The prognostic significance of tumor budding and the expression of focal adhesion kinase and survivin in lung adenocarcinoma.

OBJECTIVES: Adenocarcinoma is the tumor group with the highest incidence among lung cancers with poor prognosis. Tumor budding (TB) is the migration of single tumor cells or small clusters of cells from the neoplastic epithelium to the invasive front of the tumor. Focal adhesion kinase (FAK) and survivin are considered as poor prognostic factors in several tumors. Hence, we investigated TB, FAK, and survivin expression in lung adenocarcinoma. METHODS: The study included 103 cases of lung adenocarcinoma in the resection materials. In tumoral tissues; TB was counted and scored in one high-power field (HPF), as low if <5 in 1 HPF and high if ≥5 in 1 HPF. FAK and survivin were studied immunohistochemically. RESULTS: The mean number of TB in 1 HPF is 3.96 ± 2.8. Low-grade TB was observed in 45 (43.7 %) and high-grade TB was observed in 58 (56.3 %) patients. There was a positive correlation between TB and pT stage (p = 0.017), clinical stage (p = 0.002), lymphovascular invasion (p = 0.001), and perineural invasion (p = 0.045). The 4-year survival rate in patients was 90 % in those with low-grade TB and 60 % in those with high-grade TB (p = 0.001). FAK and survivin expressions were significantly increased in tumors with high-grade TB (p < 0.05). CONCLUSION: A significant correlation was found between the grade of TB and pT stage, clinical stage, lymphovascular and perineural invasion in lung adenocarcinoma. TB can be considered as a histological parameter showing poor prognosis. It is thought that high expression of FAK and survivin also affect the prognosis in these patients by increasing TB.

COVID-19 outcomes in patients with antiphospholipid syndrome: a retrospective cohort study.

BACKGROUND: Aim of this study is to investigate COVID-19 outcomes in patients with antiphospholipid syndrome (APS). METHODS: A retrospective cohort was formed from APS patients. Patients were screened for a record of positive SARS-CoV 2 PCR. In PCR­positive patients, clinical data and information regarding COVID-19 outcomes were collected from medical records. RESULTS: A positive PCR test was detected in 9/53 APS patients, while 66.7 %, 33.3 % and 11.1 % of APS patients with COVID-19 were under hydroxychloroquine, LMWH or warfarin, and acetylsalicylic acid, respectively. There were 3/9 patients found to be hospitalized and one died. No new thrombotic event was reported in any of the patients during COVID-19 infection. CONCLUSION: Baseline use of hydroxychloroquine, antiaggregants and anticoagulants may be associated with an absence of new thrombotic event (Tab. 2, Ref. 33).

The effect of erosive beverages and polishing systems on the surface properties of nanohybrid composite resin.

Aims and Background: The aim of this study is to evaluate the surface microhardness and roughness of composites treated with three different polishing systems exposed to two different corrosive beverages. Material and Methods: Ninety-six composite resin disks were randomly divided into four groups, one of which was the control group. The surface roughness and microhardness values were measured after 24 h in the polishing process. The samples were divided into three subgroups and kept in distilled water, cola, and ice tea for 20 min a day for 14 days. Then, the roughness and microhardness measurements of the samples were taken again. Two samples randomly selected from each group were examined using a scanning electron microscope (SEM) and analyzed statistically using the two way anova (ANOVA) and Duncan tests. Results: A statistically significant difference was found between the roughness and hardness values at the end of 24 h and 14 days. Onegloss (OG), Dentoflex (DF), and Super-snap (SNP) polish systems showed the highest roughness in the cola group, respectively. Microhardness values: The unpolished group had the lowest significant microhardness in the coke group (P < 0.05). Conclusion: In this study, it was seen that the lowest success rate was the OG polishing system.

Association between focal adhesion kinase and matrix metalloproteinase-9 expression in prostate adenocarcinoma and their influence on the progression of prostatic adenocarcinoma.

Focal adhesion kinase (FAK), a member of the non-receptor cytoplasmic tyrosine kinase family, is associated with the development and progression of cancer. Matrix metalloproteinase-9 (MMP-9) is directly involved in the degradation of the extracellular matrix, and basement membrane components promote cancer cell migration and invasion. There is a functional interaction among FAK, MMP-9 and vascular endothelial growth factor (VEGF), which leads to enhanced cancer angiogenesis, cancer cell invasion and progression of malignancy. FAK, MMP-9, VEGF and CD34-positive microvessel density (MVD) were examined in 100 patients with prostate adenocarcinoma using immunohistochemistry. The relationship among these proteins and their impact on angiogenesis and clinicopathological parameters were also evaluated. The FAK expression was found to be positively correlated with the Gleason score, WHO grade group, tumour stage, extracapsular extension and perineural invasion. The MMP-9 expression was positively correlated with the WHO grade group, tumour stage, extracapsular extension, positive surgical margin and lymphovascular and perineural invasion. The FAK expression was also positively correlated with MMP-9 expression and MVD. However, no correlation between FAK and VEGF expression was identified. The MMP-9 expression was positively correlated with FAK expression and MVD. Strong MMP-9 expression was associated with shorter disease-free survival. These results suggest that strong MMP-9 and FAK expressions play an essential role in the progression of prostate adenocarcinoma. Further investigations should be conducted to determine the importance of these proteins as therapeutic targets for patients with prostate adenocarcinomas.

Gender medicine and oncology: report and consensus of an ESMO workshop.

BACKGROUND: The importance of sex and gender as modulators of disease biology and treatment outcomes is well known in other disciplines of medicine, such as cardiology, but remains an undervalued issue in oncology. Considering the increasing evidence for their relevance, European Society for Medical Oncology decided to address this topic and organized a multidisciplinary workshop in Lausanne, Switzerland, on 30 November and 1 December 2018. DESIGN: Twenty invited faculty members and 40 selected physicians/scientists participated. Relevant content was presented by faculty members on the basis of a literature review conducted by each speaker. Following a moderated consensus session, the final consensus statements are reported here. RESULTS: Clinically relevant sex differences include tumour biology, immune system activity, body composition and drug disposition and effects. The main differences between male and female cells are sex chromosomes and the level of sexual hormones they are exposed to. They influence both local and systemic determinants of carcinogenesis. Their effect on carcinogenesis in non-reproductive organs is largely unknown. Recent evidence also suggests differences in tumour biology and molecular markers. Regarding body composition, the difference in metabolically active, fat-free body mass is one of the most prominent: in a man and a woman of equal weight and height, it accounts for 80% of the man's and 65% of the woman's body mass, and is not taken into account in body-surface area based dosing of chemotherapy. CONCLUSION: Sex differences in cancer biology and treatment deserve more attention and systematic investigation. Interventional clinical trials evaluating sex-specific dosing regimens are necessary to improve the balance between efficacy and toxicity for drugs with significant pharmacokinetic differences. Especially in diseases or disease subgroups with significant differences in epidemiology or outcomes, men and women with non-sex-related cancers should be considered as biologically distinct groups of patients, for whom specific treatment approaches merit consideration.

Clinical examination and non-invasive screening tests in the diagnosis of peripheral artery disease in people with diabetes-related foot ulceration.

AIM: Peripheral artery disease is common in people with diabetes-related foot ulceration and is a risk factor for amputation. The best method for the detection or exclusion of peripheral artery disease is unknown. This study investigated the utility of clinical examination and non-invasive bedside tests in screening for peripheral artery disease in diabetes-related foot ulceration. METHODS: Some 60 people presenting with new-onset ulceration participated. Accuracy of pulses, ankle pressure, toe pressure, toe-brachial index (TBI), ankle-brachial pressure index (ABPI), pole test at ankle, transcutaneous oxygen pressure and distal tibial waveform on ultrasound were examined. The gold standard diagnostic test used was > 50% stenosis in any artery or monophasic flow distal to calcification in any ipsilateral vessel on duplex ultrasound. RESULTS: The negative and positive likelihood ratios of pedal pulse assessment (0.75, 1.38) and the other clinical assessment tools were poor. The negative and positive likelihood ratios of ABPI (0.53, 1.69), transcutaneous oxygen pressure (1.10, 0.81) and ankle pressure (0.67, 2.25) were unsatisfactory. The lowest negative likelihood ratios were for tibial waveform assessment (0.15) and TBI (0.24). The highest positive likelihood ratios were for toe pressure (17.55) and pole test at the ankle (10.29) but the negative likelihood ratios were poor at 0.56 and 0.74. CONCLUSIONS: Pulse assessment and ABPI have limited utility in the detection of peripheral artery disease in people with diabetes foot ulceration. TBI and distal tibial waveforms are useful for selecting those needing diagnostic testing.

Using PVA and TPGS as combined emulsifier in nanoprecipitation method improves characteristics and anticancer activity of ibuprofen loaded PLGA nanoparticles.

In the preparation of nanoparticles (NPs) by the nanoprecipitation method, emulsifiers play a key role for NPs' characteristics. The present study aimed to investigate the combined emulsifier effect on ibuprofen loaded poly(lactic-co-glycolic acid) (PLGA) NPs' characteristics and anticancer activity. Ibuprofen loaded PLGA NPs were prepared by nanoprecipitation using different concentrations of PVA (poly(vinyl alcohol)) or PVA-TPGS (d-α-tocopherol polyethylene glycol 1000 succinate) combination as emulsifier. It was found that encapsulation efficiencies of NPs varied between 17.9 and 41.9 % and the highest encapsulation efficiency was obtained with 0.5% PVA + 0.1% TPGS (coded as PLGA PVA/TPGS NPs). PLGA PVA/TPGS NPs were characterized and compared with PLGA PVA NPs, which was obtained by 0.5% PVA alone. Polydispersity index of PLGA PVA/TPGS and PLGA PVA NPs were found to be 0.08 and 0.15, respectively. Incorporation of TPGS with PVA slightly decreased the initial ibuprofen release. Transmission electron microscopy analyses demonstrated a nearly uniform particle size distribution and spherical particle shape of the PLGA PVA/TPGS NPs. Additionally, PLGA PVA/TPGS NPs were significantly more cytotoxic than PLGA PVA NPs on the MCF-7 (human breast adenocarcinoma cells) and Caco-2 (human epithelial colorectal adenocarcinoma) cells (p<0.05). Also PLGA PVA/TPGS NPs were not cytotoxic on normal cells (L929, mouse healthy fibroblast cells) (p>0.05). In conclusion, these results indicated that using a combination of TPGS and PVA as an emulsifier in nanoprecipitation could be a promising approach for preparing ibuprofen loaded PLGA NPs because of their improved characteristics and anticancer activity.

Smoking and gingivitis: focus on inducible nitric oxide synthase, nitric oxide and basic fibroblast growth factor.

BACKGROUND: Periodontal disease pathogenesis has been associated with smoking. Gingivitis is a mild and reversible form of periodontal disease and it tends to progress to periodontitis only in susceptible individuals. In the present study, we aimed to examine the impact of smoking on host responses in gingivitis and to evaluate and compare the inducible nitric oxide synthase (iNOS) activity in gingival tissue and NO and basic fibroblast growth factor (bFGF) levels in the gingival crevicular fluid of patients with gingivitis and healthy individuals. MATERIAL AND METHODS: Forty-one participants were assigned to the gingivitis-smoker (n = 13), gingivitis (n = 13), healthy-smoker (n = 7) and healthy groups (n = 8). Clinical indices were recorded; gingival biopsy and gingival crevicular fluid samples were obtained from papillary regions. iNOS expression was evaluated by immunohistochemical staining. The immunoreactive cells were semiquantitatively assessed. For the quantitative determination of nitrite and nitrate in gingival crevicular fluid, the NO assay kit was used. The amount of bFGF in gingival crevicular fluid was determined by enzyme-linked immunosorbent assay. RESULTS: The gingivitis-smoker group demonstrated a stronger iNOS expression than the non-smoker gingivitis group. iNOS expression intensity was lower in the non-smoker healthy group compared to that in healthy-smokers. No significant gingival crevicular fluid NO and bFGF level changes were observed between groups. Among patients with gingivitis, a positive correlation was detected between gingival crevicular fluid NO and bFGF levels (r = 0.806, p = 0.001). CONCLUSIONS: Our data suggest that smoking has significant effects on iNOS expression but not on gingival crevicular fluid NO or bFGF levels in healthy and patients with gingivitis. However, our results suggest that bFGF might be involved in the regulation of NO production via iNOS.

Mortality of emergency general surgical patients and associations with hospital structures and processes.

BACKGROUND: Variations in patient outcomes between providers have been described for emergency admissions, including general surgery. The aim of this study was to investigate whether differences in modifiable hospital structures and processes were associated with variance in mortality, amongst patients admitted for emergency colorectal laparotomy, peptic ulcer surgery, appendicectomy, hernia repair and pancreatitis. METHODS: Adult emergency admissions in the English NHS were extracted from the Hospital Episode Statistics between April 2005 and March 2010. The association between mortality and structure and process measures including medical and nursing staffing levels, critical care and operating theatre availability, radiology utilization, teaching hospital status and weekend admissions were investigated. RESULTS: There were 294 602 emergency admissions to 156 NHS Trusts (hospital systems) with a 30-day mortality of 4.2%. Trust-level mortality rates for this cohort ranged from 1.6 to 8.0%. The lowest mortality rates were observed in Trusts with higher levels of medical and nursing staffing, and a greater number of operating theatres and critical care beds relative to provider size. Higher mortality rates were seen in patients admitted to hospital at weekends [OR 1.11 (95% CI 1.06-1.17) P<0.0001], in Trusts with fewer general surgical doctors [1.07 (1.01-1.13) P=0.019] and with lower nursing staff ratios [1.07 (1.01-1.13) P=0.024]. CONCLUSIONS: Significant differences between Trusts were identified in staffing and other infrastructure resources for patients admitted with an emergency general surgical diagnosis. Associations between these factors and mortality rates suggest that potentially modifiable factors exist that relate to patient outcomes, and warrant further investigation.

Serum vitamin D levels decrease in children with acute urticaria.

BACKGROUND: Acute urticaria is an immune-inflammatory disease, characterised by acute immune activation. There has been increasing evidence showing that vitamin D deficiency is associated with increased incidence and severity of immune-inflammatory disorders. OBJECTIVE: The aim of this study was to evaluate serum vitamin D levels in acute urticaria. METHODS: We enrolled 30 children with acute urticaria and 30 control subjects. Concentrations of 25-hydroxyvitamin D [25(OH)D], a biomarker of vitamin D status, were measured in serum of acute urticaria patients and compared with the control group. RESULTS: There were no significant differences in baseline variables (age, gender, weight) between the groups. Vitamin D deficiency (<20ng/ml) was significantly higher in patients with acute urticaria than in control patients. Serum 25(OH)D levels were significantly lower in the study group compared to those in the control group (13.1±4.3 vs 28.2±7.4ng/mL, p<0.05). Moreover, we found negative correlation between mean duration of acute urticaria and serum vitamin D levels (p<0.01). CONCLUSION: This study revealed a significant association of lower serum 25(OH)D concentrations with acute urticaria and an inverse relationship with disease duration. These findings may open up the possibility of the clinical use of vitamin D as a contributing factor in the pathogenesis of acute urticaria and a predictive marker for disease activity in acute urticaria. A potential role of vitamin D in pathogenesis and additive therapy in acute urticaria needs to be examined.

Association of hospital structures with mortality from ruptured abdominal aortic aneurysm.

BACKGROUND: There is significant variation in the mortality rates of patients with a ruptured abdominal aortic aneurysm (rAAA) admitted to hospital in England. This study sought to investigate whether modifiable differences in hospital structures and processes were associated with differences in patient outcome. METHODS: Patients diagnosed with rAAA between 2005 and 2010 were extracted from the Hospital Episode Statistics database. After risk adjustment, hospitals were grouped into low-mortality outlier, expected mortality and high-mortality outlier categories. Hospital Trust-level structure and process variables were compared between categories, and tested for an association with risk-adjusted 90-day mortality and non-corrective treatment (palliation) rate using binary logistic regression models. RESULTS: There were 9877 patients admitted to 153 English NHS Trusts with an rAAA during the study. The overall combined (operative and non-operative) mortality rate was 67·5 per cent (palliation rate 41·6 per cent). Seven hospital Trusts (4·6 per cent) were high-mortality and 15 (9·8 per cent) were low-mortality outliers. Low-mortality outliers used significantly greater mean resources per bed (doctors: 0·922 versus 0·513, P < 0·001; consultant doctors: 0·316 versus 0·168, P < 0·001; nurses: 2·341 versus 1·770, P < 0·001; critical care beds: 0·045 versus 0·019, P < 0·001; operating theatres: 0·027 versus 0·019, P = 0·002) and performed more fluoroscopies (mean 12·6 versus 9·2 per bed; P = 0·046) than high-mortality outlier hospital Trusts. On multivariable analysis, greater numbers of consultants, nurses and fluoroscopies, teaching status, weekday admission and rAAA volume were independent predictors of lower mortality and, excluding rAAA volume, a lower rate of palliation. CONCLUSION: The variability in rAAA outcome in English National Health Service hospital Trusts is associated with modifiable hospital resources. Such information should be used to inform any proposed quality improvement programme surrounding rAAA.

The association between anti-Müllerian hormone and IVF-ICSI outcome in poor responder patients performing long protocol.

PURPOSE OF INVESTIGATION: Ovarian reserve reflects the capacity of the ovaries for a successful pregnancy. Anti-Müllerian hormone (AMH) could be a useful marker to predict ovarian reserve and to adjust controlled ovarian stimulation. The aim of this study was to assess the relationship between AMH and intracytoplasmic sperm injection-in vitro fertilization (IVF-ICSI) outcome in poor responder women. MATERIALS AND METHODS: This study was conducted prospectively for a period of 12 months. Inclusion criteria were FSH value > 15 iu/l or antral follicle number < 4, on the 2nd day of cycle. All patients underwent GnRH agonist stimulation with long protocol. Serum AMH levels were measured in the treatment cycle just before the stimulation. After the treatment, patients who were pregnant formed the study group and patients who were not pregnant formed the control group. Serum AMH level was the main outcome measure. RESULTS: The study and control group consisted of 34 and 70 patients, respectively. No significant difference was found in duration of infertility, antral follicular count, basal E2 and FSH levels. The mean serum AMH level was significantly higher in study group (p = 0.005). The retrieved oocyte number, metaphase 2 oocyte number, and fertilization rate were also significantly higher in the study group. DISCUSSION: Evaluation of serum AMH seems to be a useful marker to predict IVF-ICSI outcome in poor responder patients.

Treatment with Doxycycline of Generalized Annular Elastolytic Giant Cell Granuloma Associated with Borrelia burgdorferi Infection.

This is a case of generalized annular elastolytic giant cell granuloma (AEGCG) associated with borrelia infection and genes of p-30, p-31, p-39. A possible cross-mediated reaction from the T-cell type which might have induced the AEGCG is discussed from the concept of "heat-shock proteins (HSPs) and molecular mimicry".

Failure-to-rescue and interprovider comparisons after elective abdominal aortic aneurysm repair.

BACKGROUND: The use of postoperative complication rates to derive metrics such as failure-to-rescue (FTR) is of increasing interest in assessing the quality of care. The aim of this study was to quantify FTR rates for elective abdominal aortic aneurysm (AAA) repair in England using administrative data, and to examine its validity against case-note review. METHODS: A retrospective observational study using Hospital Episode Statistics (HES) data was combined with a multicentre audit of data quality. All elective AAA repairs done in England between 2005 and 2010 were identified. Postoperative complications were extracted, FTR rates quantified, and differences in FTR and in-hospital death rates established. A multicentre case-note review was performed to establish the accuracy of coding of complications, and the impact of inaccuracies on FTR rates derived from HES data. RESULTS: A total of 19 638 elective AAA repairs were identified from HES; the overall mortality rate was 4·6 per cent. Patients with complications (19·2 per cent) were more likely to die than those without complications (odds ratio 12·22, 95 per cent c.i. 10·51 to 14·21; P < 0·001) and had longer hospital stays (P < 0·001). FTR rates correlated strongly with death rates, whereas complication rates did not. On case-note review (661 procedures), 41·5 per cent of patients had a complication recorded in the case notes. There was evidence of systematic under-reporting of complications in HES, leading to an overall misclassification rate of 36·3 (95 per cent c.i. 33·7 to 39·2) per cent (P < 0·001), which was less pronounced for surgical complications (12·6 (11·1 to 13·9) per cent; P <0·001). Despite this, the majority of FTR rates derived from HES were not significantly different from those derived from case-note data. CONCLUSION: Postoperative complication and FTR rates after elective AAA repair can be derived from HES data. However, use of the metric for interprovider comparisons should be done cautiously, and only with concurrent case-note validation given the degree of miscoding identified.

Eculizumab therapy in a patient with dense-deposit disease associated with partial lipodystropy.

BACKGROUND: Dense deposit disease (DDD) (also known as membranoproliferative glomerulonephritis type II) in childhood is a rare glomerulonephritis with frequent progression to end-stage renal disease (ESRD) and a high recurrence after kidney transplantation. The pathophysiologic basis of DDD is associated with the uncontrolled systemic activation of the alternative pathway (AP) of the complement cascade. CASE-DIAGNOSIS/TREATMENT: A 14-year-old girl presented with edema and nephrotic range proteinuria. Blood tests showed hypoalbuminemia, nephrotic range proteinuria, normal renal function, and a low C3 level. Renal biopsy confirmed the diagnosis of crescentic DDD. Complement analysis revealed strong AP activation (low C3), positive C3 nephritic factor (C3NeF), and a decreased complement factor H (CFH) levels with CFH polymorphisms. Therapy with eculizumab was considered after the failure of corticosteroid and plasmapheresis to modulate the ongoing massive proteinuria and persistence of low serum C3 levels. There was a marked clinical and biochemical response following the administration of eculizumab. CONCLUSIONS: Our case emphasizes the efficacy of eculizumab in the management of crescentic DDD in a patient with a normal renal function, in a short follow-up period. Considering previously reported cases, it appears that eculizumab represents a promising new approach which may prevent progression to ESRD in a subset of patients with DDD.

Spectral characterization of intraoperative renal perfusion using hyperspectral imaging and artificial intelligence.

Accurate intraoperative assessment of organ perfusion is a pivotal determinant in preserving organ function e.g. during kidney surgery including partial nephrectomy or kidney transplantation. Hyperspectral imaging (HSI) has great potential to objectively describe and quantify this perfusion as opposed to conventional surrogate techniques such as ultrasound flowmeter, indocyanine green or the subjective eye of the surgeon. An established live porcine model under general anesthesia received median laparotomy and renal mobilization. Different scenarios that were measured using HSI were (1) complete, (2) gradual and (3) partial malperfusion. The differences in spectral reflectance as well as HSI oxygenation (StO2) between different perfusion states were compelling and as high as 56.9% with 70.3% (± 11.0%) for "physiological" vs. 13.4% (± 3.1%) for "venous congestion". A machine learning (ML) algorithm was able to distinguish between these perfusion states with a balanced prediction accuracy of 97.8%. Data from this porcine study including 1300 recordings across 57 individuals was compared to a human dataset of 104 recordings across 17 individuals suggesting clinical transferability. Therefore, HSI is a highly promising tool for intraoperative microvascular evaluation of perfusion states with great advantages over existing surrogate techniques. Clinical trials are required to prove patient benefit.