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.

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.

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.

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.

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.

The Transcallosal Anterior Interfoniceal Approach: A Microsurgical Anatomy Study.

Objectives A plethora of surgical strategies have been described to reach deep-seated lesions situated within the third ventricle including the Rosenfeld, or transcallosal anterior interfoniceal (TAIF), approach. First introduced in 2001, it consists of a small callosotomy followed by the midline transseptal dissection of fornices to enter the roof of the third ventricle. The aim of this microsurgical anatomy study is to describe and show each stage of the surgical procedure, focusing on the possible trajectories to anatomical landmarks. Participants A total of 20 adult cadaveric specimens were used in this study. Using ×3 to ×40 magnifications, the surgical dissection was performed in a stepwise fashion, and the transcallosal anterior interforniceal approach was performed, analyzed, and described. Results In 5 specimens of 10, a cavum septum pellucidum was depicted. In 5 cases of 20 after the callosotomy ,the lateral ventricular cavities were reached. Different orientation of the microscope allowed us to define three surgical trajectories to visualize the region of interest without exposing important functional areas. Conclusion The TAIF represents a minimally invasive approach to the third ventricle; its tricky surgical steps make appropriate anatomical dissection training essential to become confident and skilled in performing this approach.

Laser ablation and 131-iodine: a 24-month pilot study of combined treatment for large toxic nodular goiter.

CONTEXT: It is normally recognized that the preferred treatment in large toxic thyroid nodules should be thyroidectomy. OBJECTIVE: The aim of the study was to assess the efficacy of combined laser ablation treatment (LAT) and radioiodine 131 (131I) treatment of large thyroid toxic nodules with respect to rapidity of control of local symptoms, of hyperthyroidism, and of reduction of administered 131I activity in patients at refusal or with contraindications to surgery. DESIGN AND SETTING: We conducted a pilot study at a single center specializing in thyroid care. PATIENTS: Fifteen patients were treated with LAT, followed by 131I (group A), and a series of matched consecutive patients were treated by 131I only (group B). INTERVENTION(S): Laser energy was delivered with an output power of 3 W (1800 J per fiber per treatment) through two 75-mm, 21-gauge spinal needles. Radioiodine activity was calculated to deliver 200 Gy to the hyperfunctioning nodule. MAIN OUTCOME MEASURE(S): Thyroid function, thyroid peroxidase antibody, thyroglobulin antibody, ultrasound, and local symptoms were measured at baseline and up to 24 months. RESULTS: Nodule volume reduction at 24 months was: 71.3 ± 13.4 vs 47.4 ± 5.5%, group A (LAT+131I) vs group B (131I), respectively; P < .001). In group A (LAT+131I), a reduction in radioiodine-administered activity was obtained (-21.1 ± 8.1%). Local symptom score demonstrated a more rapid reduction in group A (LAT+131I). In three cases, no 131I treatment was needed after LAT. CONCLUSIONS: In this pilot study, combined LAT/131I treatment induced faster and greater improvement of local and systemic symptoms compared to 131I only. This approach seems a possible alternative to thyroidectomy in patients at refusal of surgery.

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

Mortality and loss to follow-up among tuberculosis and HIV co-infected patients in rural southwestern Uganda.

BACKGROUND: We describe the presentation and outcome of care among patients with tuberculosis (TB) and human immunodeficiency virus (HIV) co-infection from a prospective observational cohort in Uganda. METHODS: We analysed basic demographics, CD4+ counts, time of initiating antiretroviral therapy (ART), clinical and haematological parameters and outcome of care of 386 patients enrolled between February 2007 and March 2010. RESULTS: At presentation, 56.7% of the patients were sputum-positive, 89.9% had new TB infection, 62.7% had wasting, 78.7% were anaemic, 72.1% had a CD4+ count of <200 cells/mm(3), 20.2% had pneumonia, 50.3% had oral thrush and 1.3% had Kaposi's sarcoma. Patients developing TB within 3 months of starting ART were less likely to have wasting, to be anaemic or to have a CD4+ count of <100 cells/mm(3). The cure, default and death rates were respectively 54.3%, 24% and 16%. At 8 months, 53 (13.7%) were confirmed dead, 119 (30.8%) were lost to follow-up, 28 (7.3%) were transferred out and 1 (0.3%) had treatment failure. Mortality and loss to follow-up were associated with failure to start ART and having a CD4+ count of <200 cells/mm(3). CONCLUSION: In Uganda, TB-HIV patients present with severe immune suppression and are at increased risk of death and loss to follow-up, particularly those not on ART. There is need for early identification and improved follow-up of TB-HIV co-infected 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.

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.

"Short Course" of Nonpegylated Liposomal Doxorubicin Plus Paclitaxel and Trastuzumb as Primary Systemic Therapy for Operable and Locally-Advanced Breast Cancer: A Phase II Study (PacLiDox 07).

BACKGROUND: Schedules with anthracyclines and taxanes are one of the best options for primary chemotherapy. The addition of trastuzumab showed an impressive percentage of pathological complete responses in Buzdar trial (66.7%). Recently, nonpegylated liposome-encapsulated doxorubicin (NLD) has been widely used in advanced breast cancer with high response rates (98.1 % in Cortes study). The aims of our study were to assess pathological responses and toxicity of NLD plus paclitaxel (and trastuzumab in patients with HER2 overexpression). METHODS: Thirty patients entered the study: 9 locally advanced and 21 operable. Median age was 58.5 years (range: 31-73). 23 patients without HER2 overexpression (or FISH not amplified) were treated with NLD 50 mg/m2 every three weeks for 3 courses and weekly paclitaxel 80 mg/m2 for 8 courses. 7 patients with HER2 overexpression or FISH amplified were treated with the same schedules plus trastuzumab (Herceptin) 4 mg/kg for the first administration and 2 mg/kg for the following 7 weekly administrations. RESULTS: Pathological complete response (pCR) was documented in 1 patient (treated with trastuzumab); no residual tumor (infiltrating or "in situ") on breast was documented in other 2 patients. Objective clinical responses were documented in 22 patients (73.3%): 8 complete, 10 partial and 4 "minimal" responses. 7 patients have shown stable and 1 progressive disease. Clinical response in patients with HER2 overexpression treated with trastuzumab was 100% (4 complete and 3 partial responses). Conservative surgery was performed in 8 (38%) and mastectomy in 13 (62%) out of 21 operable patients; however, 7 out of 14 responding patients with operable disease underwent quadrantectomy (50%). Main toxicity was neutropenia: febrile in 2 patients (7%) and gr. 3-4 in 13 (43%). Other grade 3 toxicities were as follows: vomiting in 1 patient, asthenia in 1 patient, joint symptom in 1 patient. 3 patients were withdrawn from the study. No episodes of left ventricular ejection fraction (LVEF) < 50% were recorded (with a median reduction of 8%). CONCLUSIONS: A "short course" of paclitaxel and NLD is active in terms of clinical response and conservative surgery for patients with potentially operable and locally advanced breast cancer; toxicity was manageable. High activity of the combination with trastuzumab has been confirmed. However, with this "short course" schedule, the result in term of clinical responses didn't turn into complete pathological responses.

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.

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.