Weight Gain Trajectories Associated With Elevated C-Reactive Protein Levels in Chinese Adults.

BACKGROUND: Recent longitudinal work suggests that weight change is an important risk factor for inflammation across the full range of BMI. However, few studies have examined whether the risk of inflammation differs by patterns of weight gain over time. Using latent class trajectory analysis, we test whether patterns of weight gain are associated with elevated high-sensitivity C-reactive protein (hs-CRP 2-10 mg/L). METHODS AND RESULTS: Data come from China Health and Nutrition Survey (CHNS) participants (n=5536), aged 18 at baseline to 66 years in 2009, with measured weight over 18 years. Latent class trajectory analysis was used to identify weight-change trajectories in 6 age and sex strata. Multivariable general linear mixed-effects models fit with a logit link were used to assess the risk of elevated hs-CRP across weight trajectory classes. Models were fit within age and sex strata, controlling for baseline weight, adult height, and smoking, and included random intercepts to account for community-level correlation. Steeper weight-gain trajectories were associated with greater risk of elevated hs-CRP compared to more moderate weight-gain trajectories in men and women. Initially high weight gain followed by weight loss was associated with lower risk of elevated hs-CRP in women aged 18 to 40. CONCLUSIONS: Latent class trajectory analysis identified heterogeneity in adult weight change associated with differential risk of inflammation independently of baseline weight and smoking. These results suggest that trajectories of weight gain are an important clinical concern and may identify those at risk for inflammation and the development of cardiometabolic disease.

Eighteen year weight trajectories and metabolic markers of diabetes in modernising China.

AIMS/HYPOTHESIS: Although obesity is a major risk factor for diabetes, little is known about weight gain trajectories across adulthood, and whether they are differentially associated with metabolic markers of diabetes. METHODS: We used fasting blood samples and longitudinal weight data for 5,436 adults (5,734 observations, aged 18-66 years) from the China Health and Nutrition Survey (1991-2009). Using latent class trajectory analysis, we identified different weight gain trajectories in six age and sex strata, and used multivariable general linear mixed effects models to assess elevated metabolic markers of diabetes (fasting glucose, HbA1c, HOMA-IR, insulin) across weight trajectory classes. Models were fitted within age and sex strata, and controlled for baseline weight (or baseline weight by weight trajectory interaction terms), height, and smoking habit, with random intercepts to control for community-level correlations. RESULTS: Compared with weight gain, classes with weight maintenance, weight loss, or a switch from weight gain to loss had lower values for metabolic markers of diabetes. These associations were stronger among younger women (aged 18-29 and 30-39 years) and men (18-29 years) than in older (40-66 years) men and women. An exception was HOMA-IR, which showed class differences across all ages (at least p < 0.004). CONCLUSION: Trajectory analysis identified heterogeneity in adult weight gain associated with diabetes-related metabolic markers, independent of baseline weight. Our findings suggest that variation in metabolic markers of diabetes across patterns of weight gain is masked by a homogeneous classification of weight gain.

Outcomes after management of young women with cervical intraepithelial neoplasia 2 with a 6-month observation protocol.

OBJECTIVE: Recommendations regarding treatment of cervical intraepithelial neoplasia (CIN) 2 in women have evolved over the years: young women with CIN 2 may be offered observation with Pap smears and colposcopy every 6 months instead of immediate excision or ablation of disease. The purpose of this study was to observe patient follow-up during the initiation of this management protocol for young women with CIN 2. MATERIALS AND METHODS: This was a retrospective review of clinical outcomes of women younger than 30 years with CIN 2 on index biopsy and planned follow-up at UNC between July 2009 and August 2010. A chart review for clinical variables, follow-up visits, and progression of disease was conducted. Primary analysis determined the rate of follow-up and pathology at 6 months. Secondary analysis investigated risk factors for incomplete follow-up. RESULTS: Seventy women met inclusion criteria; 46 were managed with observation. Twenty-eight (60.8%; 28/46) women completed a follow-up visit. Demographic and clinical variables did not reach statistical significance in predicting the likelihood of completion of a follow-up visit, although there was a trend toward greater follow-up in employed patients (odds ratio = 5.25, 95% confidence interval = 0.84-34.78). Approximately half (52.4%; 11/21) of women with a completed cervical biopsy demonstrated regression of disease during the study period. CONCLUSIONS: On the basis of these data, follow-up in this population was unpredictable based on basic demographic or clinical factors that we often use to judge likelihood of compliance with medical recommendations. The percentage of patients with regression at follow-up was as expected from the natural history of CIN 2.

Clinical utility of KRAS and BRAF mutations in a cohort of patients with colorectal neoplasms submitted for microsatellite instability testing.

BACKGROUND: Molecular analysis has become important in colorectal carcinoma (CRC) evaluation. Alterations in KRAS, BRAF, or mismatch repair (MMR) genes may determine therapeutic response or define a hereditary cancer syndrome. Correlation of DNA studies with clinical findings will further clarify the clinical utility of these markers. PATIENTS AND METHODS: A retrospective study was performed on 111 paraffin-embedded tumor specimens submitted for microsatellite instability (MSI) testing based on clinical history or histologic examination, or both. DNA samples were screened for 7 KRAS mutations and the BRAF p.V600E mutation using fluorescent allele-specific polymerase-chain reaction (PCR) and capillary electrophoresis. Clinical data were collected through chart review. RESULTS: Fifty-eight male and 53 female patients were studied. The incidence of KRAS and BRAF mutations was 49.5% and 7.2%, respectively. Dideoxy sequencing verified KRAS mutation status in 46 of 49 specimens tested. There was a trend toward significance of individual KRAS mutations on survival (P = .003). Dually positive KRAS and MSI tumors exclusively demonstrated p.G12D and p.G13D mutations (G>A transitions). BRAF-mutated tumors were predominantly right-sided and associated with a borderline worse prognosis. Forty-eight percent of tumors with MSI were present in the left colon or rectum. CONCLUSION: Allele-specific PCR is an accurate and convenient method to assess KRAS and BRAF mutations and may detect mutations not identified by dideoxy sequencing. KRAS mutation status, in conjunction with morphologic or clinical parameters, may be useful in determining whether a tumor should be tested for MSI. MSI testing should not be considered exclusively in right-sided lesions. BRAF analysis may not be useful in rectal adenocarcinomas and should be evaluated in larger studies.

Radiographic outcomes of volar locked plating for distal radius fractures.

PURPOSE: To assess the ability of volar locked plating to achieve and maintain normal radiographic parameters for articular stepoff, volar tilt, radial inclination, ulnar variance, and radial height in distal radius fractures. METHODS: We performed a retrospective review of 185 distal radius fractures that underwent volar locked plating with a single plate design over a 5-year period. We reviewed radiographs and recorded measurements for volar tilt, radial inclination, ulnar variance, radial height, and articular stepoff. We used logistic regression to determine the association between return to radiographic standard norms and fracture type. RESULTS: At the first and final postoperative follow-up visits, we observed articular congruence less than 2 mm in 92% of fractures at both times. Normal volar tilt (11°) was restored in 46% at the first follow-up and 48% at the final one. Radial inclination (22°) was achieved in 44% at the first follow-up and 43% at the final one, and ulnar variance (01 ± 2 mm) was achieved in 53% at the first follow-up and 53% at the final one. In addition, radial height (14 ± 1mm) was restored in 14% at the first follow-up and 12% at the final one. More complex, intra-articular fractures (AO class B and C and Frykman types 3, 4, 7, and 8) were less likely to be restored to normal radiographic parameters. However, because of the small sample size for some fracture types, it was difficult to discover significant associations between fracture type and radiographic outcome. CONCLUSIONS: Volar locked plating for distal radius fractures achieved articular stepoff less than 2 mm in most fractures but only restored and maintained normal radiographic measurements for volar tilt, radial inclination, and ulnar variance in 50% of fractures. The ability of volar locked plating to restore and maintain ulnar variance and volar tilt decreased with more complex intra-articular fracture types. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Assessing gonadal function after childhood ovarian surgery.

PURPOSE: We aimed to assess the late effects of ovarian salvage or oophorectomy on gonadal function and fertility as measured by menstrual regularity. METHODS: We performed a 10-year retrospective review of females aged 20 years or younger who required surgery to treat an ovarian disorder. A mail survey was distributed to these patients to evaluate the effects of ovarian surgery on menarche, menstrual regularity, and pregnancy. RESULTS: A total of 180 females had surgery to treat an ovarian disorder. Eighty-six of these underwent unilateral oophorectomy (48%), whereas 94 (52%) had an ovary sparing procedure. Eighty-one patients (45%) returned completed surveys. Of the respondents, 44 had oophorectomy, and 37 had ovarian salvage. Ages of menarche were similar between surgical groups. Symptoms of menstrual irregularity differed most significantly according to painful menses (oophorectomy, 27.3%; salvage, 59.5%; P < .04). Interestingly, continuation of regular menses after surgery was higher in the oophorectomy group (oophorectomy, 70%; salvage, 15%; P = .013). CONCLUSIONS: Unilateral oophorectomy does not appear to impair late gonadal function when compared with ovarian salvage. Surprisingly, oophorectomy appears to maintain more normal ovarian activity as estimated by menstrual regularity. Oophorectomy may be performed without apparent adverse effect on gonadal activity.

Incidence, risk factors, and outcome of pneumatosis intestinalis in pediatric stem cell transplant recipients.

BACKGROUND: Pneumatosis Intestinalis (PI) is a rare complication following hematopoietic stem cell transplant (HSCT). We sought to assess the incidence, risk factors, and outcome associated with PI. PROCEDURE: We retrospectively reviewed the incidence of PI among 178 patients who underwent allogeneic HSCT between September 1999 and February 2010. RESULTS: Eighteen of 178 children (10.1%) who received allogeneic HSCT developed PI at a median of 94 days (range, 11-1169) after transplant. All patients presented with either abdominal pain or distention, and half of the patients had free air on radiographs. Patients who developed PI had a significantly higher proportion of acute (83% vs. 44%, P = 0.002) and chronic graft versus host disease (GVHD; 56% vs. 18%, P < 0.001). Only 39% of patients with PI had GVHD involving the gasterointestinal track. All patients were managed conservatively without surgery. Transplant related mortality (TRM) was significantly higher in patients who developed PI compared to those who did not (OR 4.3, 95% CI: 1.3-13.1; P = 0.007), but no deaths were attributable to PI. CONCLUSIONS: We conclude that PI is a common complication associated with treatment of GVHD after HSCT, and patients who develop PI experience higher TRM. Patients who develop PI should be managed medically.

Factors associated with the career choices of hematology and medical oncology fellows trained at academic institutions in the United States.

PURPOSE: Factors that influence hematology-oncology fellows' choice of academic medicine as a career are not well defined. We undertook a survey of hematology-oncology fellows training at cancer centers designated by the National Cancer Institute (NCI) and the National Comprehensive Cancer Network (NCCN) to understand the factors fellows consider when making career decisions. METHODS: Program directors at all NCI and NCCN cancer centers were invited to participate in the study. For the purpose of analysis, fellows were grouped into three groups on the basis of interest in an academic career. Demographic data were tested with the Kruskal-Wallis test and χ² test, and nondemographic data were tested by using the multiscale bootstrap method. RESULTS: Twenty-eight of 56 eligible fellowship programs participated, and 236 fellows at participating institutions responded (62% response rate). Approximately 60% of fellows graduating from academic programs in the last 5 years chose academic career paths. Forty-nine percent of current fellows ranked an academic career as extremely important. Fellows choosing an academic career were more likely to have presented and published their research. Additional factors associated with choosing an academic career included factors related to mentorship, intellect, and practice type. Fellows selecting nonacademic careers prioritized lifestyle in their career decision. CONCLUSION: Recruitment into academic medicine is essential for continued progress in the field. Our data suggest that fewer than half the current fellows training at academic centers believe a career in academic medicine is important. Efforts to improve retention in academics should include focusing on mentorship, research, and career development during fellowship training and improving the image of academic physicians.

Operative intervention for complete pancreatic transection in children sustaining blunt abdominal trauma: revisiting an organ salvage technique.

Complete pancreatic transection (CPT) in children is managed commonly with distal pancreatectomy (DP). Alternatively, Roux-en-Y distal pancreaticojejunostomy (RYPJ) may be performed to preserve pancreatic tissue. The purpose of this study was to review our experience using either procedure in the management of children sustaining CPT after blunt abdominal trauma. We retrospectively reviewed the records of all children admitted to our institution during the last 15 years who were confirmed at operation to have CPT after blunt mechanisms. Summary statistics of demographic data were performed to describe children receiving either RYPJ or DP. CPT occurred in 28 children: 15 had DP, 10 had RYPJ, and three had cystogastrostomy. RYPJ children, compared with DP, were younger (7.5 vs. 12.3 years, P = 0.039) and sustained more grade IV pancreatic injuries (70% vs. 14%, P = 0.01). DP patients were 5.63 times more likely to tolerate full enteral feeds (P = 0.009). Nevertheless, when controlling for age, injury severity score, and pancreatic injury grade, procedure type did not statistically affect total and postoperative lengths of stay and postoperative complications. In the operative management algorithm of children sustaining CPT, DP may afford an earlier return to full enteral feeds. RYPJ seems otherwise equivalent to DP and preserves significant pancreatic glandular tissue and the spleen.

Significant 25-hydroxyvitamin D deficiency in child and adolescent survivors of acute lymphoblastic leukemia: treatment with chemotherapy compared with allogeneic stem cell transplant.

BACKGROUND: 25-hydroxyvitamin D insufficiency is common in healthy children and adolescents. There have been limited studies of the 25-hydroxyvitamin D status of survivors of pediatric and adolescent acute lymphoblastic leukemia (ALL). PROCEDURE: In a cohort of 78 ALL survivors (52 chemotherapy-treated and 26 HCT-treated), we determined the prevalence of, and host, treatment and environmental risk factors for 25-hydroxyvitamin D insufficiency and deficiency. RESULTS: There were no differences in serum 25-hydroxyvitamin D levels between ALL survivors treated with conventional chemotherapy and those treated with HCT (median 26.0 vs 25.5 ng/ml). Fifty-three percent of pediatric ALL survivors were 25-hydroxyvitamin D insufficient (15-29 ng/dl), and 12% were deficient (<15 ng/dl). Younger age, higher reported dietary vitamin D intake, use of vitamin D supplementation, and increased ambient ultraviolet light were associated with higher serum 25-hydroxyvitamin D levels. There was not enough evidence to suggest treatment type, gender, race, years since diagnosis or BMI were associated with serum 25-hydroxyvitamin D levels. Only 27% of conventional chemotherapy-treated ALL survivors and 8% of HCT-treated ALL survivors met RDA for dietary vitamin D intake. CONCLUSIONS: The prevalence of vitamin D deficiency and insufficiency in ALL survivors is similar to that of the general pediatric population in the United States, and there is no difference in serum 25-hydroxyvitamin D status between chemotherapy-treated and HCT-treated ALL survivors. ALL survivors rarely meet the RDA requirements for vitamin D. Further studies are needed to determine whether dietary and behavioral interventions can improve the vitamin D status of ALL survivors.

Prehospital statin and aspirin use and the prevalence of severe sepsis and acute lung injury/acute respiratory distress syndrome.

OBJECTIVES: To determine whether prehospital statin use is associated with a lower risk of sepsis, acute lung injury/acute respiratory distress syndrome, and mortality in critically ill patients. We also investigated the effect of combined prehospital use of both statins and aspirin. DESIGN: Cross-sectional analysis of a prospective cohort. PATIENTS: A total of 575 critically ill patients admitted to the medical or surgical intensive care unit of an academic tertiary-care hospital. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 575 patients, 149 (26%) were on statin therapy before hospitalization. A multivariable analysis including age, gender, current tobacco use, prehospital aspirin use, race, and Acute Physiology and Chronic Health Evaluation II score revealed that patients on statin therapy before hospitalization were less likely to have or develop severe sepsis (odds ratio 0.62, 95% confidence interval 0.40-0.96) or acute lung injury/acute respiratory distress syndrome (odds ratio 0.60, 95% confidence interval 0.36-0.99) during the first four intensive care unit days. In-hospital mortalities for patients with and without prehospital statin use (odds ratio 1.06, 95% confidence interval 0.62-1.83) were similar. Patients who had prehospital use of both statins and aspirin had the lowest rates of severe sepsis, acute lung injury/acute respiratory distress syndrome, and mortality. CONCLUSIONS: Prehospital use of statins may be protective against sepsis and acute lung injury. This effect may be potentiated by prehospital aspirin use.

Body mass index and blood pressure changes over the course of treatment of pediatric acute lymphoblastic leukemia.

BACKGROUND: Obesity and hypertension are reported among survivors of pediatric acute lymphoblastic leukemia (ALL). However, little is known about the trajectory of body mass index (BMI) and blood pressure over the course of ALL therapy. PROCEDURE: In a retrospective cohort of 183 pediatric ALL patients diagnosed from 2000 to 2008, prevalence, severity, and risk factors for obesity and hypertension were assessed during treatment. RESULTS: At diagnosis, 36% of patients were overweight and 19% were obese. Median BMI increased during induction therapy with a return to baseline soon after, but increased again over the first 22 months of maintenance therapy. At the end of therapy, 49% were overweight and 21% were obese. Increased BMI z-score at diagnosis was associated with increased z-score during maintenance (P < 0.001). Elevated parental BMI was associated with elevated BMI at diagnosis. Median BMI z-score increased over the first 22 months of maintenance (P < 0.001). Patients with high risk disease had lower BMI z-scores regardless of cranial radiotherapy exposure (P < 0.001). Pre-hypertension was prevalent over the course of therapy (31.1% with systolic pre-hypertension and 18.6% with diastolic pre-hypertension). Hypertension was also highly prevalent with 41.5% meeting systolic criteria and 24.0% meeting diastolic criteria. CONCLUSIONS: During ALL therapy, patients are at risk for early development of elevated BMI and blood pressure, which places them at potentially increased risk for future adverse health conditions. Future studies are needed to develop strategies to mitigate these risks, such as potential reduction of corticosteroid pulses or a family-based diet and exercise intervention during maintenance therapy.

Development of high-throughput quantitative assays for glucose uptake in cancer cell lines.

PURPOSE: Metabolism, and especially glucose uptake, is a key quantitative cell trait that is closely linked to cancer initiation and progression. Therefore, developing high-throughput assays for measuring glucose uptake in cancer cells would be enviable for simultaneous comparisons of multiple cell lines and microenvironmental conditions. This study was designed with two specific aims in mind: the first was to develop and validate a high-throughput screening method for quantitative assessment of glucose uptake in "normal" and tumor cells using the fluorescent 2-deoxyglucose analog 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxyglucose (2-NBDG), and the second was to develop an image-based, quantitative, single-cell assay for measuring glucose uptake using the same probe to dissect the full spectrum of metabolic variability within populations of tumor cells in vitro in higher resolution. PROCEDURE: The kinetics of population-based glucose uptake was evaluated for MCF10A mammary epithelial and CA1d breast cancer cell lines, using 2-NBDG and a fluorometric microplate reader. Glucose uptake for the same cell lines was also examined at the single-cell level using high-content automated microscopy coupled with semi-automated cell-cytometric image analysis approaches. Statistical treatments were also implemented to analyze intra-population variability. RESULTS: Our results demonstrate that the high-throughput fluorometric assay using 2-NBDG is a reliable method to assess population-level kinetics of glucose uptake in cell lines in vitro. Similarly, single-cell image-based assays and analyses of 2-NBDG fluorescence proved an effective and accurate means for assessing glucose uptake, which revealed that breast tumor cell lines display intra-population variability that is modulated by growth conditions. CONCLUSIONS: These studies indicate that 2-NBDG can be used to aid in the high-throughput analysis of the influence of chemotherapeutics on glucose uptake in cancer cells.

Driving with an arm immobilized in a splint: a randomized higher-order crossover trial.

BACKGROUND: The aim of this study was to determine whether immobilization of an arm has detrimental effects on driving performance. METHODS: Thirty-six healthy officers-in-training were assigned a sequence of fiberglass splints (left and right-sided above-the-elbow thumb spica and below-the-elbow splints) with use of a randomized higher-order crossover design. Runs were scored on a cone-marked driving course used for officer certification with predetermined passing requirements. Driving time, the number of cones hit per course section, and the cone-adjusted total time (a five-second penalty per hit cone) were recorded. A linear mixed-effect model with random environmental and learning effects for cone-adjusted time analysis was used. Participants rated perceived driving difficulty and safety with each splint, and ratings were compared with the Wilcoxon signed-rank test. RESULTS: Thirty participants completed the entire set of runs. Analysis of total cone-adjusted time revealed a significant performance decrease with the left arm in an above-the-elbow thumb spica splint (average, 22.2 seconds; p < 0.001) and with the left arm in a below-the-elbow splint (average, 16.2; p = 0.007). Analysis of forward-only course sections revealed poorer performance trends with all splints, with the worst performance with the left arm in an above-the-elbow thumb spica splint. Driving with the left arm in an above-the-elbow thumb spica splint had the highest perceived difficulty (median, 8.0) and lowest perceived safety (median, 3.0). CONCLUSIONS: Driving performance as measured with a standardized track and scoring system was significantly degraded with splint immobilization of the left arm. Further studies are required to determine the effect of arm immobilization on normal driving conditions.

Dopamine and cAMP regulated phosphoprotein MW 32 kDa is overexpressed in early stages of gastric tumorigenesis.

BACKGROUND: Gastric adenocarcinoma is a leading cause of cancer mortality. The role of dopamine and cAMP regulated phosphoprotein MW 32 kDa (DARPP-32) overexpression in the gastric tumorigenesis cascade remains unclear. METHODS: The expression of DARPP-32 in the multistep carcinogenesis cascade was examined using immunohistochemistry analysis on 533 samples. The contribution of DARPP-32 in cellular transformation and molecular signaling was investigated using NIH3T3, AGS, and SNU16 cells. RESULTS: The composite expression score (CES), calculated from immunostaining patterns, increased significantly from normal or gastritis to metaplasia, dysplasia, and adenocarcinoma (P < .001). In patients with normal stomach or gastritis and tumor samples, a 76% and 77% chance, respectively, was found (P < .001) that CES was higher in the tumor. High median CES correlated with well- or moderately differentiated (P = .03) gastric adenocarcinomas. NIH3T3 cells transfected with DARPP-32 demonstrated increased levels of phospho-AKT and a 5-fold increase in the number of foci as compared with the control (P = .02). DARPP-32 expression in AGS cells led to increased protein levels of phospho-AKT and BCL-2. For validation, the knockdown of endogenous DARPP-32 expression in SNU16 cells using shRNA resulted in decreased levels of phospho-AKT phosphorylation and BCL-2. CONCLUSION: Our results suggest that DARPP-32 overexpression may participate in the transition to intestinal metaplasia and in the progression to neoplasia. The ability of DARPP-32 to transform NIH3T3 cells and to regulate AKT and BCL-2 underscores its possible oncogenic potential.

Diagnostic utility of IgG and IgM immunohistochemistry in autoimmune liver disease.

AIM: To assess the role of IgM and IgG immunohistochemistry (IHC) in the evaluation of autoimmune liver conditions--autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC). METHODS: Forty one biopsies from untreated patients diagnosed with autoimmune liver disease (AIH, n = 20; PBC, n = 13; PSC, n = 8) and fourteen biopsies of patients with chronic hepatitis C were selected. IgM and IgG-positive plasma cells were counted in each sample. RESULTS: A predominance of IgG-positive plasma cells was seen in AIH (90% of cases), PSC (75% of cases), and chronic hepatitis C (100% of cases), while IgM-positive plasma cells predominated in PBC (92.8% of cases). The IgM /IgG ratio (< 1 or > or = 1) accurately distinguished PBC from AIH in 90.9% of cases (sensitivity = 92.3%, specificity = 90%), and PBC from either AIH or PSC in 87.8% of cases (sensitivity = 92.3%, specificity = 85.7%). CONCLUSION: Plasmacytic infiltrates expressing predominantly IgM are characteristic of PBC, while other forms of liver disease analyzed in this study, including AIH, typically show an IgG-predominant plasma cell infiltrate. Our data indicate that IgM and IgG IHC may be a useful tool when PBC is a diagnostic consideration.

Phase I study of intravenous vascular endothelial growth factor trap, aflibercept, in patients with advanced solid tumors.

PURPOSE: Vascular endothelial growth factor (VEGF) Trap (aflibercept) is an angiogenesis inhibitor comprising portions of the extracellular domains of human VEGF receptors 1 and 2 fused to the Fc portion of human immunoglobulin G. This phase I study was designed to evaluate the safety, pharmacokinetics, and pharmacodynamics of VEGF Trap administered intravenously (IV) every 2 weeks. PATIENTS AND METHODS: Patients with refractory solid tumors or non-Hodgkin's lymphoma with adequate organ function were eligible. Pharmacokinetic/pharmacodynamic markers included measurement of plasma VEGF bound to VEGF Trap and free VEGF Trap. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was incorporated to measure the biologic effects of the drug on tumor vascularity and permeability. RESULTS: The study enrolled 47 patients at doses ranging from 0.3 to 7.0 mg/kg IV every 2 weeks. Dose-limiting toxicities were rectal ulceration and proteinuria at the 7.0 mg/kg dose. Other mechanism-specific toxicities included hypertension. On the basis of these observations and on pharmacokinetics, the recommended phase II dose of VEGF Trap as a single agent is 4 mg/kg every 2 weeks. Three RECIST (Response Evaluation Criteria in Solid Tumors) -defined partial responses were observed, one at the 3.0 mg/kg and two at the 7.0 mg/kg dose level. Maximum plasma concentration of free VEGF Trap increased proportionally with dose. Maximal VEGF-bound VEGF Trap complex levels were reached at doses > or = 2.0 mg/kg. Changes in volume transfer constant measured by DCE-MRI at baseline and at 24 hours after administration indicate a possible dose-related change in this pharmacodynamic marker. CONCLUSION: IV VEGF Trap was well tolerated at the dose levels tested. Pharmacodynamic and pharmacokinetic markers were indicative of VEGF blockade.

Hypothyroidism as a consequence of intensity-modulated radiotherapy with concurrent taxane-based chemotherapy for locally advanced head-and-neck cancer.

PURPOSE: To conduct a retrospective review of 168 consecutively treated locally advanced head-and-neck cancer (LAHNC) patients treated with intensity-modulated radiotherapy (IMRT)/chemotherapy, to determine the rate and risk factors for developing hypothyroidism. METHODS AND MATERIALS: Intensity-modulated radiotherapy was delivered in 33 daily fractions to 69.3 Gy to gross disease and 56.1 Gy to clinically normal cervical nodes. Dose-volume histograms (DVHs) of IMRT plans were used to determine radiation dose to thyroid and were compared with DVHs using conventional three-dimensional radiotherapy (3D-RT) in 10 of these same patients randomly selected for replanning and with DVHs of 16 patients in whom the thyroid was intentionally avoided during IMRT. Weekly paclitaxel (30 mg/m(2)) and carboplatin area under the curve-1 were given concurrently with IMRT. RESULTS: Sixty-one of 128 evaluable patients (47.7%) developed hypothyroidism after a median of 1.08 years after IMRT (range, 2.4 months to 3.9 years). Age and volume of irradiated thyroid were associated with hypothyroidism development after IMRT. Compared with 3D-RT, IMRT with no thyroid dose constraints resulted in significantly higher minimum, maximum, and median dose (p < 0.0001) and percentage thyroid volume receiving 10, 20, and 60 Gy (p < 0.05). Compared with 3D-RT, IMRT with thyroid dose constraints resulted in lower median dose and percentage thyroid volume receiving 30, 40, and 50 Gy (p < 0.005) but higher minimum and maximum dose (p < 0.005). CONCLUSIONS: If not protected, IMRT for LAHNC can result in higher radiation to the thyroid than with conventional 3D-RT. Techniques to reduce dose and volume of radiation to thyroid tissue with IMRT are achievable and recommended.

A phase I trial of bortezomib with temozolomide in patients with advanced melanoma: toxicities, antitumor effects, and modulation of therapeutic targets.

PURPOSE: Preclinical studies show that bortezomib, a proteasome inhibitor, blocks NF-kappaB activation and, combined with temozolomide, enhances activity against human melanoma xenografts and modulates other critical tumor targets. We initiated a phase I trial of temozolomide plus bortezomib in advanced melanoma. Objectives included defining a maximum tolerated dose for the combination, characterizing biomarker changes reflecting inhibition of both proteasome and NF-kappaB activity in blood (if possible tumor), and characterizing antitumor activity. EXPERIMENTAL DESIGN: Cohorts were enrolled onto escalating dose levels of temozolomide (50-75 mg/m(2)) daily, orally, for 6 of 9 weeks and bortezomib (0.75-1.5 mg/m(2)) by i.v. push on days 1, 4, 8, and 11 every 21 days. Peripheral blood mononuclear cells were assayed at specified time points for proteasome inhibition and NF-kappaB biomarker activity. RESULTS: Bortezomib (1.3 mg/m(2)) and temozolomide (75 mg/m(2)) proved to be the maximum tolerated dose. Dose-limiting toxicities included neurotoxicity, fatigue, diarrhea, and rash. Nineteen melanoma patients were enrolled onto four dose levels. This melanoma population (17 M1c, 10 elevated lactate dehydrogenase, 12 performance status 1-2) showed only one partial response (8 months) and three with stable disease >or=4 months. A significant reduction in proteasome-specific activity was observed 1 hour after infusion at all bortezomib doses. Changes in NF-kappaB electrophoretic mobility shift assay and circulating chemokines in blood failed to correlate with the schedule/dose of bortezomib, inhibition of proteasome activity, or clinical outcome. CONCLUSIONS: We have defined phase II doses for this schedule of temozolomide with bortezomib. Although proteasome activity was inhibited for a limited time in peripheral blood mononuclear cells, we were unable to show consistent effects on NF-kappaB activation.

Impact of conditioning regimen in allogeneic hematopoetic stem cell transplantation for children with acute myelogenous leukemia beyond first complete remission: a pediatric blood and marrow transplant consortium (PBMTC) study.

Total body irradiation (TBI)-based conditioning regimens for pediatric patients with acute myelogenous leukemia (AML) beyond first complete remission (CR1) are controversial. Because the long-term morbidity of busulfan (Bu)-based regimens appears to be lower, determining efficacy is critical. We retrospectively evaluated 151 pediatric patients with AML beyond CR1, comparing outcomes in 90 patients who received a TBI-based conditioning regimen and 61 patients who received a Bu-based conditioning regimen. There were no differences between the 2 groups with respect to age, sex, duration of CR1, time from most recent remission to transplantation, or donor source. The probability of relapse at 2 years also did not differ between the 2 groups (26% and 27%, respectively; P=.93). No significant difference in event-free survival (EFS) (P=.29) or overall survival (OS) (P=.11) was noted between the 2 groups. These findings were supported by a multivariate analysis in which TBI was not associated with improved EFS (hazard ratio [HR]=1.17; 95% confidence interval [CI]=0.66-2.10; P=.58) or OS (HR=1.42; 95% CI=0.76-2.64; P=.27). Shorter CR1 and receiving an HLA-mismatched transplant adversely affected EFS and OS in this cohort. Our study provides no evidence of an advantage to using TBI in children with AML beyond CR1. A prospective, randomized study is needed to confirm these results.