Role of IL-6, IL-10 and TNFα Gene Variants in Preterm Birth.

Background: The association of gene variants for interleukin 6 (IL-6) (rs1800796), interleukin 10 (IL-10) (rs1800896) and tumor necrosis factorα (TNFα (rs1800629) with the occurrence of spontaneous preterm birth (PTB) was investigated to determine whether these genetic variants are a risk factor. Methods: A total of 199 blood samples from pregnant women who had given birth prematurely and 200 control blood samples were analyzed to determine single nucleotide polymorphisms (SNPs) of genes for IL-6 (rs1800796), IL-10 (rs1800896) and TNFα (rs1800629). The control samples were samples from pregnant women with term delivery. The isolation of DNA was performed on mini-spin columns according to the manufacturer's protocol. The quality and purity of the isolated DNA were tested using a Qubit 3 fluorometer. Genotyping was performed with an ABI PRISM 7500 SDS using TaqMan SNP genotyping assays. The genotypes obtained were analyzed using the 7500 Software v2.3 package. Results: Carriers of the A/A genotype for the rs1800629 SNP of the TNFα gene have a 4.81 times greater chance of late-onset PTB compared to carriers of the G/G and A/G genotypes in the recessive inheritance model. The presence of the G/G genotype in the recessive inheritance model compared with the G/A and A/A genotypes for the rs1800896 SNP of the IL-10 gene represents a potentially protective factor, with mothers in the term-birth group having an almost 2-fold lower odds of PTB in general and an almost 10-fold lower odds of early PTB. On the other hand, carriers of the A/G genotype of rs1800896 have a 1.54-fold higher chance of preterm birth in general and a 1.6-fold higher chance of late preterm birth in the superdominant inheritance model compared to the A/A and G/G genotypes in the group of mothers with PTB. In this study, no association was found between PTB and the rs1800796 SNP of the IL-6 gene. Conclusions: rs1800629 in mothers was associated with PTB. rs1800896 shows a potentially protective effect for the occurrence of PTB in this study. No association was found between PTB and rs1800796.

Long-Term Outcomes of Breast Cancer Patients Receiving Levobupivacaine Wound Infiltration or Diclofenac for Postoperative Pain Relief.

Breast cancer is the most common malignant disease in women. Preclinical studies have confirmed that the local anesthetic levobupivacaine has a cytotoxic effect on breast cancer cells. We examined whether postoperative wound infiltration with levobupivacaine influences survival in 120 patients who were operated on for breast cancer and underwent quadrantectomy or mastectomy with axillary lymph node dissection. Groups with continuous levobupivacaine wound infiltration, bolus wound infiltration, and diclofenac analgesia were compared. Long-term outcomes examined were quality of life, shoulder disability, and hand grip strength (HGS) after one year and survival after 5 and 10 years. Groups that had infiltration analgesia had better shoulder function compared to diclofenac after one year. The levobupivacaine PCA group had the best-preserved HGS after 1 year (P = 0.022). The most significant predictor of the 5-year outcome was HGS (P = 0.03). Survival at 10 years was 85%, 92%, and 77% in the diclofenac, levobupivacaine bolus, and levobupivacaine PCA groups (ns. P = 0.36). The extent of the disease at the time of surgery is the most important predictor of long-term survival (P = 0.03). A larger prospective clinical study could better confirm the effect of levobupivacaine wound infiltration on outcomes after breast cancer surgery observed in this pilot study-trial number NCT05829707.

Gastrointestinal Motility Disorders Correlate with Intracranial Bleeding, Opioid Use, and Brainstem Edema in Neurosurgical Patients.

BACKGROUND: Gastrointestinal (GI) motility disorders may be directly associated with the intensity of acute brain injury, edema of the brainstem, and opioid use in neurosurgical patients. METHODS: In this retrospective study, patient demographic characteristics, computed tomography (CT) scans, the occurrence of gastroparesis, constipation, and opioid use were registered during the intensive care unit (ICU) stay and correlated with days of mechanical ventilation, length of ICU stay, and survival. Gastroparesis was defined as residual gastric volume > 250 mL per day, and constipation was defined as the absence of stool for 3 days or more during the ICU stay. RESULTS: Of 207 neurosurgical patients screened, 69 adult patients who spent more than 4 days in the ICU were included in the study. Gastroparesis was observed in 48 (69.6%) patients, constipation was observed in 67 (97.1%) patients, and stress ulcers were observed in 4 (5.8%) patients. Patients with brainstem edema (n = 57, 82.6%) had the first stool evacuation later compared with patients with no edema (8 [interquartile range (IQR) 5.25-9.75] vs. 3.5 [IQR 2.25-4] days; P < 0.001). In the logistic regression analysis, factors that were associated with GI dysmotility were central nervous system (CNS) bleeding (odds ratio [OR] 5.1, 95% confidence interval [CI] 1.26-20.8, P = 0.02), opioid use > 19.3 morphine equivalents (ME) per day (OR 5.37, 95% CI 1.1-27.1, P = 0.04), and brainstem edema (OR 4.9, 95% CI 1.1-21.6, P = 0.04). A receiver operating characteristic curve analysis confirmed that the cutoff value of > 6.78 ME per day was a good predictor determining GI dysmotility, with 89.5% sensitivity and 72.7% specificity (95% CI 0.67-0.88, area under the curve 0.784, Youden index 0.62, P = 0.001). Poor survival correlated with lower Glasgow Coma Score values (ρ = - 520, P < 0.001), CNS bleeding (ρ = 0.393, P < 0.001), associated cardiac diseases (ρ = 0.279, P < 0.001), and cardiorespiratory arrest on admission (ρ = 0.315, P < 0.001), but not with GI dysmotility (ρ = 0.175, P = 0.402). CONCLUSIONS: Significant correlation was registered between brainstem edema, gastrointestinal dysmotility, and opioids. CNS bleeding was the most important single factor influencing GI dysmotility. Further studies with opioid and nonopioid sedation may distinguish the influence of acute brain lesions versus drugs on GI dysmotility.

Validation and Cross-Cultural Adaptation of Croatian Self-Evaluation of Communication Experiences after Laryngectomy Questionnaire.

INTRODUCTION: The Self-Evaluation of Communication Experiences after Laryngectomy (SECEL) is a 35-item patient-reported questionnaire developed to address the communication needs of patients with laryngectomies. The aim was to translate, cross-culturally adapt, and validate the Croatian version. METHODS: The SECEL was translated from English by two independent translators and back-translated by a native speaker, after which it was approved by an expert committee. The Croatian version of the Self-Evaluation of Communication Experiences after Laryngectomy questionnaire (SECEL:HR) was filled in by 50 laryngectomised patients who had completed their oncological treatment a year prior to inclusion in the study. Patients also filled in the Voice Handicap Index (VHI) and the Short Form Health Survey (SF-36) on the same day. All patients completed the SECEL:HR twice, the second time being 2 weeks after the initial test. Maximum phonation time and diadochokinesis of articulation organs were used for objective assessment. RESULTS: Among the Croatian patients, the questionnaire was well-accepted and demonstrated good test-retest reliability and internal consistency for two out of three subscales. The correlations between VHI, SF-36, and SECEL:HR were moderate to strong. There were no significant differences between patients who are using oesophageal speech, tracheoesophageal speech, or the electrolarynx based on the SECEL:HR. CONCLUSION: Preliminary findings of the research indicate that the Croatian version of the SECEL has sufficient psychometric qualities, high reliability, and good internal consistency, with a Cronbach's alpha of 0.89 for the total score. The Croatian version of SECEL can be recommended as a reliable and clinically valid measure for the assessment of substitution voices in Croatian-speaking patients.

Higher Expressions of SHH and AR Are Associated with a Positive Receptor Status and Have Impact on Survival in a Cohort of Croatian Breast Cancer Patients.

Breast cancers (BC) are usually classified into four molecular subtypes according to the expression of estrogen (ER), progesterone (PR), and human epidermal growth factor 2 (HER2) receptors and proliferation marker Ki-67. Despite available anti-hormonal therapies and due to the inherent propensity of some subtypes to develop metastasis, there is a permanent need to discover new prognostic and predictive biomarkers, as well as therapeutic targets for BC. In this study, we used immunohistochemical staining to determine the expression of androgen receptor (AR) and sonic hedgehog protein (SHH), the main ligand of the Hedgehog-GLI (HH-GLI) signaling pathway, in 185 archival primary BC tissue samples and correlated it with clinicopathological characteristics, molecular subtypes, receptors statuses, and survival in a cohort of Croatian BC patients. Results showed that higher SHH and AR expressions were associated with positive receptor status, but increased SHH expression had a negative impact on survival in receptor-negative BCs. On the contrary, higher AR expression was mostly protective. However, multivariate analysis showed that only higher AR expression could be considered as an independent prognostic biomarker for poorer overall survival in triple-negative breast cancer patients (TNBC) (HR 10.9, 95% CI 1.43-83.67; p = 0.021), what could be Croatian population-related. SHH could be a potential target for treating TNBCs and HER2-enriched BCs, in cases where HH-GLI signaling is canonical (SHH-dependent).

Osteopontin Levels in Patients with Squamous Metastatic Head and Neck Cancer.

Background and Objectives: Increased osteopontin (OPN) concentrations in the plasma of patients with head and neck squamous cancer (HNSCC) have diagnostic significance, and it can indicate more aggressive biological behavior of cancer. The aim of this study was to determine OPN levels in patients with HNSCC of different primary locations and to assess its prognostic significance in metastasis development. Materials and Methods: This cohort study included 45 patients (41 male and 4 female patients) with HNSCC with different primary localization of head and neck. All patients underwent surgery-neck dissection. All patients were categorized according to the histological findings of the resected material and tumor-node-metastasis (TNM) classification system. After surgery, N categories were determined on the basis of histological features of resected material. Results: The histological findings of our patients showed: N0 in 11 patients, N1 in 8 patients, N2a in 4 patients, N2b in 14 patients and N2c in 8 patients. Plasma OPN values in all study participants ranged from 2.24 to 109.10 ng/mL. OPN levels in plasma of patients with negative nodes compared to the group of patients with positive nodes in the neck differed significantly (16.89 ng/mL to 34.08 ng/mL, respectively; p = 0.03). There were significantly lower OPN plasma levels in the group of subjects with histologically positive one lymph node in the neck (N1) compared to the group of patients with N2b histologically positive findings of resected neck material (10.4 ng/mL to 43.9 ng/mL, respectively; p = 0.02). Conclusions: The results have shown that growing N degrees of positive neck nodes classification were accompanied by growing values of plasma osteopontin. Osteopontin might be important for the development of neck metastases.

Adenoma Characteristics and the Influence of Alcohol and Cigarette Consumption on the Development of Advanced Colorectal Adenomas.

Background: Colorectal cancer (CRC), one of the leading public health problems worldwide, is a disease that can be prevented when it is detected in time. The objectives of this cross-sectional study were to investigate the characteristics of colorectal adenomas and whether alcohol consumption and cigarette smoking correlated with the development of advanced adenomas in participants in The National Programme for Early Detection of Colorectal Cancer (NP) in Osijek-Baranja County (OBC), Croatia. Methods: The screening methods were the guaiac Faecal Occult Blood Test (gFOBT), colonoscopy, histological analysis, and risk factor questionnaire. Results: The results showed the presence of adenomas in 136 men (57.4%) and 101 women (42.6%), p < 0.001. There was one adenoma in 147 (62%) most commonly located in sigmorect, in 86 (59%) participants, and 44 (18.6%) participants had multiple adenomas, most commonly found in multi loc, p < 0.001. According to size, 118 (49.8%) of all adenomas were between 0.1 and 0.9 cm, while adenomas of 3 cm 19 (8%) were the fewest, p < 0.001. There were 142 (59.9%) advanced adenomas. Conclusions: Adenoma development in the OBC population was correlated with predictors: adenoma size, high-grade dysplasia, smoking and alcohol consumption of 20 g per day. Non-smoking was found to be a health protective behaviour.

The accuracy of breast cancer risk self-assessment does not correlate with knowledge about breast cancer and knowledge and attitudes towards primary chemoprevention.

The increase of breast cancer (BC) incidence has drawn attention to BC risk as means of reducing mortality and morbidity of the disease. The aim of this study was to determine the accuracy of BC risk perception, evaluate factors that affect risk perception and assess the correlation between BC risk perception and attitudes towards BC chemoprevention. A cross-sectional study included total of 258 women with average and high-risk for BC according to the Breast Cancer Risk Assessment Tool (BCRAT). All data were collected by face-to-face interview by three trained 6th year medical school students using a 54-item questionnaire. Each participant's actual BC risk was compared to a perceived risk and the accuracy of the BC risk self-assessment was determined. 72% of high-risk women underestimated their BC risk (p < 0.001). One third of subjects with a family history of BC have also underestimated their own risk (p = 0.002). Women who responded to screening mammography were more informed about BC risk factors (p = 0.001). General knowledge about BC chemoprevention was surprisingly low, regardless of the accuracy of BC risk self-assessment. High-risk women appear to be unrealistically optimistic, since there was a significant difference between the accuracy of self-perceived risk and the objective BC risk.

Correlation of folate receptor alpha expression with clinicopathological parameters and outcome in triple negative breast cancer.

Folate receptor alpha (FRα) is a membrane-bound protein with a high affinity for folate, which is necessary for the biosynthesis of amino acids and nucleotide bases. It has been shown to be a potential prognostic and therapeutic target, primarily in lung and ovarian cancer, as well as in breast cancer. The aim of this study was to examine FRα expression in a cohort of patients with triple negative breast cancer (TNBC), in correlation with clinicopathological parameters and prognostic factors. By using polyclonal FRα antibody on archival paraffin blocks immunohistochemistry was performed. To evaluate the expression of FRα, H-score was used, which marks both the proportion of stained cells and the intensity of staining. Statistical analysis correlating FRα expression with clinicopathologic parameters and clinical outcome were performed. FRα was expressed in most of the patients (85%). Significant correlation of expression and histologic grade (Mann Whitney U test, P = 0,03) and type of tumor (P = 0,02), was found. It was noticed that with higher Ki-67 proliferation index values, H-score has lower values (r = -0,284, P = 0,006). Multivariant regression analysis (Cox regression, Stepwise method) showed H-score as a significant predictor for the risk of disease recurrence (OR = 1,005, P = 0,04). No correlation between FRα expression and overall survival (OS) and disease-free survival (DFS) was found. In conclusion, FRα is highly expressed in TNBC, and, given the correlation with clinicopathological parameters, subpopulation of patients could be identified that could be potential targets for new therapeutic perspectives in the treatment of this breast cancer subtype.

Impact of Breast Density Awareness on Knowledge about Breast Cancer Risk Factors and the Self-Perceived Risk of Breast Cancer.

Breast density (BD) reduces sensitivity of mammography, and is a strong risk factor for breast cancer (BC). Data about women's awareness and knowledge of BD are limited. Our aim is to examine whether the BD information disclosure and BD awareness among women without BC are related to their knowledge about BC risk factors. We examined self-reported BC risk perception and its association to BD awareness and level of health literacy. A cross-sectional, single site study included 263 Croatian women without BC who had mammographic examination. Data were collected by interviews using questionnaires and a validated survey. Of the total, 77.1% had never heard of BD, and 22.9% were aware of their BD. Most participants who knew their BD (88.2%, p < 0.001) had higher levels of education. Majority of subjects (66.8%) had non-dense breasts and 33.2% had dense breasts. Subjects aware of their BD knew that post-menopausal hormone replacement therapy (p = 0.04) and higher BD (p = 0.03) are BC risk factors. They could more easily access information about health promotion (p = 0.03). High-BD informed women assessed their lifetime BC risk as significantly higher than all others (p = 0.03). Comprehension of BD awareness and knowledge is crucial for reinforcement of educational strategies and development of amendatory BC screening decisions.

Exploring Association of Breast Pain, Pregnancy, and Body Mass Index with Breast Tissue Elasticity in Healthy Women: Glandular and Fat Differences.

Breast sonoelastography is a relatively novel ultrasound (US) method that enables estimation of tissue stiffness to estimate the elasticity of normal breast tissue and seek to correlate it with well-known breast cancer risk factors. Two hundred women of different age were included in the study and completed a questionnaire about personal, familiar, and reproductive history. Glandular and fatty tissue elasticity in all breast quadrants was measured by shear wave elastography (SWE). Mean elastographic values of breast tissue were calculated and compared to personal history risk factors. Elasticity of normal glandular tissue (66.4 kilopascals (kPa)) was higher than fatty tissue (26.1 kPa) in all breast quadrants and in both breasts. Lower outer quadrant (LOQ) had the lowest elasticity values of both parenchyma and fat. Higher elasticity values of breast tissue were confirmed in the left breast than in the right breast. Glandular and fat tissue elasticity negatively correlated with body mass index (BMI). Women with mastodynia had higher glandular elastographic values compared to subjects without breast pain. Nuliparity was also associated with higher elasticity of glandular breast tissue. The results of this study are promising and could, over time, contribute to a better understanding of glandular breast tissue elasticity as a potential risk factor for breast cancer.

Representation of CYP3A4, CYP3A5 and UGT1A4 Polymorphisms within Croatian Breast Cancer Patients' Population.

Single nucleotide polymorphism (SNP) in genes encoding drug-metabolizing enzymes (DME) could have a critical role in individual responses to anastrozole. Frequency of CYP3A4*1B, CYP3A5*3 and UGT1A4*2 SNPs in 126 Croatian breast cancer (BC) patients and possible association with anastrozole-induced undesirable side effects were analyzed. Eighty-two postmenopausal patients with estrogen receptor (ER)-positive BC treated with anastrozole and 44 postmenopausal ER-positive BC patients before hormonal adjuvant therapy were included in the study. Genomic DNA was genotyped by TaqMan Real-Time PCR. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry. The homozygotes for the variant G allele of CYP3A5*3 were predominant (88%), and the homozygotes for the reference A allele were not detected. While homozygotes for the variant G allele of CYP3A4*1B were not detected, predominantly wild type homozygotes for A allele (94%) were present. CYP3A4*1B and CYP3A5*3 SNPs were in 84.3% linkage disequilibrium (D' = 0.843) and 95.1% (D' = 0.951) in group treated with anastrozole and w/o treatment, respectively. Homozygotes for the A allele of UGT1A4*2 were not detected in our study groups. Although the variant CYP3A5*3 allele, which might result in poor metabolizer phenotype and more pronounced side effects, was predominant, significant association with BMD changes induced by anastrozole were not confirmed.

Differential Expression of TFF Genes and Proteins in Breast Tumors.

The objective of this study was to determine differential expression of TFF1, TFF2 and TFF3 genes and proteins in breast tumor subtypes. In addition, we investigated the correlation between TFF genes within tumor subgroups, and TFF genes with clinical and pathologic characteristics of the tumor. Study group included 122 patients with surgically removed breast tumors. Samples were investigated using qRT-PCR and immunohistochemistry. TFF1 and TFF3 genes and proteins were expressed in breast tumors, while the levels of TFF2 gene and protein expression were very low or undetectable. TFF1 was significantly more expressed in benign tumors, while TFF3 was more expressed in malignant tumors. Gene and protein expression of both TFF1 and TFF3 was greater in lymph node-negative tumors, hormone positive tumors, tumors with moderate levels of Ki67 expression, and in grade II tumors. A strong positive correlation was found between TFF1 and TFF3 genes, and the expression of both negatively correlated with Ki67 and the level of tumor histologic differentiation. Our results suggest that TFF1 and TFF3, but not TFF2, may have a role in breast tumor pathogenesis and could be used in the assessment of tumor differentiation and malignancy.

Association of Wnt Inhibitors, Bone Mineral Density and Lifestyle Parameters in Women with Breast Cancer Treated with Anastrozole Therapy.

AIM: To determine the levels of Wnt inhibitors in patients treated with aromatase inhibitors (AIs) prior to therapy and to investigate their association with bone mineral density (BMD) and lifestyle parameters. METHODS: 137 breast cancer patients were divided into a group treated with 1 mg of anastrozole and a group w/o anastrozole therapy. Serum concentrations of sclerostin and dickkopf1 (DKK1) were measured by ELISA. BMD was measured by dual-energy X-ray absorptiometry (DXA). Lifestyle factors were investigated by a self-reported questionnaire. RESULTS: Sclerostin was significantly higher in the AI-treated group (31.8 pmol/L vs. 24.1 pmol/L; p < 0.001), whereas DKK1 was significantly lower in the AI-treated group (24.3 pmol/L vs. 26.02 pmol/L; p < 0.001). Total hip and femoral neck BMD were significantly lower in the AI-treated group. CONCLUSION: AI treatment was associated with increased levels of sclerostin and decreased levels of DKK1.

Implementation of Elastography Score and Strain Ratio in Combination with B-Mode Ultrasound Avoids Unnecessary Biopsies of Breast Lesions.

The aim of this study was to evaluate whether the combination of B-mode ultrasound, elastography score (ES) and strain ratio (SR) improves diagnostic performance with respect to breast lesions. One hundred thirty lesions were prospectively evaluated by B-mode ultrasound and strain elastography, followed by fine-needle aspiration cytology/biopsy in 117 woman who were scheduled for regular breast BUS. The median ES (4.5 vs. 2.9, p < 0.001) and SR (4.9 vs. 2.3, p < 0.001) were significantly higher for malignant than for benign lesions. A sensitivity of 90.5% and specificity of 93.2% for the ES (cutoff point = 3.8) and a sensitivity of 87.5% and specificity of 87.6% for the SR (cutoff point = 3.5) were obtained. Elastography combined with B-mode ultrasound improved the specificity, accuracy and positive predictive value. Receiver operating characteristic curves yielded a higher value for the combined technique for diagnosis of breast lesions. Routine use of such a diagnostic algorithm could reduce the number of unnecessary biopsies.

Psychotropic medications in older adults: a review.

BACKGROUND: Prevalence of prescribing psychotropic medications, particularly inappropriate prescription, is widespread in older adults, both in nursing home residents as well as community-dwelling older adults. This review describes prevalence and prevention of inappropriate prescribing and risk factors associated with psychotropic medications. METHODS: MEDLINE and GOOGLE SCHOLAR data base were searched for the key words "older adults", "psychotropic drugs", "inappropriate prescribing", "nursing home residents", "community-dwelling older adults". The study was limited to the articles published in English in the period from 2007 to 2014. The list of references includes additional articles that were searched manually. RESULTS: The utilization of different psychotropic medications is prevalent among older adults worldwide, regardless of whether they live in nursing homes or in the community. Among older adults, nursing home residents are the most vulnerable individuals for potentially inappropriate drug prescription. The most common potentially inappropriate prescribed medications in the elderly are benzodiazepines, particularly long-acting, antipsychotics and antidepressants, particularly SSRIs. All classes of listed medications have been associated with different adverse events, particularly falls and falls-related fractures and increased risk for mortality. Many different pharmacological and non-pharmacological interventions, such as monitoring polypharmacy, reviewing medications, spending more time in the institution by a physician, reducing the number of prescribers in the institution as well as greater involvement of geriatricians, general practitioners and pharmacists should be implemented to reduce this health issue. CONCLUSION: The prevalence of prescribing psychotropic medications to older adults is high. Inappropriate prescribing of psychotropic drugs and polypharmacy are present in institutionalized and non-institutionalized older adults and can cause adverse health events, and can significantly reduce the quality of life of these vulnerable groups. Multidisciplinary approach is needed in addressing widespread problem of prevalence of psychotropic medications in older adults.

Postoperative immunosuppression markers and the occurrence of sepsis in patients with benign and malignant disease.

AIM: To investigate associations between the postoperative immune response and the levels of extracellular circulating DNA (cDNA), C-reactive protein (CRP), neutrophil/lymphocyte (N/L) ratio, and regulatory T (Treg) cells in the peripheral blood and their role as potential predictors of postoperative septic complications. METHODS: This was a prospective observational study involving 115 adult patients who underwent elective surgery. Patients were divided into three groups: with benign disease, with malignant disease, and with malignant disease and administration of dexamethasone. Serum CRP levels, N/L ratio, monocyte human leukocyte antigen-DR (HLA-DR) expression, proportion of Treg cells, and cDNA levels were measured at different time points before and after surgery. RESULTS: All patients had increased CRP levels after surgery. Septic patients had higher serum CRP levels at baseline. Compared with the other groups, the dexamethasone group had significantly higher CRP levels before and after surgery, a significantly higher N/L ratio before surgery, a significantly lower rise in the N/L ratio after surgery, and a significantly lower HLA-DR expression at baseline, which remained stable after surgery. In the malignant-disease group, we observed a significant postoperative decrease in the HLA-DR expression. CONCLUSIONS: Our results suggest that the immunosuppressive effect of surgery and the presence of a malignant disease may contribute to a higher risk of postoperative sepsis. Preoperative CRP levels may be a reliable predictor of sepsis in oncological patients.