Wojciech Kaspera

Diagnostic and Therapeutic Biomarkers in Glioblastoma: Current Status and Future Perspectives

Glioblastoma (GBM) is a primary neuroepithelial tumor of the central nervous system, characterized by an extremely aggressive clinical phenotype. Patients with GBM have a poor prognosis and only 3–5% of them survive for more than 5 years. The current GBM treatment standards include maximal resection followed by radiotherapy with concomitant and adjuvant therapies. Despite these aggressive therapeutic regimens, the majority of patients suffer recurrence due to molecular heterogeneity of GBM. Consequently, a number of potential diagnostic, prognostic, and predictive biomarkers have been investigated. Some of them, such as IDH mutations, 1p19q deletion, MGMT promoter methylation, and EGFRvIII amplification are frequently tested in routine clinical practice. With the development of sequencing technology, detailed characterization of GBM molecular signatures has facilitated a more personalized therapeutic approach and contributed to the development of a new generation of anti-GBM therapies such as molecular inhibitors targeting growth factor receptors, vaccines, antibody-based drug conjugates, and more recently inhibitors blocking the immune checkpoints. In this article, we review the exciting progress towards elucidating the potential of current and novel GBM biomarkers and discuss their implications for clinical practice.

The assessment of prognostic factors in surgical treatment of low-grade gliomas: A prospective study

OBJECTIVEnA prospective volumetric analysis of extent of resection (EOR) was carried out to assess surgical outcomes in adults diagnosed with hemispheric low grade gliomas (LGGs).nnnMATERIALS AND METHODSn68 consecutive patients diagnosed with LGGs were enrolled in the study. Pre- and post-operative tumor volumes and EOR were measured based on FLAIR MRI. Dynamic susceptibility contrast perfusion magnetic resonance imaging (DSC MRI) was used for the assessment of relative cerebral blood volume (rCBV). Three outcome measures were assessed: overall survival (OS), progression-free survival (PFS), and malignant degeneration-free survival (MFS).nnnRESULTSnIn 6 (9%) patients permanent neurologic deficits were observed. No statistically significant dependence between the EOR and the occurrence of permanent deficits was found. The eloquent or close to the eloquent location was statistically connected with lower EOR (p=0.023). The preoperative volume of tumors treated with gross total resection was significantly smaller than the volume of tumors in subtotal or partial resection groups (p=0.020, p<0.001, respectively). OS was predicted by age at diagnosis (p=0.032), and rCBV (p=0.002). Progression and malignant transformation occurred in 22 (32%) and 11 (16%) out of 68 patients. PFS was predicted by preoperative tumor volume (p=0.005), postoperative tumor volume (p=0.008), the EOR (p=0.001), and by the rCBV (p=0.033). MFS was predicted by preoperative tumor volume (p=0.034), the EOR (pp=0.020), and by rCBV (p=0.022). Postoperative tumor volume was associated with a trend of improved MFS (p=0.072). The univariate analysis shows the statistical trend for the relationship between histological subtype and PFS and MFS (p=0.079, p=0.078, respectively). Multivariate analysis selected preoperative tumor volume and rCBV as independently associated with PFS (p=0.009, p=0.019, respectively) and MFS (p=0.023, p=0.035, respectively). EOR was associated with a trend of improved PFS, and MFS (p=0.069, p=0.094, respectively).nnnCONCLUSIONSnTumor resection of LGG with the use of intraoperative monitoring and neuronavigation is associated with a low risk of new permanent deficits, but EOR significantly decreases with the size of the tumor and/or its location in/close to the eloquent areas. Smaller preoperative tumor volume and greater EOR are significantly associated with longer OS, PFS and MFS. Preoperative rCBV is one of the important prognostic factors significantly connected with survival. Prognosis in LGGs is still under discussion. Other factors such as age, histopathological subtype and KPS should not be underestimated.

Morphological, Hemodynamic, and Clinical Independent Risk Factors for Anterior Communicating Artery Aneurysms

Background and Purpose— The pathogenesis of cerebral aneurysms still raises some controversies. The aim of this study was to identify morphological, hemodynamic, and clinical independent risk factors for anterior communicating artery (ACoA) aneurysm development. Methods— Computed tomography angiography and transcranial color-coded sonography were performed in 77 patients with a nonbleeding ACoA aneurysm and in 73 controls. Symmetry of A1 segments of the anterior cerebral arteries, angles between A1 and A2 segments, tortuosity, diameter, mean velocity (Vm), pulsatility index, and volume flow rate in both A1 segments were determined. Moreover, all study participants completed a survey on their medical history. Multivariate backward stepwise logistic regression analysis was performed to identify independent risk factors for ACoA aneurysm development. Results— Smoking, hypertension, asymmetry of A1 segments, the angle between A1 and A2 segments, A1 segment diameter, Vm, pulsatility index, and volume flow rate turned out to be associated with the occurrence of ACoA aneurysms on univariate analysis. Multivariate analysis identified smoking (odds ratio, 2.036; 95% confidence interval, 1.277–3.245), asymmetry of A1 segments >40% (odds ratio, 2.524; 95% confidence interval, 1.275–4.996), pulsatility index (odds ratio, 0.004; 95% confidence interval, 0.000–0.124), and the angle between A1 and A2 segments ⩽100° (odds ratio, 4.665; 95% confidence interval, 2.247–9.687) as independent strong risk factors for ACoA aneurysm development. Conclusions— The risk of ACoA aneurysm formation is determined by several independent clinical, morphological, and hemodynamic factors. The strongest independent risk factors include smoking, asymmetry of A1 segments >40%, low blood flow pulsatility, and the angle between A1 and A2 segments ⩽100°.

Transcranial color-coded Doppler assessment of cerebral arteriovenous malformation hemodynamics in patients treated surgically or with staged embolization

OBJECTIVEnThe etiology of hemodynamic disturbances following embolization or surgical resection of arteriovenous malformations (AVMs) has not been fully explained. The aim of the study was the assessment of the selected hemodynamic parameters in patients treated for cerebral AVMs using transcranial color-coded Doppler sonography (TCCS).nnnMATERIALS AND METHODSnForty-six adult patients (28 males, 18 females, aged 41 ± 13 years, mean ± SD) diagnosed with AVMs who were consecutively admitted to the Department of Neurosurgery between 2000 and 2012 treated surgically or with staged embolization were enrolled in the study. All patients were examined with TCCS assessing mean flow velocity (Vm), the pulsatility index (PI) and vasomotor reactivity (VMR) in all main intracranial arteries. The examined parameters were assessed in the vessel groups (feeding, ipsilateral and contralateral to the AVM) and they were compared between the examinations, i.e. at admission, within 24h after the first embolization or surgical resection (I control), and before the second embolization (II control).nnnRESULTSnIn feeders which were completely obliterated or surgically resected--I control examination showed a nonsignificant Vm decrease. The difference between Vm before embolization and II control examination was significant (102.0 ± 47.8 cm/s vs 54.3 ± 19.4 cm/s, p<0.01). A significant increase in PI (0.72 ± 0.18 vs 0.94 ± 0.24, p<0.01) and VMR (1.80 ± 0.59 vs 2.78 ± 0.78, p<0.01) of feeding vessels was observed in I control. No further increase in PI or in VMR was observed. In embolized feeding vessels after partial AVM embolization I control examination showed a significant decrease in Vm (116.1 ± 32.6 cm/s vs 93.4 ± 33.0 cm/s, p<0.01). No further significant decrease in Vm was noted. The pulsatility index increased significantly (I control, 0.54 ± 0.11 vs 0.66 ± 0.15, p<0.01) and then decreased nonsignificantly (II control). No statistically significant differences were found in VMR values between pretreatment, I and II control examinations. Both Vm in the ipsilateral internal carotid artery and the ratio of Vm of the embolized vessel to Vm of the corresponding contralateral vessel were significantly higher in I control examination compared to II control examination (111.8 ± 44.0 cm/s vs 101.3 ± 40.6 cm/s, p<0.01; 1.63 ± 0.61 vs 1.37 ± 0.62, p<0.01; respectively). No statistically significant correlation was observed between the decrease in Vm or the increase in PI in the embolized vessels and the reduction of AVM volume. In the nonembolized feeding vessels after partial AVM embolization II control examination revealed the increase in Vm and a significant decrease in PI (0.71 ± 0.21 vs 0.62 ± 0.16, p<0.01) compared to I examination. No statistically significant changes in the VMR value in the nonembolized feeders between the pretreatment, I and II control examinations were noted.nnnCONCLUSIONSnThe decrease in Vm and the increase in the PI in the embolized feeding vessels after the first complete embolization or surgical resection is observed, whereas the PI returned to normal values before Vm does. The observed decrease in Vm and an increase in the PI in embolized AVM feeders after complete or partial embolization do not correlate with the extent of embolization. In these vessels a relative increase in blood flow velocity is maintained within the first 24h following embolization as compared to contralateral vessels. The increase in Vm is not related to disturbances in VMR. Blood redistribution to the nonembolized AVM feeders is observed after partial AVM embolization.

Usefulness of intraoperative monitoring of oculomotor and abducens nerves during surgical treatment of the cavernous sinus meningiomas

PURPOSEnWe analyzed the usefulness and prognostic value of intraoperative monitoring for identification of the oculomotor (III) and the abducens (VI) nerve in patients with cavernous sinus meningiomas.nnnMATERIAL/METHODSn43 patients diagnosed with cavernous sinus meningiomas were divided according to their topography. Function of the nerves was scored on original clinical and neurophysiological scales.nnnRESULTSnThe percentage of nerves identified correctly with the monitoring was significantly higher (91% vs. 53% for nerve III and 70% vs. 23% for nerve VI, p<0.001). The fractions of nerves III and VI identified correctly by means of the monitoring were significantly higher in the case of tumors with intra- and extracavernous location (89% vs. 32%, p<0.01) and intracavernous tumors (80% vs. 20%, p<0.05), respectively. The quality of post-resection recording correlated with functional status of both the nerves determined 9 months after the surgery (R=0.51, p<0.001 for nerve III and R=0.57, p<0.01 for nerve VI). Even a trace or pathological response to the post-resection stimulation was associated with improved functional status (90% vs. 50%, p<0.05 for nerve III and 93% vs. 38%, p<0.01 for nerve VI).nnnCONCLUSIONSnNeurophysiological monitoring of ocular motor nerves enables their intraoperative identification during resections of the cavernous sinus meningiomas. Intraoperative monitoring of nerve III is particularly important in the case of tumors with extra- and intracavernous location, and the monitoring of nerve VI in the case of intracavernous tumors. The outcome of the post-resection monitoring has prognostic value with regard to the clinical status of the nerves on long-term follow-up.

Blood flow velocity in the arteries of the anterior cerebral artery complex in patients with an azygos anterior cerebral artery aneurysm: A transcranial color-coded sonography study

OBJECTIVEnIt is presumed that increased blood flow through the single azygos anterior cerebral artery (Az) may contribute to the formation of an Az aneurysm. The aim of this study was to assess the blood flow velocities in the arteries of the anterior cerebral artery (ACA) complex in patients with the Az aneurysm.nnnPATIENTS AND METHODSnA series of three patients (2 men, aged: 65, 52 and 41) with an aneurysm (unruptured in two cases) of the distal Az was examined. Blood flow velocities in the Az and the A1 segment of the ACA were measured by means of a transcranial color-coded duplex sonography (TCCS) and the Az to A1 segment (Az/A1) velocity ratio was calculated. The control group consisted of 22 healthy subjects (mean age: 44 years).nnnRESULTSnThere was a trend toward decreased (p=0.06) mean blood flow velocity in the Az compared to the A2 segment of the ACA of the control group. Blood velocity in the A1 segment did not differ between the study and control groups. Pulsatility and resistance indices in the Az were similar to those in the A2 segment of the control group. There were no differences between the Az/A1 ratio in the study group and the A2/A1 velocity ratio in the control group.nnnCONCLUSIONnOur results suggest that Az aneurysms are not associated with increased blood flow velocity in the Az. Possibly, a hemodynamic stress related to the Az bifurcation geometry, together with a bent course of this artery around the genu of the corpus callosum, predispose to aneurysm formation.

Medial sphenoid ridge meningiomas: early and long-term results of surgical removal using the fronto-temporo-orbito-zygomatic approach

BACKGROUND AND PURPOSEnThe fronto-temporo-orbito-zygomatic approach (FTOZA) is an alternative to the pte-rional approach in surgical resection of meningiomas of the medial part of the lesser wing of the sphenoid bone. The purpose of this study is to present our results of treatment of these meningiomas using the FTOZA.nnnMATERIAL AND METHODSnThirty patients (19 women, 11 men) with a central skull base tumour were included in the study. The neurological status of the patients was assessed before and after surgery as well as at the conclusion of treatment. The approximate volume of the operated tumour, its relation to large blood vessels, cranial nerves and brainstem, as well as consistency and vascularisation were assessed.nnnRESULTSnThe symptom duration ranged from 1 to 36 months (median: 6 months). Impaired visual acuity was the predominant symptom in 27.5% of patients. Less frequent symptoms included paresis/paralysis of the third cranial nerve, headache, psychoorganic syndrome and epilepsy. Approximate volume of the tumours ranged from 5 to 212 mL (median: 63 mL). Total or subtotal resection was achieved in 77% of patients. The postoperative performance status improved in 16.5%, did not change in 52.8% and deteriorated in 26.4% of patients. One (3.3%) patient died after the surgery.nnnCONCLUSIONnThe FTOZA is a useful technique for removal of tumours expanding superiorly to the middle cranial fossa base without significant compression of the brain. Ability to remove tumours through the described approach decreases as the degree of infiltration of the clivus increases.

Near-infrared photoimmunotherapy targeting EGFR-Shedding new light on glioblastoma treatment

Glioblastomas (GBMs) are high‐grade brain tumors, differentially driven by alterations (amplification, deletion or missense mutations) in the epidermal growth factor receptor (EGFR), that carry a poor prognosis of just 12–15 months following standard therapy. A combination of interventions targeting tumor‐specific cell surface regulators along with convergent downstream signaling pathways may enhance treatment efficacy. Against this background, we investigated a novel photoimmunotherapy approach combining the cytotoxicity of photodynamic therapy with the specificity of immunotherapy. An EGFR‐specific affibody (ZEGFR:03115) was conjugated to the phthalocyanine dye, IR700DX, which when excited with near‐infrared light produces a cytotoxic response. ZEGFR:03115–IR700DX EGFR‐specific binding was confirmed by flow cytometry and confocal microscopy. The conjugate showed effective targeting of EGFR positive GBM cells in the brain. The therapeutic potential of the conjugate was assessed both in vitro, in GBM cell lines and spheroids by the CellTiter‐Glo® assay, and in vivo using subcutaneous U87‐MGvIII xenografts. In addition, mice were imaged pre‐ and post‐PIT using the IVIS/Spectrum/CT to monitor treatment response. Binding of the conjugate correlated to the level of EGFR expression in GBM cell lines. The cell proliferation assay revealed a receptor‐dependent response between the tested cell lines. Inhibition of EGFRvIII+ve tumor growth was observed following administration of the immunoconjugate and irradiation. Importantly, this response was not seen in control tumors. In conclusion, the ZEGFR:03115–IR700DX showed specific uptake in vitro and enabled imaging of EGFR expression in the orthotopic brain tumor model. Moreover, the proof‐of‐concept in vivo PIT study demonstrated therapeutic efficacy of the conjugate in subcutaneous glioma xenografts.

Mucocoele and mucopyocoele of the frontal sinus penetrating to the cranial cavity and the orbit

BACKGROUND AND PURPOSEnMucocoele of the paranasal sinuses falls within the scope of interest for neurosurgery when erosion of the sinus wall and the osseous structures of the skull base develops and the lesion extends towards the cranial cavity, the orbit, the cavernous sinus or the sella turcica. The pa-per aims to present the method of treatment of extensive mucocoele which is used in our clinic.nnnMATERIAL AND METHODSnWe treated 7 patients (2 women and 5 men; age range: 27-68 years). Mucopyocoele was diagnosed in two cases, and mucocoele in the other five. In 5 cases, extension of the mucocoele to the cranial cavity and the orbit or to the ethmoid sinus and the orbit was observed. In the remaining 2 cases, mucopyocoele extended to the ethmoid sinus, the sphenoid and maxillary sinuses, cranial cavity and the orbit. The purpose of surgery was to remove the mucocoele or the mucopyocoele and to prevent recurrence.nnnRESULTSnThe postoperative course in all 7 patients was uneventful. All symptoms gradually receded. No relapse was observed in any patient during a follow-up period that varied from 10 months to 8 years; nor did incidents of inflammation of collateral sinuses occur.nnnCONCLUSIONSnThe treatment of mucocoele or mucopyocoele of the frontal sinus penetrating to the cranial cavity and the orbit consists of the following stages: cranialization of the frontal sinus, complete resection of the mucosa, tight closing of the frontal-nasal duct, and separating the air space of the opened collateral nasal sinuses from the cranial cavity with a large pedicled periosteal flap.

Dostęp podskroniowy rozszerzony do dołu podskroniowego i jego otoczenia – analiza techniki operacyjnej na podstawie symulacji na zwłokach

Streszczenie Celem pracy jest przedstawienie poszczegolnych etapow dostepu podskroniowego rozszerzonego (DPR). Przeprowadzono 7 symulacji dostepu na nieutrwalonych zwlokach ludzkich, u ktorych nie podejrzewano procesow patologicznych w zakresie glowy i szyi. Kolejne fazy symulacji byly dokumentowane fotograficznie oraz schematami. Punktem wyjścia dla DPR jest osteotomia luku jarzmowego i kraniektomia obejmująca dolne partie cześci luskowej kości skroniowej i skrzydlo wieksze kości klinowej. Przemieszczenie lub usuniecie zawartości dolu podskroniowego pozwala na penetracje jego wnetrza i otoczenia. Dodatkowe poszerzenie wglądu daje osteotomia wyrostka klykciowego zuchwy. Dostep podskroniowy rozszerzony stanowi powtarzalną metode penetracji dolu podskroniowego i jego otoczenia. Dostep ten jest szczegolnie przydatny w leczeniu operacyjnym guzow nowotworowych rozrastających sie w oczodole, zatoce szczekowej, dole skrzydlowo-podniebiennym, nosogardle, zatoce klinowej, zatoce jamistej, przestrzeni przygardlowej, dole zazuchwowym i otoczeniu odcinka skalistego tetnicy szyjnej wewnetrznej.The aim of the study was to present consecutive stages of the extended subtemporal approach (ESA). n nSeven simulations of ESA were performed on non-fixed human cadavers without any known pathologies in the head and neck. The consecutive stages of the procedure were documented with photographs and schemes. n nThe starting point for ESA is osteotomy of the zygomatic arch and craniectomy including the greater wing of the sphenoid bone. Dislocation or removal of subtemporal fossa contents allows one to penetrate its inside and related structures. Additional widening of inspection allows osteotomy of the condyloid process of the mandible. n nESA is a reproducible technique which provides surgical penetration of the subtemporal fossa and related structures. This approach is particularly useful in the surgical treatment of tumours expanding in the orbit, maxillary sinus, pterygopalatine fossa, nasopharynx, sphenoid sinus, cavernous sinus, parapharyngeal space, retromandibular fossa and surroundings of the petrosal part of the internal carotid artery.