New-onset persistent hyperglycemia with initiation of brentuximab treatment.

INTRODUCTION: The addition of brentuximab vedotin (BV) to adriamycin, vinblastine, and dacarbazine (AVD) has become the standard-of-care approach for advanced stage Hodgkin lymphoma (HL). This case describes a rare presentation of new-onset diabetes mellitus one month after initiation of BV + AVD therapy in a patient with HL. CASE REPORT: A 41-year-old woman with pre-diabetes and obesity was started on BV + AVD for classical HL, nodular sclerosing type. Six weeks after initiating therapy, she was admitted for abdominal pain, at which time her blood glucose was noted to be 357 mg/dL. Her Hba1c was 8.1%. She required rapid acting insulin, and throughout admission, her glucose ranged from 132 to 263 mg/dL. After discharge, a fasting glucose of over 250 mg/dL deemed her ineligible to have a PET/CT performed to assess disease status. MANAGEMENT AND OUTCOME: She was started on basal insulin, a DPP4-inhibitor, and a meglitinide analog. After initiation of therapy, her glucose levels were better controlled, and she was able to have her PET scan. Repeat Hba1c was 6.2% three months after initiation of glucose-lowering medications. She completed 6 cycles of BV + AVD therapy, with improving finger stick blood glucose (FSBG), and repeat Hba1c 1 month after completion of therapy was 5.2% on metformin monotherapy. DISCUSSION: Reports of brentuximab-induced hyperglycemia are rare in the literature, noted in just a few studies and one case report. Our case demonstrates a need to monitor blood glucose levels carefully during the initiation of BV therapy, especially in individuals with risk factors such as obesity, pre-diabetes mellitus, or diabetes mellitus.

Risky business: Changes in boldness behavior in male Siamese fighting fish, Betta splendens, following exposure to an antiandrogen.

Components of boldness, such as activity level and locomotion, influence an individual's ability to avoid predators and acquire resources, generating fitness consequences. The presence of endocrine disrupting chemicals (EDCs) in the aquatic environment may affect fitness by changing morphology or altering behaviors like courtship and exploration. Most research on EDC-generated behavioral effects has focused on estrogen mimics and reproductive endpoints. Far fewer studies have examined the effects of other types of EDCs or measured non-reproductive behaviors. EDCs with antiandrogenic properties are present in waterways yet we know little about their effects on exposed individuals although they may produce effects similar to those caused by estrogen mimics because they act on the same hormonal pathway. To examine the effects of antiandrogens on boldness, this study exposed male Siamese fighting fish, Betta splendens, to a high or low dose of one of two antiandrogens, vinclozolin or flutamide, and observed behavior in three boldness assays, both before and after exposure. Overall, antiandrogen exposure increased boldness behavior, especially following exposure to the higher dose. Whether or not antiandrogen exposure influenced boldness, as well as the nature and intensity of the effect, was assay-dependent. This demonstrates the importance of studying EDC effects in a range of contexts and, at least within this species, suggests that antiandrogenic compounds may generate distinct physiological effects in different situations. How and why the behavioral effects differ from those caused by exposure to an estrogen mimic, as well as the potential consequences of increased activity levels, are discussed. Exposure to an antiandrogen, regardless of dose, produced elevated activity levels and altered shoaling and exploration in male Siamese fighting fish. These modifications may have fitness consequences.

Capecitabine and temozolomide (CAPTEM) for metastatic, well-differentiated neuroendocrine cancers: The Pancreas Center at Columbia University experience.

PURPOSE: We evaluated the efficacy and safety of capecitabine and temozolomide (CAPTEM) in patients with metastatic neuroendocrine tumors (NETs) to the liver. This regimen was based on our studies with carcinoid cell lines that showed synergistic cytotoxicity with sequence-specific dosing of 5-fluorouracil preceding temozolomide (TMZ). METHODS: A retrospective review was conducted of 18 patients with NETs metastatic to the liver who had failed 60 mg/month of Sandostatin LAR™ (100%), chemotherapy (61%), and hepatic chemoembolization (50%). Patients received capecitabine at 600 mg/m(2) orally twice daily on days 1-14 (maximum 1,000 mg orally twice daily) and TMZ 150-200 mg/m(2) divided into two doses daily on days 10-14 of a 28-day cycle. Imaging was performed every 2 cycles, and serum tumor markers were measured every cycle. RESULTS: Using RECIST parameters, 1 patient (5.5%) with midgut carcinoid achieved a surgically proven complete pathological response (CR), 10 patients (55.5%) achieved a partial response (PR), and 4 patients (22.2%) had stable disease (SD). Total response rate was 61%, and clinical benefit (responders and SD) was 83.2%. Of four carcinoid cases treated with CAPTEM, there was 1 CR, 1 PR, 1 SD, and 1 progressive disease. Median progression-free survival was 14.0 months (11.3-18.0 months). Median overall survival from diagnosis of liver metastases was 83 months (28-140 months). The only grade 3 toxicity was thrombocytopenia (11%). There were no grade 4 toxicities, hospitalizations, opportunistic infections, febrile neutropenias, or deaths. CONCLUSIONS: CAPTEM is highly active, well tolerated and may prolong survival in patients with well-differentiated, metastatic NET who have progressed on previous therapies.

Treatment of multiple endocrine neoplasia 1/2 tumors: case report and review of the literature.

BACKGROUND: Neuroendocrine tumors are uncommon tumors that are histopathologically and biologically heterogeneous and include the multiple endocrine neoplasia (MEN) 1 and 2 syndromes. The morbidity of MEN-1 and MEN-2 is often due to the symptomatology of the endocrine hormones produced, and the mortality mainly occurs from hepatic dysfunction incurred by liver metastases. At present, there is essentially no effective cure once the tumor has metastasized to the liver. PATIENT: We present a patient with progressive, metastatic MEN-1 with the classic '3 P's' triad of neuroendocrine tumor of the pancreas, parathyroid adenoma and a pituitary adenoma. RESULTS: After progression on high-dose Sandostatin LAR (60 mg/month) and multiple surgeries, the patient had a partial response (40% decrease) to a novel regimen of capecitabine and temozolomide (CAPTEM) and progression-free survival of 18 months. He had minor grade 1 toxicities and no grade 2, 3 or 4 toxicities. DISCUSSION: The history and treatment options for MEN-1/2 cancers are reviewed, as well as the data behind our novel regimen, CAPTEM. CONCLUSION: The CAPTEM regimen is a tolerable, safe, easy to administer oral regimen with possible efficacy for MEN-1 tumors.

Parent-controlled PCA for pain management in pediatric oncology: is it safe?

Patient-controlled analgesia offers safe and effective pain control for children who can self-administer medication. Some children may not be candidates for patient-controlled analgesia (PCA) unless a proxy can administer doses. The safety of proxy-administered PCA has been studied, but the safety of parent-administered PCA in children with cancer has not been reported. In this study, we compare the rate of complications in PCA by parent proxy versus PCA by clinician (nurse) proxy and self-administered PCA. Our pediatric institution's quality improvement database was reviewed for adverse events associated with PCA from 2004 through 2010. Each PCA day was categorized according to patient or proxy authorization. Data from 6151 PCA observation days were included; 61.3% of these days were standard PCA, 23.5% were parent-proxy PCA, and 15.2% were clinician-proxy PCA days. The mean duration of PCA use was 12.1 days, and the mean patient age was 12.3 years. The mean patient age was lower in the clinician-proxy (9.4 y) and parent-proxy (5.1 y) groups, respectively. The complication rate was lowest in the parent-proxy group (0.62%). We found that proxy administration of PCA by authorized parents is as safe as clinician administered and standard PCA at our pediatric institution.

Spinal emergencies.

True spinal emergencies are rare and represent a potential loss of function if not treated properly. This review describes the most frequently encountered spinal emergencies. Early diagnosis is the key to preventing significant morbidity in the form of permanent disability. The recognition of red flags, followed by a thorough neurologic exam and appropriate imaging, should prompt a thorough examination with a heightened sense of urgency regarding the workup for serious forms of pathology. Spinal emergencies threaten loss of function if not treated properly. Providers must be aware of the presenting symptoms and be able to accurately interpret imaging results in order to promptly diagnose and treat these conditions.

Risk of catheter-associated infection in young hematology/oncology patients receiving long-term peripheral nerve blocks.

BACKGROUND: Continuous peripheral nerve blocks (CPNBs) are increasingly used to control postoperative and chronic pain. At our pediatric oncology institution, the duration of CPNBs is often prolonged. The risk of catheter-associated infection with prolonged CPNBs has not been previously investigated. AIM: We analyzed the incidence of CPNB-related infection and its relation to catheter duration, catheter site, intensive care stay, and antibiotic coverage. METHODS: All CPNBs placed at our institution between August 1, 2005 and October 31, 2010 were studied. Primary diagnosis and the site, indication, duration, and infectious adverse effects of CPNBs were obtained from our Pain Service QI database. Patients' age and sex, antibiotic administration, and number of days in intensive care were collected from patients' medical records. RESULTS: The use of 179 catheters in 116 patients was evaluated. Mean age at CPNB placement was 15.1 years (median, 14.7; range, 0.4-26.9). The most frequent indication for CPNB was surgery (89.4%), most commonly orthopedic (78.8%). Mean CPNB duration was 7.2 days (median, 5.0; range, 1-81 days). Two cases (1.12%) of CPNBs developed signs of infection, both associated with femoral catheters. The infections were mild and necessitated catheter removal at days 10 and 13, respectively. CONCLUSION: Nerve block catheter-associated infections are infrequent at our institution despite prolonged CPNB use. Both patients with infection had femoral catheters and prolonged catheter (≥ 10 days) use.

A novel approach to repair of wound dehiscence in the complicated patient.

Wound dehiscence following abdominal surgery is a rare but deadly complication and management can be challenging. Multiple risk factors can increase the likelihood of encountering a wound dehiscence, including genetic predisposition. One such genetic disorder is type IV Ehlers-Danlos syndrome, which is associated with extreme friability of tissues, including skin and fascia. Due to the friability of the tissue, closure of the wound with conventional techniques is frequently associated with reoccurrence of the dehiscence. Here, we describe a patient with an abdominal wound dehiscence who was treated successfully with a novel closure technique using the Quill SRS™ [Angiotech] barbed suture. The type of stitches and the technique employed allowed diffusion of wound forces away from the edges for distribution to a larger surface, thus decreasing the chances of ripping the skin in this challenging patient.

Outcomes of human immunodeficiency virus-infected and -exposed children undergoing surgery--a prospective study.

AIM: Human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) is a worldwide pandemic. Mother-to-child transmission programs should theoretically minimize vertical transfer of the virus, but with variable effectiveness of implementation a significant number of children become infected and may present for emergency, diagnostic, and elective surgery. The aim of this study was to prospectively document the clinical presentation, the spectrum of pathology, and surgical outcomes of patients presenting to our hospital. This formed part of a pilot study of a collaborative international working group studying HIV infection in children, which included the Buzzi Children's Hospital Milan, Italy; the University of San Diego, California, USA; and the Red Cross War Memorial Children's Hospital and University of Cape Town, School of Adolescent and Child Health, Cape Town, South Africa. METHOD: Clinical data from all children admitted to the surgical service of the Red Cross War Memorial Children's Hospital between July 2004 and December 2006 with either a history of HIV exposure (born to an HIV-infected mother) or confirmation of HIV infection by ELISA or polymerase chain reaction was collected. The clinical course was documented prospectively for the duration of admission and subsequent follow-up as recorded in case records review. The spectrum of pathology, surgical intervention, outcome, complications, World Health Organization stage of AIDS, and type of antiretroviral therapy were all noted. Comparative outcomes and subgroup analysis were not done in this part of the study. RESULTS: One hundred and thirteen patients were included in the study over the 30-month period. The average age was 24 months (1 day to 11 years). Seventy-nine (70%) of the 113 patients were infected and 34 (30%) were exposed, 9 of whom subsequently tested negative. Of the infected group, 53 (67%) patients were on antiretroviral therapy. The extent of disease in the infected group of patients according to the 2006 World Health Organization criteria was as follows: stage 1, 4 (5%); stage 2, 12 (15%); stage 3, 51 (65%); and stage 4, 12 (15%). All patients had nutritional assessments and were plotted on growth curves. Sixty-two (54%) were found to be malnourished and 41 (36%) of the children were found to have comorbid disease processes. Eighteen patients (16%) were treated with antibiotics or conservative therapy alone. The remaining 95 patients (84%) underwent an average of 1.6 procedures (range, 1-35), 59 (52%) in an elective manner and 36 (31%) as an emergency. When assessing the relationship of HIV to the presenting disease state, 58 (73.4%) had HIV-related diseases and 52 (46%) presented with sepsis. A total of 29 (25%) patients had surgical complications of which 6 (20%) were not considered to be HIV related. Nine (31%) had, in retrospect, incorrect management of the presenting disease, leaving 14 (48%) who potentially had HIV-related complications of poor wound healing and sepsis. A total of 100 (88%) were discharged alive, 6 (5.3%) died, and 7 (6 %) were lost to follow-up. Long-term follow-up of 50 patients for an average of 8 months revealed one further mortality. CONCLUSION: Human immunodeficiency virus-positive and -exposed patients present a unique challenge in management which is complicated by concomitant disease and poor nutrition. These patients require an expanded differential diagnosis. We believe that, although on the surface there may be a higher complication rate, this needs to be confirmed in an expanded comparative cohort study, which is underway and that patients should still receive the benefit of full surgical intervention.

Positron emission tomography changes management and prognostic stratification in patients with oesophageal cancer: results of a multicentre prospective study.

OBJECTIVES: The aims of this study were (1) to determine the incremental information provided by (18)F-FDG positron emission tomography (PET) in staging patients with oesophageal cancer, and (2) to determine the impact of PET staging on post-PET clinical management of oesophageal cancer, and on prognosis. METHODS: In a multicentre, single-arm open study, patients with proved oesophageal cancer without definite distant metastases and regarded as suitable for potentially curative treatment were examined by PET. Clinicians were requested to supply a management plan before and another plan after being supplied with the PET scan results. Patients were followed for at least 1 year for outcome analysis. RESULTS: A total of 129 patients (104 men, mean age 67 y) were recruited. PET detected additional sites of disease in 53 patients (41%). Significant changes in management (high or medium impact) were observed in 38% of patients, primarily as a result of identifying additional sites of disease and/or confirming previously equivocal regional and distant metastases. Progression-free survival was significantly shorter in patients found to have additional lesions on PET (p < 0.05), but was not related to SUV(max). CONCLUSION: These findings demonstrate the significant impact of PET on the clinical management of patients with newly diagnosed oesophageal carcinoma, and on prognostic stratification of these patients.

An institutional quality improvement initiative for pain management for pediatric cancer inpatients.

Health care institutions must use the principles of quality improvement to demonstrate appropriate assessment and effective management of pain. Here, we describe the quality improvement initiative implemented at our pediatric institution to improve the quality of pain management. We conducted chart audits for the previous 24 hours during which patients received inpatient care. Over six years, 2,478 charts were audited for 87 24-hour periods (average 1.2 days/month) to answer the following: (1) Was pain intensity assessed as per the institutional pain standard of care, (2) What proportion of audited inpatients had significant pain (>or=5/10), and (3) When significant pain (>or=5/10) occurred, was treatment effective (pain score

Recombinant human factor VIII-specific affinity ligands selected from phage-displayed combinatorial libraries of protein A.

Factor VIII-specific affibodies were selected from phage displayed libraries constructed by combinatorial mutagenesis of an alpha helical bacterial receptor domain derived from staphylococcal protein A. Bead-immobilized recombinant human factor VIII (rVIII) (80 and 90 kDa chains) protein was used during competitive biopannings in the presence of free 80-kDa chain protein, resulting in the selection of several binders that showed dissociation constants (Kd) in the range 100-200 nM as determined by biosensor analyses. One variant (Z[rVIII:3], 90-kDa chain specific) was further characterized in small-scale affinity chromatography experiments, and showed efficient and selective recovery of biologically active rVIII from Chinese hamster ovary cell supernatant-derived feed stocks. The purity of the enriched rVIII was comparable with rVIII material purified by immunoaffinity chromatography using a 90-kDa chain-specific monoclonal antibody. Interestingly, epitope mapping showed that the monoclonal antibody and the affibody ligand competed for the same or at least overlapping epitopes on rVIII. In addition, the Z[rVIII:3] variant was produced by peptide synthesis with a C-terminal cysteine to enable directed coupling to solid supports. This 59-residue protein was analyzed by circular dichroism and showed a secondary structure content similar to that of the parental Z domain used as scaffold. In biosensor studies, the synthetic affibody was immobilized recruiting the C-terminal cysteine residue, and demonstrated to bind both recombinantly produced and plasma-derived factor VIII. From a secondary library, constructed by re-randomization of relevant positions identified after alignment of the first-generation variants, a panel of affinity-improved second-generation affibodies were selected of which one clone showed a dissociation constant (Kd) for rVIII of 5 nM. Several of these variants also showed higher apparent binding efficiencies towards rVIII when analyzed as immobilized ligands in biosensor experiments. Taken together, the results suggest that affibody ligands produced by bacterial or synthetic routes could be of interest as an alternative to monoclonal antibodies in purification processes or as diagnostic or monitoring tools.

Suppression of experimental abdominal aortic aneurysms in the rat by treatment with angiotensin-converting enzyme inhibitors.

PURPOSE: Pathologic remodeling of the extracellular matrix is a critical mechanism in the development and progression of abdominal aortic aneurysms (AAAs). Although angiotensin-converting enzyme (ACE) inhibitors are known to alter vascular wall remodeling in other conditions, their effects on AAAs are unknown. In this study we assessed the effect of ACE inhibitors in a rodent model of aneurysm development. METHODS: Male Wistar rats underwent transient aortic perfusion with porcine pancreatic elastase, followed by treatment with one of three ACE inhibitors (captopril [CP], lisinopril [LP], or enalapril [EP]), an angiotensin (AT)1 receptor antagonist (losartan [LOS]), or water alone (9 rats in each group). Blood pressure and aortic diameter (AD) were measured before elastase perfusion and on day 14, with an AAA defined as an increase in AD (DeltaAD) of more than 100%. The structural features of the aortic wall were examined by means of light microscopy. RESULTS: Aneurysmal dilatation consistently developed within 14 days of elastase perfusion in untreated rats, coinciding with the development of a transmural inflammatory response and destruction of the elastic media (mean DeltaAD, 223% +/- 28%). All three ACE inhibitors prevented AAA development (mean DeltaAD: CP, 67% +/- 4%; LP, 18% +/- 12%; and EP, 14% +/- 3%; each P <.05 vs controls). ACE inhibitors also attenuated the degradation of medial elastin without diminishing the inflammatory response. Surprisingly, the aneurysm-suppressing effects of ACE inhibitors were dissociated from their effects on systemic hemodynamics, and LOS had no significant effect on aneurysm development compared with untreated controls (mean DeltaAD, 186% +/- 19%). CONCLUSION: Treatment with ACE inhibitors suppresses the development of elastase-induced AAAs in the rat. Although this is associated with the preservation of medial elastin, the mechanisms underlying these effects appear to be distinct from hemodynamic alterations alone or events mediated solely by AT1 receptors. Further studies are needed to elucidate how ACE inhibitors influence aortic wall matrix remodeling during aneurysmal degeneration.

Periadolescent nicotine exposure reduces cocaine reward in adult mice.

Fully mature mice exposed to low levels of nicotine during periadolescence exhibited reductions in the rewarding and subjective effects of cocaine. These results provide converging validity that periadolescent nicotine exposure can permanently decrease a subject's sensitivity to the reinforcing effects of cocaine. These changes were noted long after exposure, suggesting that nicotine may have altered neural systems mediating drug reward. Since reductions in the rewarding value of abused drugs are associated with increased self-administration, periadolescent nicotine exposure might increase the risk for substance abuse problems. The study thus provides biological support that nicotine might serve a "gateway" function for substance abuse.

Blood-brain barrier and blood volume imaging of cerebral glioma using functional CT: a pictorial review.

We present five cases of cerebral glioma that illustrate the benefit of functional CT imaging of blood-brain barrier permeability and cerebral blood volume. Functional CT uses Patlak analysis of a single location dynamic sequence to extract physiological information that is useful clinically in the assessment of cerebral gliomas. Functional CT offers distinct advantages over other functional modalities, including clearer delineation of tumour, tumour grading, measurement of tumour activity and monitoring response to therapy.

CT measurement of perfusion and permeability within lymphoma masses and its ability to assess grade, activity, and chemotherapeutic response.

PURPOSE: Structural CT criteria such as nodal size and appearance have a poor correlation with the grade and activity of a lymphoma mass. This study investigates the potential for functional CT perfusion and permeability measurements to assess lymphoma grade and activity. METHOD: Thirty-nine patients with proven lymphoma underwent 47 dynamic contrast-enhanced CT studies. Lymphoma grade was classified as low or intermediate/high. In seven patients who underwent repeated studies, measurements were correlated against change in disease activity in the intervening period. RESULTS: Median perfusion values were higher in active disease (0.55 vs. 0.37 ml/min/ml) and intermediate/high-grade lymphoma (0.56 vs. 0.46 ml/min/ml). Perfusion below 0.2 ml/min/ml implied inactive disease (p < 0.03), whereas > 0.5 ml/min/ml suggested intermediate/high-grade lymphoma (p = 0.11). Median values of permeability were little different between patient groups. Only perfusion fell when disease became inactive. CONCLUSION: Only CT perfusion measurements of nodes have potential for assessing lymphoma grade, activity, and treatment response.

Modified stages of acquisition of gateway drug use: a primary prevention application of the stages of change model.

The purpose of the study was to identify the stages of acquisition of gateway drugs in fourth, fifth, and sixth graders. The Stages of Acquisition model is a primary prevention application of the Stages of Change model. The subjects in the study were 811 students from seventeen elementary schools in Arkansas and Missouri. The instrument elicited information regarding the stages of acquisition and individual self-reported drug use. The data were analyzed using frequency, distribution, discriminant analysis, and correlation analyses. Stage placement was confirmed using a series of drug use measures. Results confirmed the existence of discrete stages of acquisition. Results supported the concept of gateway drugs in that subjects indicated they had progressed further through the stages of acquisition of alcohol use than through the stages of acquisition of cigarettes use, smokeless tobacco use, or marijuana use.

Blood-brain barrier and blood volume imaging of cerebral glioma using functional CT: a pictorial review.

Five cases of cerebral glioma are presented here that illustrate the benefit of functional CT imaging of blood-brain barrier permeability and cerebral blood volume. Functional CT uses Patlak analysis of a single location dynamic sequence to extract physiological information that is useful clinically i the assessment of cerebral gliomas. Functional CT offers distinct advantages over other functional modalities including clearer delineation of tumour, tumour grading, measurement of tumour activity and monitoring response to therapy.