Radiosurgery for brain metastases: specific indications for Gamma Knife in lieu of Linac in a single center using both methods

INTRODUCTION: Radiosurgery (RS) is gaining increasing acceptance in the upfront management of brain metastases (BM). It was initially used in so-called radioresistant metastases (melanoma, renal cell, sarcoma) because it allowed delivering higher dose to the tumor. Now, RS is also used for BM of other cancers. The risk of high incidence of new BM questions the need for associated whole-brain radiotherapy (WBRT). Recent evidence suggests that RS alone allows avoiding cognitive impairment related to WBRT, and the latter should be upheld for salvage therapy. Thus the increase use of RS for single and multiple BM raises new technical challenges for treatment delivery and dosimetry. We present our single institution experience focusing on the criteria that led to patients' selection for RS treatment with Gamma Knife (GK) in lieu of Linac. METHODS: Leksell Gamma Knife Perfexion (Elekta, Sweden) was installed in July 2010. Currently, the Swiss federal health care supports the costs of RS for BM with Linac but not with GK. Therefore, in our center, we always consider first the possibility to use Linac for this indication, and only select patients for GK in specific situations. All cases of BM treated with GK were retrospectively reviewed for criteria yielding to GK indication, clinical information, and treatment data. Further work in progress includes a posteriori dosimetry comparison with our Linac planning system (Brainscan V.5.3, Brainlab, Germany). RESULTS: From July 2010 to March 2012, 20 patients had RS for BM with GK (7 patients with single BM, and 13 with multiple BM). During the same period, 31 had Linac-based RS. Primary tumor was melanoma in 9, lung in 7, renal in 2, and gastrointestinal tract in 2 patients. In single BM, the reason for choosing of GK was the anatomical location close to, or in highly functional areas (1 motor cortex, 1 thalamic, 1 ventricular, 1 mesio-temporal, 3 deep cerebellar close to the brainstem), especially since most of these tumors were intended to be treated with high-dose RS (24 Gy at margin) because of their histology (3 melanomas, 1 renal cell). In multiple BM, the reason for choosing GK in relation with the anatomical location of the lesions was either technical (limitations of Linac movements, especially in lower posterior fossa locations) or closeness of multiple lesions to highly functional areas (typically, multiple posterior fossa BM close to the brainstem), precluding optimal dosimetry with Linac. Again, this was made more critical for multiple BM needing high-dose RS (6 melanoma, 2 hypernephroma). CONCLUSION: Radiosurgery for BM may represent some technical challenge in relation with the anatomical location and multiplicity of the lesions. These considerations may be accentuated for so-called radioresistant BM, when higher dose RS in needed. In our experience, Leksell Gamma Knife Perfexion proves to be useful in addressing these challenges for the treatment of BM.

A novel IFN-gamma regulated human melanoma associated antigen gp33-38 defined by monoclonal antibody Me14/D12. I. Identification and immunochemical characterization.

A novel melanoma-associated differentiation Ag whose surface expression can be enhanced or induced by IFN-gamma was identified by mAb Me14/D12. Testing of numerous tumor cell lines and tumor tissue sections showed that Me14/D12-defined Ag was present not only on melanoma but also on other tumor lines of neuroectodermal origin such as gliomas and neuroblastomas and on some lymphoblastic B cell lines, on monocytes and macrophages. Immunoprecipitation by mAb Me14/D12 of lysates from [35S]methionine-labeled melanoma cells analyzed by SDS-PAGE revealed two polypeptide chains of 33 and 38 KDa, both under reducing and nonreducing conditions. Cross-linking experiments indicated that the two chains were present at the cell surface as a dimeric structure. Two-dimensional gel electrophoresis showed that the two chains of 33 and 38 KDa had isoelectric points of 6.2 and 5.7, respectively. Treatment of the melanoma cells with tunicamycin, an inhibitor of N-linked glycosylation, resulted in a reduction of the Mr from 33 to 24 KDa and from 38 to 26 KDa. Peptide maps obtained after Staphylococcus aureus V8 protease digestion showed no shared peptides between the two chains. Although biochemical data indicate that Me14/D12 molecules do not correspond to any known MHC class II Ag, their dimeric structure, tissue distribution, and regulation of IFN-gamma suggest that they could represent a new member of the MHC class II family.

Rapid IL-4 production by Leishmania homolog of mammalian RACK1-reactive CD4(+) T cells in resistant mice treated once with anti-IL-12 or -IFN-gamma antibodies at the onset of infection with Leishmania major instructs Th2 cell development, resulting in nonhealing lesions.

Rapid production of IL-4 by Leishmania homolog of mammalian RACK1 (LACK)-reactive CD4(+) T cells expressing the V beta 4-V alpha 8 TCR chains has been shown to drive aberrant Th2 cell development and susceptibility to Leishmania major in BALB/c mice. In contrast, mice from resistant strains fail to express this early IL-4 response. However, administration of either anti-IL-12 or -IFN-gamma at the initiation of infection allows the expression of this early IL-4 response in resistant mice. In this work we show that Leishmania homolog of mammalian RACK1-reactive CD4(+) T cells also expressing the V beta 4-V alpha 8 TCR chains are the source of the early IL-4 response to L. major in resistant mice given anti-IL-12 or -IFN-gamma Abs only at the onset of infection. Strikingly, these cells were found to be required for the reversal of the natural resistance of C57BL/6 mice following a single administration of anti-IL-12 or -IFN-gamma Abs. Together these results suggest that a deficiency in mechanisms capable of down-regulating the early IL-4 response to L. major contributes to the exquisite susceptibility of BALB/c mice to L. major.

Patterns of pain-free response in 497 cases of classic trigeminal neuralgia treated with Gamma Knife surgery and followed up for least 1 year.

Object The goal of this study was to establish whether clear patterns of initial pain freedom could be identified when treating patients with classic trigeminal neuralgia (TN) by using Gamma Knife surgery (GKS). The authors compared hypesthesia and pain recurrence rates to see if statistically significant differences could be found. Methods Between July 1992 and November 2010, 737 patients presenting with TN underwent GKS and prospective evaluation at Timone University Hospital in Marseille, France. In this study the authors analyzed the cases of 497 of these patients, who participated in follow-up longer than 1 year, did not have megadolichobasilar artery- or multiple sclerosis-related TN, and underwent GKS only once; in other words, the focus was on cases of classic TN with a single radiosurgical treatment. Radiosurgery was performed with a Leksell Gamma Knife (model B, C, or Perfexion) using both MR and CT imaging targeting. A single 4-mm isocenter was positioned in the cisternal portion of the trigeminal nerve at a median distance of 7.8 mm (range 4.5-14 mm) anterior to the emergence of the nerve. A median maximum dose of 85 Gy (range 70-90 Gy) was delivered. Using empirical methods and assisted by a chart with clear cut-off periods of pain free distribution, the authors were able to divide patients who experienced freedom from pain into 3 separate groups: patients who became pain free within the first 48 hours post-GKS; those who became pain free between 48 hours and 30 days post-GKS; and those who became pain free more than 30 days after GKS. Results The median age in the 497 patients was 68.3 years (range 28.1-93.2 years). The median follow-up period was 43.75 months (range 12-174.41 months). Four hundred fifty-four patients (91.34%) were initially pain free within a median time of 10 days (range 1-459 days) after GKS. One hundred sixty-nine patients (37.2%) became pain free within the first 48 hours (Group PF(≤ 48 hours)), 194 patients (42.8%) between posttreatment Day 3 and Day 30 (Group PF((>48 hours, ≤ 30 days))), and 91 patients (20%) after 30 days post-GKS (Group PF(>30 days)). Differences in postoperative hypesthesia were found: in Group PF(≤ 48 hours) 18 patients (13.7%) developed postoperative hypesthesia, compared with 30 patients (19%) in Group PF((>48 hours, ≤ 30 days)) and 22 patients (30.6%) in Group PF(>30 days) (p = 0.014). One hundred fifty-seven patients (34.4%) who initially became free from pain experienced a recurrence of pain with a median delay of 24 months (range 0.62-150.06 months). There were no statistically significant differences between the patient groups with respect to pain recurrence: 66 patients (39%) in Group PF(≤ 48 hours) experienced pain recurrence, compared with 71 patients (36.6%) in Group PF((>48 hours, ≤ 30 days)) and 27 patients (29.7%) in Group PF(>30 days) (p = 0.515). Conclusions A substantial number of patients (169 cases, 37.2%) became pain free within the first 48 hours. The rate of hypesthesia was higher in patients who became pain free more than 30 days after GKS, with a statistically significant difference between patient groups (p = 0.014).

The effects of gamma-hydroxybutyrate, baclofen and GABAB receptors on brain activity and sleep in mice and humans

Currently, there is an increased interest in γ-hydroxybutyric acid (GHB) and its effects onsleep. This compound, sometimes referred to as 'rape drug', was recently approved as atreatment for the sleep disorder narcolepsy. Although several studies suggest that GHBinduces slow-wave sleep duration and improves sleep quality by increasing EEG slow-waveactivity, others question its ability to induce physiological sleep. GHB's mechanism of actionis still unclear, although in vivo and in vitro it seems to act at high doses as a low-affinityagonist of GABAB receptors. Furthermore, the role GABAB receptors play in sleep and theelectroencephalogram (EEG) is largely unknown.The aim of this project was therefore to investigate the effects of GHB on sleep and EEG, theinvolvement of GABAB receptors in mediating these effects, as well as the intrinsic role ofeach GABAB receptor subunit in the regulation of sleep. Thus, we administered GHB andbaclofen (BAC, a high-affinity agonist at GABAB receptor) to mice lacking the different GABABreceptor subunits and to healthy human volunteers.Our results, both in mice and humans, showed that GHB produced slow waves exclusivelythrough the stimulation of GABAB receptors, but did not induce physiological sleepnecessary to reduce sleep need and to increase cognitive performance. Unlike GHB, BACaffected the homeostatic regulation of sleep (sleep need) and induced a delayedhypersomnia. Finally, GABAB receptor and its subunits seem to play an important role insleep and in particular its circadian distribution.

Résultats à très long terme après Radiochirurgie Gamma Knife pour une Névralgie Faciale: à propos d'une série prospective de 737 patients

Introduction.- La radiochirurgie Gamma Knife (GKS) est une approche maintenant courante du traitement de la névralgie faciale (NF). Nous proposons les résultats d'une évaluation prospective a très long terme. Patients et méthode.- Entre décembre 1992 et novembre 2010, 737 patients présentant une NF typique (selon HIS 2003) ont été prospectivement sélectionnés, opérés par radiochirurgie et suivi cliniquement. Un isocentre unique de 4 mm avec une dose au maximum en moyenne de 85 Gy (70-90) été positionné sur la portion cisternale rétrogassérienne du trijumeau (IRM et CTscan stéréotaxiques). Les patients souffrant d'une SEP (n = 45) et ceux présentant un mégadolichotronc basilaire (MTB) sont exclus du fait d'une plus forte incidence des échecs dans ces deux sous-groupes (n = 45 et 29) (p = 0,0001). Ceux traités à plusieurs reprises (n = 14) par radiochirurgie le furent en raison d'un risque d'hypoesthésie plus élevé (p = 0,0193). Résultats ou cas rapporté.- Sont présentés les résultats des 497 patients avec un suivi de plus d'un an. Leur suivi médian est de 43 mois (12-174,41) ; et l'âge médian de 79 ans (28-93 ans). La douleur a disparu chez 91,75 % des patients et ce en moyenne en dix jours (1-459 jours). Une hypoesthésie est apparue chez 14,4 % des patients dans un délai médian de 12 mois (1-65). Le taux d'hypoesthésie gênante et très gênante est de 4,42 % et 2,21 % (BNI III et IV). Une récurrence survint chez 34,42 % des patients dans un délai médian de 24 mois (0,6-150). À 10 ans, 67,8 % des patients étaient libres de crise sans nouvelle chirurgie et 45,3 % sans traitement médicamenteux. Conclusion.- Cette étude prospective, unique par sa taille et la longueur de son suivi, démontre qu'en utilisant une cible rétrogassérienne, la majorité des patients présentent un soulagement durable après la GKS. L'hypoesthésie, seule complication rapportée, reste limitée à un petit pourcentage de patients et n'est pas nécessaire à une bonne efficacité de la GKS. Cette série rend légitime le recours à la GKS de première intention.

Neutral and selection-driven decay of sexual traits in asexual stick insects.

Environmental shifts and lifestyle changes may result in formerly adaptive traits becoming non-functional or maladaptive. The subsequent decay of such traits highlights the importance of natural selection for adaptations, yet its causes have rarely been investigated. To study the fate of formerly adaptive traits after lifestyle changes, we evaluated sexual traits in five independently derived asexual lineages, including traits that are specific to males and therefore not exposed to selection. At least four of the asexual lineages retained the capacity to produce males that display normal courtship behaviours and are able to fertilize eggs of females from related sexual species. The maintenance of male traits may stem from pleiotropy, or from these traits only regressing via drift, which may require millions of years to generate phenotypic effects. By contrast, we found parallel decay of sexual traits in females. Asexual females produced altered airborne and contact signals, had modified sperm storage organs, and lost the ability to fertilize their eggs, impeding reversals to sexual reproduction. Female sexual traits were decayed even in recently derived asexuals, suggesting that trait changes following the evolution of asexuality, when they occur, proceed rapidly and are driven by selective processes rather than drift.

Trigeminal neuralgia related to megadolichobasilar artery compression: a prospective series of twenty-nine patients treated with gamma knife surgery, with more than one year of follow-up.

BACKGROUND: Trigeminal neuralgia (TN) secondary to megadolichobasilar artery (MBA) compression is considerably difficult to manage surgically. OBJECTIVE: This study aims to evaluate the safety/efficacy of Gamma Knife surgery (GKS) in this special group of patients. METHODS: Between July 1992 and November 2010, 29 patients with >1 year of follow-up presenting with MBA compression were treated with GKS at Timone University Hospital. Radiosurgery was performed using a Gamma Knife (model B, C or Perfexion). A single 4-mm isocenter was positioned in the cisternal portion of the trigeminal nerve at a median distance of 9.1 mm (range: 6-18.2 mm) from the emergence. RESULTS: The median follow-up period was 46.1 months (range: 12.9-157.9 months). Initially, all patients (100%) were pain free; the average time to complete pain relief was 13.5 days (range: 0-240 days). Their actuarial probability of remaining pain free without medication at 0.5, 1 and 2 years was 93.1, 79.3 and 75.7%, respectively, and remained stable until 13 years after treatment. The actuarial probability of hypoesthesia onset at 6 months was 4.3%; at 1 year it reached 13% and remained stable until 13 years after treatment. CONCLUSIONS: GKS proved to be reasonably safe and effective on a long-term basis as a first- and/or second-line surgical treatment for TN due to MBA compression.

T cell receptor delta gene rearrangement and T early alpha (TEA) expression in immature alpha beta lineage thymocytes: implications for alpha beta/gamma delta lineage commitment.

Mature T cells comprise two mutually exclusive lineages expressing heterodimeric alpha beta or gamma delta antigen receptors. During development, beta, gamma, and delta genes rearrange before alpha, and mature gamma delta cells arise in the thymus prior to alpha beta cells. The mechanism underlying commitment of immature T cells to the alpha beta or gamma delta lineage is controversial. Since the delta locus is located within the alpha locus, rearrangement of alpha genes leads to deletion of delta. We have examined the rearrangement status of the delta locus immediately prior to alpha rearrangement. We find that many thymic precursors of alpha beta cells undergo VDJ delta rearrangements. Furthermore, the same cells frequently coexpress sterile T early alpha (TEA) transcripts originating 3' of C delta and 5' of the most upstream J alpha, thus implying that individual alpha beta lineage cells undergo sequential VDJ delta and VJ alpha rearrangements. Finally, VDJ delta rearrangements in immature alpha beta cells appear to be random, supporting models in which alpha beta lineage commitment is determined independently of the rearrangement status at the TCR delta locus.