Heterogeneity of familial medulloblastoma and contribution of germline PTCH1 and SUFU mutations to sporadic medulloblastoma

PTCH1 and SUFU are both regulators of the sonic hedgehog signalling pathway. Germline inactivating mutations in both genes are associated with multisystem phenotypes including medulloblastoma. Somatic inactivating mutations in PTCH1 and SUFU each occur in approximately 10% of medulloblastomas. Recently, SUFU mutations were reported in familial medulloblastoma pedigrees without additional phenotypic features. We sought to further investigate the contribution of germline PTCH1 and SUFU mutations to familial and sporadic medulloblastoma. We performed full-gene mutational analysis of both PTCH1 and SUFU in three familial medulloblastoma pedigrees and 83 individuals with sporadic non-familial medulloblastoma. We identified no mutations in PTCH1 or SUFU in the three familial medulloblastoma pedigrees. We identified no PTCH1 mutations and two SUFU mutations that cause premature protein truncating in the series of sporadic non-familial medulloblastomas. The SUFU mutations were identified in two of the 16 individuals with desmoplastic medulloblastomas. These data indicate that familial medulloblastoma is a genetically heterogeneous disorder with at least one further susceptibility gene to be discovered. Furthermore, although both PTCH1 and SUFU play a key role in the sonic hedgehog signalling pathway, PTCH1 does not make an appreciable contribution to non-familial sporadic medulloblastoma, whereas inactivating germline mutations of SUFU cause ~2–3% of sporadic medulloblastomas and > 10% of desmoplastic medulloblastomas.     

Generation of trisomies in cancer cells by multipolar mitosis and incomplete cytokinesis

One extra chromosome copy (i.e., trisomy) is the most common type of chromosome aberration in cancer cells. The mechanisms behind the generation of trisomies in tumor cells are largely unknown, although it has been suggested that dysfunction of the spindle assembly checkpoint (SAC) leads to an accumulation of trisomies through failure to correctly segregate sister chromatids in successive cell divisions. By using Wilms tumor as a model for cancers with trisomies, we now show that trisomic cells can form even in the presence of a functional SAC through tripolar cell divisions in which sister chromatid separation proceeds in a regular fashion, but cytokinesis failure nevertheless leads to an asymmetrical segregation of chromosomes into two daughter cells. A model for the generation of trisomies by such asymmetrical cell division accurately predicted several features of clones having extra chromosomes in vivo, including the ratio between trisomies and tetrasomies and the observation that different trisomies found in the same tumor occupy identical proportions of cells and colocalize in tumor tissue. Our findings provide an experimentally validated model explaining how multiple trisomies can occur in tumor cells that still maintain accurate sister chromatid separation at metaphase-anaphase transition and thereby physiologically satisfy the SAC.     

Brain injury severity, litigation status, and self-report of postconcussive symptoms

The Postconcussive Symptom Questionnaire (PCSQ) was developed to assess the symptoms associated with the controversial diagnosis of postconcussion syndrome. We examined item endorsement on the PCSQ in two groups. The first group was made up of individuals diagnosed with moderate to severe traumatic brain injury. The second group was made up of individuals meeting criteria for mild traumatic brain injury who exhibited no evidence of neurological injury. In addition, they demonstrated poor effort during neuropsychological examination. Significant differences in item endorsement were found the majority of individual items as well as on the PCSQ indices. The poor effort mild traumatic brain injury group consistently reported more symptoms with greater severity. The results raise further questions about the validity of postconcussion symptoms.     

What Dose of External-Beam Radiation is High Enough for Prostate Cancer?

PURPOSE: To quantify the radiotherapy dose-response of prostate cancer, adjusted for prognostic factors in a mature cohort of men treated relatively uniformly at a single institution. PATIENTS AND METHODS: The study cohort consisted of 1,530 men treated with three-dimensional conformal external-beam radiotherapy between 1989 and 2002. Patients were divided into four isocenter dose groups: <70 Gy (n = 43), 70-74.9 Gy (n = 552), 75-79.9 Gy (n = 568), and > or =80 Gy (n = 367). The primary endpoints were freedom from biochemical failure (FFBF), defined by American Society for Therapeutic Radiology and Oncology (ASTRO) and Phoenix (nadir + 2.0 ng/mL) criteria, and freedom from distant metastases (FFDM). Multivariate analyses were performed and adjusted Kaplan-Meier estimates were calculated. Logit regression dose-response functions were determined at 5 and 8 years for FFBF and at 5 and 10 years for FFDM. RESULTS: Radiotherapy dose was significant in multivariate analyses for FFBF (ASTRO and Phoenix) and FFDM. Adjusted 5-year estimates of ASTRO FFBF for the four dose groups were 60%, 68%, 76%, and 84%. Adjusted 5-year Phoenix FFBFs for the four dose groups were 70%, 81%, 83%, and 89%. Adjusted 5-year and 10-year estimates of FFDM for the four dose groups were 96% and 93%, 97% and 93%, 99% and 95%, and 98% and 96%. Dose-response functions showed an increasing benefit for doses > or =80 Gy. CONCLUSIONS: Doses of > or =80 Gy are recommended for most men with prostate cancer. The ASTRO definition of biochemical failure does not accurately estimate the effects of radiotherapy at 5 years because of backdating, compared to the Phoenix definition, which is less sensitive to follow-up and more reproducible over time.     

Psychometric evaluation of the interpersonal relationship inventory for early adolescents

ABSTRACT The purposes of this methodological study were to factor analyze the short form of the Tilden Interpersonal Relationship Inventory (IPRI) for early adolescents, and to assess construct validity of the social support and conflict subscales with early adolescents. The sample consisted of 147 early adolescents, aged 12–14, who completed instrument packets in classrooms in a suburban middle school. Data obtained on the IPRI were subjected to principal components factor analysis with Varimax rotation. The two factors that emerged are consistent with the theories underlying the instrument. Factor I was social support, and had a coefficient α reliability of .90. Factor II was conflict, and had a coefficient α reliability of .86. Construct validity was assessed by testing hypotheses derived from theoretical propositions linking support or conflict to general humor, self-esteem, and symptom patterns; the results of the hypotheses were statistically significant and in the predicted direction. The findings indicate that the social support and conflict subscales of the IPRI have evidence of reliability and validity for early adolescents.     

Operating room efficiency and hospital capacity: factors affecting operating room use during maximum hospital census

BACKGROUND: Academic medical centers are faced with increasing volumes, higher acuity, and, as a consequence, capacity issues. These affect operating room (OR) use and patient throughput, with negative impact on finances and patient and physician satisfaction. We evaluated our experiences in dealing with OR efficiency at a time of maximum hospital capacity and occupancy. STUDY DESIGN: Using a multidisciplinary approach, we put in place seven agreed-upon strategies: daily communication, improved bed planning, discharge by noon program, internal staffing pool, special assignments for a patient transition unit, incentives, and stepped up environmental services. RESULTS: After institution of these strategies, we were able to realize a gain in OR patient volume of 8% and a decrease in OR holds of 37%. This resulted in a decrease in canceled OR cases from 4.3% to 3.1%. CONCLUSIONS: Academic medical centers face occupancy issues that are not likely to go away and will have an impact on OR volume and productivity. To improve the situation in a short-term fashion, a multidisciplinary approach involving several strategies will be needed.     

Use of small suture anchors in cervical laminoplasty to maintain canal expansion: a technical note

OBJECTIVE: Open door laminoplasty is a commonly performed procedure for the treatment of cervical spine pathology. One complication of this procedure is closure of the hinge and subsequent restenosis. A simple and effective method of using suture anchors to stabilize posterior elements has been previously described. The aim of this paper is to describe our experience using 2.0-mm suture anchors to maintain canal expansion. METHODS: Results of 42-consecutive patients who were treated with a modified cervical open-door laminoplasty were reviewed. The modification involves the use of original Hirabayashi technique, but augmenting the canal expansion with 2.0-mm suture anchors at C3, C5, and C7 levels. Additionally, nonabsorbable sutures are placed at C4 and C6 levels as described by Hirabayashi. The technical issues and short-term radiographic outcomes were evaluated. RESULTS: None of the 42 patients who had the door secured with 2.0-mm suture anchors had closure of the hinge. Additionally, the suture anchors maintained their position without loosening or "pull-outs" on postoperative follow-up radiographs. There were 3 short-term complications: 1 was a small dural-tear which was repaired intraoperatively without further sequelae, and the other 2 were both epidural hematomas that required emergent return to the operating room for evacuation. All 3 patients had an uneventful recovery without a new neurologic deficit. CONCLUSIONS: This paper reviews a simple and effective method for maintaining canal expansion in open-door laminoplasty. Because of its technical simplicity, 2.0-mm suture anchors may be a safer alternative than other devices currently popular for this purpose.     

Enhanced activation of human dendritic cells by inducible CD40 and Toll-like receptor-4 ligation

Despite the potency of dendritic cells (DC) as antigen-presenting cells for priming adaptive immunity, DC-based cancer vaccines have been largely insufficient to effectively reduce tumor burden or prevent tumor progression in most patients. To enhance DC-based vaccines, we used the combination of a synthetic ligand-inducible CD40 receptor (iCD40) along with Toll-like receptor-4 (TLR-4) ligation in human monocyte-derived DCs. The iCD40 receptor permits targeted, reversible activation of CD40 in vivo, potentially bypassing the essential role of CD4(+) T cells for activation of DCs. As a rigorous preclinical study of this approach, we evaluated key parameters of DC activation and function. Whereas neither iCD40 nor TLR-4 signaling alone led to high levels of interleukin (IL)-12p70 and IL-6, using iCD40 in combination with lipopolysaccharide (LPS) or monophosphoryl lipid A led to strongly synergistic production of both. Furthermore, this approach led to high expression of DC maturation markers, epitope-specific CTL and T helper 1 responses, as well as DC migration in vitro and in vivo. Moreover, use of iCD40-modified and LPS-stimulated DCs led to targeted expansion of autologous T cells against tumor-associated antigens, including prostate-specific membrane antigen, and elimination of preestablished tumors, supporting this technology as a potent strategy for DC-based cancer immunotherapy.