Independent Poor Prognostic Factors for True Progression after Radiation Therapy and Concomitant Temozolomide in Patients with Glioblastoma: Subependymal Enhancement and Low ADC Value

BACKGROUND AND PURPOSE:Subependymal enhancement and DWI have been reported to be useful MR imaging markers for identifying true progression. Our aim was to determine whether the subependymal enhancement pattern and ADC can differentiate true progression from pseudoprogression in patients with glioblastoma multiforme treated with concurrent chemoradiotherapy by using temozolomide.MATERIALS AND METHODS:Forty-two patients with glioblastoma multiforme with newly developed or enlarged enhancing lesions on the first follow-up MR images obtained within 2 months of concurrent chemoradiotherapy completion were included. Subependymal enhancement was analyzed for the presence, location, and pattern (local or distant relative to enhancing lesions). The mean ADC value and the fifth percentile of the cumulative ADC histogram were determined. A multiple logistic regression analysis was performed to identify independent factors associated with true progression.RESULTS:Distant subependymal enhancement (ie, extending >1 cm or isolated from the enhancing lesion) was significantly more common in true progression (n = 24) than in pseudoprogression (n = 18) (P = .042). The fifth percentile of the cumulative ADC histogram was significantly lower in true progression than in pseudoprogression (P = .014). Both the distant subependymal enhancement and the fifth percentile of the cumulative ADC histogram were independent factors associated with true progression (P = .041 and P = .033, respectively). Sensitivity and specificity for the diagnosis of true progression were 83% and 67%, respectively, by using both factors.CONCLUSIONS:Both the distant subependymal enhancement and the fifth percentile of the cumulative ADC histogram were significant independent factors predictive of true progression.

Glioblastoma multiforme (GBM) is the most common form of malignant primary brain tumor in adults,¹ which is notorious for its intrinsic aggressiveness and a dismal prognosis.^2,3 The current standard treatment for GBM is maximal safe tumor resection followed by radiation therapy with concurrent temozolomide (TMZ) and adjuvant TMZ.⁴Recently, the criteria for assessing therapeutic responses in high-grade gliomas have been updated by the Response Assessment in Neuro-Oncology (RANO) Working Group to address the limitations of the previous guideline.⁵ For instance, contrast enhancement, which has been regarded as a surrogate marker for tumor progression, has been reassessed as a nonspecific finding merely reflecting the passage of contrast material across a disrupted blood-tumor barrier.^6–11 In particular, radiologists and clinicians have increasingly recognized the occurrence of progressive MR imaging lesions immediately after completion of concurrent chemoradiotherapy (CCRT) with TMZ, which spontaneously improved without further treatment other than the adjuvant TMZ.^12–14 The treatment-related reaction is termed pseudoprogression and has received attention as a potential pitfall in the response evaluation. At present, owing to the lack of established findings in conventional contrast-enhanced MR imaging for the differential diagnosis of true progression from pseudoprogression,^9,10 RANO stresses that the diagnosis of true progression can be made within the first 12 weeks after completion of radiation therapy only if most of the new enhancement is located outside the radiation field or if there is pathologic confirmation of progressive disease.⁵During the past few decades, there has been extensive effort to identify imaging biomarkers for tumor progression. Among the many parameters derived from advanced MR imaging techniques, DWI has been consistently reported to be helpful in differentiating tumor progression from treatment-related changes or necrosis.^15–22 Meanwhile, most previous studies pertaining to the role of conventional MR imaging have not shown promising results.^9,23 Nevertheless, a recent study focusing on the conventional MR imaging findings has proposed subependymal enhancement as a useful MR imaging marker for differentiating true progression from pseudoprogression.²⁴ To our knowledge, however, no previous studies have conducted in-depth analysis of the subependymal enhancement, and its potential as an independent predictor for true progression remains elusive.The purpose of the present study was to determine whether the subependymal enhancement pattern and ADC can differentiate true progression from pseudoprogression in patients with GBM treated with radiation therapy and concomitant TMZ.     

Quadriceps neural alterations in anterior cruciate ligament reconstructed patients: A 6‐month longitudinal investigation

The purpose of this investigation was to evaluate differences in quadriceps corticospinal excitability, spinal‐reflexive excitability, strength, and voluntary activation before, 2 weeks post and 6 months post‐anterior cruciate ligament reconstruction (ACLr). This longitudinal, case‐control investigation examined 20 patients scheduled for ACLr (11 females, 9 males; age: 20.9 ± 4.4 years; height:172.4 ± 7.5 cm; weight:76.2 ± 11.8 kg) and 20 healthy controls (11 females, 9 males; age:21.7 ± 3.7 years; height: 173.7 ± 9.9 cm; weight: 76.1 ± 19.7 kg). Maximal voluntary isometric contractions (MVIC), central activation ratio (CAR), normalized Hoffmann spinal reflexes, active motor threshold (AMT), and normalized motor‐evoked potential (MEP) amplitudes at 120% of AMT were measured in the quadriceps muscle at the specific time points. ACLr patients demonstrated bilateral reductions in spinal‐reflexive excitability compared with controls before surgery (P = 0.02) and 2 weeks post‐surgery (P ≤ 0.001). ACLr patients demonstrated higher AMT at 6 months post‐surgery (P ≤ 0.001) in both limbs. No MEP differences were detected. Quadriceps MVIC and CAR were lower in both limbs of the ACLr group before surgery and 6 months post‐surgery (P ≤ 0.05) compared with controls. Diminished excitability of spinal‐reflexive and corticospinal pathways are present at different times following ACLr and occur in combination with clinical deficits in quadriceps strength and activation. Early rehabilitation strategies targeting spinal‐reflexive excitability may help improve postoperative outcomes, while later‐stage rehabilitation may benefit from therapeutic techniques aimed at improving corticospinal excitability.     

Role of the ATP-binding cassette transporter Abcg2 in the phenotype and function of cardiac side population cells

Recently, the side population (SP) phenotype has been introduced as a reliable marker to identify subpopulations of cells with stem/progenitor cell properties in various tissues. We and others have identified SP cells from postmitotic tissues, including adult myocardium, in which they have been suggested to contribute to cellular regeneration following injury. SP cells are identified and characterized by a unique efflux of Hoechst 33342 dye. Abcg2 belongs to the ATP-binding cassette (ABC) transporter superfamily and constitutes the molecular basis for the dye efflux, hence the SP phenotype, in hematopoietic stem cells. Although Abcg2 is also expressed in cardiac SP (cSP) cells, its role in regulating the SP phenotype and function of cSP cells is unknown. Herein, we demonstrate that regulation of the SP phenotype in cSP cells occurs in a dynamic, age-dependent fashion, with Abcg2 as the molecular determinant of the cSP phenotype in the neonatal heart and another ABC transporter, Mdr1, as the main contributor to the SP phenotype in the adult heart. Using loss- and gain-of-function experiments, we find that Abcg2 tightly regulates cell fate and function. Adult cSP cells isolated from mice with genetic ablation of Abcg2 exhibit blunted proliferation capacity and augmented cell death. Conversely, overexpression of Abcg2 is sufficient to enhance cell proliferation, although with a limitation of cardiomyogenic differentiation. In summary, for the first time, we reveal a functional role for Abcg2 in modulating the proliferation, differentiation, and survival of adult cSP cells that goes beyond its distinct role in Hoechst dye efflux.     

Telomere length changes in patients with aplastic anaemia

To investigate telomere changes in patients with aplastic anaemia (AA) and clinical factors influencing the telomere dynamics, telomere length (TL) was measured in peripheral blood mononuclear cells using Southern blot analysis of 42 patients with AA and 39 healthy normal controls. Nineteen patients received supportive treatment only, while the remaining 23 patients received immunosuppressive therapy with anti-thymocyte globulin or anti-lymphocyte globulin +/- cyclosporin A. In AA patients, TL was on average 1.41 kb shorter than that of age-matched normal controls (P < 0.001). In patients treated with immunosuppression, the mean TL of non-responders was significantly shorter than that of age-matched normal controls (P < 0.001), while no difference in TL was detected in responders compared with controls. Positive correlation was observed between the extent of telomere shortening, the severity of neutropenia (P = 0.05) and the degree of mean corpuscular volume elevation (P = 0.005) at the time of the study. However, there was no correlation with time elapsed since diagnosis (P = 0.214). These findings suggest that haematopoietic stem cells in patients with AA rapidly lose TL at the onset of the disease. The TL shortening may reflect the severity of impairment of haematopoiesis.     

NAD(P)H oxidase-dependent platelet superoxide anion release increases platelet recruitment

Platelets, although not phagocytotic, have been suggested to release O. Since O-producing reduced nicotinamide adenine dinucleotide (phosphate) (NAD(P)H) oxidases can be specifically activated by certain agonists and are found in several nonphagocytotic tissues, we investigated whether such an enzyme is the source of platelet-derived O. We further studied which agonists cause platelet O release and whether platelet-derived O influences thrombus formation in vitro. Collagen, but not adenosine 5'-diphosphate (ADP) or thrombin, increased O formation in washed human platelets. This was a reduced nicotinamide adenine dinucleotide (NADH)-dependent process, as shown in platelet lysates. Consistent with a role of a platelet, NAD(P)H oxidase expression of its subunits p47(phox) and p67(phox) and inhibition of platelet O formation by diphenylene-iodoniumchloride (DPI) and by the specific peptide-antagonist gp91ds-tat were observed. Whereas platelet-derived O did not influence initial aggregation, platelet recruitment to a preformed thrombus following collagen stimulation was significantly attenuated by superoxide dismutase (SOD) or DPI. It was also inhibited when ADP released during aggregation was cleaved by the ectonucleotidase apyrase. ADP in supernatants of collagen-activated platelets was decreased in the presence of SOD, resulting in lower ADP concentrations available for recruitment of further platelets. Exogenous O increased ADP- concentrations in supernatants of collagen-stimulated platelets and induced irreversible aggregation when platelets were stimulated with otherwise subthreshold concentrations of ADP. These results strongly suggest that collagen activation induces NAD(P)H oxidase-dependent O release in platelets, which in turn enhances availability of released ADP, resulting in increased platelet recruitment.