Gilteritinib with or without venetoclax for relapsed/refractory FLT3-mutated acute myeloid leukaemia.

Patients with FLT3-mutated acute myeloid leukaemia (AML) that relapse or are refractory (R/R) to intensive induction have poor outcomes. Gilteritinib has recently become standard-of-care for patients with R/R FLT3-mutated AML. We investigated whether adding venetoclax to gilteritinib (gilt-ven) improves outcomes as compared with gilteritinib monotherapy. We included patients treated with gilteritinib (n = 19) and gilt-ven (n = 17) for R/R AML after intensive chemotherapy. Gilteritinib and gilt-ven groups did not differ in terms of mCRc rates (53% and 65%, p = 0.51) and realization of allogeneic haematopoietic stem-cell transplantation (HSCT, 47% and 35%, p = 0.5). Overall survival (OS) was comparable between groups, although a trend towards better OS was seen with gilt-ven (12-month OS 58.8% [95% CI 39.5%-87.6%]) versus gilteritinib (42.1% [95% CI 24.9%-71.3%] for gilteritinib). Early salvage with gilt-ven versus any other gilteritinib-based approach was associated with the best outcome (p = 0.031). Combination therapy was associated with increased haematological toxicity. In summary, gilt-ven did not improve remissions or HSCT-realization rates in patients with R/R FLT3-mutated AML as compared with gilteritinib and was associated with increased haematological toxicity. Although OS did not differ, a trend towards better survival was suggested with gilt-ven and a survival benefit was shown for gilt-ven approach when sequenced early for salvage.

Historical Perspective of High-Dose Therapy Followed by Autologous Stem Cell Transplantation in Multiple Myeloma.

BACKGROUND: High-dose therapy (HDT) followed by autologous stem cell transplantation (ASCT) has become part of standard of care (SOC) in newly diagnosed multiple myeloma. In this review, we provide a historical perspective on ASCT since its introduction in the 1990s. SUMMARY: Overall survival (OS) benefit for HDT followed by ASCT was demonstrated in studies comparing HDT with ASCT to standard-dose therapy (SDT) before the era of novel agents. Conditioning is done with melphalan 200 mg/m2. Lower doses (MEL140, MEL150) for older patients with comorbidities are safe and have comparable results. The addition of busulfan to melphalan improves progression-free survival (PFS) but not OS. HDT with ASCT after induction with novel agents prolongs PFS but not OS compared to SDT alone. The benefit is more evident in patients with high-risk cytogenetics. Mobilization can be achieved with granulocyte colony-stimulating factor alone, but is improved with the addition of chemotherapy. Plerixafor reduces mobilization failure and enables sufficient stem cell collection after induction with novel agents. ASCT is safe with a low rate of mortality (1%), and selected patients can be managed as outpatients. KEY MESSAGES: HDT followed by ASCT remains part of SOC due to its PFS benefit and relatively low toxicity.

Targeted therapies for immune thrombocytopenic purpura: a meta-analysis of randomized controlled trials.

Several targeted therapies have been approved in recent years for second-line treatment of immune thrombocytopenic purpura (ITP), providing an alternative to rituximab and splenectomy. The extent to which these drugs reduce bleeding risk has not been well defined. Targeted therapies recently approved for the treatment of ITP in adults were identified through a search of recently published professional guidelines. Randomized controlled trials (RCTs) supporting regulatory approval were identified through a search of drug labels on FDA@gov. Odds ratios (ORs) and associated 95% confidence intervals (CIs) were computed for pre-specified efficacy outcomes including platelet recovery to ≥ 50,000/µL, major and minor bleeding events, and survival. ORs for all adverse events were also computed. Four targeted therapies were identified, including three thrombopoietin receptor agonists and one tyrosine kinase inhibitor. Six RCTs, comprising 752 patients, were included in the meta-analysis. More patients treated with targeted therapies for ITP as compared to placebo achieved platelet counts over ≥ 50,000/µL (OR 8.29, 95% CI 5.59-12.29). Compared to placebo, targeted therapies for ITP were associated with significantly lower odds for major bleeding (OR 0.43, 95% CI 0.21-0.91), minor bleeding (OR 0.66, 95% CI 0.45-0.97), and with numerically lower mortality rates (OR 0.24, 95% CI 0.05-1.07). The odds for adverse events were comparable between the two arms (OR 1.43 95% CI 0.76-2.67). Compared to placebo, targeted therapies for ITP increase platelet counts, decrease bleeding events, and show a trend towards lower mortality, without increased toxicity. These findings support their use as a second-line ITP treatment.

Nervous System Hemangiopericytoma.

The management of patients harboring central nervous system (CNS) hemangiopericytomas (HPCs) is a partially answered challenge. These are rare locally aggressive lesions, with potential for local recurrence, distal neural metastasis (DNM), and extraneural metastasis (ENM). Resection, when feasible, remains the initial treatment option, providing histological diagnosis and immediate relief of tumor-related mass effect. Patients receiving surgery alone or surgery and external beam radiotherapy (EBRT) show improved overall survival (OS) and progression-free survival as compared to those undergoing a biopsy alone (p = 0.01 and p = 0.02, respectively). Yet, in many instances, patient and tumor-related parameters preclude complete resection. EBRT or stereotactic radiosurgery (SRS) shares a significant role in achieving local tumor control, not shown to impact OS in HPC patients. The benefits of SRS/EBRT are clearly limited to improved local tumor volume control and neurologic function, not affecting DNM or ENM development. SRS provides acceptable rates of local tumor volume control coupled with treatment safety and a patient-friendly apparatus and procedure. Single-session SRS is most effective for lesions measuring <2 cm in their largest diameter (10 cm3 volume), with prescription doses of at >15 Gy. Systemic HPC disease is managed with various chemotherapeutic, immunotherapeutic, and anti-angiographic agents, with limited success. We present a short discussion on CNS HPCs, focusing our discussion on available evidence regarding the role of microsurgical resection, EBRT, SRS, chemotherapy, and immunotherapy for upfront, part of adoptive hybrid surgery approach or for recurrent HPCs.

L'hémangiopéricytome du système nerveux central. La prise en charge des patients atteints d'un hémangiopéricytome du système nerveux central demeure un défi auquel on n'a pas tout à fait encore répondu. Il s'agit en effet de lésions fulminantes qui présentent un potentiel de récurrence locale mais aussi d'apparition de métastases affectant la partie distale des neurones et de métastases hors neurones. Lorsque cela est possible, la résection constitue la première option thérapeutique. Cette dernière permet d'assurer un diagnostic histologique ainsi qu'un soulagement immédiat de l'effet de masse associé à la tumeur cérébrale. Les patients bénéficiant uniquement d'une intervention chirurgicale ou d'une intervention combinant la chirurgie et la radiothérapie ont montré une amélioration de leur taux de survie globale et de leur taux de survie sans aggravation si on les compare aux autres patients soumis à une seule biopsie (respectivement p = 0,01 et p = 0,02). Dans bien des cas, il est des paramètres se rapportant aux patients et aux tumeurs elles-mêmes qui excluent une résection complète. À cet égard, rappelons qu'une intervention combinant chirurgie et radiothérapie ou bien encore la radiochirurgie stéréotaxique peuvent jouer un rôle clé dans le contrôle d'une tumeur locale, et ce, sans que le taux de survie globale des patients atteints d'un hémangiopéricytome soit affecté. Cela dit, les bénéfices de la radiochirurgie stéréotaxique et d'une intervention combinant chirurgie et radiothérapie demeurent clairement limités à une amélioration du contrôle des tumeurs locales et des fonctions neurologiques et n'ont pas d'impact sur le développement des métastases affectant la partie distale des neurones et des métastases hors neurones. Ajoutons aussi que la radiochirurgie stéréotaxique offre des taux de contrôle des tumeurs locales acceptables en plus de représenter un traitement sécuritaire pour les patients et de sous-tendre l'utilisation de procédures et d'équipements conviviaux. Une simple séance de radiochirurgie stéréotaxique sera particulièrement indiquée dans le cas de lésions mesurant moins de 2 cm dans leur plus grand diamètre (volume de 10 cm3), les doses prescrites étant de >15 Gy. Un hémangiopéricytome de caractère systémique pourra être traité avec un succès limité au moyen de nombreux agents chimiothérapeutiques, immunothérapeutiques et anti-angiographiques. Nous voulons donc faire ici un bref exposé au sujet des hémangiopéricytomes du système nerveux central. Nous voulons aussi mettre l'accent sur les preuves disponibles concernant l'impact de la résection microchirurgicale, des interventions combinant chirurgie et radiothérapie, de la radiochirurgie stéréotaxique, de la chimiothérapie et de l'immunothérapie dans le cadre d'une approche chirurgicale hybride initiale pour des cas récurrents d'hémangiopéricytomes.

Stereotactic radiosurgery for small brain metastases and implications regarding management with systemic therapy alone.

While stereotactic radiosurgery (SRS) has been shown effective in the management of brain metastases, small brain metastases (≤10 mm) can pose unique challenges. Our aim was to investigate the efficacy of SRS in the treatment of small brain metastases, as well as elucidate clinically relevant factors impacting local failure (LF). We utilized a large, single-institution cohort to perform a retrospective analysis of patients with brain metastases up to 1 cm in maximal dimension. Clinical and radiosurgical parameters were investigated for an association with LF and compared using a competing risk model to calculate cumulative incidence functions, with death and whole brain radiotherapy serving as competing risks. 1596 small brain metastases treated with SRS among 424 patients were included. Among these tumors, 33 developed LF during the follow-up period (2.4% at 12 months following SRS). Competing risk analysis demonstrated that LF was dependent on tumor size (0.7% if ≤2 mm and 3.0% if 2-10 mm at 12 months, p = 0.016). Other factors associated with increasing risk of LF were the decreasing margin dose, increasing maximal tumor diameter, volume, and radioresistant tumors (each p < 0.01). 22 tumors (0.78%) developed radiographic radiation necrosis following SRS, and this incidence did not differ by tumor size (≤2 mm and 2-10 mm, p = 0.200). This large analysis confirms that SRS remains an effective modality in treatment of small brain metastases. In light of the excellent local control and relatively low risk of toxicity, patients with small brain metastases who otherwise have a reasonable expected survival should be considered for radiosurgical management.

Prognostic significance of corticotroph staining in radiosurgery for non-functioning pituitary adenomas: a multicenter study.

Silent corticotroph staining pituitary adenoma (SCA) represents an uncommon subset of Non-Functioning adenomas (NFAs), hypothesized to be more locally aggressive. In this retrospective multicenter study, we investigate the safety and effectiveness of Stereotactic Radiosurgery (SRS) in patients with SCA compared with other non-SCA NFA's. Eight centers participating in the International Gamma-Knife Research Foundation (IGKRF) contributed to this study. Outcomes of 50 patients with confirmed SCAs and 307 patients with confirmed non-SCA NFA's treated with SRS were evaluated. Groups were matched. SCA was characterized by a lack of clinical evidence of Cushing disease, yet with positive immunostaining for corticotroph. Median age was 55.2 years (13.7-87). All patients underwent at least one trans-sphenoidal tumor resection prior to SRS. SRS parameters were comparable as well. Median follow-up 40 months (6-163). Overall tumor control rate (TCR) 91.2% (n = 280). In the SCA group, TCR were 82% (n = 41) versus 94.1% (n = 289) for the control-NFA (p = 0.0065). The SCA group showed a significantly higher incidence of new post-SRS visual deficit (p < 0.0001) assigned to tumor progression and growth, and post-SRS weakness and fatigue (p < 0.0001). In univariate and multivariate analysis, only the status of silent corticotroph staining (p = 0.005, p = 0.009 respectively) and margin dose (p < 0.0005, p = 0.0037 respectively) significantly influenced progression rate. A margin dose of ≥17 Gy was noted to influence the adenoma progression rate in the entire cohort (p = 0.003). Silent corticotroph staining represents an independent factor for adenoma progression and hypopituitarism after SRS. A higher margin dose may convey a greater chance of TCR.

[RADIOSURGERY FOR PITUITARY ADENOMAS].

INTRODUCTION: Pituitary adenomas represent one of the most common types of intracranial tumors, accounting for 10-20% of intracranial tumors. While their macroscopic appearance and anatomical location are relatively homogeneous, pituitary tumors differ widely, generating a variety of neurological and endocrine clinical sequelae. Treatment options include hormone suppressive medical therapy, microscopic or endoscopic neurosurgical resection, radiosurgery, radiation therapy, or observation depending on the biochemical profile and the clinical status of the patient. Some pituitary adenomas spread locally to invade surrounding meninges (Dura) and cavernous sinus, hampering a complete surgical resection. Radiosurgery is most commonly utilized as adjunctive treatment following incomplete surgical resection leaving residual tumor, tumor recurrence, or failure of medical therapy. We present a comprehensive literature review of the radiosurgery series for treatment of different pituitary adenomas including nonfunctioning adenomas, ACTH- and GH-secreting adenomas, as well as prolactinomas. While post-radiosurgery radiographic tumor control for nonfunctioning adenomas is excellent, typically at 90%, the rates of endocrine biochemical remission for functioning adenomas are lower than the tumor control rates. A higher dose is needed to attain endocrine remission as compared to attaining only tumor control. The highest endocrine remission rates are achieved by patients with Cushing's disease and the lowest in those with prolactinomas. The most common complication of radiosurgery is delayed hypopituitarism followed by cranial neuropathies. The effect of suppressive medications on radiosurgery outcomes remains controversial. Due to the rare but well-documented occurrence of late recurrence following endocrine remission, long-term and rigorous clinical and radiographic follow-up is necessary for all pituitary adenoma patients.

Gamma knife radiosurgery in patients with persistent acromegaly or Cushing's disease: long-term risk of hypopituitarism.

INTRODUCTION: For patient with a recurrent or residual acromegaly or Cushing's disease (CD) after resection, gamma knife radiosurgery (GKRS) is often used. Hypopituitarism is the most common adverse effect after GKRS treatment. The paucity of studies with long-term follow-up has hampered understanding of the latent risks of hypopituitarism in patients with acromegaly or CD. We report the long-term risks of hypopituitarism for patients treated with GKRS for acromegaly or CD. METHODS: From a prospectively created, IRB-approved database, we identified all patients with acromegaly or CD treated with GKRS at the University of Virginia from 1989 to 2008. Only patients with a minimum endocrine follow-up of 60 months were included. The median follow-up is 159·5 months (60·1-278). Thorough radiological and endocrine assessments were performed immediately before GKRS and at regular follow-up intervals. New onset of hypopituitarism was defined as pituitary hormone deficits after GKRS requiring corresponding hormone replacement. RESULTS: Sixty patients with either acromegaly or CD were included. Median tumour volume at time of GKRS was 1·3 cm(3) (0·3-13·4), and median margin dose was 25 Gy (6-30). GKRS-induced new pituitary deficiency occurred in 58·3% (n = 35) of patients. Growth hormone deficiency was most common (28·3%, n = 17). The actuarial overall rates of hypopituitarism at 3, 5 and 10 years were 10%, 21·7% and 53·3%, respectively. The median time to hypopituitarism was 61 months after GKRS (range, 12-160). Cavernous sinus invasion of the tumour was found to correlate with the occurrence of a new or progressive hypopituitarism after GKRS (P = 0·018). CONCLUSIONS: Delayed hypopituitarism increases as a function of time after radiosurgery. Hormone axes appear to vary in terms of radiosensitivity. Patients with adenoma in the cavernous sinus are more prone to develop loss of pituitary function after GKRS.

Time-delayed contrast-enhanced MRI improves detection of brain metastases: a prospective validation of diagnostic yield.

The radiological detection of brain metastases (BMs) is essential for optimizing a patient's treatment. This statement is even more valid when stereotactic radiosurgery, a noninvasive image guided treatment that can target BM as small as 1-2 mm, is delivered as part of that care. The timing of image acquisition after contrast administration can influence the diagnostic sensitivity of contrast enhanced magnetic resonance imaging (MRI) for BM. Investigate the effect of time delayed acquisition after administration of intravenous Gadavist® (Gadobutrol 1 mmol/ml) on the detection of BM. This is a prospective IRB approved study of 50 patients with BM who underwent post-contrast MRI sequences after injection of 0.1 mmol/kg Gadavist® as part of clinical care (time-t0), followed by axial T1 sequences after a 10 min (time-t1) and 20 min delay (time-t2). MRI studies were blindly compared by three neuroradiologists. Single measure intraclass correlation coefficients were very high (0.914, 0.904 and 0.905 for time-t0, time-t1 and time-t2 respectively), corresponding to a reliable inter-observer correlation. The delayed MRI at time-t2 delayed sequences showed a significant and consistently higher diagnostic sensitivity for BM by every participating neuroradiologist and for the entire cohort (p = 0.016, 0.035 and 0.034 respectively). A disproportionately high representation of BM detected on the delayed studies was located within posterior circulation territories (compared to predictions based on tissue volume and blood-flow volumes). Considering the safe and potentially high yield nature of delayed MRI sequences, it should supplement the standard MRI sequences in all patients in need of precise delineation of their intracranial disease.

Leukoencephalopathy in long term brain metastases survivors treated with radiosurgery.

Brain metastases (BM) develop in 10-30 % of patients. Stereotactic radiosurgery (SRS) was shown to improve local control, and performance status, in certain cohorts of brain metastasis patients. The cumulative neurocognitive effect of numerous SRS sessions remains unknown. Leukoencephalopathy is significant diffuse white matter changes and it usually implies a neurocognitive decline. We report patients with BM who survived >2 years after SRS. Clinical and treatment parameters were analyzed for development of leukoencephalopathy. Multiple parameters as well as leukoencephalopathy grade changes were recorded. The median clinical and radiological follow-up was 42 and 41 months (range 24­115 and 24­115) respectively. The cohort included 92 patients and 704 lesions. The most common malignancies were non-small cell lung carcinoma (44.5 % n = 41), breast adenocarcinoma (23.9 %, n = 22) and melanoma (16.3 %,n = 15). 27.6 % (n = 26) of patients underwent adjuvant WBRT. At last follow up, local tumor control was achieved in 76.3 % (n = 61) of patients and 71.8 % (n = 461) of lesions. Overall prevalence of leukoencephalopathy was 42, 60, 73 and 84 % at 1, 2, 3, and 4 years after SRS. Moderate-severe leukoencephalopathy development was related to an integral dose to skull >3 Joules (p = 0.012) at any radiosurgical treatment and prior WBRT (p<0.042). Leukoencephalopathy incidence was consistently higher in the WBRT + SRS group at each following year of survival from initial SRS. Long-term BM survivors treated with SRS are at progressive risk for developing leukoencephalopathy.Those with a higher BM burden, higher integral SRS dose to the skull, and treatment with WBRT are at increased risk of leukoencephalopathy.

Immunological Aspects of Malignant Gliomas.

Glioblastoma Multiforme (GBM) is the most common malignant primary brain neoplasm having a mean survival time of <24 months. This figure remains constant, despite significant progress in medical research and treatment. The lack of an efficient anti-tumor immune response and the micro-invasive nature of the glioma malignant cells have been explained by a multitude of immune-suppressive mechanisms, proven in different models. These immune-resistant capabilities of the tumor result in a complex interplay this tumor shares with the immune system. We present a short review on the immunology of GBM, discussing the different unique pathological and molecular features of GBM, current treatment modalities, the principles of cancer immunotherapy and the link between GBM and melanoma. Current knowledge on immunological features of GBM, as well as immunotherapy past and current clinical trials, is discussed in an attempt to broadly present the complex and formidable challenges posed by GBM.

Radiosurgery for infundibulum adenoma: stalk dose implications.

Treating pituitary adenomas in the infundibulum with stereotactic radiosurgery (SRS), achieving tumor volume control while preserving pituitary endocrine function and visual function, is challenging. We present a case of a recurrent remnant infundibular lesion treated with Gamma Knife surgery (GKS). The mass was treated with microsurgical resection twice, and the residual stalk lesion was treated with single-session SRS employing a margin dose of 15 Gy to the infundibulum. Five years after GKS, tumor regression persists without visual dysfunction or hypopituitarism. Radiosurgical doses of 30 Gy to the pituitary stalk may be tolerated by patients while maintaining endocrine function.

[THE MULTIDISCIPLINARY TREATMENT OF VESTIBULAR SCHWANNOMA (ACOUSTIC NEUROMA)].

UNLABELLED: GENERAL: Treatment of vestibular schwannoma (VS) via microsurgery, radiosurgery (SRS), or fractionated radiotherapy (FRT), is advocated for symptomatic patients or those with rapid tumor growth, despite older age and comorbidities. VS growth rate >2.5 mm/year is associated with lower hearing preservation rates. Regardless of growth rate, conservative management is associated with a progressive hearing loss, ranging 2.77-5.39 dB/year. MICROSURGERY: The retrosigmoid approach is associated with higher hearing preservation and facial nerve function rates for VS >1.5 cm in largest diameter, while the middle fossa approach seems to offer better outcomes for patients with VS <1.5 cm. The retrosigmoid approach harbors higher rates of CSF leak and post-operative headaches compared to other surgical approaches. The translabyrinthine approach is reserved for patients in whom hearing is severely compromised. SRS: SRS offers excellent tumor control and facial nerve function preservation rates with modest rates of hearing preservation. Current level 2 studies suggest that SRS is associated with higher facial nerve function and hearing preservation rates and better functional outcomes with similar rates of tumor control compared to microsurgical approaches. SUMMARY: SRS is the treatment of choice for VS <3 cm in largest diameter. For VS >3 cm, microsurgery remains the treatment of choice. For functional preservation, larger VS can be safety and maximally debulked with the residual tumor treated with SRS. In patients with large VS who either refuse or are unable to undergo surgical resection, fractionated SRS or FRT may prove to be effective in treating large tumors >3 cm.

[HYPOFRACTIONATED RADIOSURGERY FOR BENIGN BRAIN LESIONS--THE BEST OF ALL WORLDS].

Despite advances in neurosurgical technique, postoperative morbidity continues to taint open complete removal of many benign cranial base tumors (meningioma, pituitary adenomas, schwannomas). The incidence of temporary and permanent cranial nerve deficits is reported to be as high as 44% and 56% respectively, with postoperative mortality rates as high as 9%. As a consequence, many neurosurgeons choose to perform partial resections in order to preserve neurological functions. Progression rates after partial removal of a meningioma with no radiosurgery have been reported to be as high as 70%, compared to > 90% post-radiosurgical progression free survival rates. This resulted in a change of paradigms from an attempted radical resection to a combined neurosurgical-radiosurgical approach due to the high surgical morbidity the former entails. Radiosurgery has traditionally been used to treat lesions < 3.5-4 cm (or 14-16 cm³). Radiosurgery is thought to inactivate target cells regardless of their mitotic activity or inherent radio-sensitivity. When the distance between the tumor and anterior visual pathways is < 3 mm, radiosurgery is contraindicated because of the difficulty in delivering an effective dose to the tumor while maintaining a tolerable dose to the optic apparatus. Fractionated Radiosurgery (Temporal or spatial fractionation) may help overcome these limitations associated with larger volume target and dose fall-off. It should be considered in patients with sellar, parasellar or para-acoustic tumors involving major vasculature or when there is broad contact with the optic apparatus or cranial nerves. Fractionated radiosurgery offers a substantial reduction in radiation-related toxicity and with maintaining high tumor control rates.

Post-radiosurgical edema associated with parasagittal and parafalcine meningiomas: a multicenter study.

Stereotactic radiosurgery (SRS) offers a high degree of tumor control for benign meningiomas. However, radiosurgery can occasionally incite edema or exacerbate pre-existing peri-tumoral edema. The current study investigates the incidence, timing, and extent of edema around parasagittal or parafalcine meningiomas following SRS. A retrospective multicenter review was undertaken through participating centers in the International Gamma Knife Research Foundation (previously the North American Gamma Knife Consortium or NAGKC). All included patients had a parafalcine or parasagittal meningioma and a minimum of 6 months follow up. The median follow up was 19.6 months (6-158 months). Extent of new or worsening edema was quantitatively analyzed using volumetric analysis; edema indices were longitudinally computed following radiosurgery. Analysis was performed to identify prognostic factors for new or worsening edema. A cohort of 212 patients comprised of 51.9 % (n = 110) females, 40.1 % upfront SRS and 59.9 % underwent adjuvant SRS for post-surgical residual tumor. The median tumor volume at SRS was 5.2 ml. Venous sinus compression or invasion was demonstrated in 25 % (n = 53). The median marginal dose was 14 Gy (8-20 Gy). Tumor volume control was determined in 77.4 % (n = 164 out of 212 patients). Tumor edema progressed and then regressed in 33 % (n = 70), was stable or regressed in 52.8 % (n = 112), and progressively worsened in 5.2 % (n = 11). Tumor location, tumor volume, venous sinus invasion, margin, and maximal dose were found to be significantly related to post-SRS edema in multivariate analysis. SRS affords a high degree of tumor control for patients with parasagittal or parafalcine meningiomas. Nevertheless, SRS can lead to worsening peritumoral edema in a subset of patients such as those with larger tumors (>10 cc) and venous sinus invasion/compression. Long-term follow up is required to detect and appropriately manage post-SRS edema.

Gamma Knife radiosurgery for medically and surgically refractory prolactinomas: long-term results.

INTRODUCTION: Prolactinomas are the most common functioning pituitary adenomas. Dopamine agonists (DA) are generally very effective in treating prolactinomas by inducing tumor volume regression and endocrine remission. A minority of patients do not respond to DA or are intolerant because of side-effects. Microsurgical resection when possible is the next treatment option, but cavernous sinus, dural, or bone involvement may not allow for complete resection. OBJECTIVE: We reviewed the outcome of patients with medically and surgically refractory prolactinomas treated with Gamma Knife radiosurgery (GKRS) during a 22 years follow-up period. METHODS: We reviewed the patient database at the University of Virginia Gamma Knife center during a 25-year period (1989-2014), identifying 38 patients having neurosurgical, radiological and endocrine follow-up. RESULTS: Median age at GKRS treatment was 43 years. Median follow-up was 42.3 months (range 6-207.9). 55.3 % (n = 21) were taking a dopamine agonist at time of GKRS. 63.2 % (n = 24) had cavernous sinus tumor invasion. Endocrine remission (normal serum prolactin off of a dopamine agonist) was achieved in 50 % (n = 19). GKRS induced hypopituitarism occurred in 30.3 % (n = 10). Cavernous sinus involvement was shown to be a significant negative prognosticator of endocrine remission. Taking a dopamine agonist drug at the time of GKRS showed a tendency to decrease the probability for endocrine remission. CONCLUSION: GKRS for refractory prolactinomas can lead to endocrine remission in many patients. Hypopituitarism is the most common side effect of GKRS.

Stereotactic radiosurgery and immunotherapy for metastatic spinal melanoma.

The management of metastatic spinal melanoma involves maximizing local control, preventing recurrence, and minimizing treatment-associated toxicity and spinal cord damage. Additionally, therapeutic measures should promote mechanical stability, facilitate rehabilitation, and promote quality of life. These objectives prove difficult to achieve given melanoma's elusive nature, radioresistant and chemoresistant histology, vascular character, and tendency for rapid and early metastasis. Different therapeutic modalities exist for metastatic spinal melanoma treatment, including resection (definitive, debulking, or stabilization procedures), stereotactic radiosurgery, and immunotherapeutic techniques, but no single treatment modality has proven fully effective. The authors present a conceptual overview and critique of these techniques, assessing their effectiveness, separately and combined, in the treatment of metastatic spinal melanoma. They provide an up-to-date guide for multidisciplinary treatment strategies. Protocols that incorporate specific, goal-defined surgery, immunotherapy, and stereotactic radiosurgery would be beneficial in efforts to maximize local control and minimize toxicity.

The Geriatric Scoring System (GSS) in meningioma patients--validation.

BACKGROUND: Meningiomas are the most common primary brain tumor, the incidence of which rises with age. The Geriatric Scoring System (GSS) was constructed in an attempt to answer which elderly subpopulation will benefit from a surgical intervention in terms of their overall physical and functional state of health. The GSS incorporates different prognostic indicators, both clinical and radiological, for risk stratification. OBJECTIVE: The purpose of the study was to validate the previously defined GSS for the evaluation and risk stratification of elderly patients suffering from intracranial meningioma. METHODS: One hundred and twenty patients aged over 65 years admitted to the RAMBAM Medical Center with meningiomas during the years 2005-2010 were characterized, forming an independent cohort. We report the presenting symptoms, chronic illness and radiological features, as well as perioperative and long-term follow-up results up to 5 years after the surgery. RESULTS: Nine outcome parameters were tested against the GSS score on admission. Survival, Barthel Index, Karnofsky Performance Scale (KPS), consciousness expressed by the Glasgow Coma Scale (GCS) [14] score 5 years after surgery, recurrence within and beyond 12 months of surgery, the length of hospitalization both overall and in a neurosurgical intensive care unit. A GSS score higher than 16 was associated with a significantly more favorable outcome. CONCLUSION: The present results suggest that common experience-based considerations may be optimized and implemented into a simple scoring system that in turn may allow for outcome prediction and evidence-based decision making.

Diabetes, but not pre-diabetes, is associated with shorter time to second-line therapy and worse outcomes in patients with multiple myeloma.

About 20% of MM patients have T2DM. We assessed the impact of T2DM/pre-T2DM on MM progression and OS. We collected retrospective data of newly diagnosed MM patients in Maccabi health services, Israel, between 2012 and 2016. The study included 503 MM patients, median age 67.2 years (IQR: 33.5-91.2). Median follow-up was 32 months (IQR 19.4-47). T2DM and pre-T2DM were recorded in 24.1% and 51% patients, respectively. Median TT2T and OS in the cohort were 17.5 months (95% confidence interval (CI) 15-20) and unreached, respectively. T2DM patients had shorter TT2T (HR = 1.31, 95%CI 1.0-1.72, p=.047), particularly transplanted patients; 20.2 vs. 40 months (HR = 2.09, 95%CI 1.18-3.71, p=.012). In a multivariable model, T2DM had a borderline significant risk of all-cause mortality, adjusted HR 1.38 (p=.09). Pre-diabetes had no impact on TT2T or OS. T2DM predicted a shorter TT2T, particularly in transplanted patients, and tended to be associated with shorter survival.

Meningiomas in the elderly, the surgical benefit and a new scoring system.

OBJECTIVE: The purpose of the study was to define and identify prognostic indicators within an elderly population of patients suffering from intracranial meningiomas. The clinical presentation of the patient with meningioma is diverse, manifesting as a different clinical entity in the elderly patient compared to a similar type of tumor in a young patient. METHODS: Two hundred fifty patients aged over 65 years admitted to RAMBAM Medical Center with meningiomas from 1995-2005 were characterized. We report the presenting symptoms, chronic illnesses, perioperative and longterm follow-up results for a 5-year period. RESULTS: Based on univariate and multivariate analysis,significant prognostic indicators were identified and were implemented into a new geriatric scoring system (GSS)including tumor size and location, peritumoral edema,neurological deficits, Karnofsky score (Clancey J Neurosci Nurs 27:220, 1995; Crooks et al. J Gerontol 46:M139-M144, 1991), and associated diabetes, hypertension or lung disease. Seven outcome parameters were retrospectively tested using the scoring system, namely mortality,Barthel Index score (Mahoney and Barthel Md State Med J 14:61-65, 1965), Karnofsky score and consciousness expressed by the Glasgow Coma Scale score (Jennett and Bond Lancet 1:480-484, 1975) 5 years after surgery, as well as recurrence within and beyond 12 months. Age proved to inversely correlate with outcome. Morbidity and mortality were significantly lower in women. The extent of surgical resection (Simpson J Neurol Neurosurg Psychiatry 20:22-39, 1957) had no influence on functional outcome, although radical resection was associated with significantly lower mortality. Generally, a GSS score higher than 14 was associated with a significantly more favorable outcome. CONCLUSION: The present results suggest that common experience-based considerations may be optimized and implemented into a simple scoring system that in turn may allow for outcome prediction and evidence-based decision making