Tag: Oncology

Posted on

The molecular biology and novel treatments of vestibular schwannomas

J Neurosurg 115:906–914, 2011. DOI: 10.3171/2011.6.JNS11131

Vestibular schwannomas are histopathologically benign tumors arising from the Schwann cell sheath surrounding the vestibular branch of cranial nerve VIII and are related to the NF2 gene and its product merlin.

Merlin acts as a tumor suppressor and as a mediator of contact inhibition. Thus, deficiencies in both NF2 genes lead to vestibular schwannoma development.

Recently, there have been major advances in our knowledge of the molecular biology of vestibular schwannomas as well as the development of novel therapies for its treatment.

In this article the authors comprehensively review the recent advances in the molecular biology and characterization of vestibular schwannomas as well as the development of modern treatments for vestibular schwannoma. For instance, merlin is involved with a number of receptors including the CD44 receptor, EGFR, and signaling pathways, such as the Ras/raf pathway and the canonical Wnt pathway. Recently, merlin was also shown to interact in the nucleus with E3 ubiquitin ligase CRL4DCAF1.

A greater understanding of the molecular mechanisms behind vestibular schwannoma tumorigenesis has begun to yield novel therapies. Some authors have shown that Avastin induces regression of progressive schwannomas by over 40% and improves hearing. An inhibitor of VEGF synthesis, PTC299, is currently in Phase II trials as a potential agent to treat vestibular schwannoma.

Furthermore, in vitro studies have shown that trastuzumab (an ERBB2 inhibitor) reduces vestibular schwannoma cell proliferation.

With further research it may be possible to significantly reduce morbidity and mortality rates by decreasing tumor burden, tumor volume, hearing loss, and cranial nerve deficits seen in vestibular schwannomas.

Posted on

Bilateral subfrontal approach for tuberculum sellae meningiomas in long-term postoperative visual outcome

J Neurosurg 115:802–810, 2011.DOI: 10.3171/2011.5.JNS101812

Various surgical approaches, such as uni- and bifrontal, frontolateral, and pterional approaches, havebeen advocated for tuberculum sellae meningiomas. The authors retrospectively reviewed the effectiveness of a bilateralsubfrontal approach for tuberculum sellae meningiomas with special attention to ophthalmological outcomesand complications.

Methods. Between 1993 and 2009, 34 patients underwent surgery for removal of tuberculum sellae meningiomasat Osaka City University. Tumor size ranged from 14 to 45 mm. Thirty-two of 34 patients presented with visualdisturbances before the surgery. The visual functions in all patients were assessed using a visual impairment score(VIS) before and after surgery. Postoperative visual examination was performed 2 weeks after surgery. Long-termfollow-up examinations were conducted 1 year after surgery.

Results. Radical resection (Simpson Grades I and II) was accomplished in 27 patients, and subtotal or partialresection (Simpson Grades III and IV) was achieved in 7. There was no deterioration in postoperative visual outcome.Twenty-nine (90.6%) of 32 patients showed improved VIS compared with preoperative VIS. The average VIS was38.1 preoperatively, 23.5 in the short-term postoperative period, and 21.8 in the long-term postoperative period. Inthe short-term postoperative period, the visual function in 6 patients normalized, and visual problems persisted in theremaining 26. Six (23%) of 26 patients showed further improvement in VIS during the long-term follow-up period,and no patient exhibited a worsened VIS during this time. One patient complained of hyposmia after surgery, butthere was no indication of related complications such as CSF leakage or frontal brain contusion.

Conclusions. The bilateral subfrontal approach was previously avoided because of the relatively high rate ofcomplications in earlier surgical series of tuberculum sellae meningiomas. However, after developments in microsurgicaltechniques in recent years, the bilateral subfrontal approach can now provide satisfactory visual outcomes withminimal postoperative complications. Careful preservation of the blood supply to optic apparatus and early unroofingof the optic canal using a bilateral subfrontal approach led to further improvement in long-term postoperative visual outcome.

Posted on

Intraoperative confocal microscopy in the visualization of 5-aminolevulinic acid fluorescence in low-grade gliomas

J Neurosurg 115:740–748, 2011. DOI: 10.3171/2011.6.JNS11252

Greater extent of resection (EOR) for patients with low-grade glioma (LGG) corresponds with improved clinical outcome, yet remains a central challenge to the neurosurgical oncologist. Although 5-aminolevulinic acid (5- ALA)–induced tumor fluorescence is a strategy that can improve EOR in gliomas, only glioblastomas routinely fluoresce following 5-ALA administration. Intraoperative confocal microscopy adapts conventional confocal technology to a handheld probe that provides real-time fluorescent imaging at up to 1000× magnification. The authors report a combined approach in which intraoperative confocal microscopy is used to visualize 5-ALA tumor fluorescence in LGGs during the course of microsurgical resection.

Methods. Following 5-ALA administration, patients with newly diagnosed LGG underwent microsurgical resection. Intraoperative confocal microscopy was conducted at the following points: 1) initial encounter with the tumor; 2) the midpoint of tumor resection; and 3) the presumed brain-tumor interface. Histopathological analysis of these sites correlated tumor infiltration with intraoperative cellular tumor fluorescence.

Results. Ten consecutive patients with WHO Grades I and II gliomas underwent microsurgical resection with 5-ALA and intraoperative confocal microscopy. Macroscopic tumor fluorescence was not evident in any patient. However, in each case, intraoperative confocal microscopy identified tumor fluorescence at a cellular level, a finding that corresponded to tumor infiltration on matched histological analyses.

Conclusions. Intraoperative confocal microscopy can visualize cellular 5-ALA–induced tumor fluorescence within LGGs and at the brain-tumor interface. To assess the clinical value of 5-ALA for high-grade gliomas in conjunction with neuronavigation, and for LGGs in combination with intraoperative confocal microscopy and neuronavigation, a Phase IIIa randomized placebo-controlled trial (BALANCE) is underway at the authors’ institution.

Posted on

Convexity meningiomas: study of recurrence factors with special emphasis on the cleavage plane in a series of 100 consecutive patients

J Neurosurg 115:491–498, 2011. DOI: 10.3171/2011.4.JNS101922

Convexity meningiomas are expected to have a low recurrence rate given their classically “easy resectability.” Nonetheless, recurrence can occur. Factors playing a role in their recurrence are analyzed here, including the extent of resection and tumor histological type, among others, with a special emphasis on the cleavage plane.

Methods. The authors reviewed 100 cases of convexity meningiomas surgically treated between 1987 and 2001 with a median follow-up of 86 months (range 2–16 years). Preoperative and postoperative functional status, Simpson resection grade, histological type, and intraoperative surgical plane with pial vessel invasion were studied and cor- related with the recurrence rate.

Results. The average tumor size was 3.6 ± 0.4 cm. The pre- and postoperative Karnofsky Performance Scale scores were 92.6 ± 4.6 and 97.9 ± 2.2, respectively. Ninety-five lesions were benign (WHO Grade I) and 5 were atypical (WHO Grade II). Ninety-one and 9 tumors were subjected to Simpson Grade 1 and 3 resections (three Grade 3a and six Grade 3b), respectively. Surgical deaths did not occur. After a mean follow-up of 7.2 years, 4 meningiomas recurred; 2 (2.2%) after Simpson Grade 1 resections and 2 after Simpson Grade 3 (3a and 3b) resections (22.2%; p = 0.0034). When just the subgroup of Simpson Grade 1/WHO Grade I was studied, the recurrence rate decreased to 1.2% (1 of 86 cases). The recurrence of WHO Grade I tumors was higher in the subpial group than in the extrapial group (p = 0.025). No difference in recurrence according to the cleavage plane was seen in the WHO Grade II sub- group (p = 0.361). As for the subpial group, no difference in recurrence was noted between the WHO Grade I and II subgroups (p = 0.608). Importantly, however, the extrapial subgroup of WHO Grade II lesions had a higher recurrence rate compared with its counterpart in the WHO Grade I subgroup (p = 0.005).

Conclusions. Pial and vascular invasion affect the recurrence rate in convexity meningioma surgery. The recurrence rate of WHO Grade I tumors was higher among those with a subpial plane of dissection than among those with an extrapial one. Histological type did not determine the degree of pial invasion in WHO Grade I and II lesions.

Posted on

Awake surgery for WHO Grade II gliomas within “noneloquent” areas in the left dominant hemisphere: toward a “supratotal” resection

J Neurosurg 115:232–239, 2011. DOI: 10.3171/2011.3.JNS101333

It has been demonstrated that an extensive resection (total or subtotal) may significantly increase the overall survival in patients with WHO Grade II gliomas (low-grade gliomas [LGGs]). Yet, recent data have shown that conventional MR imaging underestimates the spatial extent of LGG, since tumor cells were found up to 20 mm around MR imaging abnormalities. Thus, it was hypothesized that an extended resection with a margin beyond MR imaging–defined abnormalities—a “supratotal” resection—might improve the outcome of LGG. However, because of the frequent location of LGG within “eloquent” brain areas, it is often difficult to achieve such a supratotal resection. This could nevertheless be possible when LGGs involve “noneloquent” areas, even in the left dominant hemisphere.

The authors report on their use of awake electrical mapping to tailor the resection according to functional boundaries, that is, to pursue the resection beyond MR imaging–defined abnormalities, until corticosubcortical eloquent structures are encountered. Their aim was to apply this reliable surgical technique to LGGs located not within eloquent areas but distant from eloquent areas, to take a margin around the LGG visible on MR imaging while preserving brain function.

Methods. Fifteen right-handed patients with a total of 17 tumors underwent resection of WHO Grade II gliomas involving nonfunctional areas within the left dominant hemisphere. In all patients, seizures were the initial manifestation of the tumors. Awake surgery with intraoperative electrostimulation was performed in all cases. The resection was continued until the surgeon reached cortical and subcortical areas crucial for brain function, especially language, as defined by the intrasurgical electrical mapping. The extent of resection was evaluated on postoperative FLAIRweighted MR images.

Results. Despite transient neurological worsening in 60% of cases, all patients recovered and returned to a normal life. Seizure control was obtained in all patients with a decrease of antiepileptic drug therapy. Postoperative MR imaging showed that total resection was achieved in all 17 tumors and supratotal resection in 15. The average volume of the postoperative cavity (36.8 cm3) was significantly larger than the mean preoperative tumor volume (26.6 cm3) (p = 0.009). Neuropathological examination confirmed the diagnosis of WHO Grade II glioma in all cases. The mean duration of postoperative follow-up was 35.7 months (range 6–135 months). Only 4 of 15 patients experienced recurrence (without anaplastic transformation); the average time to recurrence in these cases was 38 months; radiotherapy was performed 6 years after the relapse in 1 case; no other patients received any adjuvant treatment. This series was compared with a control group of 29 patients who had “only” complete resection: anaplastic transformation was observed in 7 cases in the control group but not in any case in the series of patients who underwent supracomplete resection (p = 0.037). Furthermore, adjuvant treatment was administered in 10 patients in the control group compared with 1 patient who underwent supracomplete resection (p = 0.043).

Conclusions. These findings support the usefulness of awake surgery with intraoperative functional (language) mapping with the attempt to perform supratotal resection of LGGs involving noneloquent areas in the left hemisphere. Indeed, the extent of resection was significantly increased in all cases but 2, with no additional permanent deficit and with control of seizures in all patients. The goal of supracomplete resection is currently to delay the anaplastic transformation, even if it does not (yet) enable a cure.

Posted on

An extent of resection threshold for newly diagnosed glioblastomas

J Neurosurg 115:3–8, 2011. DOI: 10.3171/2011.2.JNS10998

The value of extent of resection (EOR) in improving survival in patients with glioblastoma multiforme (GBM) remains controversial. Specifically, it is unclear what proportion of contrast-enhancing tumor must be resected for a survival advantage and how much survival improves beyond this threshold. The authors attempt to define these values for the patient with newly diagnosed GBM in the modern neurosurgical era.

Methods. The authors identified 500 consecutive newly diagnosed patients with supratentorial GBM treated at the University of California, San Francisco between 1997 and 2009. Clinical, radiographic, and outcome parameters were measured for each case, including MR imaging–based volumetric tumor analysis.

Results. The patients had a median age of 60 years and presented with a median Karnofsky Performance Scale (KPS) score of 80. The mean clinical follow-up period was 15.3 months, and no patient was unaccounted for. All patients underwent resection followed by chemotherapy and radiation therapy. The median postoperative tumor volume was 2.3 cm3, equating to a 96% EOR. The median overall survival was 12.2 months. Using Cox proportional hazards analysis, age, KPS score, and EOR were predictive of survival (p < 0.0001). A significant survival advantage was seen with as little as 78% EOR, and stepwise improvement in survival was evident even in the 95%–100% EOR range. A recursive partitioning analysis validated these findings and provided additional risk stratification parameters related to age, EOR, and tumor burden.

Conclusions. For patients with newly diagnosed GBMs, aggressive EOR equates to improvement in overall survival, even at the highest levels of resection. Interestingly, subtotal resections as low as 78% also correspond to a survival benefit.

Posted on

Quantitative fluorescence in intracranial tumor: implications for ALA-induced PpIX as an intraoperative biomarker

J Neurosurg 115:11–17, 2011. DOI: 10.3171/2011.2.JNS101451

Accurate discrimination between tumor and normal tissue is crucial for optimal tumor resection. Qualitative fluorescence of protoporphyrin IX (PpIX), synthesized endogenously following d-aminolevulinic acid (ALA) administration, has been used for this purpose in high-grade glioma (HGG). The authors show that diagnostically significant but visually imperceptible concentrations of PpIX can be quantitatively measured in vivo and used to discriminate normal from neoplastic brain tissue across a range of tumor histologies.

Methods. The authors studied 14 patients with diagnoses of low-grade glioma (LGG), HGG, meningioma, and metastasis under an institutional review board–approved protocol for fluorescence-guided resection. The primary aim of the study was to compare the diagnostic capabilities of a highly sensitive, spectrally resolved quantitative fluorescence approach to conventional fluorescence imaging for detection of neoplastic tissue in vivo.

Results. A significant difference in the quantitative measurements of PpIX concentration occurred in all tumor groups compared with normal brain tissue. Receiver operating characteristic (ROC) curve analysis of PpIX concentration as a diagnostic variable for detection of neoplastic tissue yielded a classification efficiency of 87% (AUC = 0.95, specificity = 92%, sensitivity = 84%) compared with 66% (AUC = 0.73, specificity = 100%, sensitivity = 47%) for conventional fluorescence imaging (p < 0.0001). More than 81% (57 of 70) of the quantitative fluorescence measurements that were below the threshold of the surgeon’s visual perception were classified correctly in an analysis of all tumors.

Conclusions. These findings are clinically profound because they demonstrate that ALA-induced PpIX is a targeting biomarker for a variety of intracranial tumors beyond HGGs. This study is the first to measure quantitative ALA-induced PpIX concentrations in vivo, and the results have broad implications for guidance during resection of intracranial tumors.

Proudly powered by WordPress