Increased expression of programmed death ligand 1 (PD-L1) in human pituitary tumors

PURPOSE: Subsets of pituitary tumors exhibit an aggressive clinical courses and recur despite surgery, radiation, and chemotherapy. Because modulation of the immune response through inhibition of T-cell checkpoints has led to durable clinical responses in multiple malignancies, we explored whether pituitary adenomas express immune-related biomarkers that could suggest suitability for immunotherapy. Specifically, programmed death ligand 1 (PD-L1) has emerged as a potential biomarker whose expression may portend more favorable responses to immune checkpoint blockade therapies. We thus investigated the expression of PD-L1 in pituitary adenomas. METHODS: PD-L1 RNA and protein expression were evaluated in 48 pituitary tumors, including functioning and non-functioning adenomas as well as atypical and recurrent tumors. Tumor infiltrating lymphocyte populations were also assessed by immunohistochemistry. RESULTS: Pituitary tumors express variable levels of PD-L1 transcript and protein. PD-L1 RNA and protein expression were significantly increased in functioning (growth hormone and prolactin-expressing) pituitary adenomas compared to non-functioning (null cell and silent gonadotroph) adenomas. Moreover, primary pituitary adenomas harbored higher levels of PD-L1 mRNA compared to recurrent tumors. Tumor infiltrating lymphocytes were observed in all pituitary tumors and were positively correlated with increased PD-L1 expression, particularly in the functional subtypes. CONCLUSIONS: Human pituitary adenomas harbor PD-L1 across subtypes, with significantly higher expression in functioning adenomas compared to non-functioning adenomas. This expression is accompanied by the presence of tumor infiltrating lymphocytes. These findings suggest the existence of an immune response to pituitary tumors and raise the possibility of considering checkpoint blockade immunotherapy in cases refractory to conventional management

Rapid improvement in verbal fluency and aphasia following perispinal etanercept in Alzheimer's disease

<p>Abstract</p> <p>Background</p> <p>Recent clinical studies point to rapid and sustained clinical, cognitive, and behavioral improvement in both Alzheimer's disease and primary progressive aphasia following weekly perispinal administration of etanercept, a TNF-alpha inhibitor that acts by blocking the binding of this cytokine to its receptors. This outcome is concordant with recent basic science studies suggesting that TNF-alpha functions <it>in vivo </it>as a gliotransmitter that regulates synaptic function in the brain. We hypothesized that perispinal etanercept had the potential to improve verbal function in Alzheimer's disease, so we included several standarized measures of verbal ability to evaluate language skills in a clinical trial of perispinal etanercept for Alzheimer's disease.</p> <p>Methods</p> <p>This was a prospective, single-center, open-label, pilot study, in which 12 patients with mild-to-severe Alzheimer's disease were administered etanercept, 25–50 mg, weekly by perispinal administration for six months. Two additional case studies are presented.</p> <p>Results</p> <p>Two-tailed, paired t-tests were conducted comparing baseline performance to 6-month performance on all neuropsychological measures. Test batteries included the California Verbal Learning Test-Second Edition, Adult Version; Logical Memory I and II(WMS-LM-II) from the Wechsler Memory Scale-Abbreviated; the Comprehensive Trail Making Test (TMT); Boston Naming Test; and letter(FAS) and category verbal fluency. All measures revealed a significant effect except for the Boston Naming Test and the TMT-4, with WMS-LM-II being marginally significant at p = .05. The FAS test for letter fluency was most highly significant with a p < 0.0007. In addition, rapid improvement in verbal fluency and aphasia in two patients with dementia, beginning minutes after perispinal etanercept administration, is documented.</p> <p>Conclusion</p> <p>In combination with the previously reported results of perispinal etanercept in Alzheimer's disease and primary progressive aphasia, these results further argue that larger scale studies of this therapeutic intervention, including Phase 3 trials, are warranted in dementias. In addition, these results may provide insight into the basic pathophysiologic mechanisms underlying Alzheimer's disease and related forms of dementia, and suggest the existence of novel, rapidly reversible, TNF-mediated pathophysiologic mechanisms in Alzheimer's disease which are worthy of further investigation.</p

Surgical management of intracranial gliomas--does radical resection improve outcome

This paper discusses the arguments for and against radical tumor resection as a strategy for treatment of cerebral gliomas. METHOD: Data from the Glioma Outcome Project were analyzed to determine whether survival could be related to extent of resection in 666 patients treated by biopsy or resection for malignant cerebral gliomas. FINDINGS: Consistent survival advantages were noted for those patients treated with resection. INTERPRETATION: This observational study, although undoubtedly reflecting selection bias, provides data that support resection as a major factor in survival after surgery for malignant gliomas

Cranial approaches to sellar and parasellar tumors

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Endoscopic transsphenoidal surgery for cushing disease: techniques, outcomes, and predictors of remission

The efficacy of endoscopic transsphenoidal surgery (ETS) for Cushing disease has not been clearly established. To assess efficacy of a pure endoscopic approach for treatment of Cushing disease and determine predictors of remission. A prospectively acquired database of 61 patients undergoing ETS was reviewed. Remission was defined as postoperative morning serum cortisol of <5 μg/dL or normal or decreased 24-hour urine-free cortisol level in follow-up. Overall, hypercortisolemia resolved in 58 of 61 patients (95%) by discharge. Tumor size did not predict resolution of hypercortisolemia at discharge (microadenomas [97%], magnetic resonance imaging-negative Cushing [100%], macroadenomas [87%]). At 2- to 3-month evaluations, 45 of 49 patients (91.8%) were in remission. Fifty patients were followed for at least 12 months (mean, 28 months; range, 12-72). Forty-two (84%) achieved remission from a single ETS. In these patients, there was no significant difference in remission rates between microadenomas (93%), magnetic resonance imaging-negative (70%), and macroadenomas (77%). Patients with history of previous surgery (n = 14, 23%) were 9 times less likely to achieve follow-up remission (P = .021). In-house cortisol level of <5.7 μg/dL provided the best prediction of follow-up remission (sensitivity 88.6%, specificity 83.3%). Postoperative diabetes insipidus occurred transiently in 7 patients (9%) and permanently in 3 (5%). One patient experienced postoperative cerebrospinal fluid leak that resolved with further surgery. ETS for Cushing disease provides high rates of remission with low rates of complications regardless of size. Although patients with a history of previous surgery are less likely to achieve remission, the majority can still achieve remission following treatment

Depression in patients with high-grade glioma: results of the Glioma Outcomes Project

OBJECTIVE: To study the incidence of depression among patients undergoing surgery for high-grade glioma, document factors associated with the presence of depression, and examine the relationship between depression and patient outcome. METHODS: Physician and patient reports of depression were analyzed immediately postoperatively and again 3 and 6 months after surgery for high-grade glioma. Physician-reported depression was defined according to the Diagnostic and Statistical Manual of Mental Disorders, ed 4. Patient self-assessment of depression was based on responses to questions contained in two validated functional status surveys. Concordance of physician- and patient-reported depression was examined, along with the extent of use of pharmacological treatment for depression. Additional outcomes examined included quality of life, survival, patient satisfaction, and posttreatment complications. RESULTS: Data from 598 patients were analyzed. In the early postoperative period, physicians reported depression in 15% of patients, whereas 93% of patients reported symptoms consistent with depression. The incidence of patient self-reported depression remained similar at 3- and 6-month follow-up, whereas physician reported depression increased from 15% in the early postoperative period to 22% at both 3- and 6-month follow-up. Concordance between physician recognition of depression and treatment of depression was low initially (33%) and increased at 3 and 6 months (51 and 60%, respectively). As compared with patients who were not depressed, survival was shorter and complications were more common among depressed patients. CONCLUSION: Symptoms of depression were common immediately after surgery for glioma, and they increased throughout the 6-month period after surgery. These findings support the hypothesis that clinically important depression is a common complication in patients with high-grade glioma. Concordance between physician recognition of depression and self-reports of depression by patients was low. Concordance between physician recognition of depression and initiation of pharmacological antidepressant therapy was fair in the early postoperative period and improved somewhat over the subsequent 6-month period; however, within the 6-month period after surgery for glioma, antidepressant therapy was provided for only 60% of patients in whom the physician recognized depressive symptoms and in only 15% of patients who self-reported symptoms of depression. Findings from this observational study suggest the need for a controlled trial that is designed to test the hypothesis that more attention to the identification of postoperative depression and aggressive treatment of depressive symptoms can improve the quality of life and survival of patients after surgery for high-grade glioma

Functional outcomes and survival in patients with high-grade gliomas in dominant and nondominant hemispheres

OBJECT: The goal of this study was to investigate survival and functional outcomes in patients with high-grade intracranial astrocytomas as a function of the location of the lesion in the dominant or nondominant hemisphere (DH and NDH, respectively), and to suggest management strategies for such patients based on these data. METHODS: Data were collected from the Glioma Outcomes Project database, a longitudinal database of demographic, clinical, and outcome data for patients with high-grade intracranial gliomas. From the entire database of 788 patients, a subset of all 280 right-handed patients with newly diagnosed, unilateral gliomas involving potentially eloquent cortex was selected as the sample population. Two cohorts were defined based on the location of the tumor in the right or left cerebral hemisphere. All other relevant demographic and clinical data were nearly identical between the cohorts. A Kaplan-Meier analysis was conducted to assess survival, and Karnofsky Performance Scale scores assigned at 6 and 12 months postoperatively were compared as a measure of functional outcome. The analysis demonstrated no difference in survival between patients with lesions in the DH and those with tumors in the NDH. Additionally, no statistically significant difference in functional outcomes was observed between the two groups. CONCLUSIONS: Laterality of high-grade gliomas is not an independent prognostic factor for predicting survival or functional outcome. The findings in this study demonstrate that fears of increased postoperative morbidity or mortality in otherwise resectable tumors of the DH are unfounded, and the authors therefore advocate that the surgeon\u27s decision to operate be guided by validated outcome predictors and not biased by tumor lateralization