Patient-reported outcome measures more than fifteen years after treatment of sagittal or metopic craniosynostosis: a prospective cohort study.

PURPOSE: To evaluate the long-term anthropometric measurements, cosmetic satisfaction, and other patient-reported outcome measures (PROMs) of patients who underwent surgical treatment or observation only of sagittal or metopic single-suture craniosynostosis (SSC). METHODS: A prospective study was designed for all patients diagnosed with non-syndromic sagittal and metopic craniosynostosis at the British Columbia Children's Hospital, Vancouver, Canada, in the period July 1986 to July 2006. After a minimum of 15 years post-diagnosis, all eligible patients were invited to fill out the Craniofacial Surgery Outcomes Questionnaire (CSO-Q) and to attend a scheduled follow-up appointment for the collection of anthropometric measurements. A descriptive analysis of the cosmetic results was performed. Statistical analyses compared the differences in anthropometric measurements between treated and non-treated patients. RESULTS: Of the 253 eligible patients, 52 participants were willing to share patient data for use in the study. Of those 52 former patients, 36 (69.2%) filled out and returned the CSO-Q and 23 (44.2%) attended the follow-up appointment. The mean follow-up period between surgical treatment and the CSO-Q was 20.2 ± 2.5 years and between surgical treatment and the follow-up appointment was 20.9 ± 2.7 years. In patients with sagittal SSC, the mean cephalic index (CI) was significantly larger in treated than in non-treated patients (74.6 versus 69.1, p = 0.04), while the mean pupillary distance and forehead to back index were significantly smaller (pupillary distance 6.0 cm versus 6.7 cm [p = 0.04] and forehead to back index 19.6 cm versus 21.1 cm [p = 0.03]). Focusing more on the patient reported outcome measures, overall cosmetic satisfaction was found to be high (80.6%) and no differences were found between sagittal and metopic synostosis patients, nor between treated or non-treated craniosynostosis patients. Overall outcomes regarding self-esteem (RSES) and fear of negative evaluation (FNE) were comparable with population based outcomes. CONCLUSION: This is the first prospective study of sagittal and metopic craniosynostosis patients regarding long-term anthropometric outcome and patient reported outcome measures, including patients who were treated surgically and those who received observation only. Although study participation two decades after initial diagnosis was difficult to obtain, our data provide a platform from which one can develop an inclusive and uniform approach to assess patients' subjective cosmetic satisfaction using the CSO-Questionnaire and might be useful in preoperative counseling and psychosocial care for patients and their families.

Performance of a diagnostic model for the presence of unruptured intracranial aneurysms in the general population.

INTRODUCTION: The prevalence of unruptured intracranial aneurysms (UIAs) in the general population is 3%. Aneurysmal subarachnoid hemorrhage (aSAH) can be prevented by screening for UIAs followed by monitoring and, if needed, preventive neurosurgical or endovascular treatment of identified UIAs. Therefore, we developed a diagnostic model for presence of UIAs in the general population to help identify persons at high risk of having UIAs. METHODS: Between 2005-2015, participants from the population-based Rotterdam Study underwent brain magnetic resonance imaging at 1.5 Tesla, on which presence of incidental UIAs was evaluated. We developed a multivariable logistic regression model using candidate diagnostic markers that were selected based on the literature, including sex, age, hypertension, smoking, hypercholesterolemia, diabetes, alcohol, and their interactions. We corrected for overfitting using bootstrapping. Model performance was assessed with discrimination, calibration, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). RESULTS: 5835 persons were included (55.0% women, mean age 64.9 ± 10.9 years) with a 2.2% UIA prevalence. Sex, age, hypertension, smoking, diabetes, and interactions of sex with age, hypertension, and smoking were independent diagnostic markers. The resulting model had a c-statistic of 0.65 (95% confidence interval [CI] 0.60 - 0.68) and 56% sensitivity, 52% specificity, 98% PPV, and 3% NPV for UIA presence at a cut-off value of 4%. Because of interactions with sex, additional models for men and women separately were developed. The model for men had a c-statistic of 0.70 (95% CI 0.62 - 0.78) with age, hypertension, and smoking as diagnostic markers and comparable additional performance values as for the full model. The model for women had a c-statistic of 0.58 (95% CI 0.52 - 0.63) with smoking as the only diagnostic marker. CONCLUSION: Our diagnostic model had insufficient performance to help identify persons at high risk of having UIAs in the general population. Rather, it provides insight in risk factors contributing to UIA risk and shows that these may be in part sex-specific.

Cosmetic satisfaction and patient-reported outcomes following surgical treatment of single-suture craniosynostosis: a systematic review.

PURPOSE: This study provides a systematic review on cosmetic satisfaction and other patient-reported outcomes (PROMs) of patients who underwent surgical treatment of SSC. METHODS: A systematic review of all articles published from inception to 1 June 2022 was performed. Articles were included if they reported on subjective assessment of cosmetic satisfaction or other PROMs by patients or their families using questionnaires or interviews. RESULTS: Twelve articles, describing 724 surgical treatments of SSC, met the inclusion criteria. Cosmetic satisfaction was evaluated in the following ways: 1) use of the VAS score, binary questions or a 5-point scale to rate general, facial or skull appearance; 2) use of an aesthetic outcome staging in which personal opinion was added to the treating surgeon's opinion; and 3) use of an evaluation of anatomical proportions of the skull and face. A trend towards an overall improvement in cosmetic satisfaction following surgical treatment of SSC was observed. Reported PROMs included general health, socioeconomic status, patients' and their families' rating of the normalcy and noticeability of their appearance and how much this bothered them, and patients' answers to the Youth Quality of Life with Facial Differences (YQOL-FD) questionnaire. No clear overall trend of the reported PROMs was identified. CONCLUSION: This systematic review illuminates that there is a wide variation in outcomes for evaluating cosmetic satisfaction and other PROMs of patients who underwent surgical treatment of SSC, suggesting that further research is needed to develop an inclusive and uniform approach to assess these outcomes.

Cranial decompression and expansion surgery for the treatment of refractory idiopathic intracranial hypertension: case report and systematic review.

OBJECTIVE: The purpose of this study is to systematically review the literature on the clinical outcomes following different surgical techniques in patients with refractory idiopathic intracranial hypertension (IIH). BACKGROUND: IIH is a condition characterised by increased cranial pressure (ICP) in the absence of an intracranial lesion that does not adequately respond to different medical and surgical therapies. Cranial decompression or expansion surgeries are a last resort therapy for patients with refractory IIH. METHODS: A systematic literature search of the databases of PubMed, Embase and Medline from inception to 2019 was performed. Searches were limited to the English language and to clinical studies. Studies were included if clinical outcomes following different cranial decompression or expansion techniques were reported. We also add one case of our own experience with performing a bilateral frontoparietal expansion craniotomy and subtemporal craniectomy. RESULTS: Five manuscripts, describing 38 procedures, met the inclusion criteria. Thirty-one patients were female (82%). The mean age was 26.2 years. The techniques studied included subtemporal craniectomy (27/38, 71%), internal cranial expansion (10/38, 26%), and cranial morcellation decompression (1/38, 3%). Thirty-five patients presented with headaches of which 17 noted postoperative improvement or resolution (49%). Visual deficits were documented in 30 patients and 25 reported postoperative improvement (83%). Papilledema disappeared in 23 of 32 patients with this sign at presentation (72%). In our patient, symptoms completely resolved postoperatively and a 6% increase in intracranial volume was measured. CONCLUSIONS: Cranial vault decompression or expansion surgeries may be an effective last resort therapy for patients with refractory IIH. These surgeries expand the intracranial volume, and thus may normalise ICP, leading to clinical improvement.

AGE-RELATED MACULAR DEGENERATION - CURRENT STATE OF THE PROBLEM AND PROPHYLAXIS METHODS.

OBJECTIVE: The aim: Analyze the ophthalmic studies on diagnostics and treatment of patients with age-related macular degeneration to optimize diagnostics and management tactics. PATIENTS AND METHODS: Materials and methods: The analysis of scientific papers due to age-related macular degeneration, vitamin D and its functions from scientometric databases: PubMed, Scopus, Web of Science. The methods were next: systematic approach, analysis, summarization and comparison. CONCLUSION: Conclusions: Age-related macular degeneration is a chronic, progressive disease among people older than 50 years. Late diagnostics and inappropriate treatment may lead to irreversible central vision loss and social disadaptation. Modern studies on the pathogenesis and treatment of this pathology (that are due to the role of the immune system, antioxidants and microelements) demonstrate the effectiveness and prospects for further development around the world to find new ways to solve this problem.

BIOFILM FORMING ACTIVITY OF NON-FERMENTING GRAM-NEGATIVE BACTERIA.

OBJECTIVE: The aim: To study the influence of chemical, physical factors on the biofilm forming activity of P. aeruginosa, A. baumannii. PATIENTS AND METHODS: Materials and methods: Biofilm forming activity of P. aeruginosa (10 isolates) and A. baumannii (10 isolates) was studied in nutrient media of different composition. There was used the method in 96-well crystalline violet staining plates with spectrophotometry (STAT FAX®4300, wavelength of 620 nm). RESULTS: Results: Results showed that in standard medium (trypto-soy broth), strains of P. aeruginosa (90%) and A. baumannii (60%) obtained high biofilm forming activity. A. baumannii formed biofilms even in sterile water. Biofilm forming activity of urease positive P. aeruginosa increased in the medium with 1.0% urea. Both Acinetbacteria and Pseudomonas intensively produced their biofilms in the presence of 5% serum or sub-bacteriostatic concentrations of levofloxacin in the media. High concentrations of sodium chloride inhibited their biofilm activity. CONCLUSION: Conclusions: Isolates of Acinetobacter and Pseudomonas obtain the protective biofilm-forming ability under such adverse environmental conditions as insufficient nutrients, high osmotic pressure, the presence of antibiotics but at high concentrations sodium chloride biofilm-formation is stimulated only in the first bacteria and suppressed in the second one.

Cranioplasty after craniectomy in pediatric patients-a systematic review.

INTRODUCTION: Complications following cranioplasty with either autografts or cranial implants are commonly reported in pediatric patients. However, data regarding cranioplasty strategies, complications and long-term outcomes are not well described. This study systematically reviews the literature for an overview of current cranioplasty practice in children. METHODS: A systematic review of articles published from inception to July 2018 was performed. Studies were included if they reported the specific use of cranioplasty materials following craniectomy in patients younger than 18 years of age, and had a minimum follow-up of at least 1 year. RESULTS: Twenty-four manuscripts, describing a total of 864 cranioplasty procedures, met the inclusion criteria. The age of patients in this aggregate ranged from 1 month to 20 years and the weighted average was 8.0 years. The follow-up ranged from 0.4 months to 18 years and had a weighted average of 40.4 months. Autologous bone grafts were used in 484 cases (56.0%). Resorption, infection and/or hydrocephalus were the most frequently mentioned complications. In this aggregate group, 61 patients needed a revision cranioplasty. However, in 6/13 (46%) papers studying autologous cranioplasties, no data was provided on resorption, infection and revision cranioplasty rates. Cranial implants were used in 380 cases (44.0%), with custom-made porous hydroxyapatite being the most commonly used material (100/380, 26.3%). Infection and migration/fracturing/loosening were the most frequently documented complications. Eleven revision cranioplasties were reported. Again, no data was reported on infection and revision cranioplasty rates, in 7/16 (44%) and 9/16 (56%) of papers, respectively. CONCLUSION: Our systematic review illuminates that whether autografts or cranial implants are used, postcranioplasty complications are quite common. Beyond this, the existing literature does not contain well documented and comparable outcome parameters, suggesting that prospective, long-term multicenter cohort studies are needed to be able to optimize cranioplasty strategies in children who will undergo cranioplasty following craniectomy.

Cranioplasties following craniectomies in children-a multicenter, retrospective cohort study.

OBJECTIVE: Complications following pediatric cranioplasty after craniectomy with either autologous bone flaps or cranial implants are reported to be common, particularly bone flap resorption. However, only sparse data are available regarding cranioplasty strategies, complications, and outcomes. This manuscript describes a Canadian-Dutch multicenter pediatric cohort study with autografts and cranial implant cranioplasties following craniectomies for a variety of indications. METHODS: The study included all children (< 18 years) who underwent craniectomy and subsequent cranioplasty surgeries from 2008 to 2014 (with a minimum of 1-year follow-up) at four academic hospitals with a dedicated pediatric neurosurgical service. Data were collected regarding initial diagnosis, age, time interval between craniectomy and cranioplasty, bone flap storage method, type of cranioplasty for initial procedure (and redo if applicable), and the postoperative outcome including surgical site infection, wound breakdowns, bone flap resorption, and inadequate fit/disfigurement. RESULTS: Sixty-four patients (46 males, average age 9.7 ± 5.5 years) were eligible for inclusion, with mean follow-up of 82.3 ± 31.2 months after craniectomy. Forty cranioplasties (62.5%) used autologous bone re-implant, 23 (57.5%) of which showed resorption. On average, resorption was documented at 434 days (range 62-2796 days) after reimplantation. In 20 cases, a revision cranioplasty was needed. In 24 of the post-craniectomy cases (37.5%), a cranial implant was used with one of ten different implant types. Implant loosening prompted a complete revision cranioplasty in 2 cases (8.3%). Cranial implants were associated with low morbidity and lower reoperation dates compared to the autologous cranioplasties. CONCLUSION: The most prominent finding in this multicenter cohort study was that bone flap resorption in children remains a common and widespread problem following craniectomy. Cranioplasty strategies varied between centers and evolved over time within centers. Cranial implants were associated with low morbidity and low reoperation rates. Still, longer term and prospective multicenter cohort studies are needed to optimize cranioplasty strategies in children after craniectomies.

Clostridium difficile infection in children: epidemiology and risk of recurrence in a low-prevalence country.

Clostridium difficile infection (CDI) is increasingly found in children worldwide, but limited data are available from children living in southern Europe. A 6-year retrospective study was performed to investigate the epidemiology, clinical features, treatment, and risk of recurrence in Italy. Data of children with community- and hospital-acquired CDI (CA-CDI and HA-CDI, respectively) seen at seven pediatric referral centers in Italy were recorded retrospectively. Annual infection rates/10,000 hospital admissions were calculated. Logistic regression was used to investigate risk factors for recurrence. A total of 177 CDI episodes was reported in 148 children (83 males, median age 55.3 months), with a cumulative infection rate of 2.25/10,000 admissions, with no significant variability over time. The majority of children (60.8 %) had CA-CDI. Children with HA-CDI (39.2 %) had a longer duration of symptoms and hospitalization (p = 0.003) and a more common previous use of antibiotics (p = 0.0001). Metronidazole was used in 70.7 % of cases (87/123) and vancomycin in 29.3 % (36/123), with similar success rates. Recurrence occurred in 16 children (10.8 %), and 3 (2 %) of them presented a further treatment failure. The use of metronidazole was associated with a 5-fold increase in the risk of recurrence [odds ratio (OR) 5.18, 95 % confidence interval (CI) 1.1-23.8, p = 0.03]. Short bowel syndrome was the only underlying condition associated with treatment failure (OR 5.29, 95 % CI 1.17-23.8, p = 0.03). The incidence of pediatric CDI in Italy is low and substantially stable. In this setting, there is a limited risk of recurrence, which mainly concerns children treated with oral metronidazole and those with short bowel syndrome.

Efficacy of focal adhesion kinase inhibition in non-small cell lung cancer with oncogenically activated MAPK pathways.

BACKGROUND: Focal adhesion kinase (FAK) is overexpressed in many types of tumours, including lung cancer. Y15, a small molecule which inhibits Y397 FAK autophosphorylation, decreases growth of human neuroblastoma, breast and pancreatic cancers. In this study, we investigated the in vitro and in vivo effects of Y15, and the underlying mechanism on non-small cell lung cancer cells. METHODS: The cytotoxic effects of Y15 targeting FAK signalling were evaluated. Gene-knockdown experiments were performed to determine the anti-cancer mechanism. Xenografts with RAS or EGFR mutations were selected for in vivo Y15 treatment. RESULTS: Y15 blocked autophosphorylation of FAK in a time- and dose-dependent manner. It caused dose-dependent decrease of lung cancer cell viability and clonogenicity. Y15 inhibited tumour growth of RAS-mutant (A549 with KRAS mutation and H1299 with NRAS mutation), as well as epidermal growth factor receptor (EGFR) mutant (H1650 and H1975) lung cancer xenografts. JNK activation is a mechanism underlying Y15-induced Bcl-2 and Mcl-1 downregulation. Moreover, knockdown of Bcl-2 or Bcl-xL potentiated the effects of Y15. The combination of various inhibitors of the Bcl-2 family of proteins with FAK inhibitors demonstrated synergy in multiple lung cancer cell lines in vitro. CONCLUSIONS: FAK inhibition demonstrated efficacy both in vitro and in vivo in lung cancers with either oncogenic RAS or EGFR mutations. In addition, FAK inhibition in combination with inhibitors of Bcl-2 family of anti-apoptotic proteins has synergistic activity in these MAPK-activated non-small cell lung cancer cell line models.

The vertebrate-specific Kinesin-6, Kif20b, is required for normal cytokinesis of polarized cortical stem cells and cerebral cortex size.

Mammalian neuroepithelial stem cells divide using a polarized form of cytokinesis, which is not well understood. The cytokinetic furrow cleaves the cell by ingressing from basal to apical, forming the midbody at the apical membrane. The midbody mediates abscission by recruiting many factors, including the Kinesin-6 family member Kif20b. In developing embryos, Kif20b mRNA is most highly expressed in neural stem/progenitor cells. A loss-of-function mutant in Kif20b, magoo, was found in a forward genetic screen. magoo has a small cerebral cortex, with reduced production of progenitors and neurons, but preserved layering. In contrast to other microcephalic mouse mutants, mitosis and cleavage furrows of cortical stem cells appear normal in magoo. However, apical midbodies show changes in number, shape and positioning relative to the apical membrane. Interestingly, the disruption of abscission does not appear to result in binucleate cells, but in apoptosis. Thus, Kif20b is required for proper midbody organization and abscission in polarized cortical stem cells and has a crucial role in the regulation of cerebral cortex growth.

Rootstock-scion interaction affecting citrus response to CTV infection: a proteomic view.

Citrus tristeza virus (CTV) is the causal agent of various diseases with dramatic effects on citrus crops worldwide. Most Citrus species, grown on their own roots, are symptomless hosts for many CTV isolates. However, depending on different scion-rootstock combination, CTV infection should result in distinct syndromes, being 'tristeza' the more severe one, leading to a complete decline of the susceptible plants in a few weeks. Transcriptomic analyses revealed several genes involved either in defense response, or systemic acquired resistance, as well as transcription factors and components of the phosphorylation cascades, to be differentially regulated during CTV infection in Citrus aurantifolia species. To date little is known about the molecular mechanism of this host-pathogen interaction, and about the rootstock effect on citrus response to CTV infection. In this work, the response to CTV infection has been investigated in tolerant and susceptible scion-rootstock combinations by two-dimensional gel electrophoresis (2DE). A total of 125 protein spots have been found to be differently accumulated and/or phosphorylated between the two rootstock combinations. Downregulation in tolerant plants upon CTV infection was detected for proteins involved in reactive oxygen species (ROS) scavenging and defense response, suggesting a probable acclimation response able to minimize the systemic effects of virus infection. Some of these proteins resulted to be modulated also in absence of virus infection, revealing a rootstock effect on scion proteome modulation. Moreover, the phospho-modulation of proteins involved in ROS scavenging and defense response, further supports their involvement either in scion-rootstock crosstalk or in the establishment of tolerance/susceptibility to CTV infection.

Synthesis and bioactivity of a Goralatide analog with antileukemic activity.

Natural tetrapeptide Goralatide (AcSDKP) is a selective inhibitor of primitive haematopoietic cell proliferation. It is not stable in vivo and decomposes within 4.5min when applied to live cells. In this work we developed an analog of Goralatide that exhibits cytotoxicity towards human myeloid HL-60, HEL, Nalm-6 leukemia cells, endothelial HUVEC, glioblastoma U251 and transformed kidney 293T cells. The Goralatide analog showed significant stability in organic solution with no tendency to degrade oxidatively.

High focal adhesion kinase expression in breast carcinoma is associated with lymphovascular invasion and triple-negative phenotype.

BACKGROUND: Focal adhesion Kinase (FAK) is a nonreceptor protein tyrosine kinase that is overexpressed in tumors and plays a significant role in tumor survival and metastasis. The purpose of the study is to perform correlation of FAK expression with patient prognostic factors using tissue microarrays (TMA) samples. METHODS: We analyzed FAK expression by immunohistochemical staining in 196 breast primary tumor samples from stage II-IV patients and in 117 metastatic tissues matched to the primary tumors using TMA that were stained with FAK monoclonal antibody. RESULTS: High FAK expression in primary tumors was associated with a younger age of patients (p = 0.033), lymphovascular invasion (p = 0.001) and with the triple-negative phenotype (p = 0.033). FAK expression in 117 metastatic tissues positively correlated with FAK expression in matched primary tumors by Spearman correlation analysis. In addition, a strong positive correlation was observed between high FAK expression and shorter overall survival and progression free survival in patients with metastatic tumors. CONCLUSIONS: The data demonstrate a high potential for FAK as a therapeutic target, especially in triple-negative breast cancer patients with high FAK expression.

Performance of Fully-Automated High-Throughput Plasma Biomarker Assays for Alzheimer's Disease in Amnestic Mild Cognitive Impairment Subjects.

INTRODUCTION: Novel plasma biomarkers are promising for identifying Alzheimer's disease (AD) pathological processes in vivo, but most currently employed assays have limitations precluding widespread use. METHODS: CSF and plasma samples were collected from seventy amnestic mild cognitive impairment (aMCI) subjects, stratified as A+ and A-. CSF Aß40, Aß42, p-tau181 and t-tau and plasma Aß40, Aß42 and p-tau181 quantification were conducted using the Lumipulse G assays (Fujirebio), to evaluate the diagnostic performance of plasma biomarkers and assess their associations with CSF biomarkers. RESULTS: All plasma biomarkers except Aß40 showed a very good accuracy in distinguishing A+ aMCI from A- aMCI, Aß42/p-tau181 ratio being the most accurate (AUC 0.895, sensitivity 95.1%, specificity 82.8%). Plasma biomarkers levels were significantly associated with CSF biomarkers concentration. DISCUSSION: High-throughput and fully-automated plasma assays could be helpful in discriminating with high accuracy between aMCI in the AD continuum and aMCI unlikely due to AD in clinical settings.

Nanog increases focal adhesion kinase (FAK) promoter activity and expression and directly binds to FAK protein to be phosphorylated.

Nanog and FAK were shown to be overexpressed in cancer cells. In this report, the Nanog overexpression increased FAK expression in 293, SW480, and SW620 cancer cells. Nanog binds the FAK promoter and up-regulates its activity, whereas Nanog siRNA decreases FAK promoter activity and FAK mRNA. The FAK promoter contains four Nanog-binding sites. The site-directed mutagenesis of these sites significantly decreased up-regulation of FAK promoter activity by Nanog. EMSA showed the specific binding of Nanog to each of the four sites, and binding was confirmed by ChIP assay. Nanog directly binds the FAK protein by pulldown and immunoprecipitation assays, and proteins co-localize by confocal microscopy. Nanog binds the N-terminal domain of FAK. In addition, FAK directly phosphorylates Nanog in a dose-dependent manner by in vitro kinase assay and in cancer cells in vivo. The site-directed mutagenesis of Nanog tyrosines, Y35F and Y174F, blocked phosphorylation and binding by FAK. Moreover, overexpression of wild type Nanog increased filopodia/lamellipodia formation, whereas mutant Y35F and Y174F Nanog did not. The wild type Nanog increased cell invasion that was inhibited by the FAK inhibitor and increased by FAK more significantly than with the mutants Y35F and Y174F Nanog. Down-regulation of Nanog with siRNA decreased cell growth reversed by FAK overexpression. Thus, these data demonstrate the regulation of the FAK promoter by Nanog, the direct binding of the proteins, the phosphorylation of Nanog by FAK, and the effect of FAK and Nanog cross-regulation on cancer cell morphology, invasion, and growth that plays a significant role in carcinogenesis.

Disruption of focal adhesion kinase and p53 interaction with small molecule compound R2 reactivated p53 and blocked tumor growth.

BACKGROUND: Focal Adhesion Kinase (FAK) is a 125 kDa non-receptor kinase that plays a major role in cancer cell survival and metastasis. METHODS: We performed computer modeling of the p53 peptide containing the site of interaction with FAK, predicted the peptide structure and docked it into the three-dimensional structure of the N-terminal domain of FAK involved in the complex with p53. We screened small molecule compounds that targeted the site of the FAK-p53 interaction and identified compounds (called Roslins, or R compounds) docked in silico to this site. RESULTS: By different assays in isogenic HCT116p53+/+ and HCT116 p53-/- cells we identified a small molecule compound called Roslin 2 (R2) that bound FAK, disrupted the binding of FAK and p53 and decreased cancer cell viability and clonogenicity in a p53-dependent manner. In addition, dual-luciferase assays demonstrated that the R2 compound increased p53 transcriptional activity that was inhibited by FAK using p21, Mdm-2, and Bax-promoter targets. R2 also caused increased expression of p53 targets: p21, Mdm-2 and Bax proteins. Furthermore, R2 significantly decreased tumor growth, disrupted the complex of FAK and p53, and up-regulated p21 in HCT116 p53+/+ but not in HCT116 p53-/- xenografts in vivo. In addition, R2 sensitized HCT116p53+/+ cells to doxorubicin and 5-fluorouracil. CONCLUSIONS: Thus, disruption of the FAK and p53 interaction with a novel small molecule reactivated p53 in cancer cells in vitro and in vivo and can be effectively used for development of FAK-p53 targeted cancer therapy approaches.

Dissemination metastasis after laparoscopic colorectal surgery versus conventional open surgery for colorectal cancer: a metanalysis.

PURPOSE: The purpose of this systematic review is to evaluate and compare the risk of dissemination metastasis (wound, port-side metastases and peritoneal seeding) after laparoscopic colorectal surgery and conventional open surgery for colorectal cancer. MATERIALS AND METHODS: The Authors searched relevant randomized controlled trials between January 1998 and July 2012. RESULTS: Wound, port-site metastases and peritoneal seeding were rare and no significant differences occurred between the two groups. The port-site and extraction site recurrence were likely to be the results of suboptimal surgical techniques and occurred in the early phase of the learning curve. The authors also found no significant differences in overall, local and distant recurrences. No significant differences between laparoscopic and open surgery were found in cancer-related mortality during the follow up period of the study (7 RCTs, 3525 patients, 12.8% vs. 14.00%; OR (fixed) 0.83, 95% CI 0.68-1.02), with no significant heterogeneity (p = 0.35). CONCLUSIONS: The literature supports the implementation of laparoscopic surgery into daily practice. Laparoscopic surgery can be used for safe and radical resection of cancer in the right, left, sigmoid colon and rectum. However further studies should address whether laparoscopic surgery is superior to open surgery in this setting.

Development of a Prediction Model for Cranioplasty Implant Survival Following Craniectomy.

BACKGROUND: Cranioplasty after craniectomy can result in high rates of postoperative complications. Although determinants of postoperative outcomes have been identified, a prediction model for predicting cranioplasty implant survival does not exist. Thus, we sought to develop a prediction model for cranioplasty implant survival after craniectomy. METHODS: We performed a retrospective cohort study of patients who underwent cranioplasty following craniectomy between 2014 and 2020. Missing data were imputed using multiple imputation. For model development, multivariable Cox proportional hazards regression analysis was performed. To test whether candidate determinants contributed to the model, we performed backward selection using the Akaike information criterion. We corrected for overfitting using bootstrapping techniques. The performance of the model was assessed using discrimination and calibration. RESULTS: A total of 182 patients were included (mean age, 43.0 ± 19.7 years). Independent determinants of cranioplasty implant survival included the indication for craniectomy (compared with trauma-vascular disease: hazard ratio [HR], 0.65 [95% confidence interval (CI), 0.36-1.17]; infection: HR, 0.76 [95% CI, 0.32-1.80]; tumor: HR, 1.40 [95% CI, 0.29-6.79]), cranial defect size (HR, 1.01 per cm2 [95% CI, 0.73-1.38]), use of an autologous bone flap (HR, 1.63 [95% CI, 0.82-3.24]), and skin closure using staples (HR, 1.42 [95% CI, 0.79-2.56]). The concordance index of the model was 0.60 (95% CI, 0.47-0.73). CONCLUSIONS: We have developed the first prediction model for cranioplasty implant survival after craniectomy. The findings from our study require external validation and deserve further exploration in future studies.

Cosmetic satisfaction and patient-reported outcome measures following cranioplasty after craniectomy - A prospective cohort study.

Introduction: Evaluating patient-reported outcomes (PROMs) helps optimize preoperative counseling and psychosocial care for patients who underwent cranioplasty. Research question: This study aimed to evaluate cosmetic satisfaction, level of self-esteem, and fear of negative evaluation (FNE) of patients who underwent cranioplasty. Material and methods: Patients who underwent cranioplasty from 1 January 2014 to 31 December 2020 â€‹at University Medical Center Utrecht and a control group consisting of our center' employees were invited to fill out the Craniofacial Surgery Outcomes Questionnaire (CSO-Q), consisting of an assessment of cosmetic satisfaction, the Rosenberg Self-Esteem Scale (RSES), and the FNE scale. To test for differences in results, chi-square tests and T-tests were performed. Logistic regression was used to study the effect of cranioplasty-related variables on cosmetic satisfaction. Results: Cosmetic satisfaction was seen in 44/80 patients (55.0%) and 52/70 controls (74.3%) (p â€‹= â€‹0.247). Thirteen patients (16.3%) and 8 controls (11.4%) had high self-esteem (p â€‹= â€‹0.362), 51 patients (63.8%) and 59 controls (84.3%) had normal self-esteem (p â€‹= â€‹0.114), and 7 patients (8.8%) and 3 controls (4.3%) had low self-esteem (p â€‹= â€‹0.337). Forty-nine patients (61.3%) and 39 controls (55.7%) had low FNE (p â€‹= â€‹0.012), 8 patients (10.0%) and 18 controls (25.7%) had average FNE (p â€‹= â€‹0.095), and 6 patients (7.5%) and 13 controls (18.6%) had high FNE (p â€‹= â€‹0.215). Cosmetic satisfaction was associated with glass fiber-reinforced composite implants (OR 8.20, p-value â€‹= â€‹0.04). Discussion and conclusion: This study prospectively evaluated PROMs following cranioplasty, for which we found favorable results.