Pulsed radiofrequency energy device (PEAK plasmablade™) and CustomBone® Cranioplasty: an appealing surgical rendez-vous.

BACKGROUND: CustomBone® prosthesis is a widely recognized effective and successful technique for the reconstruction of cranial bone defects. Prior the cranioplasty implant, meticulous dissection within thick scar tissue is required. During this delicate surgical manoeuvre is vital to avoid damage to the skin flap itself and to the underlying cerebrovascular structures. We report our experience and potential applications of a novel, pulsed monopolar radiofrequency energy device (PEAK PlasmaBlade™, Medtronic plc). It reduced the incidence of post operativesubgaleal hematoma, the operative times and the intra operative blood loss following cranioplasty compared to the traditional scalpel and scissor dissection. METHODS: The authors present a one centre case series study to review the indications, safety and efficacy of the PEAK PlasmaBlade™ in adult patientsunderwent cranioplasty. Two surgical techniques for tissue dissection were compared: PEAK PlasmaBlade™ versus scalpel and scissor dissection (SSD). Treatment outcomes following each of these surgical approaches, relative to rate of post-operative subgalealhematoma formation, hospital admission, and operative times were compared. RESULTS: A total of 10 patients that had cranioplasty treatment were evaluated. In patients underwent scalp dissection with the PEAKPlasmaBlade™, we observed a reduction in the operative times, in the subgaleal hematoma formation and then in the hospital stay. CONCLUSION: PEAK PlasmaBlade™ revealed to be a safe and effective device in tissues dissection for cranioplasty implant. It provided reduction of the rate of subgaleal hematoma formation, operating times and less potential risk to damage cerebrovascular structures.

MTHFR, TS and XRCC1 genetic variants may affect survival in patients with myelodysplastic syndromes treated with supportive care or azacitidine.

We evaluated the impact of genomic polymorphisms in folate-metabolizing, DNA synthesis and DNA repair enzymes on the clinical outcome of 108 patients with myelodysplastic syndromes (MDS) receiving best supportive care (BSC) or azacitidine. A statistically significant association between methylenetetrahydrofolate reductase (MTHFR) 677T/T, thymidylate synthase (TS) 5'-untranslated region (UTR) 3RG, TS 3'-UTR -6 bp/-6 bp, XRCC1 399G/G genotypes and short survival was found in patients receiving BSC by multivariate analysis (P<0.001; P=0.026; P=0.058; P=0.024). MTHFR 677T/T, TS 3'-UTR -6 bp/-6 bp and XRCC1 399G/G genotypes were associated with short survival in patients receiving azacitidine by multivariate analysis (P<0.001; P=0.004; P=0.002). We then performed an exploratory analysis to evaluate the effect of the simultaneous presence of multiple adverse variant genotypes. Interestingly, patients with ⩾1 adverse genetic variants had a short survival, independently from their International Prognostic Scoring System (IPSS) and therapy received. To our knowledge, this is the first study showing that polymorphisms in folate-metabolizing pathway, DNA synthesis and DNA repair genes could influence survival of MDS patients.

Dihydropyrimidine dehydrogenase pharmacogenetics for predicting fluoropyrimidine-related toxicity in the randomised, phase III adjuvant TOSCA trial in high-risk colon cancer patients.

BACKGROUND: Dihydropyrimidine dehydrogenase (DPD) catabolises ∼85% of the administered dose of fluoropyrimidines. Functional DPYD gene variants cause reduced/abrogated DPD activity. DPYD variants analysis may help for defining individual patients' risk of fluoropyrimidine-related severe toxicity. METHODS: The TOSCA Italian randomised trial enrolled colon cancer patients for 3 or 6 months of either FOLFOX-4 or XELOX adjuvant chemotherapy. In an ancillary pharmacogenetic study, 10 DPYD variants (*2A rs3918290 G>A, *13 rs55886062 T>G, rs67376798 A>T, *4 rs1801158 G>A, *5 rs1801159 A>G, *6 rs1801160 G>A, *9A rs1801265 T>C, rs2297595 A>G, rs17376848 T>C, and rs75017182 C>G), were retrospectively tested for associations with ⩾grade 3 fluoropyrimidine-related adverse events (FAEs). An association analysis and a time-to-toxicity (TTT) analysis were planned. To adjust for multiple testing, the Benjamini and Hochberg's False Discovery Rate (FDR) procedure was used. RESULTS: FAEs occurred in 194 out of 508 assessable patients (38.2%). In the association analysis, FAEs occurred more frequently in *6 rs1801160 A allele carriers (FDR=0.0083). At multivariate TTT analysis, significant associations were found for *6 rs1801160 A allele carriers (FDR<0.0001), *2A rs3918290 A allele carriers (FDR<0.0001), and rs2297595 GG genotype carriers (FDR=0.0014). Neutropenia was the most common FAEs (28.5%). *6 rs1801160 (FDR<0.0001), and *2A rs3918290 (FDR=0.0004) variant alleles were significantly associated with time to neutropenia. CONCLUSIONS: This study adds evidence on the role of DPYD pharmacogenetics for safety of patients undergoing fluoropyrimidine-based chemotherapy.

Germline polymorphisms as biomarkers of tumor response in colorectal cancer patients treated with anti-EGFR monoclonal antibodies: a systematic review and meta-analysis.

Studies of germline polymorphisms as predictors of tumor response to anti-epidermal growth factor receptor (EGFR) monoclonal antibody agents in metastatic colorectal cancer have reported inconsistent results. We performed a systematic review of studies from 1990 to September 2015, followed by random-effects meta-analyses for polymorphisms examined in at least three studies. Of 87 studies, 40 passed the criteria for systematic review and 23 for meta-analysis. The polymorphisms suitable for meta-analysis were CCND1 (rs17852153), COX2 (rs20417), EGF (rs4444903), EGFR (rs712829, rs11543848, 3'UTR CA repeat), FCGR2A (rs1801274), FCGR3A (rs396991), IL8 (rs4073), KRAS (rs61764370) and VEGFA (rs3025039). Meta-analysis yielded nominal significance (at α=0.05) for rs4444903 and rs11543848, but showed no significant results after multiple testing correction; this was unchanged by sensitivity analyses to address subgroups, funnel-plot asymmetries, and study quality. This highlights a tendency for lack of replication in the face of initial positive results, and possibly the unsuitability of relying on tumor response as a surrogate marker in this setting.

Glycolysis gene expression analysis and selective metabolic advantage in the clinical progression of colorectal cancer.

Production of lactate even in the presence of sufficient levels of oxygen (aerobic glycolysis) seems the prevalent energy metabolism pathway in cancer cells. The analysis of altered expression of effectors causing redirection of glucose metabolism would help to characterize this phenomenon with possible therapeutic implications. We analyzed mRNA expression of the key enzymes involved in aerobic glycolysis in normal mucosa (NM), primary tumor (PT) and liver metastasis (LM) of colorectal cancer (CRC) patients (pts) who underwent primary tumor surgery and liver metastasectomy. Tissues of 48 CRC pts were analyzed by RT-qPCR for mRNA expression of the following genes: hexokinase-1 (HK-1) and 2 (HK-2), embryonic pyruvate kinase (PKM-2), lactate dehydrogenase-A (LDH-A), glucose transporter-1 (GLUT-1), voltage-dependent anion-selective channel protein-1 (VDAC-1). Differences in the expression of the candidate genes between tissues and associations with clinical/pathologic features were studied. GLUT-1, LDH-A, HK-1, PKM-2 and VDAC-1 mRNA expression levels were significantly higher in PT/LM tissues compared with NM. There was a trend for higher expression of these genes in LM compared with PT tissues, but differences were statistically significant for LDH-A expression only. RAS mutation-positive disease was associated with high GLUT-1 mRNA expression levels only. Right-sided colon tumors showed significantly higher GLUT-1, PKM-2 and LDH-A mRNA expression levels. High glycolytic profile was significantly associated with poor prognosis in 20 metastatic, RAS-mutated pts treated with first-line chemotherapy plus Bevacizumab. Altered expression of effectors associated with upregulated glucose uptake and aerobic glycolysis occurs in CRC tissues. Additional analyses are warranted for addressing the role of these changes in anti-angiogenic resistance and for developing novel therapeutics.

Meditation training for people with amyotrophic lateral sclerosis: a randomized clinical trial.

BACKGROUND AND PURPOSE: Studies investigating psychological interventions for the promotion of well-being in people with amyotrophic lateral sclerosis (ALS) are lacking. The purpose of the current study was to examine the use of an ALS-specific mindfulness-based intervention for improving quality of life in this population. METHODS: A randomized, open-label and controlled clinical trial was conducted on the efficacy of an ALS-specific meditation programme in promoting quality of life. Adults who received a diagnosis of ALS within 18 months were randomly assigned either to usual care or to an 8-week meditation training based on the original mindfulness-based stress reduction programme and tailored for people with ALS. Quality of life, assessed with the ALS-Specific Quality of Life Revised scale, represented the primary outcome, whilst secondary outcomes included anxiety and depression, assessed with the Hospital Anxiety and Depression Scale, and specific quality of life domains. Participants were assessed at recruitment and after 2, 6 and 12 months. The efficacy of the treatment was assessed on an intention-to-treat basis of a linear mixed model. RESULTS: A hundred participants were recruited between November 2012 and December 2014. Over time, there was a significant difference between the two groups in terms of quality of life (ß = 0.24, P = 0.015, d = 0.89). Significant differences between groups over time were also found for anxiety, depression, negative emotions, and interaction with people and the environment. CONCLUSIONS: An ALS-specific meditation programme is beneficial for the quality of life and psychological well-being of people with ALS.

Probing the factor structure of metabolic syndrome in Sardinian genetic isolates.

BACKGROUND AND AIMS: Owing to the multiplicity of the key components of metabolic syndrome (MetS), its diagnosis is very complex. The lack of a unique definition is responsible for the prevalence variability observed among studies; therefore, a definition based on continuous variables was recommended. The aim of this study was to compare competing models of the MetS factor structure for selecting the one that explains the best clustering pattern and to propose an algorithm for computing MetS as a continuous variable. METHODS AND RESULTS: Data were from isolated Sardinian populations (n = 8102). Confirmatory factor analysis (CFA) and two-group CFA by gender were performed to evaluate the sex-specific factor structure of MetS. After selecting the best model, an algorithm was obtained using factor loadings/residual variances. The quality of the MetS score was evaluated by the receiver operating characteristics curve and the area under the curve. Cross-validation was performed to validate the score and to determine the best cut point. The best fit model was a bifactor one with a general factor (MetS) and three specific factors (f1: obesity/adiposity trait; f2: hypertension/blood pressure trait; and f3: lipid trait). Gender-specific algorithms were implemented to obtain MetS scores showing a good diagnostic performance (0.80 specificity and 0.80 sensitivity for the cut point). Furthermore, cross-validation confirmed these results. CONCLUSION: These analyses suggested that the bifactor model was the most representative one. In addition, they provided a score and a cut point that are both clinically accessible and interpretable measures for MetS diagnosis and likely useful for evaluating the association with adverse cardiovascular disease and diabetes and for investigating the MetS genetic component.

Clinical impact of the HGF/MET pathway activation in patients with advanced gastric cancer treated with palliative chemotherapy.

In gastric cancer, available clinical studies focusing on the activated hepatocyte growth factor (HGF)/MET pathway are limited to surgical and often heterogeneous series. MET copy number gain (CNG) and an activating truncation in the HGF promoter (deoxyadenosine tract element, DATE+) were studied in tumors of 95 patients with advanced gastric cancer treated with palliative chemotherapy. Associations with overall survival (OS) and the pattern of metastatic disease were studied. Median OS was 9.7 months in 80 MET CNG <5 copies cases (MET-), and 6.4 months in 15 MET CNG was ⩾5 copies cases (MET+) (P=0.001). MET+ status confirmed the adverse prognostic effect in the multivariate model. A significantly different distribution of MET+/DATE+ and MET-/DATE- cases was observed between patients with and without peritoneal carcinomatosis (PC). MET+ status confirms its adverse prognostic role in advanced gastric cancer patients. The activated MET/HGF axis seems to be associated with PC. These findings are relevant to the development of anti-MET/HGF compounds.

Prospective study of EGFR intron 1 (CA)n repeats variants as predictors of benefit from cetuximab and irinotecan in chemo-refractory metastatic colorectal cancer (mCRC) patients.

The number of CA tandem repeats (CA)n in a highly polymorphic region of EGFR (epidermal growth factor receptor) intron 1 may affect gene transcription; the potential impact of allelic variants on the efficacy of cetuximab in metastatic colorectal cancer (mCRC) patients is debated for long. This study aimed at prospectively estimating the impact of EGFR intron 1 (CA)n variants on clinical outcome in KRAS exon 2 and BRAF wild-type chemo-refractory mCRC patients, receiving cetuximab and irinotecan. Variants presenting

EEG Resting-State Functional Networks in Amnestic Mild Cognitive Impairment.

Background. Alzheimer's cognitive-behavioral syndrome is the result of impaired connectivity between nerve cells, due to misfolded proteins, which accumulate and disrupt specific brain networks. Electroencephalography, because of its excellent temporal resolution, is an optimal approach for assessing the communication between functionally related brain regions. Objective. To detect and compare EEG resting-state networks (RSNs) in patients with amnesic mild cognitive impairment (aMCI), and healthy elderly (HE). Methods. We recruited 125 aMCI patients and 70 healthy elderly subjects. One hundred and twenty seconds of artifact-free EEG data were selected and compared between patients with aMCI and HE. We applied standard low-resolution brain electromagnetic tomography (sLORETA)-independent component analysis (ICA) to assess resting-state networks. Each network consisted of a set of images, one for each frequency (delta, theta, alpha1/2, beta1/2). Results. The functional ICA analysis revealed 17 networks common to groups. The statistical procedure demonstrated that aMCI used some networks differently than HE. The most relevant findings were as follows. Amnesic-MCI had: i) increased delta/beta activity in the superior frontal gyrus and decreased alpha1 activity in the paracentral lobule (ie, default mode network); ii) greater delta/theta/alpha/beta in the superior frontal gyrus (i.e, attention network); iii) lower alpha in the left superior parietal lobe, as well as a lower delta/theta and beta, respectively in post-central, and in superior frontal gyrus(ie, attention network). Conclusions. Our study confirms sLORETA-ICA method is effective in detecting functional resting-state networks, as well as between-groups connectivity differences. The findings provide support to the Alzheimer's network disconnection hypothesis.

An EZH2 polymorphism is associated with clinical outcome in metastatic colorectal cancer patients.

BACKGROUND: Despite therapeutic innovations, metastatic colorectal cancer (mCRC) is still characterized by poor prognosis and few molecular markers predict the risk of progression. Polycomb group genes (PcGs) are epigenetic modifiers involved in tumor suppressor gene silencing. PcG member EZH2 mediates gene silencing through histone-H3 lysine-27 methylation. In colorectal cancer (CRC), EZH2 overexpression predicts shorter survival. Recently, four EZH2 single-nucleotide polymorphisms (SNPs) have been described. The present study was aimed at evaluating the correlation between EZH2 SNPs and outcome parameters in mCRC patients. PATIENTS AND METHODS: DNA was extracted from blood samples of 110 mCRC patients treated with first-line 5-fluorouracil, folinic acid, irinotecan (FOLFIRI) and bevacizumab. Genotyping was carried out by real-time PCR. Genotype was used to predict objective response, progression-free survival (PFS) and overall survival (OS). EZH2 messenger RNA levels were evaluated on lymphocytes of a parallel cohort of 50 CRC patients. RESULTS: One allelic variant (rs3757441 C/C versus C/T or T/T) was significantly associated with shorter PFS and OS (P < 0.01 and P < 0.05, respectively). At multivariate analysis, the same variant resulted an independent predictor of PFS and OS (P < 0.05). The C/C variant was associated with significantly higher EZH2 expression (P < 0.05). CONCLUSION: An EZH2 SNP may be useful to predict clinical outcome in mCRC patients.

Prognosis of mucinous histology for patients with radically resected stage II and III colon cancer.

BACKGROUND: Previous studies investigating the prognostic role of mucinous histology of colorectal cancer produced conflicting results. This retrospective analysis was carried out in order to explore whether mucinous adenocarcinoma (MC) is associated with a comparatively worse prognosis than that of nonmucinous adenocarcinoma (NMC) for patients undergoing curative resection for stage II and III colon cancer. PATIENTS AND METHODS: This study involved 1025 unselected patients who underwent curative surgery for sporadic colon cancer and follow-up procedures at six different oncology departments. RESULTS: MCs accounted for 17.4% (n=178) of tumours. Patients with MC had 5- and 8-year overall survival rates of 78.6% and 68.8%, respectively, compared with 72.3% and 63.8%, respectively, for patients with nonmucinous tumours. Multivariate analysis using the Cox proportional hazards model showed that the clinically significant prognostic factors were stage of disease and adjuvant chemotherapy. No statistically significant interaction between mucinous histology and adjuvant chemotherapy was found. CONCLUSIONS: For patients with stage II and III colon cancer who underwent curative surgery, mucinous histology has no significant correlation with prognosis compared with NMC. This retrospective analysis suggests a comparable benefit from adjuvant chemotherapy for MC compared with NMC.

Women in Neurosurgery: Historical Path to Self-Segregation and Proposal for an Integrated Future.

Despite the rising percentage of women accessing the medical profession over the last few decades, surgical specialties are still largely male-dominated; in particular, a remarkable gender disparity is evident in neurosurgery, where only 19% of practitioners are females. Although women may be reluctant to choose a challenging specialty like neurosurgery due to concerns around how to balance family and career, it must be admitted that prejudices against female neurosurgeons have been deeply rooted for long, prompting many to give up and switch track to less demanding subspecialties. Among those who have persisted, many, if not most, have experienced difficulties in career progression and received unequal treatment in comparison with their male counterparts. In 1989, a group of 8 female neurosurgeons founded Women in Neurosurgery (WINS), an organization that aimed to guarantee inclusivity in neurosurgery, encouraging a better and more egalitarian working environment. Thereafter, WINS sessions were regularly promoted at international conferences, offering female neurosurgeons a platform to report issues related to gender discrimination. Over recent years, the mission of WINS sessions in national and international conferences has taken an unexpected deviation; they have progressively become supplementary scientific sessions with only women neurosurgeons as speakers, thus paving the road to a form of self-segregation. This tendency has also resulted in the establishment of sections of only female neurosurgeons within some national societies. Although there remains a faction that fiercely supports the WINS mindset of reserved spaces for women, such segregation is an upsetting prospect for those who believe that science and professionalism have no gender; a growing part of the global neurosurgical community believes that the conception of a "female neurosurgery" and a "male neurosurgery" is misguided and counterproductive and consider the existence of the WINS as anachronistic and no longer necessary.

Early magnesium modifications as a surrogate marker of efficacy of cetuximab-based anticancer treatment in KRAS wild-type advanced colorectal cancer patients.

BACKGROUND: KRAS wild-type mutational status is necessary but not sufficient to get benefit from epidermal growth factor receptor inhibition. Predictive markers are currently being evaluated. In this study, we investigated early hypomagnesemia as a predictor of efficacy and outcome in terms of time to progression (TtP) and overall survival (OS) in a cohort of patients affected by advanced colorectal adenocarcinoma KRAS wild-type cetuximab-treated. PATIENTS AND METHODS: One hundred and forty-three patients affected by stage IV colorectal adenocarcinoma KRAS wild type receiving cetuximab + irinotecan (CTX+IRI) as third-line anticancer treatment and resistant to oxaliplatin- and irinotecan-based chemotherapy were retrospectively included. Magnesium plasma levels were measured before the first day and 7, 14, 21 and 28 days after CTX+IRI infusion. RESULTS: The median magnesium basal value showed a statistically significant decrease after the start of CTX+IRI treatment (at 28 days, P < 0.0001). Patients with an early decrease of magnesium levels >50% compared with the basal level had a higher tumor response rate (55.8% versus 16.7%, P < 0.0001), a longer TtP (6.3 versus 3.6, P < 0.0001) and a longer median OS (11.0 versus 8.1, P = 0.002). CONCLUSIONS: We have shown that early hypomagnesemia could be a predictor of efficacy and outcome in those patients. Magnesium circulating level is an easy and inexpensive biomarker to routinely be detected in patients treated with cetuximab.

Can biomechanical analysis shed some light on aneurysmal pathophysiology? Preliminary study on ex vivo cerebral arterial walls.

BACKGROUND: The pathophysiology of cerebral aneurysm is complex and poorly understood, and it can have the most catastrophic clinical presentation. Flow dynamics is a key player in the initiation and progression of aneurysm. Better understanding the interaction between hemodynamic loading and biomechanical wall responses can help to add the missing piece on aneurysmal pathophysiology. In this laboratory study we aimed to analyze the effect of the application of a mechanical force to cerebral arterial walls. METHODS: Displacement control tests were performed on five porcine cerebral arteries. The test machine was the T150 Nanotensile. The stiffness variation with the increment of the strain level is modeled as the outcome of an isotropic hyperelastic material model. FINDINGS: Through the application of an axial force we obtained Stress/Strain curves that showed a marked isotropic hyperelastic behavior, characterized by an increasing of stiffness with the level of strain. This behavior of the cerebral arterial wall is different from the well-established behavior of other arterial vessel (as the aortic vessel) characterized by a marked anisotropic behavior. Additionally, the data scattering observed for higher values of the applied stress are related to different individual packing of collagen fibers that represent the load-bearing mechanics at higher level of the strain. INTERPRETATION: The data obtained by test in this paper represent a first step in our ongoing research about the mechanics of multi-axial loads on cerebral arterial walls, and in producing more comprehensive patient-specific calculations for potential applications on cerebral aneurysm management.

Genetic modulation of the Let-7 microRNA binding to KRAS 3'-untranslated region and survival of metastatic colorectal cancer patients treated with salvage cetuximab-irinotecan.

There is increasing evidence that the Let-7 microRNA (miRNA) exerts an effect as a tumor suppressor by targeting the KRAS mRNA. The Let-7 complementary site (LCS6) T>G variant in the KRAS 3'-untranslated region weakens Let-7 binding. We analyzed whether the LCS6 variant may be clinically relevant to patients with metastatic colorectal cancer (MCRC) treated with anti-epidermal growth factor receptor (EGFR) therapy. LCS6 genotypes and KRAS/BRAF mutations were determined in the tumor DNA of 134 patients with MCRC who underwent salvage cetuximab-irinotecan therapy. There were 34 G-allele (T/G+G/G) carriers (25%) and 100 T/T genotype carriers (75%). G-allele carriers were significantly more frequent in the KRAS mutation group than in patients with KRAS wild type (P=0.004). In the 121 patients without BRAF V600E mutation, overall survival (OS) and progression-free survival (PFS) times were compared between carriers of the LCS6 G-allele genotypes and carriers of the wild-type T/T genotype. LCS6 G-allele carriers showed worse OS (P=0.001) and PFS (P=0.004) than T/T genotype carriers (confirmed in the multivariate model including the KRAS status). In the exploratory analysis of the 55 unresponsive patients with KRAS mutation, LCS6 G-allele carriers showed adverse OS and PFS times. These findings deserve additional investigations as they may open novel perspectives for the treatment of patients with MCRC.

Cervical spine chondroma arising from C5 right hemilamina: a rare cause of spinal cord compression. Case report and review of the literature.

Chondromas are rare primary spine tumors. Only 12 cases of chondromas located in the cervical spine have been reported in the literature up to now. The authors report a case of a cervical periosteal chondroma in a 38-year-old man presenting with neck pain and a syndrome of spinal cord compression. Magnetic resonance imaging revealed a lesion that was hypo- or isointense on T1-weighted images and iso-hyperintense on T2-weighted images. Administration of Gd-DPTA resulted in margin enhancement on T1-weighted images. CT scans revealed a hyperdense calcified lesion arising from the internal surface of C5 right hemi-lamina. The patient underwent a right C5 hemi-laminectomy, with complete en-bloc removal of the lesion. The authors emphasize that early identification of the initial lesion should be coupled with total surgical resection, as a definitive treatment, in order to prevent malignant transformation.