.2 months), respectively. All responders were females with adenocarcinoma, two were remote or never smokers and three were former smokers. CONCLUSION: Gefitinib plus celecoxib in an unselected population of chemotherapy naive patients with advanced NSCLC and a PS of 0-1 has a lower response rate and overall efficacy compared with historical controls of combination chemotherapy.

Financial impact of palliative care consultation in a public hospital.

BACKGROUND: Palliative care programs assist with prognostication, symptom control, and communication with patient and family. Hospitals often require financial justification for new programs Objective: Study the financial impact of the palliative care consultation (PCc) service in a public hospital. SETTING/SUBJECTS: From January to December 2005, 258 deaths occurred on the medicine service. Of those deceased patients, 116 were studied. DESIGN: Inclusion criteria were 50 or more years of age, length of stay (LOS) 3 days or more, admission to an internal medicine service, and death during that hospitalization. MEASUREMENTS: Charges, diagnosis-related groups (DRGs), DRG weights, and demographic variables were examined. RESULTS: Of the 116 deceased patients studied, 61 patients received a PCc, while 55 did not. Most patients had Medicare or Medicaid (82.8%). Both groups were similar in terms of demographic characteristics. Average LOS was 14.4 days for patients with a PCc versus 12.2 days for those without (p = 0.57). Median charges for the group without a PCc were $42,731, versus a median of $35,824 for those with a PCc. There was no significant variation of DRG weights within the same DRG. DRG weight was significantly positively correlated with charges. Both PCc and DRG weight were significant predictors of charges, with 36% of charges variability explained by PCc and DRG weight. CONCLUSIONS: PCc significantly reduced charges in adult patients who died during their last hospitalization, even though the average LOS was higher for those who received a PCc versus those who did not.

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.

Phase II study of paclitaxel plus gemcitabine salvage chemotherapy for germ cell tumors after progression following high-dose chemotherapy with tandem transplant.

PURPOSE: To determine long-term survival and potential cure with salvage chemotherapy with paclitaxel plus gemcitabine after progression after both cisplatin combination chemotherapy and subsequent high-dose chemotherapy with tandem transplantation. PATIENTS AND METHODS: One hundred eighty-four patients received salvage high-dose chemotherapy at Indiana University (Indianapolis, IN) from February 1996 to December 2004. After further evidence of progressive disease, 32 patients were subsequently treated with paclitaxel 100 mg/n2 over 1 hour plus gemcitabine 1,000 mg/m2 over 30 minutes, days 1, 8, and 15 every 4 weeks for a maximum of six courses. This is a retrospective review of this patient population. Patients were evaluated for response, duration of response, and survival. Patients were ineligible if they received prior paclitaxel or gemcitabine. RESULTS: Ten (31%) of 32 patients achieved objective response, including four partial remissions (2- to 6-month duration) and six complete responses (CRs). Four of these six CRs (12.5% of total patient population) are continuously disease free (NED) with paclitaxel plus gemcitabine alone (no postchemotherapy surgery) at more than 20, 40, 44, and 57 months from start of paclitaxel plus gemcitabine, respectively. One additional CR is currently NED more than 63 months after paclitaxel plus gemcitabine with two subsequent resections of carcinoma. CONCLUSION: Long-term disease-free survival is possible with paclitaxel plus gemcitabine in this patient population that progressed after high-dose chemotherapy, and had not received prior paclitaxel or gemcitabine.

The effect of telephone versus print tailoring for mammography adherence.

OBJECTIVE: The purpose of this intervention was to increase mammography adherence in women who had not had a mammogram in the last 15 months. METHODS: A prospective randomized intervention trial used four groups: (1) usual care, (2) tailored telephone counseling, (3) tailored print, (4) tailored telephone counseling and print. Participants included a total of 1244 women from two sites-a general medicine clinic setting serving predominately low-income clientele and a Health Maintenance Organization (HMO). Computer-tailored interventions addressed each woman's perceived risk of breast cancer, benefits and/or barriers and self-efficacy related to mammography screening comparing delivery by telephone and mail. RESULTS: Compared to usual care all intervention groups increased mammography adherence significantly (odds ratio 1.60-1.91) when the entire sample was included. CONCLUSIONS: All interventions groups demonstrated efficacy in increasing mammography adherence as compared to a usual care group. When the intervention analysis considered baseline stage, pre contemplators (women who did not intend to get a mammogram) did not significantly increase in mammography adherence as compared to usual care. PRACTICE IMPLICATIONS: Women who are in pre contemplation stage may need a more intensive intervention.

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.