Role of the Neuroradiologist and Neurosurgeon in Contouring with the Clinical Oncologist for Stereotactic Radiosurgery.

AIM: To evaluate the value of a multidisciplinary team (MDT), including a neuroradiologist and a neurosurgeon, review of contouring in stereotactic radiosurgery (SRS). MATERIALS AND METHODS: A sequential audit of all patients receiving intracranial SRS at local institution was conducted. Lesions were contoured first by a clinical oncologist, then reviewed/edited by the MDT. The initial contour was compared with the final contour using Jaccard conformity (JCI) and geographical miss indices (GMI). The dosimetric impact of a contouring change was assessed using plan metrics to both original and final contours. RESULTS: In total, 113 patients and 142 lesions treated over 22 months were identified. The mean JCI was 0.92 (0.32-1.00) and 38% needed significant editing (JCI <0.95). The mean GMI was 0.03 (0.0-0.65) and 17% showed significant miss (GMI >0.05). Resection cavities showed more changes, with lower JCI and higher GMI (P < 0.05). There was no significant improvement on JCI or GMI shown over time. The dosimetric analysis indicated a strong association of conformity metrics with planning target volume dose metrics; a 0.1 change in gross tumour volume conformity metric association with a 6-17% change in dose to 95% of the resulting planning target volume. Greater association was seen in the resection cavity, suggesting the geographical nature of a typical contouring error gives rise to greater potential change in dose. Clinical outcomes compared well with published series. The median survival was 20 months; the local relapse-free rate in the treated areas was 0.89 (0.8-0.94) at 40 months; the radionecrosis-free rate at 40 months was 0.9 (0.83-0.95) with a median of 17 months to developing radionecrosis. CONCLUSIONS: This work highlights that MDT contour review adds significant value to SRS and the approach translates into reduced local recurrence rates at the local institution compared with previously published data. No improvement in clinical oncologist contouring over time was shown, indicating that a collaborative approach is needed regardless of the experience of the clinical oncologist. MDT input is recommended in particular for contouring of resection cavities.

Pore-forming bioinks to enable spatio-temporally defined gene delivery in bioprinted tissues.

The regeneration of complex tissues and organs remains a major clinical challenge. With a view towards bioprinting such tissues, we developed a new class of pore-forming bioink to spatially and temporally control the presentation of therapeutic genes within bioprinted tissues. By blending sacrificial and stable hydrogels, we were able to produce bioinks whose porosity increased with time following printing. When combined with amphipathic peptide-based plasmid DNA delivery, these bioinks supported enhanced non-viral gene transfer to stem cells in vitro. By modulating the porosity of these bioinks, it was possible to direct either rapid and transient (pore-forming bioinks), or slower and more sustained (solid bioinks) transfection of host or transplanted cells in vivo. To demonstrate the utility of these bioinks for the bioprinting of spatially complex tissues, they were next used to zonally position stem cells and plasmids encoding for either osteogenic (BMP2) or chondrogenic (combination of TGF-ß3, BMP2 and SOX9) genes within networks of 3D printed thermoplastic fibers to produce mechanically reinforced, gene activated constructs. In vivo, these bioprinted tissues supported the development of a vascularised, bony tissue overlaid by a layer of stable cartilage. When combined with multiple-tool biofabrication strategies, these gene activated bioinks can enable the bioprinting of a wide range of spatially complex tissues.

Mesenchymal stem cell fate following non-viral gene transfection strongly depends on the choice of delivery vector.

Controlling the phenotype of mesenchymal stem cells (MSCs) through the delivery of regulatory genes is a promising strategy in tissue engineering (TE). Essential to effective gene delivery is the choice of gene carrier. Non-viral delivery vectors have been extensively used in TE, however their intrinsic effects on MSC differentiation remain poorly understood. The objective of this study was to investigate the influence of three different classes of non-viral gene delivery vectors: (1) cationic polymers (polyethylenimine, PEI), (2) inorganic nanoparticles (nanohydroxyapatite, nHA) and (3) amphipathic peptides (RALA peptide) on modulating stem cell fate after reporter and therapeutic gene delivery. Despite facilitating similar reporter gene transfection efficiencies, these nanoparticle-based vectors had dramatically different effects on MSC viability, cytoskeletal morphology and differentiation. After reporter gene delivery (pGFP or pLUC), the nHA and RALA vectors supported an elongated MSC morphology, actin stress fibre formation and the development of mature focal adhesions, while cells appeared rounded and less tense following PEI transfection. These changes in MSC morphology correlated with enhanced osteogenesis following nHA and RALA transfection and adipogenesis following PEI transfection. When therapeutic genes encoding for transforming growth factor beta 3 (TGF-ß3) and/or bone morphogenic protein 2 (BMP2) were delivered to MSCs, nHA promoted osteogenesis in 2D culture and the development of an endochondral phenotype in 3D culture, while RALA was less osteogenic and appeared to promote a more stable hyaline cartilage-like phenotype. In contrast, PEI failed to induce robust osteogenesis or chondrogenesis of MSCs, despite effective therapeutic protein production. Taken together, these results demonstrate that the differentiation of MSCs through the application of non-viral gene delivery strategies depends not only on the gene delivered, but also on the gene carrier itself. STATEMENT OF SIGNIFICANCE: Nanoparticle-based non-viral gene delivery vectors have been extensively used in regenerative medicine, however their intrinsic effects on mesenchymal stem cell (MSC) differentiation remain poorly understood. This paper demonstrates that different classes of commonly used non-viral vectors are not inert and they have a strong effect on cell morphology, stress fiber formation and gene transcription in MSCs, which in turn modulates their capacity to differentiate towards osteogenic, adipogenic and chondrogenic lineages. These results also point to the need for careful and tissue-specific selection of nanoparticle-based delivery vectors to prevent undesired phenotypic changes and off-target effects when delivering therapeutic genes to damaged or diseased tissues.

A phase 2 multimodality trial of docetaxel/prednisone with sunitinib followed by salvage radiation therapy in men with PSA recurrent prostate cancer after radical prostatectomy.

BACKGROUND: In men with high Gleason PC and rapid PSA progression after surgery, failure rates remain unacceptably high despite salvage radiation. We explored a novel multimodality approach of docetaxel with anti-angiogenic therapy before salvage radiotherapy (RT). METHODS: This was a phase 2 single-arm prospective open-label trial with historic controls. Eligible men had a rising PSA of 0.1-3.0 ng ml(-1) within 4 years of radical prostatectomy, no metastases except resected nodal disease, no prior androgen-deprivation therapy (ADT) and Gleason 7-10. Men received four cycles of docetaxel 70 mg m(-2) every 3 weeks with low dose prednisone and sunitinib 37.5 mg daily for 14/21 days each cycle, with no ADT. Salvage prostate bed RT (66 Gy) started at day 100. The primary end point was progression-free survival (PFS) rate at 24 months. Safety data, quality of life (QOL) and dose-limiting toxicities (DLTs) were measured over time. RESULTS: Thirty-four men accrued in this multi-institutional clinical trial: 24% of men were node positive, 47% were Gleason 8-10, median PSA at entry was 0.54. The trial was terminated prematurely owing to excess DLTs (nine) including grade 3 hand-foot syndrome (n=4), neutropenic fever (n=2), AST increase (n=1), fatigue (n=1) and vomiting with diarrhea (n=1). PFS rate at 24 months was 51% (95% CI: 33, 67%) with a median PFS of 26.2 months (95% CI: 12.5, -). Six men (17.6%) had an undetectable PSA at 2 years. CONCLUSIONS: Sunitinib and docetaxel/prednisone followed by salvage RT resulted in excess pre-specified DLTs. Although nearly half of the men experienced durable disease control, efficacy was not greater than expected with radiation alone. The use of the intermediate end point of PFS in this salvage setting permitted an early decision on further development of this combination.

Endoscopic, endonasal, trans-sphenoidal hypophysectomy: retrospective analysis of 171 procedures.

INTRODUCTION: Endoscopic, transnasal management of pituitary gland neoplasms is a widely accepted alternative to the traditional microscopic approach. This study aimed to determine outcomes and complication rates for the largest UK series of endoscopic, trans-sphenoidal hypophysectomies reported to date. METHODS: We performed a retrospective analysis of 136 primary resections and 35 revision cases performed at a tertiary referral centre. RESULTS AND ANALYSIS: Total tumour resection was confirmed in over 85 per cent of primary and revision cases, with biochemical remission in 60 per cent. The incidence of complications such as epistaxis, sphenoid sinus problems, endocrine insufficiency, visual disturbance, post-operative haemorrhage, cranial nerve injury and mortality was significantly lower, compared with similar series using the microscopic approach. CONCLUSION: Despite its steep 'learning curve', our series demonstrates that the endoscopic approach not only allows superior anatomical visualisation and therefore facilitates full oncological resection of tumours, but also reduces the incidence of peri-operative complications.

Management of intra-operative cerebrospinal fluid leak following endoscopic trans-sphenoidal pituitary surgery.

OBJECTIVE: Cerebrospinal fluid leakage is the most common complication of endoscopic trans-sphenoidal pituitary surgery. However, there is no uniformly accepted way of managing this complication when it occurs intra-operatively. This paper describes a quick, simple technique, involving layered fibrin glue and gelatin sponge, which does not compromise post-operative patient follow up. METHOD: Retrospective review of all endoscopic pituitary surgery cases conducted at a single institution since the introduction of this technique in 2002. RESULTS: A total of 120 endoscopic pituitary operations were performed (96 primary procedures and 24 revisions). All intra-operative cerebrospinal fluid leaks were managed using the described method, with a failure rate of 3.6 per cent. The overall post-operative leakage rate was 1.7 per cent. CONCLUSION: This simple, conservative technique avoids the need for further dissection and the use of non-absorbable foreign material, and has a low incidence of post-operative cerebrospinal fluid leakage.

Assisted reproductive technology and major structural birth defects in the United States.

BACKGROUND: With >1% of US births occurring following use of assisted reproductive technology (ART), it is critical to examine whether ART is associated with birth defects. METHODS: We analyzed data from the National Birth Defects Prevention Study, a population-based, multicenter, case-control study of birth defects. We included mothers of fetuses or live-born infants with a major birth defect (case infants) and mothers who had live-born infants who did not have a major birth defect (control infants), delivered during the period October 1997-December 2003. We compared mothers who reported ART use (IVF or ICSI) with those who had unassisted conceptions. Multiple logistic regression was used to adjust for the following confounders: maternal race/ethnicity, maternal age, smoking and parity; we stratified by plurality. RESULTS: ART was reported by 1.1% of all control mothers, and by 4.5% of control mothers 35 years or older. Among singleton births, ART was associated with septal heart defects (adjusted odds ratio [aOR] = 2.1, 95% confidence intervals [CI] 1.1-4.0), cleft lip with or without cleft palate (aOR = 2.4, 95% CI 1.2-5.1), esophageal atresia (aOR = 4.5, 95% CI 1.9-10.5) and anorectal atresia (aOR = 3.7, 95% CI 1.5-9.1). Among multiple births, ART was not significantly associated with any of the birth defects studied. CONCLUSIONS: These findings suggest that some birth defects occur more often among infants conceived with ART. Although the mechanism is not clear, couples considering ART should be informed of all potential risks and benefits.

The population-based prevalence of achondroplasia and thanatophoric dysplasia in selected regions of the US.

There have been no large population-based studies of the prevalence of achondroplasia and thanatophroic dysplasia in the United States. This study compared data from seven population-based birth defects monitoring programs in the United States. We also present data on the association between older paternal age and these birth defects, which has been described in earlier studies. The prevalence of achondroplasia ranged from 0.36 to 0.60 per 10,000 livebirths (1/27,780-1/16,670 livebirths). The prevalence of thanatophoric dysplasia ranged from 0.21 to 0.30 per 10,000 livebirths (1/33,330-1/47,620 livebirths). In Texas, fathers that were 25-29, 30-34, 35-39, and > or =40 years of age had significantly increased rates of de novo achondroplasia among their offspring compared with younger fathers. The adjusted prevalence odds ratios were 2.8 (95% CI; 1.2, 6.7), 2.8 (95% CI; 1.0, 7.6), 4.9 (95% CI; 1.7, 14.3), and 5.0 (95% CI; 1.5, 16.1), respectively. Using the same age categories, the crude prevalence odds ratios for de novo cases of thanatophoric dysplasia in Texas were 5.8 (95% CI; 1.7, 9.8), 3.9 (95% CI; 1.1, 6.7), 6.1 (95% CI; 1.6, 10.6), and 10.2 (95% CI; 2.6, 17.8), respectively. These data suggest that thanatophoric dysplasia is one-third to one-half as frequent as achondroplasia. The differences in the prevalence of these conditions across monitoring programs were consistent with random fluctuation. Birth defects monitoring programs may be a good source of ascertainment for population-based studies of achondroplasia and thanatophoric dysplasia, provided that diagnoses are confirmed by review of medical records.

Incomplete seating of the liner with the Trident acetabular system: a cause for concern?

We reviewed the initial post-operative radiographs of the Trident acetabulum and identified a problem with seating of the metal-backed ceramic liner. We identified 117 hips in 113 patients who had undergone primary total hip replacement using the Trident shell with a metal-backed alumina liner. Of these, 19 (16.4%) were noted to have incomplete seating of the liner, as judged by plain anteroposterior and lateral radiographs. One case of complete liner dissociation necessitating early revision was not included in the prevalence figures. One mis-seated liner was revised in the early post-operative period and two that were initially incompletely seated were found on follow-up radiographs to have become correctly seated. There may be technical issues with regard to the implanting of this prosthesis of which surgeons should be aware. However, there is the distinct possibility that the Trident shell deforms upon implantation, thereby preventing complete seating of the liner.

Major histocompatibility complex class I expression in human tonsillar and laryngeal epithelium.

Understanding the immunological structure of the upper aerodigestive tract is important for analysing the interaction between incident challenges, such as human papillomavirus infection, and disease, particularly head and neck cancer. We have shown previously that tonsillar and laryngeal epithelium express major histocompatibility complex (MHC) class II locus products, but that expression of human leucocyte antigen (HLA)-DQ is reduced compared to HLA-DR. This may confer a decreased repertoire of presented T cell epitopes generated by the processing of exogenous peptides in upper airway mucosa. To determine whether the peptide repertoire presented by MHC class I loci varies in stratified squamous epithelium, laryngeal and tonsillar biopsies were taken from 19 otherwise healthy patients (M : F 6 : 13, 16-64 years). Quantitative immunofluorescence microscopy, using antibodies to MHC class I alpha-chain (pan-locus specific, HLA-A, HLA-B + C) and beta(2)-microglobulin, showed lower expression of the alpha-chain in laryngeal and tonsillar epithelium than in either lamina propria (tonsil 73% versus 89%, P < 0.0001; larynx 68% versus 85%, P < 0.005). Within the epithelium itself, the intensity of alpha-chain expression decreased from the basal to apical layers. In paired squamous epithelia from the two sites, alpha-chain expression was significantly higher in the tonsil compared to the larynx (79% versus 62%, P < 0.05). We suggest that these findings reflect functional stratification of these epithelia with the superficial layer, most exposed to incident challenges, less equipped to present antigens to conventional T cells. This may affect immunosurveillance directed at viral and tumour-related epitopes in the upper airway.

Human papillomavirus and head and neck cancer: a systematic review and meta-analysis.

It has been suggested that the link between human papillomavirus (HPV) and head and neck squamous cell carcinoma (HNSCC) is specific to carcinoma of the tonsil. We systematically reviewed studies that tested for HPV16 exposure in anatomically defined sites in the head and neck and a control group. The association between HPV16 and cancer was strongest for tonsil (OR: 15.1, 95% CI: 6.8-33.7), intermediate for oropharynx (OR: 4.3, 95% CI: 2.1-8.9) and weakest for oral (OR: 2.0, 95% CI: 1.2-3.4) and larynx (OR: 2.0, 95% CI: 1.0-4.2). To investigate heterogeneity, further stratification by method of HPV16 detection, suggested that variation in the magnitude of the HPV-cancer association with cancer site was restricted to studies using ELISA: among studies using PCR, the magnitude of the summary odds ratios was similar across the four sites. The association between HPV16 infection and HNSCC in specific sites suggests the strongest and most consistent association is with tonsil cancer, and the magnitude of this association is consistent with an infectious aetiology. However, the method of viral detection may be an important source of heterogeneity. Resolution of this issue will require further studies using both methods, examining associations separately in different sites.

Epistaxis: an update on current management.

Epistaxis is one of the commonest ENT emergencies. Although most patients can be treated within an accident and emergency setting, some are complex and may require specialist intervention. There are multiple risk factors for the development of epistaxis and it can affect any age group, but it is the elderly population with their associated morbidity who often require more intensive treatment and subsequent admission. Treatment strategies have been broadly similar for decades. However, with the evolution of endoscopic technology, new ways of actively managing epistaxis are now available. Recent evidence suggests that this, combined with the use of stepwise management plans, should limit patient complications and the need for admission. This review discusses the various treatment options and integrates the traditional methods with modern techniques.

Spontaneous enophthalmos: silent sinus syndrome.

Spontaneous enophthalmos unrelated to trauma or surgery is rare. The term 'silent sinus syndrome' has been used to describe this process where, in particular, there is an absence of any sino-nasal symptoms. The enophthalmos and hypoglobus that occurs in these subjects is caused by atelectasis of the maxillary antrum, which itself appears to be due to chronic maxillary hypoventilation. We report a case of silent sinus syndrome that arose following insertion of a nasogastric tube. Whilst acute paranasal sinusitis is a well-described sequela of nasal intubation, this association with a rare, and as yet unexplained, phenomenon may go some way to explain its aetiology.

Effects of subchronic inhalation exposure of rats to emissions from a diesel engine burning soybean oil-derived biodiesel fuel.

There is increasing interest in diesel fuels derived from plant oils or animal fats ("biodiesel"), but little information on the toxicity of biodiesel emissions other than bacterial mutagenicity. F344 rats were exposed by inhalation 6 h/day, 5 days/wk for 13 wk to 1 of 3 dilutions of emissions from a diesel engine burning 100% soybean oil-derived fuel, or to clean air as controls. Whole emissions were diluted to nominal NO(x) concentrations of 5, 25, or 50 ppm, corresponding to approximately 0.04, 0.2, and 0.5 mg particles/m(3), respectively. Biologically significant, exposure-related effects were limited to the lung, were greater in females than in males, and were observed primarily at the highest exposure level. There was a dose-related increase in the numbers of alveolar macrophages and the numbers of particles in the macrophages, as expected from repeated exposure, but no neutrophil response even at the highest exposure level. The macrophage response was reduced 28 days after cessation of the exposure. Among the high-level females, the group mean lung weight/body weight ratio was increased, and minimal, multifocal bronchiolar metaplasia of alveolar ducts was observed in 4 of 30 rats. Lung weights were not significantly increased, and metaplasia of the alveolar ducts was not observed in males. An increase in particle-laden macrophages was the only exposure-related finding in lungs at the intermediate and low levels, with fewer macrophages and fewer particles per macrophage at the low level. Alveolar histiocytosis was observed in a few rats in both exposed and control groups. There were statistically significant, but minor and not consistently exposure-related, differences in body weight, nonpulmonary organ weights, serum chemistry, and glial fibrillary acidic protein in the brain. There were no significant exposure-related effects on survival, clinical signs, feed consumption, ocular toxicity, hematology, neurohistology, micronuclei in bone marrow, sister chromatid exchanges in peripheral blood lymphocytes, fertility, reproductive toxicity, or teratology. This study demonstrated modest adverse effects at the highest exposure level, and none other than the expected physiological macrophage response to repeated particle exposure at the intermediate level.