Henning Leske

Soluble α-klotho: a novel serum biomarker for the activity of GH-producing pituitary adenomas.

OBJECTIVE Klotho is a lifespan-influencing gene expressed mainly in the kidneys. Soluble α-Klotho (αKL) is released into the circulation. In this study, we present baseline αKL serum levels of patients with acromegaly compared with controls with other pituitary adenomas and assess changes following transsphenoidal surgery. DESIGN Prospective controlled study. METHODS We measured soluble αKL (sandwich ELISA) and IGF1 (RIA) in sera of 14 patients (eight females and six males) with active acromegaly and in 22 control patients (13 females and nine males) operated for non-GH-producing pituitary adenomas. Immunohistochemical staining for Klotho was performed in resected adenomas and in normal pituitary tissue samples. RESULTS Soluble αKL was high in the acromegaly group preoperatively (median 4217 pg/ml, interquartile range (IQR) 1812-6623 pg/ml) and declined after surgery during early follow-up (2-6 days; median 645 pg/ml, IQR 550-1303 pg/ml) (P<0.001) and during late follow-up (2-3 months post-operatively; median 902 pg/ml, IQR 497-1340 pg/ml; P<0.001). In controls, preoperative soluble αKL was significantly lower than in acromegalics, 532 pg/ml (400-677 pg/ml; P<0.001). Following surgery, soluble αKL remained low during early and late follow-up - changes over time within the control group were not statistically significant. These results were independent of age, sex and kidney function. Klotho staining was equal or slightly decreased in GH-positive adenomas compared with controls. CONCLUSION High soluble αKL serum levels were specific to GH-producing adenomas and decreased rapidly following adenoma removal. Thus, soluble αKL appears to be a new specific and sensitive biomarker reflecting disease activity in acromegaly. Similar Klotho staining patterns in controls and acromegalics suggest that the rise in serum αKL is caused by systemic actions of pituitary GH rather than due to increased expression of Klotho by the pituitary (adenoma).

Cilengitide in newly diagnosed glioblastoma: biomarker expression and outcome.

Integrins αvβ3 and αvβ5 regulate angiogenesis and invasiveness in cancer, potentially by modulating activation of the transforming growth factor (TGF)-β pathway. The randomized phase III CENTRIC and phase II CORE trials explored the integrin inhibitor cilengitide in patients with newly diagnosed glioblastoma with versus without O6-methylguanine DNA methyltransferase (MGMT) promoter methylation. These trials failed to meet their primary endpoints. Immunohistochemistry was used to assess the levels of the target integrins of cilengitide, αvβ3 and αvβ5 integrins, of αvβ8 and of their putative target, phosphorylation of SMAD2, in tumor tissues from CENTRIC (n=274) and CORE (n=224). αvβ3 and αvβ5 expression correlated well in tumor and endothelial cells, but showed little association with αvβ8 or pSMAD2 levels. In CENTRIC, there was no interaction between the biomarkers and treatment for prediction of outcome. In CORE, higher αvβ3 levels in tumor cells were associated with improved progression-free survival by central review and with improved overall survival in patients treated with cilengitide. Integrins αvβ3, αvβ5 and αvβ8 are differentially expressed in glioblastoma. Integrin levels do not correlate with the activation level of the canonical TGF-β pathway. αvβ3 integrin expression may predict benefit from integrin inhibition in patients with glioblastoma lacking MGMT promoter methylation.

Synchronous pituitary adenoma and pituicytoma.

Pituicytoma is a rare benign neoplasm arising in the sellar region, usually found in the posterior lobe and/or pituitary stalk. Here, we report the case of a 67-year-old woman who presented with bitemporal hemianopsia and visual impairment accompanied by mildly elevated prolactin. Pathologic and molecular examination of the tissue removed transsphenoidally revealed 2 distinct tumors: pituitary adenoma and pituicytoma. To the best of our knowledge, histologically proven pituicytoma and pituitary adenoma have never been reported together.

Case Report: Encephalitis, with Brainstem Involvement, Following Checkpoint Inhibitor Therapy in Metastatic Melanoma

Checkpoint inhibitors are increasingly being used in the treatment of malignant melanoma and other cancers. With the use of such therapies, autoimmune-mediated adverse events in the central and peripheral nervous system are likely to occur more frequently. We report a unique case of brainstem encephalitis with a sudden lethal outcome following ipilimumab and pembrolizumab therapy in a patient with malignant melanoma. The autopsy showed a diffuse nodular activation of microglia in the whole encephalon with prominent intraparenchymal and perivascular lymphocytic infiltration of the brainstem. Non-infectious brainstem encephalitis is a well-recognized subset of paraneoplastic encephalitis. Brainstem involvement is usually accompanied by a wide spectrum of signs and symptoms, which were not observed in this case. The timing of the clinical symptoms as well as the histopathological findings suggest an autoimmune-adverse event of ipilimumab and pembrolizumab administration rather than a paraneoplastic disorder. In the presence of neurological symptoms, immediate cessation of the immunotherapy and immunosuppressive therapy may lead to successful therapeutic intervention, as described in previous reports. Therefore, it is crucial that physicians are aware of the possible side effects of immunotherapies on the nervous system. IMPLICATIONS FOR PRACTICE Metastatic melanoma patients treated with the anti-CTLA-4 inhibitor ipilimumab have a high utilization of various types of health care services, such as inpatient hospital stays or doctor visits. There are differences across countries regarding patterns of health care utilization and economic burden of the disease. Health care services are used more frequently after patients experience progression of their disease. The study highlights that better therapies leading to durable response in patients with metastatic melanoma have the potential to decrease health care costs and patient burden in terms of hospitalizations and other health care services.

Expression of somatostatin receptors, angiogenesis and proliferation markers in pituitary adenomas: an immunohistochemical study with diagnostic and therapeutic implications.

PRINCIPLES Pituitary adenomas are common intracranial neoplasms that generate symptoms as a result of either mass effect or the increased production of pituitary hormones. Although mostly benign, these tumours can be associated with considerable morbidity. We investigated a panel of immunohistochemical preparations to identify potential therapeutic targets and surrogate markers of clinical outcome. METHODS Tumour tissue from 25 patients was evaluated for immunohistochemical expression of somatostatin receptors 1‒5, von Willebrand-factor (vWF), interleukin-8 (IL-8), vascular endothelial growth factor receptor 2 (VEGFR-2), kinesin spindle protein (Eg5) and MIB-1 (Ki-67), and its relationship with clinical features was analysed. RESULTS The proliferation marker MIB-1 (Ki-67) was the only marker predictive of adenoma recurrence. Of note, 67% of all relapses were associated with tumours showing luteinising hormone expression. All pituitary adenomas showed variable somatostatin receptor, IL-8, Eg5, vWF and VEGFR-2 expression; a relationship between these parameters and clinical outcome could not be demonstrated in this cohort. CONCLUSIONS This study validates MIB-1 (Ki-67) as a reliable marker of tumour recurrence in pituitary adenomas. Considering the consistently increased expression of Eg5, IL-8, VEGFR-2, somatostatin receptors and vWF in these tumours, further investigation as potential therapeutic targets is warranted.

A 44‐Year Old Male with Right‐Sided Facial Numbness

A 44-year-old man with a past medical history of arterial hypertension, hypercholesterolemia, cigarette smoking (45 pack-years) and obesity (BMI 32.8) presented to our department with a 3-month history of right-sided facial numbness. Four weeks prior to admission he experienced a single episode of involuntary muscle movements on the left-side of his body. His neurologic exam was normal and initial laboratory results including CBC and blood chemistry were within normal range. A magnetic resonance imaging (MRI) scan of the patient’s brain (Figure 1) showed a 7.3 × 4.9 × 3.6 cm, right fronto-parietal, extra-axial space-occupying lesion with lobulated contrast-enhancement and mild perifocal edema. The superior sagittal sinus was slightly compressed and the overlying cranium was infiltrated. The patient underwent angio-embolization of the lesion and two days later a right fronto-temporo-parietal craniectomy was performed. The tumor was resected subtotally, leaving a thin superficial infiltrative layer on eloquent cortex. The infiltrated cranium was reconstructed using polymethyl-methacrylate (PMMA) cranioplasty and the resected dura was replaced by a neuropatch. Postoperatively, an MRI of the spine and a lumbar puncture did not show any evidence for disease dissemination. The patient had no neurological deficit and underwent adjuvant radiation therapy of the tumor bed (36 Gy) and 2-years after diagnosis he was clinically and radiologically disease-free.

Protease resistance of infectious prions is suppressed by removal of a single atom in the cellular prion protein

Resistance to proteolytic digestion has long been considered a defining trait of prions in tissues of organisms suffering from transmissible spongiform encephalopathies. Detection of proteinase K-resistant prion protein (PrPSc) still represents the diagnostic gold standard for prion diseases in humans, sheep and cattle. However, it has become increasingly apparent that the accumulation of PrPSc does not always accompany prion infections: high titers of prion infectivity can be reached also in the absence of protease resistant PrPSc. Here, we describe a structural basis for the phenomenon of protease-sensitive prion infectivity. We studied the effect on proteinase K (PK) resistance of the amino acid substitution Y169F, which removes a single oxygen atom from the β2–α2 loop of the cellular prion protein (PrPC). When infected with RML or the 263K strain of prions, transgenic mice lacking wild-type (wt) PrPC but expressing MoPrP169F generated prion infectivity at levels comparable to wt mice. The newly generated MoPrP169F prions were biologically indistinguishable from those recovered from prion-infected wt mice, and elicited similar pathologies in vivo. Surprisingly, MoPrP169F prions showed greatly reduced PK resistance and density gradient analyses showed a significant reduction in high-density aggregates. Passage of MoPrP169F prions into mice expressing wt MoPrP led to full recovery of protease resistance, indicating that no strain shift had taken place. We conclude that a subtle structural variation in the β2–α2 loop of PrPC affects the sensitivity of PrPSc to protease but does not impact prion replication and infectivity. With these findings a specific structural feature of PrPC can be linked to a physicochemical property of the corresponding PrPSc.

A 44-year old male with right-sided facial numbness. Dura-associated extranodal marginal zone B cell lymphoma (MALT lymphoma).

A 44-year-old man with a past medical history of arterial hypertension, hypercholesterolemia, cigarette smoking (45 pack-years) and obesity (BMI 32.8) presented to our department with a 3-month history of right-sided facial numbness. Four weeks prior to admission he experienced a single episode of involuntary muscle movements on the left-side of his body. His neurologic exam was normal and initial laboratory results including CBC and blood chemistry were within normal range. A magnetic resonance imaging (MRI) scan of the patient’s brain (Figure 1) showed a 7.3 × 4.9 × 3.6 cm, right fronto-parietal, extra-axial space-occupying lesion with lobulated contrast-enhancement and mild perifocal edema. The superior sagittal sinus was slightly compressed and the overlying cranium was infiltrated. The patient underwent angio-embolization of the lesion and two days later a right fronto-temporo-parietal craniectomy was performed. The tumor was resected subtotally, leaving a thin superficial infiltrative layer on eloquent cortex. The infiltrated cranium was reconstructed using polymethyl-methacrylate (PMMA) cranioplasty and the resected dura was replaced by a neuropatch. Postoperatively, an MRI of the spine and a lumbar puncture did not show any evidence for disease dissemination. The patient had no neurological deficit and underwent adjuvant radiation therapy of the tumor bed (36 Gy) and 2-years after diagnosis he was clinically and radiologically disease-free.

A 40-Year-Old Female with Dural-Based Lesions: Correspondence

A 40-year-old female presented to the neurosurgery department with a history of new onset, severe, pressure-like headaches. MRI (Figure 1A) revealed multiple mass lesions in the spinal cord, at C4–6 and T3 with infiltration of the neuroforamina. An epidural component was associated with spinal cord compression. In addition, there were lesions in the hip and shoulder, liver and small intestine, as well as right parietal and frontal, dural-based lesions, 3 3 3 3 4 and 1.5 3 1 3 1 cm. Subsequent surgical removal of the dural tumors was complete. The postoperative course was uneventful and the patient described relief from the headaches. The intracranial tumors recurred at 1 and 2 years after the initial surgery. MICROSCOPIC PATHOLOGY

A 49-year old female with multiple extra-axial tumors

A 49-year old female with no significant past medical history except for psoriasis presented to our department complaining of increasing neck pain over 4 weeks accompanied by hoarseness and dysphagia. In addition, she reported general fatigue as well as problems with fine motor skills of her right arm and right leg. MRI scans showed three lesions: a large mass in the foramen magnum, a smaller mass near the torcula (Figure 1a), and a supratentorial extraaxial mass over the right sylvian fissure. Considering the clinical symptoms of the patients, we opted for surgery of the foramen magnum tumor and the small peritorcular lesion of the left cerebellar convexity due to its proximity. After angioembolization of the supratentorial tumor and foramen magnum mass, a far lateral suboccipital craniotomy was performed on the left side in park bench position. Surgery was complicated by the difficult anatomy with the lower cranial nerves and brain stem perforators of the vertebral artery running on the surface of the tumor. Using a combination of intratumoral ultrasonic aspiration and peritumoral microdissection, the foramen magnum mass could be removed completely and the dural attachment was coagulated (corresponding to a Simpson grade II resection in meningioma surgery). The small para-torcular lesion had a clear arachnoidal plane and could be completely resected without complications. The patient had no new postoperative neurological deficits and the postoperative contrast-enhanced MRI showed a complete resection of both lesions (Figure 1b). At three-month follow-up, the preoperative symptoms recovered completely. The foramen magnum mass was diagnosed as a WHO grad I meningothelial meningioma. However, the diagnosis of the smaller cerebellar para-torcular mass was unexpected.