Management of newly diagnosed glioblastoma multiforme: current state of the art and emerging therapeutic approaches.

Glioblastoma multiforme represent > 50% of primary gliomas and have five year survival rates of ~ 5%. Maximal safe surgical resection followed by radiotherapy with concurrent and adjuvant temozolomide remains the standard treatment since published by Stupp et al. (in N Engl J Med 352:987-996, 2005), with additional benefit for patients with MGMT-methylated tumors. We review the current treatment landscape and ongoing efforts to improve these outcomes. An extensive literature search of Pubmed and Google Scholar involving the search terms "glioblastoma," "glioblastoma multiforme," or "GBM" for papers published to July 2021 was conducted and papers evaluated for relevance. As well as current data that informs clinical practice, we review ongoing clinical research in both newly diagnosed and recurrent settings that provides hope for a breakthrough. The Stupp protocol remains standard of care in 2021. Addition of tumor treating fields improved mOS modestly, with benefit seen in MGMT-methylated and unmethylated cohorts and also improved time to cognitive decline but has not been widely adopted. The addition of lomustine to temozolomide, in MGMT-methylated patients, also showed a mOS benefit but further investigation is required. Other promising therapeutic strategies including anti-angiogenic therapy, targeted therapy, and immunotherapy have yet to show a survival advantage. Improvements in the multidisciplinary management, surgical techniques and equipment, early palliative care, carrier support, and psychological support may be responsible for improving survival over time. Despite promising preclinical rationale, immunotherapy and targeted therapy are struggling to impact survival. A number of ongoing clinical trials provide hope for a breakthrough.

A new semi-orthotopic bone defect model for cell and biomaterial testing in regenerative medicine.

In recent decades, an increasing number of tissue engineered bone grafts have been developed. However, expensive and laborious screenings in vivo are necessary to assess the safety and efficacy of their formulations. Rodents are the first choice for initial in vivo screens but their size limits the dimensions and number of the bone grafts that can be tested in orthotopic locations. Here, we report the development of a refined murine subcutaneous model for semi-orthotopic bone formation that allows the testing of up to four grafts per mouse one order of magnitude greater in volume than currently possible in mice. Crucially, these defects are also "critical size" and unable to heal within the timeframe of the study without intervention. The model is based on four bovine bone implants, ring-shaped, where the bone healing potential of distinct grafts can be evaluated in vivo. In this study we demonstrate that promotion and prevention of ossification can be assessed in our model. For this, we used a semi-automatic algorithm for longitudinal micro-CT image registration followed by histological analyses. Taken together, our data supports that this model is suitable as a platform for the real-time screening of bone formation, and provides the possibility to study bone resorption, osseointegration and vascularisation.

Leptomeningeal Relapse of Embryonal Rhabdomyosarcoma after 15 years.

Aim Rhabdomyosarcoma (RMS) is the most common malignant soft tissue tumour of childhood. We present the case of a late relapse of RMS to the leptomeninges after 15 years. Methods A 20 year old male presented with a 3 week history of headaches and nausea. He previously had RMS of his right ear diagnosed at age 5 years which was treated with concurrent chemoradiotherapy. An MRI Brain and Spine confirmed extensive leptomeningeal disease and CSF analysis confirmed the presence of recurrent embryonal RMS. Results He completed two cycles of cyclophosphamide and topotecan followed by 45Gy/25Fr of craniospinal radiotherapy. Conclusion Late relapses beyond five years can be seen in up to 9% of patients, however very late recurrences (>10 years) are exceedingly rare. Molecular based methods such as gene expression profiling can aid risk stratification and survivorship clinics may become increasingly useful in following patients with high risk features.

Synchronous diffuse large B cell lymphomas of the endometrium and breast: a staging dilemma.

BACKGROUND: A 66 years old presented with abnormal postmenopausal vaginal bleeding and was diagnosed with an endometrial lymphoma (diffuse large B cell type, DLBCL). A left breast lesion was found on PET CT which was subsequently biopsy-proven as a separate stage IE DLBCL, but she had no lymph node, bone marrow or spleen involvement. AIMS: This study aimed to review the available literature and discuss the management and staging of synchronous extra-nodal DLBCL's. RESULTS: Our patient was staged as having synchronous stage IE DLBCL's of the endometrium and breast. Subsequent molecular analysis (IgH gene rearrangement analysis) on both lesions, confirmed the two lesions to be clonally unrelated. CONCLUSIONS: Staging of synchronous extra-nodal lymphomas, particularly when they arise in rare sites such as the endometrium and breast, is difficult and previously unreported. We present our rationale for defining our patient's disease as synchronous stage IE DLBCL's.

Effects of ageing, prolonged estrogen deficiency and zoledronate on bone tissue mineral distribution.

The quantity and distribution of bone tissue mineral are key determinants of bone strength. Recent research revealed altered mineral distribution within sheep femora following estrogen deficiency. Rapid increases in bone remodeling occur at the onset of estrogen deficiency and abate over time. Therefore, altered tissue mineralization might be a transient characteristic of osteoporosis. Bisphosphonates reduce fracture incidence by 40-60% but increases in bone mineral density are insufficient to explain such changes. In this study the hypotheses that bone tissue mineralization is altered over prolonged estrogen depletion and bisphosphonate treatment were tested. Quantitative backscattered imaging (qBEI) was used to quantify bone mineral density distribution (BMDD) parameters (mean, FWHM) in trabeculae from the proximal femora of an ovariectomized sheep model that underwent estrogen deficiency for 31 months, an ovariectomized group administered with Zoledronic acid and age-matched controls. To assess the effects of normal ageing and prolonged estrogen deficiency, data were compared to BMDD data from sheep that were estrogen deficient for 12 months and age-matched controls. This study reports that normal ageing increases mean mineralization and mineral heterogeneity at a trabecular level. In contrast, prolonged estrogen deficiency leads to significantly decreased mean mineralization and further exacerbates increases in mineral heterogeneity. Interestingly, ZOL treatment of OVX sheep significantly reduced tissue mineral variability, both at a trabecular level and between femoral regions. Together, these findings indicate that ZOL treatment acts to reverse the increased mineral heterogeneity occurring during estrogen deficiency, which may contribute to its capacity to reduce osteoporotic fractures.

Site specific increase in heterogeneity of trabecular bone tissue mineral during oestrogen deficiency.

Although osteoporosis reduces overall bone mass causing bone fragility, recent studies report that the remaining bone tissue is significantly stiffer. Preliminary studies indicate that alterations in bone tissue mineral content might explain these changes, albeit that other studies report conflicting observations. The objective of this study is to quantify whether the distribution of bone tissue mineral is altered during oestrogen deficiency. Individual trabeculae were harvested from the proximal femur of 7 ovariectomised sheep (OVX), sacrificed 12 months post-surgery, and 5 age-matched controls. Mineral content (wt% Ca) was determined using a quantitative backscattered scanning electron microscopy imaging approach. Mineral heterogeneity within individual trabeculae was compared by calculating the full width at half maximum (FWHM) of mineral density distributions. Mean calcium content, the spatial distribution of mineral within trabeculae and the inter-trabecular variation between regions of proximal femora were also compared. Oestrogen deficiency increased mineral heterogeneity within individual trabeculae compared to healthy controls, as measured by FWHM (3.57 ± 0.68 vs. 3.17 ± 0.36 wt% Ca, p = 0.04). In particular mineral variability increased between superficial and deep regions of trabeculae of OVX animals (p = 0.04). Interestingly, mineralisation variability between greater and lesser trochanters (i.e. intertrochanteric fracture line) was increased in OVX compared to CON, as indicated by a greater % difference in the standard deviation of trabecular mineral content (77.11 ± 11.70 vs. 45.64 ± 23.70 %, p = 0.03). Such changes are undetectable by evaluating the mean mineral content of bone tissue, but may contribute to changes in bone mechanical strength following osteoporotic bone loss.

Addition of hydroxyapatite improves stiffness, interconnectivity and osteogenic potential of a highly porous collagen-based scaffold for bone tissue regeneration.

There is an enduring and unmet need for a bioactive, load-bearing tissue-engineering scaffold, which is biocompatible, biodegradable and capable of facilitating and promoting osteogenesis when implanted in vivo. This study set out to develop a biomimetic scaffold by incorporating osteoinductive hydroxyapatite (HA) particles into a highly porous and extremely biocompatible collagen-based scaffold developed within our laboratory over the last number of years to improve osteogenic performance. Specifically we investigated how the addition of discrete quantities of HA affected scaffold porosity, interconnectivity, mechanical properties, in vitro mineralisation and in vivo bone healing potential. The results show that the addition of HA up to a 200 weight percentage (wt%) relative to collagen content led to significantly increased scaffold stiffness and pore interconnectivity (approximately 10 fold) while achieving a scaffold porosity of 99%. In addition, this biomimetic collagen-HA scaffold exhibited significantly improved bioactivity, in vitro mineralisation after 28 days in culture, and in vivo healing of a critical-sized bone defect. These findings demonstrate the regenerative potential of these biodegradable scaffolds as viable bone graft substitute materials, comprised only of bone's natural constituent materials, and capable of promoting osteogenesis in vitro and in vivo repair of critical-sized bone defects.

Accuracy of whole-body low-dose multidetector CT (WBLDCT) versus skeletal survey in the detection of myelomatous lesions, and correlation of disease distribution with whole-body MRI (WBMRI).

AIM: The aim of the study is to assess the feasibility of whole-body low-dose computed tomography (WBLDCT) in the diagnosis and staging of multiple myeloma and compare to skeletal survey (SS), using bone marrow biopsy and whole-body magnetic resonance imaging (WBMRI; where available) as gold standard. MATERIALS AND METHODS: Patients referred over an 18-month period for investigation of suspected multiple myeloma or restaging of myeloma were randomized to undergo one of two WBLDCT protocols using high kVp, low mAs technique (140 kVp, 14 mAs; or 140 kVp, 25 mAs). Recent WBMRI scans were reviewed in 23 cases. Each imaging modality was assessed by two radiologists in consensus and scored from 0-3 (0 = normal, 1 = 1-4 lesions, 2 = 5-20 lesions, 3 >or= 20 lesions/diffuse disease) in ten anatomical areas. Overall stage of disease, image quality score, and the degree of confidence of diagnosis were recorded. Diagnostic accuracy of skeletal survey and WBLDCT were determined using a gold standard of bone marrow biopsy and distribution of disease was compared to WBMRI. RESULTS: Thirty-nine patients were evaluated. WBLDCT identified more osteolytic lesions than skeletal survey with a greater degree of diagnostic confidence and led to restaging in 18 instances (16 upstaged, two downstaged). In those with recent WBMRI, distribution of disease on WBLDCT showed superior correlation with WBMRI when compared with SS. Overall reader impression of stage on WBLDCT showed significant correlation with WBMRI (kappa = 0.454, p < 0.05). WBLDCT provided complementary information to WBMRI in nine patients with normal marrow signal following treatment response, but which were shown to have diffuse residual cortical abnormalities on CT. CONCLUSION: WBLDCT at effective doses lower than previously reported, is superior to SS at detecting osteolytic lesions and at determining overall stage of multiple myeloma, and provides complementary information to WBMRI.

Kramers' law for a bistable system with time-delayed noise.

We demonstrate that the classical Kramers' escape problem can be extended to describe a bistable system under the influence of noise consisting of the superposition of a white Gaussian noise with the same noise delayed by time tau . The distribution of times between two consecutive switches decays piecewise exponentially, and the switching rates for 0

Upping the ante: relative caregivers' perceptions of changes in child welfare policies.

Thirty-five caregivers of related children who were in the custody of the child welfare system were interviewed individually or in focus groups as the state child welfare system implemented new federal and state policies encouraging these caregivers to adopt or assume guardianship of the children in their care. Interviews were transcribed and analyzed using qualitative methods. Issues of concern included emergency entrance into caregiving; the simultaneous satisfaction and burden of caregiving; obstacles to caregiving, adoption, or guardianship; complex changes in family dynamics following placement of children; sources of support; and caution regarding adoption or guardianship. The caregivers also offered recommendations for the child welfare system. Policy, practice, and research implications are discussed.

Solid phase organic synthesis of piperazinone containing enkephalin mimetics: a readily derivatized, traceless scaffold.

The solid phase synthesis of a series of piperazinone-derived Leu-enkephalin analogues is presented. The initial step in the synthesis involved the N-alkylation of Wang resin bound N-(4-tert-butyloxy-phenethyl)-glycine with D or L Boc-serine-beta-lactone (the Vederas lactone). The resulting carboxylic acid was then coupled to a variety of monosubstituted benzylamine derivatives using benzotriazol-1-yloxy-tris(dimethyl-amino)phosphonium hexafluorophosphate (the BOP reagent) to yield a series of resin bound tertiary amides. Treatment with 5% H2O in TFA resulted in the facile cleavage, deprotection, and cyclization of this linear precursor to yield a series of piperazinones (compounds 1-8).