Reassessment of Prostate Biopsy Specimens for Patients Referred for Robot-assisted Radical Prostatectomy Rarely Influences Surgical Planning.

BACKGROUND: The minimum volume standard is 100 robot-assisted radical prostatectomy (RARP) procedures per hospital in the Netherlands, so patients have to be referred to high-volume surgical centers for RARP. During preoperative work-up, prostate biopsies taken elsewhere are reassessed, with upgrading or downgrading of the initial Gleason grade group a possible consequence. OBJECTIVE: To determine if prostate biopsy reassessment leads to adjustment of the surgical plan regarding a nerve-sparing approach and extended pelvic lymph node dissection (ePLND) during RARP. DESIGN SETTING AND PARTICIPANTS: For 125 men who were referred to the Prosper prostate center at Canisius Wilhelmina Hospital (CWH) in the Netherlands between 2013 and 2016, results for the initial assessment of prostate biopsy by a local uropathologist were compared to results for biopsy reassessment by dedicated uropathologists at CWH. RESULTS AND LIMITATIONS: The pathologists reached agreement in 80% of the cases. In cases for which there was disagreement (n = 25), biopsy revision involved upgrading of the initial grade group in 68% and downgrading in 32%. Biopsy reassessment led to a change in surgical plan in ten cases (8%). As a result of upgrading, ePLND was performed in three patients (2%). ePLND was omitted in one patient (1%) because of downgrading. For three patients (2%) a non-nerve-sparing procedure was planned after upgrading of the initial grade group. For four patients (3%), a unilateral nerve-sparing procedure was performed after downgrading. CONCLUSIONS: This study shows that there is large interobserver agreement between uropathologists in the assessment of Gleason grade group in prostate biopsy specimens. Reassessment rarely leads to a change in surgical plan regarding the indication for a nerve-sparing approach and ePLND. Therefore, reassessment of prostate biopsy before radical prostatectomy can be omitted when the initial pathological assessment was performed by a dedicated uropathologist. PATIENT SUMMARY: Reassessment of the initial prostate biopsy specimen for patients referred to a specialist center for robot-assisted removal of the prostate rarely influences surgical planning and can be omitted.

Surgical delivery of drug releasing poly(lactic-co-glycolic acid)/poly(ethylene glycol) paste with in vivo effects against glioblastoma.

INTRODUCTION: The median survival of patients with glioblastoma multiforme (astrocytoma grade 4) remains less than 18 months despite radical surgery, radiotherapy and systemic chemotherapy. Surgical implantation of chemotherapy eluting wafers into the resection cavity has been shown to improve length of survival but the current licensed therapy has several drawbacks. This paper investigates in vivo efficacy of a novel drug eluting paste in glioblastoma. METHODS: Poly(lactic-co-glycolic acid)/poly(ethylene glycol) (PLGA/PEG) self-sintering paste was loaded with the chemotherapeutic agent etoposide and delivered surgically into partially resected tumours in a flank murine glioblastoma xenograft model. RESULTS: Surgical delivery of the paste was successful and practical, with no toxicity or surgical morbidity to the animals. The paste was retained in the tumour cavity, and preliminary results suggest a useful antitumour and antiangiogenic effect, particularly at higher doses. Bioluminescent imaging was not affected significantly by the presence of the paste in the tumour. CONCLUSIONS: Chemotherapy loaded PLGA/PEG paste seems to be a promising technology capable of delivering active drugs into partially resected tumours. The preliminary results of this study suggest efficacy with no toxicity and will lead to larger scale efficacy studies in orthotopic glioblastoma models.

The role of the WNT/ß-catenin pathway in central nervous system primitive neuroectodermal tumours (CNS PNETs).

BACKGROUND: Central nervous system primitive neuroectodermal tumours (CNS PNETs) are embryonal tumours occurring predominantly in children. Current lack of knowledge regarding their underlying biology hinders development of more effective treatments. We previously identified WNT/ß-catenin pathway activation in one-third of CNS PNETs, which was potentially linked to a better prognosis. In this study, we have extended our cohort, achieving a statistically significant correlation with prognosis. We additionally investigated the biological effects of WNT/ß-catenin pathway activation in tumour pathogenesis. METHODS: A total of 42 primary and 8 recurrent CNS PNETs were analysed for WNT/ß-catenin pathway status using ß-catenin immunohistochemistry. Genomic copy number and mRNA expression data were analysed to identify a molecular profile linked to WNT/ß-catenin pathway activation. RESULTS: Pathway activation was seen in 26% of CNS PNETs and was significantly associated with longer overall survival. Genes displaying a significant difference in expression levels, between tumours with and without WNT/ß-catenin pathway activation, included several involved in normal CNS development suggesting aberrant pathway activation may be disrupting this process. CONCLUSION: We have identified WNT/ß-catenin pathway status as a marker, which could potentially be used to stratify disease risk for patients with CNS PNET. Gene expression data suggest pathway activation is disrupting normal differentiation in the CNS.

Recurrent epistaxis as a presenting sign of androgen-sensitive metastatic prostate cancer.

Prostate cancer is a common cancer, especially among elderly men. It is sometimes not diagnosed until it has metastasised. Disseminated intravascular coagulopathy (DIC) can be the presenting manifestation of prostate cancer, and can present with bleeding (varying from isolated epistaxis to generalised haemorrhage), intravascular thrombosis, or both. A case of recurrent epistaxis from DIC due to metastatic prostate cancer occurring in an 84-year-old Caucasian man is presented, and the pathophysiology and management of DIC in association with androgen-sensitive prostate cancer are discussed.

Phase II trial of imatinib mesylate in recurrent, biomarker positive, ovarian cancer (Southwest Oncology Group Protocol S0211).

Platinum-resistant ovarian cancer continues to be a difficult therapeutic problem. Clearly, molecularly targeted agents should be evaluated in this patient population. Patients were eligible for this phase II study with stage III or IV ovarian cancer, whose tumor expressed Kit (CD117) or platelet-derived growth factor receptor (PDGFR) and with relapse of measurable disease within 6 months of completing frontline, platinum- and taxane-based chemotherapy. Patients were treated daily with 400 mg of imatinib mesylate orally. It was assumed that the agent would be of no further interest if the population response rate was less than 10%. A two-stage design was used for patient accrual. A total of 34 patients were registered to the study. Of these, 15 were found to be ineligible or not evaluable (8 because their tumor samples were negative for both DC117 and PDGFR). Of 19 evaluable patients, 2 (11%) tested positively for c-Kit and 17 (89%) tested positively for PDGFR. There were no objective responders. Thirteen patients (68%) had increasing disease or symptomatic deterioration, and six (32%) went off protocol during the first month due to adverse events. Median progression-free survival was 2 months (95% CI 1-3 months) and median overall survival was 10 months (95% CI 6-18 months). Eleven percent of patients experienced grade 4 hematologic/metabolic toxicity and 37% experienced grade 3 nonhematologic toxicity. We conclude that imatinib mesylate as a single agent does not appear to have useful clinical activity in c-Kit and/or PDGFR positive, recurrent ovarian cancer in heavily pretreated patients with ovarian cancer.

Effects of levocetirizine as add-on therapy to fluticasone in seasonal allergic rhinitis.

BACKGROUND: Addition of H(1) antagonists to intranasal corticosteroid treatment of allergic rhinitis (AR) is common in clinical practice and recommended by guidelines, despite some evidence that the additive benefits are negligible. OBJECTIVE: To assess additional benefits of 5 mg levocetirizine dihydrochloride in seasonal AR patients using 200 mcg fluticasone propionate nasal spray once daily. METHODS: In a double-blind placebo-controlled crossover study of 27 patients, following 2 weeks without treatment, subjects used fluticasone with levocetirizine or identical placebo for 2 weeks each. Assessments were the Juniper mini Rhinoconjunctivitis Quality-of-Life Questionnaire (mini-RQLQ), domiciliary peak nasal inspiratory flow (PNIF), total nasal symptoms (TNS) scores and nasal nitric oxide concentrations. Effects were interpreted and tested against minimal clinically important differences. RESULTS: Add-on effects for levocetirizine vs. placebo excluded any clinically significant benefits: mean effects (one sided 95% confidence intervals) were mini-RQLQ -0.11 (-0.34), PNIF +0.57 (+5.23), and TNS -0.11 (-0.60). Numbers needed to treat (95% confidence intervals) by outcome were mini-RQLQ 14 (5 to 49), PNIF 4 (3-7), and TNS 3 (2-6). No significant within or between treatment effects were seen for nasal nitric oxide. CONCLUSION: Contrary to current practice, the present results demonstrate that for the majority of patients, antihistamine add-on to effective nasal steroid treatment is inappropriate. Further work is required to confirm that this is also true in the most severe cases, and the available evidence needs to be put into guidelines and implemented.

Inheritance of hypoadrenocorticism in bearded collies.

OBJECTIVE: To assess heritability and mode of inheritance for hypoadrenocorticism in Bearded Collies. ANIMALS: 635 Bearded Collies. PROCEDURES: Dogs were classified as affected by hypoadrenocorticism or unaffected. Phenotypic and pedigree data were analyzed. Heritability was estimated by use of Bayesian statistical methods. Regressive logistic models for complex segregation analyses were used to characterize mode of inheritance. RESULTS: Hypoadrenocorticism was diagnosed in 60 (9.4%) dogs. Heritability of hypoadrenocorticism was estimated to be 0.76 with both sexes affected with equal probability. Evaluation of the pedigrees did not support a Mendelian autosomal dominant mode of inheritance. Evidence from the complex segregation analysis for a single locus of large effect on hypoadrenocorticism was not convincing. CONCLUSIONS AND CLINICAL RELEVANCE: Hypoadrenocorticism in Bearded Collies is highly heritable. Although a precise genetic mechanism responsible for inheritance of the disorder remains undetermined, breeding decisions must include consideration of the genetic likelihood of passing on this deleterious disorder to offspring of affected dams and sires.

Micropatterning of biomedical polymer surfaces by novel UV polymerization techniques.

The "living" radical polymerization with an iniferter was used to create micropatterned biomedical surfaces. Novel, photosensitive biomedical polymers were created by the incorporation of dithiocarbamate groups from iniferters. A second monomer layer was then irradiated onto the photosensitive polymer substrate created with the iniferter to form a copolymer. Patterns were created on the films by application of modified microfabrication-based photolithographic techniques. The technique was used to create patterns with depths from 5 to 80 microm. In addition, various polymers were incorporated, including polyethylene glycol methacrylates, styrene, and methacrylic acid, to synthesize regions with different physico-chemical properties. Applications include novel surfaces for biosensors and biomaterials for the selective adhesion of cells and proteins.

Preparation of controlled release systems by free-radical UV polymerizations in the presence of a drug.

UV free-radical polymerization techniques are often used to synthesize hydrogels for controlled release applications. Numerous techniques exist for immobilizing drugs or solutes in the gel. This work focuses on the entrapment of solute in a hydrogel by conducting a photopolymerization in the presence of the monomer and the solute. A kinetic gelation model has been developed to examine the effect of the solute material on the polymerization process and the ensuing network structure. Kinetic experiments have also been conducted of the polymerization of poly(ethylene glycol) methacrylate in the presence of theophylline. It was found that the presence of the solute led to a more heterogeneous network with numerous microgel regions present. The effect of the size of the solute on the polymerization was also investigated.

Autoimmunity in chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is associated with the immune-mediated disorders autoimmune hemolytic anemia and immune thrombocytopenia. Initial treatment with corticosteroids is often successful in controlling these manifestations, but splenectomy should be considered if a rapid and complete response is not obtained. For those with persistent anemia or thrombocytopenia after splenectomy, treatment directed against the underlying CLL may be considered, although the use of purine analogues has also precipitated autoimmune hemolytic anemia. Pure red cell aplasia has been reported in CLL, and usually responds to immunosuppressive therapy.

NCCN Practice Guidelines for Breast Cancer.

The therapeutic options for patients with noninvasive or invasive breast cancer are complex and varied. In many situations, the patient and physician have the responsibility to jointly explore and ultimately select the most appropriate option from among the available alternatives. With rare exception, the evaluation, treatment, and follow-up recommendations contained within these guidelines were based largely on the results of past and present clinical trials. However, there is not a single clinical situation in which the treatment of breast cancer has been optimized with respect to either maximizing cure or minimizing toxicity and disfigurement. Therefore, patient and physician participation in prospective clinical trials allows patients not only to receive state-of-the-art cancer treatment but also to contribute to the improvement of treatment of future patients.

Physicochemical foundations and structural design of hydrogels in medicine and biology.

Hydrogels are cross-linked hydrophilic polymers that can imbibe water or biological fluids. Their biomedical and pharmaceutical applications include a very wide range of systems and processes that utilize several molecular design characteristics. This review discusses the molecular structure, dynamic behavior, and structural modifications of hydrogels as well as the various applications of these biohydrogels. Recent advances in the preparation of three-dimensional structures with exact chain conformations, as well as tethering of functional groups, allow for the preparation of promising new hydrogels. Meanwhile, intelligent biohydrogels with pH- or temperature-sensitivity continue to be important materials in medical applications.

Acid-fast-positive Legionella pneumophila: a possible pitfall in the cytologic diagnosis of mycobacterial infection in pulmonary specimens.

The acid-fast stain is commonly used in the rapid cytologic assessment of bronchoalveolar lavage (BAL) fluid to detect pulmonary mycobacterial infections, particularly in immunocompromised patients. The identification of acid-fast, rod-shaped organisms may be taken as presumptive evidence of such an infection, in the appropriate clinical setting. However, this determination is made less specific by the occasional acid-fast positivity of microorganisms other than mycobacteria. We report on the occurrence of a fatal pneumonia caused by acid-fast positive Legionella pneumophila detected by BAL. This is a potential pitfall in the rapid diagnosis of pulmonary mycobacterial infections.

Effects of total parental nutrition (TPN) during high-dose interleukin-2 treatment for metastatic cancer.

Patients treated with high doses of interleukin-2 (IL-2) develop profound anorexia, malaise, loss of energy, mucositis, nausea, and vomiting, which may contribute to poor nutrition. We hypothesized that total parenteral nutrition (TPN) administration would ameliorate these changes and could improve fluid and electrolyte balance. A retrospective analysis of protein and energy intake was performed in 21 sequential patients who received a normal diet (controls) and 16 subsequent patients who received TPN during IL-2 treatment. The effect of TPN on laboratory abnormalities induced by IL-2 was also evaluated. Within 24 h of starting IL-2, mean energy intake declined to 2.5-2.8 kcal/kg in controls in contrast to the energy intake of 25-29 kcal/kg in patients receiving TPN. Protein nutrition was affected in a similar fashion, with a markedly lower protein intake in controls (0.08-0.12 g/kg) than in the TPN group (1.02-1.10 g/kg). TPN improved serum calcium and potassium concentrations, particularly during spontaneous diuresis after completion of IL-2 treatment. Unexpectedly, TPN decreased the frequency and severity of cholestatic jaundice caused by IL-2. Patients receiving TPN had an increased propensity for hyperglycemia and hypophosphatemia. High-dose intravenous bolus IL-2 therapy resulted in a markedly negative nutritional balance in control patients. A brief period of TPN during IL-2 treatment was well tolerated and corrected calorie and protein malnutrition. TPN administration also improved control of serum electrolytes. TPN did not adversely affect tumor progression or patient survival.

Models for early chemoprevention trials in breast cancer.

Several models are being explored for use in the phase I and phase II evaluation of breast cancer chemoprevention agents. The short-term DCIS/small invasive cancer model is probably best used in late phase I trials in conjunction with agents likely to have activity in the progression phase of neoplastic development in addition to activity in earlier phases. The core biopsy or FNA hyperplasia models may be best used with drugs that are likely to have activity primarily in the promotion phase of neoplastic development and that are suitable for longer duration trials lasting several months to years. Morphology currently is the key surrogate endpoint biomarker for assessing efficacy in phase II trials. Other biomarkers that may undergo modulation will have to be validated, in that modulation will have to be shown to be directly related to decreased cancer risk in subsequent phase III trials. Only then can they be considered as validated surrogate endpoint biomarkers and used as stand-alone efficacy markers in phase II trials. Despite accrual challenges and technologic hurdles, interest in phase I and phase II chemoprevention trials is high.

Acute dyslipoproteinemia induced by interleukin-2: lecithin:cholesteryl acyltransferase, lipoprotein lipase, and hepatic lipase deficiencies.

Recombinant human interleukin-2 (rIL-2) is used to treat refractory cancers. During such treatment, patients develop severe hypocholesterolemia along with striking alterations in the concentration and composition of the circulating lipoproteins. The present study was undertaken to gather information about the pathogenesis of these abnormalities. Patients were studied before-, during- and after a 5-day course of high dose i.v. rIL-2. Whole plasma cholesterol was markedly reduced by rIL-2 administration (52%; P < 0.001), whereas the triglyceride concentration did not change. Thus, the lipoproteins became triglyceride enriched (P = 0.004). Low density lipoprotein cholesterol, apolipoprotein B (apoB), high density lipoprotein cholesterol, and apoA-I concentrations all decreased. Esterified cholesterol levels were markedly reduced. Total plasma apoE increased markedly, and two kinds of abnormal particles appeared: 1) beta-migrating, very low density lipoproteins; and 2) discoidal, apoE- and phospholipid-containing particles with abnormal density and electrophoretic mobility. The activities of two lipoprotein triglyceride hydrolases, lipoprotein lipase and hepatic lipase, fell significantly during treatment and returned promptly to pretreatment levels after rIL-2 was discontinued. Lecithin:cholesteryl acyltransferase (LCAT) activity also decreased significantly (64%) during treatment, but in contrast to the lipases, remained low for at least 5 days after the last dose of rIL-2 (P < 0.001). High dose i.v. rIL-2 induces severe dyslipidemia with deficiencies of both postheparin lipases and acute LCAT deficiency. Most, if not all, of the lipoprotein changes observed are explained by the LCAT deficiency that follows IL-2-induced hepatocellular injury and cholestasis.

Methotrexate-associated lymphoma in patients with rheumatoid arthritis: report of two cases.

This report describes 2 patients with longstanding seropositive rheumatoid arthritis (RA) treated with oral methotrexate (MTX) who developed large cell lymphoma of B cell phenotype. In situ hybridization studies showed nuclear staining for Epstein-Barr virus (EBV) within the malignant lymphoid cells. In both cases, the lymphoma was undetectable several weeks after diagnostic biopsy followed by discontinuation of MTX. These observations suggest that, in patients with RA who develop an EBV-associated lymphoproliferative disorder, a trial of discontinuation of immunosuppressive agents may be warranted before chemotherapy is considered. In addition, there is a need for a heightened awareness of the development of lymphoma in this patient population.