Non-Contrast-Enhancing Tumor: A New Frontier in Glioblastoma Research.

There is a growing understanding of the prognostic importance of non-contrast-enhancing tumor in glioblastoma, and recent attempts at more aggressive management of this component using neurosurgical resection and radiosurgery have been shown to prolong survival. Optimizing these therapeutic strategies requires an understanding of the features that can distinguish non-contrast-enhancing tumor from other processes, in particular vasogenic edema; however, the limited and heterogeneous manner in which it has been defined in the literature limits clinical translation. This review covers pertinent literature on our growing understanding of non-contrast-enhancing tumor and focuses on key conventional MR imaging features for improving its delineation. Such features include subtle differences in the degree of FLAIR hyperintensity, gray matter involvement, and focal mass effect. Improved delineation of tumor from edema will facilitate more aggressive management of this component and potentially realize associated survival benefits.

MRI Features Can Predict 1p/19q Status in Intracranial Gliomas.

BACKGROUND AND PURPOSE: The 2016 revision of the World Health Organization Classification of Tumors of the Central Nervous System mandates codeletion of chromosomes 1p and 19q for the diagnosis of oligodendroglioma. We studied whether conventional MR imaging features could predict 1p/19q status. MATERIALS AND METHODS: Patients with previous 1p/19q testing were identified through pathology department records, typically performed on the basis of an oligodendroglial component on routine histology; 69 patients met the inclusion criteria. Preoperative imaging of patients with grade II or III gliomas was retrospectively assessed by 2 neuroradiologists, blinded to the 1p/19q status. Thirteen MR imaging features were first assessed in a small initial cohort (n = 10), after which the criteria were narrowed for the remaining patients as a validation cohort. RESULTS: There was 85% agreement between radiologists for the overall prediction of 1p/19q status in the validation cohort, with an accuracy of 84%. The presence of >50% T2-FLAIR mismatch and calcification was found to be the most useful for predicting 1p/19q status. The >50% T2-FLAIR mismatch variable was demonstrated in 14 tumors and had 100% specificity for identifying a noncodeleted tumor (P = .001), with 97% interobserver correlation. Calcification was visualized in 7 tumors, 6 of which were 1p/19q codeleted (specificity, 97%; P = .006), with 100% interobserver correlation. CONCLUSIONS: The presence of >50% T2-FLAIR mismatch is highly predictive of a noncodeleted tumor, while calcifications suggest a 1p/19q codeleted tumor. If formal 1p/19q testing is not possible, a combined MR imaging-histologic assessment may improve the diagnostic accuracy over histology alone.

Global fit concept in revision hip arthroplasty for cementless press-fit femoral stems.

A revision stem may be required after a femoral extended trochanteric osteotomy (ETO) is made during revision hip arthroplasty. The two main complications of straight cementless femoral stems are subsidence due to inadequate osteointegration and stress-shielding. We will describe an original revision method with ETO that uses a straight cementless stem. The goal of this method was to achieve the most extensive press-fit possible during stem implantation to improve the transmission of stresses to the bone and to prevent reduction in bone density. The intramedullary preparation was done after closure and fixation of the ETO, which allows impaction of the revision stem with metaphyseal and diaphyseal press-fit. We report encouraging results with preservation of periprosthetic bone stock and good osteointegration of these revision stems at the final follow-up. Pronounced sagittal curvature or large bone defects are contraindications for this technique.

Intracranial involvement by multiple myeloma.

Intracranial involvement is a rare complication of multiple myeloma. It results either from direct extra-osseous spread from adjacent skeletal plasmacytomas or extra-medullary disease via haematogenous dissemination. The imaging appearances are non-specific, and dural, leptomeningeal, and parenchymal involvement can all occur. The purpose of this review is to illustrate the various neuroimaging appearances of this rare entity, focusing on MRI.

MRI grading versus histology: predicting survival of World Health Organization grade II-IV astrocytomas.

BACKGROUND AND PURPOSE: Histologic grading of intracranial astrocytomas is affected by sampling error and substantial inter- and intraobserver variability. We proposed that incorporating MR imaging into grading will predict patient survival more accurately than histopathology alone. MATERIALS AND METHODS: Patients with a new diagnosis of World Health Organization grades II-IV astrocytoma or mixed oligoastrocytoma diagnosed between September 2007 and December 2010 were identified. Two hundred forty-five patients met the inclusion criteria. Preoperative MRIs were independently reviewed by 2 readers blinded to the histologic grade, and an MR imaging grade was given. The MR imaging and histopathologic grades were compared with patient survival. RESULTS: Patients with grade II or III astrocytomas on histology but evidence of necrosis on MR imaging (consistent with a grade IV tumor) had significantly worse survival than patients with the same histology but no evidence of necrosis on MR imaging (P = .002 for grade II histology and P = .029 for grade III). Their survival was not significantly different from that in patients with grade IV tumors on histology (P = .164 and P = .385, respectively); this outcome suggests that all or most are likely to have truly been grade IV tumors. MR imaging evidence of necrosis was less frequent in grade II and III oligoastrocytomas, preventing adequate subgroup analysis. CONCLUSIONS: MR imaging can improve grading of intracranial astrocytomas by identifying patients suspected of being undergraded by histology, with high interobserver agreement. This finding has the potential to optimize patient management, for example, by encouraging more aggressive treatment earlier in the patient's course.

Microglial changes accompanying the promotion of retinal ganglion cell axonal regeneration into peripheral nerve grafts.

Intravitreal injection of the microglia inhibitor tuftsin 1-3 leads to an increase in retinal ganglion cell axonal regeneration into peripheral nerve grafts and a decrease in phagocytic cells in the retina. However, the relation of phagocytic cells and particularly microglia towards axonal regeneration remains unclear. Initially, to assess this, tuftsin 1-3's effect on axonal regeneration was reexamined by doing a dose-response study. Optimal doses were found to be 2.5 microg/ml and 250 microg/ml in rats and hamsters respectively. We then studied retinal phagocytic cells in rats. Microglial cells were classified as resting or activated based on their morphology following OX42 immunolabelling. In controls, most microglial cells were in the resting state. Optic nerve cut led to an increase in the total number of microglia and a ten-fold elevation in the proportion of activated cells; changes were more pronounced at the optic nerve stump. Anastomosis of an autologous segment of sciatic nerve to the stump of the freshly cut optic nerve minimized the overall increase in microglia, and combined with 2.5 microg/ml tuftsin 1-3, lead to a marked blunting of activation. Preservation within the retina of a higher proportion of resting over active form of microglia, and not the prevention of microglial proliferation per se, may be a crucial factor in allowing additional retinal ganglion cell axons to regenerate into peripheral nerve grafts.

Autologous stem cell transplantation for anaplastic large-cell lymphomas: results of a prospective trial.

Autologous stem cell transplantation (ASCT) in the front line treatment of non-Hodgkin's lymphoma (NHL) remains controversial. Anaplastic large-cell lymphoma (ALCL) is known to have its own clinical and biological features. The outcome of ALCL patients treated with high-dose chemotherapy and ASCT as part of their first-line therapy was analysed in 202 intermediate or high-grade NHL patients in a prospective randomized trial. First-line chemotherapy comprised two alternating anthracycline-containing regimens. Responding patients were autografted after a BEAM (BCNU, cytarabine, etoposide and melphalan) regimen. Patients with bulky or residual masses were irradiated. Fifteen patients with ALCL were identified by morphological and immunological features (CD30 was expressed in 14 out of 15 patients, three patients expressed B-cell markers, five patients expressed T-cell markers and seven patients did not express cell markers). Anaplastic lymphoma kinase (ALK) expression was confirmed in seven cases. The median age was 39 years with a predominant male sex ratio (2.75). Thirteen patients were stage >/= III and six presented with two or more adverse prognostic factors. According to the international age-adjusted prognostic index, the expected complete remission (CR), event-free survival (EFS) and overall survival (OS) rates were 69%, 71% and 69%. Two deaths were observed (one due to interstitial pneumonitis, one due to pulmonary carcinoma). All patients entered CR, no relapse occurred and EFS and survival reached 87% with a follow-up of more than 5 years. These results differ significantly from those observed in the other 176 lymphoma patients: event-free survival was only 53 +/- 5% and OS reached 60 +/- 4% with a median follow-up of 56 months (P = 0.006). Intensified chemotherapy with autologous stem cell support appeared effective in the treatment of ALCL, offering patients the real chance of a cure.

Salvage extended-field irradiation in follicular non-Hodgkin's lymphoma after failure of chemotherapy.

PURPOSE: To evaluate the efficacy of total abdominopelvic (TAI) and total body irradiation (TBI) in heavily pretreated follicular non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: From 1983 to 1998, 34 patients received TAI (n = 22) or TBI (n = 12). All had Stage III or IV, Class B, C, D NHL in the working formulation and failed after receiving 1-5 regimens of chemotherapy. TAI was given at 20 Gy over a 3-week period. TBI was delivered in two successive half-body irradiations of 15 Gy over a 2-week period with a 4-week interval between each. RESULTS: Mean follow-up from TAI or TBI was 120 months (range, 6-180). Seventy-six percent of patients achieved complete response and 24% partial response. Median survival was 62 months, 5-year and 10-year overall survival was 59% and 41%, and disease-free survival was 56% and 30%, respectively. Grade III or IV toxicity was gastrointestinal in 38% of patients and hematologic in 30%. No toxic death or delayed complications were observed. CONCLUSION: Extended-field irradiation is feasible and efficient after failure of chemotherapy in follicular NHL.

IgG-secreting lymphoplasmacytoid leukaemia: a B-cell disorder with extensively mutated VH genes undergoing Ig isotype-switching frequently associated with trisomy 12.

We investigated 16 patients with elevated serum monoclonal IgG and a leukaemic B-cell lymphocytic disorder different from multiple myeloma. Their clinical history was that of a non-aggressive disease with dominant splenomegaly and long survival. Whereas abnormal blood and bone marrow cells were predominantly small lymphocytes with a few lymphoplasmacytoid cells, histopathological features included a lymphoplasmacytic infiltrate in eight cases. Most frequently, abnormal blood cells displayed a CD19+CD5-CD23+/- immunophenotype different from that of chronic lymphocytic leukaemia, except in two cases with a CD19+CD5+CD23+ phenotype. Interestingly, a coexistent serum monoclonal IgM and/or surface IgMG+ with identical light chain was identified in 10 patients, whereas in the remaining six patients only IgG expression was determined. VH gene analysis was performed in eight patients to investigate the clonal origins of tumour cells. All cases utilized the VH3 family, with evidence of extensive somatic mutations and intraclonal homogeneity in all cases. VH gene analysis indicated a clonal relationship between cells expressing IgM and IgG, with one case being biclonal. Cytogenetic evaluation showed a high incidence of trisomy 12 (60%) and 13q14 deletion (40%). In conclusion, we have described an unusual subset of low-grade lymphoma with high-serum IgG and frequent lymphoplasmacytoid features in which tumour cells derive from post-follicular memory B cells undergoing isotype switching with some cases arrested at both the IgM and IgG stage and others as IgG-positive cells only.

Epidermal growth factor stimulates 3-hydroxy-3-methylglutaryl-coenzyme A reductase expression via the ErbB-2 pathway in human breast adenocarcinoma cells.

HMG-CoA reductase is the key enzyme for the biosynthesis of isoprenoid compounds essential for cell growth and differentiation. Its tyrosine kinase-dependent modulation has recently been suggested and described in the ErbB-2 overexpressing cell line SKBR-3 [Asslan et al. (1998) Biochem. J. 330, 241-246]. Epidermal growth factor (EGF) increased the HMG-CoA reductase activity, protein, and mRNA levels only in ErbB-2-expressing cells (SKBR-3 and MCF-7) but not in MDA-MB-468 cells that do not express ErbB-2 even though their EGF receptor was efficiently phosphorylated. Tyrphostin AG 879, a specific inhibitor of ErbB-2 tyrosine kinase activity, decreased HMG-CoA reductase activity only in cells that expressed ErbB-2. A functional EGF receptor appeared to be necessary since its inhibition by the specific tyrphostin AG 1478 abolished the EGF effects. Phosphatidylinositol 3-kinase (PI 3-kinase) might be a crucial enzyme in the signaling pathway since the specific inhibitor, LY 294002, was shown to inhibit HMG-CoA reductase activity and to completely abolish the stimulation by EGF in SKBR-3 cells.

Detection of translocation t(11;14)(q13;q32) in mantle cell lymphoma by fluorescence in situ hybridization.

To assess an unequivocal diagnosis of mantle cell lymphoma (MCL), we have developed a fluorescence in situ hybridization (FISH) assay, enabling the demonstration of t(11;14)(q13;q32) directly on pathological samples. We have first selected CCND1 and IGH probes encompassing the breakpoint regions on both chromosomes. Then, we have defined experimental conditions enabling us to obtain bright clear-cut signals in all of the samples, independently of the initial fixation conditions. We have analyzed single-cell suspensions from 26 formalin-fixed, paraffin-embedded MCL samples with this set of probes. In all cases, we have found a fusion signal (ie, a t(11;14)(q13;q32) translocation) in 14% to 99% of cells (median, 87%). So far, IGH-CCND1 fusions have been detected in all of the 51 MCL patients that we have analyzed by FISH (either on paraffin-embedded tumor samples or on peripheral blood samples). Regarding the low sensitivity of other techniques used to diagnose t(11;14)(q13;q32) (ie, 70% to 75% for cytogenetics and 50% to 60% for polymerase chain reaction), our FISH assay is by far the most sensitive technique. Moreover, because of the quality of the fluorescent signals and the rapidity of the experiment, this technique is widely applicable, even in routine cytogenetics or pathology laboratories. As MCL patients are usually refractory to standard therapy, an unambiguous diagnosis is needed to propose adapted therapeutic strategies, and this highly sensitive assay may be of great value for accurate diagnosis in difficult cases.

High-dose therapy with stem cell transplantation for mantle cell lymphoma: results and prognostic factors, a single center experience.

From 1991 to 1997 18 consecutive patients with well-defined mantle cell lymphoma (MCL) underwent high-dose therapy with unpurged autologous (17 patients) or allogeneic (one patient) stem cell transplantation. Tissue sections were reviewed for morphology, immunophenotype, cyclin D1 and P53 expression as well as proliferation index (PI). Median age of patients was 47 years (range 40-60). Sixteen had stage IV disease with bone marrow involvement in 12 and performance status was > or =1 in 12 patients. At the time of high-dose therapy 10 patients were in first partial response (PR), one was in second complete remission (CR), four were in second PR and three were refractory to conventional anthracycline-containing chemotherapy. The conditioning regimen consisted of TBI plus chemotherapy in 13 patients and chemotherapy only (BEAM) in five patients. No treatment-related deaths were observed. With a median follow-up of 36 months (range 13-80) after transplant, disease-free survival (DFS) and overall survival (OS) are estimated to be 48 and 80% at 4 years, respectively. Significantly better results are achieved for patients transplanted after a TBI containing regimen with a 4 year OS and DFS estimated at 89 and 71%, respectively compared to 60 and 0% respectively for patients who were conditioned without TBI (P = 0.07 for OS and P < 0.0001 for DFS). There is a trend towards better DFS when the transplant is performed in PR1 (4 year DFS: 80% with eight patients out of 10 in continuous CR 13 to 80 months, median 36 months after transplant) compared to more advanced stages (4 year DFS: 18% with only three patients out of eight in continuous CR 16, 17 and 58 months after transplant). Blastic histology and P53 overexpression are also associated with a trend towards a worst prognosis.

Detection of t(11;14) using interphase molecular cytogenetics in mantle cell lymphoma and atypical chronic lymphocytic leukemia.

The chromosomal translocation t(11;14)(q13;q32) fuses the IGH and CCND1 genes and leads to cyclin D1 overexpression. This genetic abnormality is the hallmark of mantle cell lymphoma (MCL), but is also found in some cases of atypical chronic lymphocytic leukemia (CLL), characterized by a poor outcome. For an unequivocal assessment of this specific chromosomal rearrangement on interphase cells, we developed a set of probes for fluorescence in situ hybridization (FISH). Northern blotting was performed for analysis of the cyclin D1 expression in 18 patients. Thirty-eight patients, with either a typical MCL leukemic phase (17 patients) or atypical CLL with an MCL-type immunophenotype, i.e., CD19-, CD5+, CD23-/low, CD79b/sIgM(D)++, and FMC7+ (21 patients), were analyzed by dual-color interphase FISH. We selected an IGH-specific BAC probe (covering the JH and first constant regions) and a commercially available CCND1 probe. An IGH-CCND1 fusion was detected in 28 of the 38 patients (17 typical MCL and 11 cases with CLL). Cyclin D1 was not overexpressed in two patients with typical MCL and an IGH-CCND1 fusion. In view of the poor prognosis associated with MCL and t(11;14)-positive CLL, we conclude that this set of probes is a valuable and reliable tool for a rapid diagnosis of these entities.

Long-term results of total abdominopelvic irradiation in non-Hodgkin's lymphomas after failure of chemotherapy.

PURPOSE: To evaluate the therapeutic efficacy of moderate-dose total abdominopelvic irradiation (TAI) in a retrospective series of pretreated non-Hodgkin's lymphomas (NHL). METHODS AND MATERIALS: From 1977 to 1994, 45 patients received TAI after failure of chemotherapy (CT). According to the Working Formulation, 10 patients were diagnosed with class A (group I), 19 with class B, C, or D (follicular) (group II), and 16 with class E or more severe (group III) NHL. Irradiation consisted of two daily fractions of 0.80 Gy each for a total dose of 20 Gy. RESULTS: Mean follow-up after TAI was 102 months (range 8-156). For the entire group, the complete response (CR) rate was 66%, the partial response (PR) rate 29%, 10-year overall survival (OS) 35%, 10-year disease-free survival (DFS) 29%, and median survival 32 months. When results between subgroups were compared, CR was 70% in group I, 84% in group II, and 44% in group III; and survival was statistically higher in group II than in groups I and III: 10-year OS 52% vs. 10% (p < 0.01) and 31% (p < 0.05), respectively, 10-year DFS 37% vs. 10% (p < 0.03) and 19% (p < 0.05), respectively. Grade III or IV complications were gastrointestinal in 27% of patients and hematologic in 25%. CONCLUSION: Large-field irradiation in moderate doses could provide an alternative to bone marrow transplantation in refractory NHL, especially in cases showing a follicular growth pattern.

Tyrosine kinase-dependent modulation of 3-hydroxy-3-methylglutaryl-CoA reductase in human breast adenocarcinoma SKBR-3 cells.

3-Hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase is the major rate-limiting enzyme in sterol and non-sterol isoprenoid synthesis. Isoprenoids are involved in the mechanisms of cell proliferation and transformation leading notably to crucial post-translational maturation of small G-proteins of the Ras superfamily. HMG-CoA reductase is among the most highly regulated enzymes. It is controlled by several feedback regulation mechanisms induced by sterol and non-sterol metabolites. The present results show that tyrosine kinase activity is also involved in the regulation of HMG-CoA reductase activity in the human breast cancer cell line SKBR-3. Incubation of SKBR-3 cells with the tyrosine kinase inhibitor, herbimycin A, induces a concentration-dependent reduction of HMG-CoA reductase activity with an IC50 of 80nM. The inhibition of HMG-CoA reductase activity by herbimycin A is also time-dependent. A similar effect of herbimycin A was obtained on the steady-state level of the HMG-CoA reductase protein. The effect of herbimycin A is probably specific as it abolished the stimulation of reductase activity by epidermal growth factor. To elucidate the molecular basis of the inhibition of HMG-CoA reductase activity and protein level by herbimycin A, we performed experiments to study the metabolic turnover of this enzyme using [35S]methionine and [35]cysteine. Herbimycin A (1 microM) did not have any significant effect on the rate of HMG-CoA reductase protein degradation but did affect its rate of synthesis and mRNA levels. The decrease in protein synthesis rate correlates with the lower reductase protein level but is more pronounced than the decrease in mRNA levels. Taken together, the results reveal a novel pathway of regulation of HMG-CoA reductase expression and activity by cellular tyrosine kinase activities.

Visual integration of data and basic motor skills under laparoscopy. Influence of 2-D and 3-D video-camera systems.

BACKGROUND: The qualities of visual perception and of motor reaction to the visual stimulus have never been studied in reference to the type of video-camera system (2-D vs 3-D) used during laparoscopy. METHODS: The study was designed in two parts. The first evaluated the ability of the eye to discriminate how objects are spaced relative to one another. The second investigated the motor reaction to the visual stimulus in an environment where depth was the preponderent cue. The tests were performed in a pelvi-trainer in which were inserted different modules built either for visual observation (Part 1) or for evaluation of motor ability (Part 2). Variables studied during Part 1 were the time required to do the test and the number of errors committed during its performance. The variable evaluated during Part 2 was the time needed to terminate the test. Each of these two parts of the study were completed alternating the 2-D and 3-D systems. A total of 304 observations were recorded. Statistics used were the paired t-test, the independent group t-test, and the Newman-Keuls multiple comparisons test. RESULTS: Results of Part 1 of the study confirm that visual perception varies significantly among individuals (n = 10) (p < 0.05) and that a true 3-D video-camera system facilitates visual perception when compared to a 2-D system (p < 0.001). Results of Part 2 of the study also show significant differences among participants (n = 9)(p < 0.05). The true 3-D system allowed significantly faster motor performances than the 2-D system (p < 0.001). CONCLUSION: Our experiment shows that the 3-D system allowed significant improvements in the execution of the evaluated parameters. Also noted were significant differences among participants in term of visual and motor skills.

Comparative genomic hybridization detects genomic abnormalities in 80% of follicular lymphomas.

Comparative genomic hybridization (CGH) was used to analyse 34 follicular lymphoma (FL) samples. 27 samples showed DNA sequence copy number changes of at least one genomic region (26 samples with at least one gain and nine with at least one loss). Some chromosomes or chromosomal regions were preferentially involved. The most frequently gained regions were chromosome 18q (29% of samples), chromosome X (21%), chromosome 7 (18%), chromosomes 2, 6p and 8q (12%). Two regions were preferentially lost: 6q (12%) and 17p (9%). All these gained and lost regions have been previously reported in cytogenetic studies, confirming the accuracy of CGH in detecting genetic abnormalities in FL. 21% of samples displayed normal profiles, probably reflecting the absence of unbalanced abnormality, which is also in agreement with the cytogenetic data. In conclusion, we showed that CGH is an accurate, reliable and rapid method and we propose the inclusion of CGH in the evaluation of FL at diagnosis.

Experimental laparoscopic aortobifemoral bypass for occlusive aortoiliac disease.

OBJECTIVE: To describe a totally laparoscopic technique for aortobifemoral bypass to treat aortoiliac atheromatous occlusive disease. DESIGN: A feasibility study. SETTING: A university teaching hospital. SUBJECTS: Six piglets weighing between 70 and 80 kg were submitted to a totally laparoscopic retroperitoneal aortobifemoral bypass, performed through six trocar sites, with abdominal suspension and a gasless technique. No minilaparotomy was performed. After systemic heparinization, the infrarenal aorta was cross-clamped and the aortic bifurcation stapled. An end-to-end aorto-prosthetic anastomosis was performed. Retroperitoneal tunnels were created to allow each limb of the graft to join its corresponding femoral artery by a conventional anastomosis. INTERVENTION: Totally laparoscopic aortobifemoral bypass. MAIN OUTCOME MEASURES: Duration of the procedure, intraoperative blood loss and operative complications, bleeding in the immediate postoperative period. Evaluation of the aortic anastomosis at autopsy. RESULTS: All aortobifemoral bypasses were completed in less than 4 hours. Intraoperative blood loss did not exceed 250 mL. No intraoperative complication was encountered except occasional bleeding at the aortic anastomosis upon releasing the arterial clamp. This was controlled with a collagen sponge (three cases) or extra stitches (two cases). The animals were observed for 15 minutes before sacrifice. Autopsy revealed a normal aortic anastomosis in all cases and a normal progression of the limbs of the graft under the ureters in the retroperitoneal tunnels. CONCLUSIONS: This animal model demonstrates the feasibility of the aortobifemoral bypass through a laparoscopic approach. The retroperitoneal anatomy of the piglet is similar to that of man. Aortic surgery can be conducted as for the standard technique. We used a similar approach to perform the first human, totally laparoscopic aortobifemoral bypass with an end-to-end anastomosis.

Atrial myxoma mimicking systemic disease. Profile modified by flurbiprofen administration.

A patient had a left atrial myxoma which was modified by flurbiprofen administration. The diagnosis was made 42 months after the first symptoms appeared. Flurbiprofen may have reduced interleukin-6 secretion by the tumor, leading to a delayed diagnosis.