The RANO process is intended to produce end-point criteria for clinical trials that take into account the effects of prior and ongoing therapies. The RANO criteria will continue to evolve as new therapies and technologies are introduced into clinical trial and/or practice.

Central nervous system neoplasms with combined features of malignant glioma and primitive neuroectodermal tumor (MG-PNET) are rare, poorly characterized, and pose diagnostic as well as treatment dilemmas. We studied 53 MG-PNETs in patients from 12 to 80 years of age (median = 54 years). The PNET-like component consisted of sharply demarcated hypercellular nodules with evidence of neuronal differentiation. Anaplasia, as seen in medulloblastomas, was noted in 70%. Within the primitive element, N-myc or c-myc gene amplifications were seen in 43%. In contrast, glioma-associated alterations involved both components, 10q loss (50%) being most common. Therapy included radiation (78%), temozolomide (63%) and platinum-based chemotherapy (31%). Cerebrospinal fluid (CSF) dissemination developed in eight patients, with response to PNET-like therapy occurring in at least three. At last follow-up, 27 patients died, their median survival being 9.1 months. We conclude that the primitive component of the MG-PNET: (i) arises within a pre-existing MG, most often a secondary glioblastoma; (ii) may represent a metaplastic process or expansion of a tumor stem/progenitor cell clone; (iii) often shows histologic anaplasia and N-myc (or c-myc) amplification; (iv) has the capacity to seed the CSF; and (v) may respond to platinum-based chemotherapy regimens.

In this study we examine whether the systemic administration of FK506 or Cyclosporin A (CsA) expedited functional recovery following an axonotmetic nerve injury, and compared their effects in a rat model. Seventy-five adult Buffalo rats received a crush injury to the right posterior tibial nerve and subsequently underwent either no treatment (group I), daily injections of FK506 (group II), or daily injections of CsA (group III). Walking track analysis demonstrated return of hindlimb function by 20 days postoperatively in group I, 14 days in group II, and 18 days in group III. The blood-nerve barrier (BNB) was reconstituted by postoperative day (POD) 7 in both FK506-and CsA-treated animals and by POD 13 in control animals. These results suggest that recovery of function is more rapid with daily administration of FK506 than with CsA or no treatment, perhaps because of earlier restoration of the blood-nerve barrier. Agents that facilitate nerve regeneration have the potential to limit the extent of motor endplate loss and muscle atrophy seen with prolonged denervation, thereby limiting permanent functional loss. Prolonged muscle denervation is characterized by muscle atrophy and irreversible destruction of motor endplates. In an experimental rodent model, when tibial nerve reconstruction is delayed 1 month after transection, an irreversible loss of muscle mass is seen and is associated with poor functional recovery. 13 Similarly, clinical experience dictates that the shorter the time period of denervation, the more likely that muscle function will recover. 21A number of agents have been studied for their potential efficacy in expediting nerve regeneration, and thereby limiting the extent of permanent functional loss and hastening functional recovery after nerve injury. Cyclosporin A (CsA) and FK506 are both systemic immunosuppressants that have been shown to facilitate nerve repair by ill-understood mechanisms. We have previously observed, in a rat model of axonal regeneration across sciatic nerve isografts, that animals treated with CsA had a significantly earlier return of function than untreated controls.1 More recently, in a rat sciatic nerve axonotmesis model, FK506 increased the rate of nerve regeneration in a dose-dependent fashion. 22 The objective of this study was to compare the effects of FK506 to the effects of CsA on the rate of functional recovery in an axonotmesis model of nerve injury. MATERIALS AND METHODSAll animals received treatment in accordance with the guidelines of the National Society for Medical Research and the National Institutes of Health. Seventy-five male Buffalo rats (Harlan-Sprague), weighing 220-250 g, were used. All animals were housed in beta-chip, lined plastic cages. The rats were fed rat chow (#5001, Purina Mills, St. Louis, MO ) and water ad libitum.The 75 rats were randomly assigned to one of three groups. Group I rats (n = 25) received no treatAbbreviations: ANOVA, analysis of variance; BNB, blood-nerve barrier; CsA, Cyclosporin A; EBA, Evans blue albumin; EPL, exp...

No abstract

Small-animal tumor models are essential for developing translational therapeutic strategies in oncology research, with imaging having an increasingly important role. Magnetic Resonance Imaging (MRI) offers tumor localization, volumetric measurement, and the potential for advanced physiologic imaging, but is less well suited to high throughput studies and has limited capacity to assess early tumor growth. Bioluminescence imaging (BLI) identifies tumors early, monitors tumor growth, and efficiently measures response to therapeutic intervention. Generally, BLI signals have been found to correlate well with MR measurements of tumor volume. However, in our studies of small-animal models of malignant brain tumors, we have observed specific instances in which BLI data do not correlate with corresponding MR images. These observations led us to hypothesize that use of BLI and MR imaging together, rather than in isolation, would allow more effective and efficient measures of tumor growth in preclinical studies. Herein, we describe combining BLI and MRI studies to characterize tumor growth in a mouse model of glioblastoma. Results lead us to suggest a cost-effective, multi-modality strategy for selecting cohorts of animals with similar tumor growth patterns that improves the accuracy of longitudinal in vivo measurements of tumor growth and treatment response in pre-clinical therapeutic studies.