Intraoperative monopolar mapping during 5-ALA-guided resections of glioblastomas adjacent to motor eloquent areas: evaluation of resection rates and neurological outcome.

OBJECT Resection of glioblastoma adjacent to motor cortex or subcortical motor pathways carries a high risk of both incomplete resection and postoperative motor deficits. Although the strategy of maximum safe resection is widely accepted, the rates of complete resection of enhancing tumor (CRET) and the exact causes for motor deficits (mechanical vs vascular) are not always known. The authors report the results of their concept of combining monopolar mapping and 5-aminolevulinic acid (5-ALA)-guided surgery in patients with glioblastoma adjacent to eloquent tissue. METHODS The authors prospectively studied 72 consecutive patients who underwent 5-ALA-guided surgery for a glioblastoma adjacent to the corticospinal tract (CST; < 10 mm) with continuous dynamic monopolar motor mapping (short-train interstimulus interval 4.0 msec, pulse duration 500 μsec) coupled to an acoustic motor evoked potential (MEP) alarm. The extent of resection was determined based on early (< 48 hours) postoperative MRI findings. Motor function was assessed 1 day after surgery, at discharge, and at 3 months. RESULTS Five patients were excluded because of nonadherence to protocol; thus, 67 patients were evaluated. The lowest motor threshold reached during individual surgery was as follows (motor threshold, number of patients): > 20 mA, n = 8; 11-20 mA, n = 13; 6-10 mA, n = 10; 4-5 mA, n = 13; and 1-3 mA, n = 23. Motor deterioration at postsurgical Day 1 and at discharge occurred in 30% (n = 20) and 10% (n = 7) of patients, respectively. At 3 months, 3 patients (4%) had a persisting postoperative motor deficit, 2 caused by vascular injury and 1 by mechanical injury. The rates of intra- and postoperative seizures were 1% and 0%, respectively. Complete resection of enhancing tumor was achieved in 73% of patients (49/67) despite proximity to the CST. CONCLUSIONS A rather high rate of CRET can be achieved in glioblastomas in motor eloquent areas via a combination of 5-ALA for tumor identification and intraoperative mapping for distinguishing between presumed and actual motor eloquent tissues. Continuous dynamic mapping was found to be a very ergonomic technique that localizes the motor tissue early and reliably.

Extending resection and preserving function: modern concepts of glioma surgery

Recent studies have demonstrated that the improved prognosis derived from resection of gliomas largely depends on the extent and quality of the resection, making maximum but safe resection the ultimate goal. Simultaneously, technical innovations and refined neurosurgical methods have rapidly improved efficacy and safety. Because gliomas derive from intrinsic brain cells, they often cannot be visually distinguished from the surrounding brain tissue during surgery. In order to appreciate the full extent of their solid compartment, various technologies have recently been introduced. However, radical resection of infiltrative glioma puts neurological function at risk, with potential detrimental consequences for patients' survival and quality of life. The allocation of various neurological functions within the brain varies in each patient and may undergo additional changes in the presence of a tumour (brain plasticity), making intra-operative localisation of eloquent areas mandatory for preservation of essential brain functions. Combining methods that visually distinguish tumour tissue and detect tissues responsible for critical functions now enables resection of tumours in brain regions that were previously considered off-limits, and benefits patients by enabling a more radical resection, while simultaneously lowering the risk of neurological deficits. Here we review recent and expected developments in microsurgery for glioma and their respective benefits.

Computer planned, image-guided combined resection and ablation for bilobar colorectal liver metastases

For patients with extensive bilobar colorectal liver metastases (CRLM), initial surgery may not be feasible and a multimodal approach including microwave ablation (MWA) provides the only chance for prolonged survival. Intraoperative navigation systems may improve the accuracy of ablation and surgical resection of so-called "vanishing lesions", ultimately improving patient outcome. Clinical application of intraoperative navigated liver surgery is illustrated in a patient undergoing combined resection/MWA for multiple, synchronous, bilobar CRLM. Regular follow-up with computed tomography (CT) allowed for temporal development of the ablation zones. Of the ten lesions detected in a preoperative CT scan, the largest lesion was resected and the others were ablated using an intraoperative navigation system. Twelve months post-surgery a new lesion (Seg IVa) was detected and treated by trans-arterial embolization. Nineteen months post-surgery new liver and lung metastases were detected and a palliative chemotherapy started. The patient passed away four years after initial diagnosis. For patients with extensive CRLM not treatable by standard surgery, navigated MWA/resection may provide excellent tumor control, improving longer-term survival. Intraoperative navigation systems provide precise, real-time information to the surgeon, aiding the decision-making process and substantially improving the accuracy of both ablation and resection. Regular follow-ups including 3D modeling allow for early discrimination between ablation zones and recurrent tumor lesions.

Laparoscopic management of bowel endometriosis: resection margins as a predictor of recurrence.

OBJECTIVE To evaluate possible predictive factors for recurrence after laparoscopic segmental bowel resection for bowel endometriosis. DESIGN Cohort study. SETTING Academic tertiary referral center. METHODS 95 symptomatic women with bowel endometriosis who underwent laparoscopic segmental bowel resection at the Endometriosis clinic, University of Berne, between 2002 and 2012 were enrolled. Since 14 women were lost to follow-up, 81 formed the final cohort. Clinical and histological characteristics were examined as possible predictive factors for disease recurrence. MAIN OUTCOME MEASURES Recurrence, defined as a subsequent operation due to recurrent endometriosis-associated pain with a histologically confirmed endometriotic lesion. RESULTS Recurrence was observed in 13 (16%) patients. Variables that were significantly associated to recurrence by the Cox regression analysis were positive bowel resection margins (hazard ratio 6.5, 95% confidence interval 1.8-23.5, p = 0.005), age <31 years (hazard ratio 5.6, 95% confidence interval 1.7-18.6, p = 0.005) and body mass index ≥23 kg/m(2) (hazard ratio 11.0, 95% confidence interval 2.7-44.6, p = 0.001). CONCLUSIONS Positive bowel resection margins as well as age <31 years and body mass index ≥23 kg/m(2) appear to be independent predictors of disease recurrence.

REV7 counteracts DNA double-strand break resection and affects PARP inhibition

Error-free repair of DNA double-strand breaks (DSBs) is achieved by homologous recombination (HR), and BRCA1 is an important factor for this repair pathway. In the absence of BRCA1-mediated HR, the administration of PARP inhibitors induces synthetic lethality of tumour cells of patients with breast or ovarian cancers. Despite the benefit of this tailored therapy, drug resistance can occur by HR restoration. Genetic reversion of BRCA1-inactivating mutations can be the underlying mechanism of drug resistance, but this does not explain resistance in all cases. In particular, little is known about BRCA1-independent restoration of HR. Here we show that loss of REV7 (also known as MAD2L2) in mouse and human cell lines re-establishes CTIP-dependent end resection of DSBs in BRCA1-deficient cells, leading to HR restoration and PARP inhibitor resistance, which is reversed by ATM kinase inhibition. REV7 is recruited to DSBs in a manner dependent on the H2AX-MDC1-RNF8-RNF168-53BP1 chromatin pathway, and seems to block HR and promote end joining in addition to its regulatory role in DNA damage tolerance. Finally, we establish that REV7 blocks DSB resection to promote non-homologous end-joining during immunoglobulin class switch recombination. Our results reveal an unexpected crucial function of REV7 downstream of 53BP1 in coordinating pathological DSB repair pathway choices in BRCA1-deficient cells.

Endothelial- and Platelet-Derived Microparticles Are Generated During Liver Resection in Humans.

BACKGROUND Cell-derived plasma microparticles (<1.5 μm) originating from various cell types have the potential to regulate thrombogenesis and inflammatory responses. The aim of this study was to test the hypothesis that microparticles generated during hepatic surgery co-regulate postoperative procoagulant and proinflammatory events. METHODS In 30 patients undergoing liver resection, plasma microparticles were isolated, quantitated, and characterized as endothelial (CD31+, CD41-), platelet (CD41+), or leukocyte (CD11b+) origin by flow cytometry and their procoagulant and proinflammatory activity was measured by immunoassays. RESULTS During liver resection, the total numbers of microparticles increased with significantly more Annexin V-positive, endothelial and platelet-derived microparticles following extended hepatectomy compared to standard and minor liver resections. After liver resection, microparticle tissue factor and procoagulant activity increased along with overall coagulation as assessed by thrombelastography. Levels of leukocyte-derived microparticles specifically increased in patients with systemic inflammation as assessed by C-reactive protein but are independent of the extent of liver resection. CONCLUSIONS Endothelial and platelet-derived microparticles are specifically elevated during liver resection, accompanied by increased procoagulant activity. Leukocyte-derived microparticles are a potential marker for systemic inflammation. Plasma microparticles may represent a specific response to surgical stress and may be an important mediator of postoperative coagulation and inflammation.

Significant lethality following liver resection in A20 heterozygous knockout mice uncovers a key role for A20 in liver regeneration

Hepatic expression of A20, including in hepatocytes, increases in response to injury, inflammation and resection. This increase likely serves a hepatoprotective purpose. The characteristic unfettered liver inflammation and necrosis in A20 knockout mice established physiologic upregulation of A20 as integral to the anti-inflammatory and anti-apoptotic armamentarium of hepatocytes. However, the implication of physiologic upregulation of A20 in modulating hepatocytes' proliferative responses following liver resection remains controversial. To resolve the impact of A20 on hepatocyte proliferation and the liver's regenerative capacity, we examined whether decreased A20 expression, as in A20 heterozygous knockout mice, affects outcome following two-third partial hepatectomy. A20 heterozygous mice do not demonstrate a striking liver phenotype, indicating that their A20 expression levels are still sufficient to contain inflammation and cell death at baseline. However, usually benign partial hepatectomy provoked a staggering lethality (>40%) in these mice, uncovering an unsuspected phenotype. Heightened lethality in A20 heterozygous mice following partial hepatectomy resulted from impaired hepatocyte proliferation due to heightened levels of cyclin-dependent kinase inhibitor, p21, and deficient upregulation of cyclins D1, E and A, in the context of worsened liver steatosis. A20 heterozygous knockout minimally affected baseline liver transcriptome, mostly circadian rhythm genes. Nevertheless, this caused differential expression of >1000 genes post hepatectomy, hindering lipid metabolism, bile acid biosynthesis, insulin signaling and cell cycle, all critical cellular processes for liver regeneration. These results demonstrate that mere reduction of A20 levels causes worse outcome post hepatectomy than full knockout of bona fide liver pro-regenerative players such as IL-6, clearly ascertaining A20's primordial role in enabling liver regeneration. Clinical implications of these data are of utmost importance as they caution safety of extensive hepatectomy for donation or tumor in carriers of A20/TNFAIP3 single nucleotide polymorphisms alleles that decrease A20 expression or function, and prompt the development of A20-based liver pro-regenerative therapies.

Hepatic resection during cytoreductive surgery for primary or recurrent epithelial ovarian cancer.

PURPOSE Surgical cytoreduction remains a cornerstone in the management of patients with advanced and recurrent epithelial ovarian cancer. Parenchymal liver metastases determine stage VI disease and are commonly considered a major limit in the achievement of an optimal cytoreduction. The purpose of this manuscript was to discuss the rationale of liver resection and the morbidity related to this procedure in advanced and recurrent ovarian cancer. METHODS A search of the National Library of Medicine's MEDLINE/PubMed database until March 2015 was performed using the keywords: "ovarian cancer," "hepatic," "liver," and "metastases." RESULTS In patients with liver metastases, hepatic resection is associated with a similar prognosis as stage IIIC patients. The length of the disease-free interval between primary diagnosis and occurrence of liver metastases, as well as residual disease after resection, is the most important prognostic factors. In addition, the number of liver lesions, resection margins, and the gynecologic oncology group performance status seem to play also an important role in determining outcome. CONCLUSIONS In properly selected patients, liver resections at the time of cytoreduction increase rates of optimal cytoreduction and improve survival in advanced-stage and recurrent ovarian cancer patients.

The ROAM/EORTC-1308 trial: Radiation versus Observation following surgical resection of Atypical Meningioma: study protocol for a randomised controlled trial.

BACKGROUND Atypical meningiomas are an intermediate grade brain tumour with a recurrence rate of 39-58 %. It is not known whether early adjuvant radiotherapy reduces the risk of tumour recurrence and whether the potential side-effects are justified. An alternative management strategy is to perform active monitoring with magnetic resonance imaging (MRI) and to treat at recurrence. There are no randomised controlled trials comparing these two approaches. METHODS/DESIGN A total of 190 patients will be recruited from neurosurgical/neuro-oncology centres across the United Kingdom, Ireland and mainland Europe. Adult patients undergoing gross total resection of intracranial atypical meningioma are eligible. Patients with multiple meningioma, optic nerve sheath meningioma, previous intracranial tumour, previous cranial radiotherapy and neurofibromatosis will be excluded. Informed consent will be obtained from patients. This is a two-stage trial (both stages will run in parallel): Stage 1 (qualitative study) is designed to maximise patient and clinician acceptability, thereby optimising recruitment and retention. Patients wishing to continue will proceed to randomisation. Stage 2 (randomisation) patients will be randomised to receive either early adjuvant radiotherapy for 6 weeks (60 Gy in 30 fractions) or active monitoring. The primary outcome measure is time to MRI evidence of tumour recurrence (progression-free survival (PFS)). Secondary outcome measures include assessing the toxicity of the radiotherapy, the quality of life, neurocognitive function, time to second line treatment, time to death (overall survival (OS)) and incremental cost per quality-adjusted life year (QALY) gained. DISCUSSION ROAM/EORTC-1308 is the first multi-centre randomised controlled trial designed to determine whether early adjuvant radiotherapy reduces the risk of tumour recurrence following complete surgical resection of atypical meningioma. The results of this study will be used to inform current neurosurgery and neuro-oncology practice worldwide. TRIAL REGISTRATION ISRCTN71502099 on 19 May 2014.