Memory-like NK cells armed with a neoepitope-specific CAR exhibit potent activity against NPM1 mutated acute myeloid leukemia.

Acute myeloid leukemia (AML) remains a therapeutic challenge, and a paucity of tumor-specific targets has significantly hampered the development of effective immune-based therapies. Recent paradigm-changing studies have shown that natural killer (NK) cells exhibit innate memory upon brief activation with IL-12 and IL-18, leading to cytokine-induced memory-like (CIML) NK cell differentiation. CIML NK cells have enhanced antitumor activity and have shown promising results in early phase clinical trials in patients with relapsed/refractory AML. Here, we show that arming CIML NK cells with a neoepitope-specific chimeric antigen receptor (CAR) significantly enhances their antitumor responses to nucleophosphmin-1 (NPM1)-mutated AML while avoiding off-target toxicity. CIML NK cells differentiated from peripheral blood NK cells were efficiently transduced to express a TCR-like CAR that specifically recognizes a neoepitope derived from the cytosolic oncogenic NPM1-mutated protein presented by HLA-A2. These CAR CIML NK cells displayed enhanced activity against NPM1-mutated AML cell lines and patient-derived leukemic blast cells. CAR CIML NK cells persisted in vivo and significantly improved AML outcomes in xenograft models. Single-cell RNA sequencing and mass cytometry analyses identified up-regulation of cell proliferation, protein folding, immune responses, and major metabolic pathways in CAR-transduced CIML NK cells, resulting in tumor-specific, CAR-dependent activation and function in response to AML target cells. Thus, efficient arming of CIML NK cells with an NPM1-mutation-specific TCR-like CAR substantially improves their innate antitumor responses against an otherwise intracellular mutant protein. These preclinical findings justify evaluating this approach in clinical trials in HLA-A2+ AML patients with NPM1c mutations.

Ziv-aflibercept plus pembrolizumab in patients with advanced melanoma resistant to anti-PD-1 treatment.

BACKGROUND: Vascular endothelial growth factor is associated with reduced immune response and impaired anti-tumor activity. Combining antiangiogenic agents with immune checkpoint inhibition can overcome this immune suppression and enhance treatment efficacy. METHODS: This study investigated the combination of ziv-aflibercept anti-angiogenic therapy with pembrolizumab in patients with advanced melanoma resistant to anti-PD-1 treatment. Baseline and on-treatment plasma and PBMC samples were analyzed by multiplex protein assay and mass cytometry, respectively. RESULTS: In this Phase 1B study (NCT02298959), ten patients with advanced PD-1-resistant melanoma were treated with a combination of ziv-aflibercept (at 2-4 mg/kg) plus pembrolizumab (at 2 mg/kg), administered intravenously every 2 weeks. Two patients (20%) achieved a partial response, and two patients (20%) experienced stable disease (SD) as the best response. The two responders had mucosal melanoma, while both patients with SD had ocular melanoma. The combination therapy demonstrated clinical activity and acceptable safety, despite the occurrence of adverse events. Changes in plasma analytes such as platelet-derived growth factor and PD-L1 were explored, indicating potential alterations in myeloid cell function. Higher levels of circulating CXCL10 in non-responding patients may reflect pro-tumor activity. Specific subsets of γδ T cells were associated with poor clinical outcomes, suggesting impaired γδ T-cell function in non-responding patients. CONCLUSIONS: Although limited by sample size and follow-up, these findings highlight the potential of the combination of ziv-aflibercept antiangiogenic therapy with pembrolizumab in patients with advanced melanoma resistant to anti-PD-1 treatment and the need for further research to improve outcomes in anti-PD-1-resistant melanoma. TRIAL REGISTRATION NUMBER: NCT02298959.

Optimizing a Diagnostic Model of Periodontitis by Using Targeted Proteomics.

Periodontitis (PD), a widespread chronic infectious disease, compromises oral health and is associated with various systemic conditions and hematological alterations. Yet, to date, it is not clear whether serum protein profiling improves the assessment of PD. We collected general health data, performed dental examinations, and generated serum protein profiles using novel Proximity Extension Assay technology for 654 participants of the Bialystok PLUS study. To evaluate the incremental benefit of proteomics, we constructed two logistic regression models assessing the risk of having PD according to the CDC/AAP definition; the first one contained established PD predictors, and in addition, the second one was enhanced by extensive protein information. We then compared both models in terms of overall fit, discrimination, and calibration. For internal model validation, we performed bootstrap resampling (n = 2000). We identified 14 proteins, which improved the global fit and discrimination of a model of established PD risk factors, while maintaining reasonable calibration (area under the curve 0.82 vs 0.86; P < 0.001). Our results suggest that proteomic technologies offer an interesting advancement in the goal of finding easy-to-use and scalable diagnostic applications for PD that do not require direct examination of the periodontium.

Profiling of Natural Killer Interactions With Cancer Cells Using Mass Cytometry.

We developed a comprehensive method for functional assessment of the changes in immune populations and killing activity of peripheral blood mononuclear cells after cocultures with cancer cells using mass cytometry. In this study, a 43-marker mass cytometry panel was applied to a coculture of immune cells from healthy donors' peripheral blood mononuclear cells with diverse cancer cell lines. DNA content combined with classical CD45 surface staining was used as gating parameters for cocultures of immune cells (CD45high/DNAlow) with hematological (CD45low/DNAhigh) and solid cancer cell lines (CD45neg/DNAhigh). This strategy allows for universal discrimination of cancer cells from immune populations without the need for a specific cancer cell marker and simultaneous assessment of phenotypical changes in both populations. The use of mass cytometry allows for simultaneous detection of changes in natural killer, natural killer T cell, and T cell phenotypes and degranulation of immune populations upon target recognition, analysis of target cells for cytotoxic protein granzyme B content, and cancer cell death. These findings have broad applicability in research and clinical settings with the aim to phenotype and assess functional changes following not only NK-cancer cell interactions but also the effect of those interactions on other immune populations.

Targeted proteomics in a population-based study identifies serum PECAM-1 and TRIM21 as inflammation markers for periodontitis.

OBJECTIVES: Periodontitis (PD) can cause systematic inflammation and is associated with various metabolic processes in the body. However, robust serum markers for these relationships are still lacking. This study aims to identify novel circulating inflammation-related proteins associated with PD using targeted proteomics. MATERIALS AND METHODS: We used population-based, cross-sectional data from 619 participants of the Polish Longitudinal University Study (Bialystok PLUS). Mean pocket probing depth (mPPD) and proportion of bleeding on probing (pBOP) served as exposure variables. Fifty-two inflammation-related proteins were measured using the Olink Target 96 Cardiovascular III and the Olink Target 96 Immune Response panels. Associations between periodontal measures and proteins were tested using covariate-adjusted linear regression models. RESULTS: At a false discovery rate of < 0.05, we identified associations of mPPD and pBOP with platelet-endothelial cell adhesion molecule-1 (PECAM-1) and tripartite motif-containing protein 21 (TRIM21). CONCLUSION: This study revealed novel associations between PD and serum levels of PECAM-1 and TRIM21. Our results suggest that these proteins might be affected by molecular processes that take place in the inflamed periodontium. CLINICAL RELEVANCE: Novel associations of PECAM-1 and TRIM21 with PD indicate promising serum markers for understanding the disease's pathophysiological processes and call for further biomedical investigations.

Cytokine changes during immune-related adverse events and corticosteroid treatment in melanoma patients receiving immune checkpoint inhibitors.

BACKGROUND: Immune checkpoint inhibitors (ICIs) often cause immune-related adverse events (irAEs), most of which are treated with corticosteroids despite evidence suggesting that corticosteroids may blunt antitumor efficacy. We sought to identify cytokine changes that correlate with irAEs and study the impact of corticosteroid treatment on cytokine levels. METHODS: We analyzed expression of 34 cytokines in 52 melanoma patients who developed irAEs during therapy with ICIs. Luminex serum assay was performed at baseline, 1, 2, and 3 months after starting ICI. Baseline cytokine levels and longitudinal log2 fold-change was compared with incidence and grade of irAEs. Cytokine patterns were compared between patients based on development of irAEs and steroid treatment. RESULTS: There were no differences in baseline cytokine levels between patients who developed grade 1-2 irAEs (N = 28) vs. grade 3-4 irAEs (N = 24). Dermatitis patients (N = 8) had significantly higher baseline Ang-1 (p = 0.006) and CD40L (p = 0.005). Pneumonitis patients (N = 4) had significantly higher baseline IL-17 (p = 0.009). Colitis patients (N = 8) had a trend toward decreased GCSF (p = 0.08). Through Spearman's correlation analysis, patients who developed irAEs without receiving corticosteroids (N = 23) exhibited harmonization of cytokine fold-change, with 0/276 pairwise comparisons demonstrating significant divergence. In contrast, corticosteroid treatment in patients with irAEs (N = 15) altered fold-change to a discordant pattern (42/276 diverged, 15.2%). This discordant cytokine pattern in patients receiving corticosteroids is similar to the cytokine pattern in patients who did not develop irAEs (N = 8) during the longitudinal profiling period (41/276, 14.9%). CONCLUSIONS: Baseline levels of certain cytokines correlate with specific irAEs in melanoma patients receiving ICIs. irAEs drive a concordant pattern of cytokine fold-change, which is disrupted by corticosteroid treatment.

The role of appetite-regulating hormones: Ghrelin and leptin in the nutritional status of children with neurogenic bladder due to myelomeningocele.

AIM: We wanted to investigate serum levels of ghrelin and leptin - appetite-regulating hormones - and their correlation with the nutritional status of children with neurogenic bladder (NB) due to myelomeningocele (MMC) in comparison to healthy individuals. METHODS: This prospective analysis was conducted on 67 children with NB after MMC and 20 healthy children. Children's medical charts were analysed to determine age, gender, anthropometric measurements, body mass index (BMI), activity assessment using Hoffer's scale and renal function parameters. Serum total ghrelin and leptin levels were measured using the enzyme-linked immunosorbent assay. RESULTS: There were no differences in the age, gender, weight and BMI between the studied groups. Median serum levels of ghrelin and leptin were higher compared with the reference group. A significant negative correlation between serum leptin concentration and Hoffer's scale was found in children with NB. CONCLUSIONS: Elevated levels of leptin and ghrelin could be considered factors influencing nutritional status in children with NB due to MMC. Children with NB after MMC may have disturbed endocrine regulation of energy homeostasis. Physical activity may be the factor that affects serum leptin concentration.

Unstimulated salivary flow, pH, proteins and oral health in patients with Juvenile Idiopathic Arthritis.

BACKGROUND: There have been inconsistent conclusions regarding salivary abnormalities and their effect on oral health of Juvenile Idiopathic Arthritis (JIA) patients. The purpose of the study was to evaluate the flow rate and selected biochemical parameters of unstimulated whole saliva in correlation to oral health in JIA children. METHODS: Thirty-four JIA patients and 34 age- and sex-matched controls not affected by JIA (C) were divided into two groups: with mixed and permanent dentition. DMFT/dmft, gingival and simplified oral hygiene indices were evaluated. Salivary flow rate, pH, lysozyme, lactoferrin, salivary protein concentrations and peroxidase activity were assessed. RESULTS: The salivary flow rate was significantly lower in the total JIA group (0.41 ml/min) as compared with the C (0.51 ml/min) and in the permanent dentition of JIA children (0.43 ml/min) as compared with the C (0.61 ml/min). A significantly lower pH was observed in total (6.74), mixed (6.7) and permanent (6.76) dentition of JIA groups in comparison to the C (7.25, 7.21, 7.28 respectively). The specific activity of peroxidase was significantly higher in JIA patients (total 112.72 IU/l, mixed dentition 112.98 IU/l, permanent dentition 112.5 IU/l) than in the C group (total 70.03 IU/l, mixed dentition 71.83 IU/l, permanent dentition 68.61 IU/l). The lysozyme concentration in JIA patients (total and permanent dentition groups) was significantly higher than in the C group. There were no significant differences in lactoferrin and salivary protein concentrations. There were no statistically significant differences in oral status between JIA patients and C, respectively: DMFT = 5.71, dmft = 3.73, OHI-S = 0.95, GI = 0.25 and DMFT 5.71, dmft = 3.73, OHI-S = 0.85, GI = 0.24. The specific activity of peroxidase in the unstimulated whole saliva was inversely correlated with the GI index, whereas the salivary lysozyme concentration was inversely correlated with the dmft index in JIA patients. CONCLUSION: In the course of JIA occur a reduction of the resting salivary flow rate and a decrease of saliva pH. In spite of this, no differences in the clinical oral status between the JIA children population and the control group were found. The mobilisation of salivary peroxidase and lysozyme contributes to the maintenance of healthy oral tissues.

Granzyme B degradation by autophagy decreases tumor cell susceptibility to natural killer-mediated lysis under hypoxia.

Recent studies demonstrated that autophagy is an important regulator of innate immune response. However, the mechanism by which autophagy regulates natural killer (NK) cell-mediated antitumor immune responses remains elusive. Here, we demonstrate that hypoxia impairs breast cancer cell susceptibility to NK-mediated lysis in vitro via the activation of autophagy. This impairment was not related to a defect in target cell recognition by NK cells but to the degradation of NK-derived granzyme B in autophagosomes of hypoxic cells. Inhibition of autophagy by targeting beclin1 (BECN1) restored granzyme B levels in hypoxic cells in vitro and induced tumor regression in vivo by facilitating NK-mediated tumor cell killing. Together, our data highlight autophagy as a mechanism underlying the resistance of hypoxic tumor cells to NK-mediated lysis. The work presented here provides a cutting-edge advance in our understanding of the mechanism by which hypoxia-induced autophagy impairs NK-mediated lysis in vitro and paves the way for the formulation of more effective NK cell-based antitumor therapies.

Caries Assessment Spectrum and Treatment (CAST) Index in the Primary Molars of 6- to 7-year-old Polish Children.

PURPOSE: To evaluate the caries prevalence and experience in primary molars in Polish 6- to 7-year-old children using the Caries Assessment Spectrum and Treatment index. MATERIALS AND METHODS: This cross-sectional study was carried out on a sample of 332 out of 468 invited children (140 6- and 192 7-year-olds). Cluster sampling was used to select the participating schools. Dental status was evaluated according to the criteria dedicated to CAST. The means of the individual CAST scores were assessed. Data were statistically analysed using the Mann-Whitney U-test (p < 0.05). The percentage of children according to the highest CAST score was calculated. The mean values of the dmft index, based on three different caries thresholds--CAST codes 3 to 7 (d3-7t), 4 to 7 (d4-7t) and 5 to 7 (d5-7t)--were calculated. RESULTS: The response rate was 70.9%. One-fifth of the participants showed a healthy, functional dentition (CAST codes 0-2). The highest percentage of children had at least one carious tooth with pulpal involvement (26.2%), followed by children having an obvious dentin caries lesion (20.8%). The means for CAST codes 3, 4 and 5 were 0.61 ± 1.0, 0.19 ± 0.53 and 1.23 ± 1.61, respectively. The means of molars with pulpal involvement was 0.83 ± 1.32 and with dental sepsis 0.07 ± 0.33. Apart from filled teeth, no age-dependent differences were observed. The d3-7mft, d4-7mft and d5-7mft were as follows: 5.18, 4.61 and 4.41, respectively. CONCLUSION: The surveyed Polish children showed high caries prevalence and severe caries experience in the primary molars. The CAST index was a useful tool for the epidemiological analysis of primary molars.

Polish school nurses' knowledge of the first-aid in tooth avulsion of permanent teeth.

BACKGROUND: The frequency of dental trauma in schools is secondary only to accidents at home. The aim of this study was to evaluate the knowledge of first aid in the avulsion of permanent teeth presented by Polish school nurses from different areas. METHODS: A cross-sectional study with the use of a structured self-administrative questionnaire was conducted in 2014 on school nurses working in randomly selected Polish provinces. The instrument consisted of demographic questions, questions referring to nurses' experience and training in dental trauma and questions checking knowledge of first-aid in the avulsion of permanent teeth. The maximum number of points to be scored was eight. Data were analyzed with the Kruskal-Wallis, the Mann-Whitney U and Chi(2) tests with the level of statistical significance at p < 0.05. RESULTS: The final sample consisted of 164 nurses of which 70.1 % had experience with dental injuries and 45.7 % witnessed a tooth avulsion in pupils. 10.4 % nurses participated in training courses concerning tooth avulsion and 67.1 % of them independently broadened their knowledge. The knowledge of the first-aid management of an avulsed tooth was moderate (4.72 ± 1.95 points). 78.1 % of nurses chose a correct definition of the term of 'tooth avulsion'. Only 7.3 % of them were aware that the replantation could be conducted by any witness of an accident. Saline was most often chosen as a proper transport medium for an avulsed tooth (57.9 %), whereas 16.1 % of nurses indicated milk. 13.4 % of evaluated nurses showed readiness to conduct an immediate replantation. Most respondents preferred calling child's parents and advising them to bring the child to a dentist (63.4 %). The main factor influencing nurses' level of knowledge was self-education (p < 0.001). Being a witness to dental trauma (p = 0.0032) and working in schools with sports classes (p = 0.0423) were positive determinants of improved knowledge. Nurses from large agglomerations had significantly lower knowledge (p = 0.005). The main source of information for self-education was the Internet. CONCLUSIONS: The evaluated nurses were in need of education with regard to the management of dental trauma cases. The Internet should be used to deliver evidence-based knowledge to medical staff working at schools.

Urodynamic Findings and Renal Function in Children with Neurogenic Bladder after Myelomeningocele.

INTRODUCTION: Myelomeningocele (MMC) is a congenital central nervous system malformation caused by a failure of the neurulation process in early pregnancy. Patients with MMC present many abnormalities and the nervous, skeletal and urinary systems are the most affected. The aim of this study was to clinically evaluate patients with MMC, estimate renal and lower urinary tract (LUT) function and to ascertain whether urodynamic findings can predict the deterioration of urinary tract function. MATERIALS AND METHODS: Medical records of 112 patients were gathered from a database and evaluated retrospectively. The data included age, sex, BMI Z-score WHO, physical activity, urodynamic parameters and diagnosis and renal function. RESULTS: A total of 112 patients with MMC were enrolled in the study. There were no differences in age, sex, BMI Z-score WHO, physical activity, renal function and urodynamic findings (apart from cystometric capacity) between boys and girls. Detrusor overactivity was the most frequent urodynamic diagnosis in all groups of physical activity, level of lesion and in catheterized and non-catheterized children. The correlations between urodynamic findings and renal function tests were found. CONCLUSIONS: Patients with neurogenic bladder after MMC most often present detrusor overactivity. LUT function is disturbed in all MMC patients independent of lesion level and physical activity.

Quality of life measured by OHIP-14 and GOHAI in elderly people from Bialystok, north-east Poland.

BACKGROUND: The Oral Health Impact Profile-14 (OHIP-14) and the Geriatric/General Oral Health Assessment Index (GOHAI) have never been compared for a group of the same subjects in the Polish population. The aim of the study was to compare the OHIP-14 and GOHAI measures. METHODS: 178 independently living people over the age of 55 were included in the study. The GOHAI and OHIP-14 measures were used. Other variables included age, gender, self-ratings of oral general health, education, number of missing teeth, chewing problems and dry mouth. RESULTS: The mean age of respondents was 70.8 years. The internal reliability (Cronbach's alpha) showed a high internal consistency for both measures. Spearman's rank correlation coefficient between the GOHAI and OHIP-14 scores was 0.81. Using the additive method of creating scores, 1.1% of respondents had the GOHAI score of zero, indicating no impact from oral conditions, while 13.5% of them had an OHIP-14 score of zero. Dental status, partial dentures, chewing problems, dry mouth and self-rated oral health were significantly associated with the results of the GOHAI and the OHIP-14 (Kruskal-Wallis test, Mann-Whitney U test). The numbers of preserved and missing teeth significantly correlated with the GOHAI and the OHIP-14, while DMF was significantly associated with the GOHAI only. 6 individuals with discrepant results were revealed. After the exclusion of the abovementioned patients, the internal reliability (Cronbach's alpha) still showed a high internal consistency, and the correlation between the GOHAI and OHIP-14 scores using Spearman's rank-correlation coefficient increased to 0.87. This phenomenon was identified as a "fatigue effect". CONCLUSIONS: There was a strong correlation between the GOHAI and the OHIP-14. Both instruments demonstrated good discriminant properties and helped capture the respondents' oral health problems. The questionnaires should be randomly distributed to avoid the influence of "fatigue effect" on the results of a comparison of different measures.

Dental caries in primary and permanent molars in 7-8-year-old schoolchildren evaluated with Caries Assessment Spectrum and Treatment (CAST) index.

BACKGROUND: No reports on a caries pattern covering the full spectrum of the disease could be found in the literature. The aim of this study was to evaluate caries in primary and first permanent molars of 7-8-year-old Polish children by the Caries Assessment Spectrum and Treatment (CAST) index and to find whether there was any correlation between the caries stages in such teeth. METHODS: The study covered 284 7-8-year-old children from randomly selected schools in the Bialystok District, Poland. The prevalence of CAST categories was evaluated with regard to the first and second primary, and first permanent, molars. The Spearman's rank correlation coefficient was used to explore the correlation of the distribution of CAST codes among the evaluated teeth. The level of statistical significance was established at p < 0.05. The intra-examiner reliability was determined by the unweighted kappa coefficient. RESULTS: With regard to the permanent molars, caries was observed in 14.8% to 17.3% of the molar and most lesions were scored at the non-cavitation level. Caries in primary molars was most often recorded at the stage of cavitated dentine lesion. Teeth with pulpal involvement, sepsis and extracted due to caries were found to be more prevalent in first, and then in second primary molars. A strong correlation was found between the status of teeth from the right and left sides of the oral cavity. The correlation of the status of first and second primary teeth was stronger for the left than for the right side of the mouth, r was 0.627 and 0.472 in maxilla and 0.513 and 0.483 in mandible (p < 0.001), respectively. For the neighbouring primary and permanent molars the correlation was assessed to be weak. With regard to the teeth situated in opposite jaws the study revealed that the correlations were moderate - r between 0.33 and 0.49. The intra-examiner reliability was established at 0.96 for the primary dentition and at 0.878 for permanent molars. CONCLUSION: The strongest correlation found in the evaluated population concerned the distribution of caries in primary molars on the left side of the mouth. The study proved the usefulness of the CAST index in epidemiological surveys.

Evaluation of Urinary L-FABP as a Tubular Damage Marker in Pediatric Neurogenic Bladder-A Pilot Study.

The article aims to find potential biomarker for the detection of tubular damage in pediatric neurogenic bladder (NB) by investigating urinary levels of liver-type fatty acid-binding protein (uL-FABP). This prospective analysis was conducted on two groups: 42 children with NB and 18 healthy children. The uL-FABP concentrations were measured using ELISA methods. The medical charts of the children were examined to determine age, sex, anthropometric measurements, activity assessment using Hoffer's scale, and renal function parameters. The results revealed that the uL-FABP/creatinine ratio was higher in the study group compared with the reference group, but the difference was not statistically significant (p = 0.52, p > 0.05). However, the uL-FABP/creatinine ratio exhibited a wider range in NB patients compared to the reference group. NB children with proteinuria and the history of high-grade vesicoureteral reflux (VUR) tended to have the highest uL-FABP concentrations. In conclusion, uL-FABP may be considered a potential tubular damage biomarker in children with NB. Proteinuria and the history of VUR may be the factors influencing the uL-FABP.

Phase II Study of Eribulin plus Pembrolizumab in Metastatic Soft-tissue Sarcomas: Clinical Outcomes and Biological Correlates.

PURPOSE: Eribulin modulates the tumor-immune microenvironment via cGAS-STING signaling in preclinical models. This non-randomized phase II trial evaluated the combination of eribulin and pembrolizumab in patients with soft-tissue sarcomas (STS). PATIENTS AND METHODS: Patients enrolled in one of three cohorts: leiomyosarcoma (LMS), liposarcomas (LPS), or other STS that may benefit from PD-1 inhibitors, including undifferentiated pleomorphic sarcoma (UPS). Eribulin was administered at 1.4 mg/m2 i.v. (days 1 and 8) with fixed-dose pembrolizumab 200 mg i.v. (day 1) of each 21-day cycle, until progression, unacceptable toxicity, or completion of 2 years of treatment. The primary endpoint was the 12-week progression-free survival rate (PFS-12) in each cohort. Secondary endpoints included the objective response rate, median PFS, safety profile, and overall survival (OS). Pretreatment and on-treatment blood specimens were evaluated in patients who achieved durable disease control (DDC) or progression within 12 weeks [early progression (EP)]. Multiplexed immunofluorescence was performed on archival LPS samples from patients with DDC or EP. RESULTS: Fifty-seven patients enrolled (LMS, n = 19; LPS, n = 20; UPS/Other, n = 18). The PFS-12 was 36.8% (90% confidence interval: 22.5-60.4) for LMS, 69.6% (54.5-89.0) for LPS, and 52.6% (36.8-75.3) for UPS/Other cohorts. All 3 patients in the UPS/Other cohort with angiosarcoma achieved RECIST responses. Toxicity was manageable. Higher IFNα and IL4 serum levels were associated with clinical benefit. Immune aggregates expressing PD-1 and PD-L1 were observed in a patient that completed 2 years of treatment. CONCLUSIONS: The combination of eribulin and pembrolizumab demonstrated promising activity in LPS and angiosarcoma.

Pulpal involvement-roots-sepsis index: a new method for describing the clinical consequences of untreated dental caries.

OBJECTIVES: To describe a modification of the index of clinical consequences of untreated dental caries [pulpal involvement, ulceration, fistula and abscess (PUFA/pufa) index] to pulpal involvement-roots-sepsis (PRS/prs) and to compare the two indices using the example of caries in primary molar teeth in children aged 6-8 years. SUBJECTS AND METHODS: The study sample included 542 children aged 6-8 years, from five randomly selected schools in the Bialystok District, Poland. The occurrence of clinical consequences of untreated caries in deciduous molars using the pufa and prs indices was evaluated. Data were analysed to express the prevalence, the experience and the distribution of particular pufa and prs codes in the sample population. The differences in layout of the pufa and prs components were expressed. RESULTS: The response rate was 77.6%. The prevalence of the clinical consequences of untreated caries was 40.77%, mean pufa and prs were the same (0.85 ± 1.33). According to the pufa index, the following mean values were obtained: p = 0.79, u = 0.01, f = 0.04 and a = 0.01. For the prs index, the mean values were as follows: p = 0.45, r = 0.35 and s = 0.05. CONCLUSION: The proposed prs index was a useful epidemiological instrument for the evaluation of the clinical consequences of untreated caries in the surveyed population. The PRS instrument could be a good alternative to the PUFA index.

Radiation-guided breast sentinel lymph node biopsies - is a handling delay for radiation protection necessary?

AIMS: Radiation-guided sentinel lymph node (SLN) biopsy is a well-established procedure in many countries. However, histopathology protocols in different centres specify widely differing sample handling delays of between 0 and 72 h. Introducing a delay reduces the radiation exposure of pathologists, but has a detrimental effect on the quality and validity of histology. This study aims to show that a sample handling delay is not justified by the radiation doses to pathologists handling samples received directly from surgery. METHODS AND RESULTS: Radiation doses to the body and hands of pathologists handling samples delivered directly from theatres were measured using personal dose meters. These measurements were supplemented by dose assessments undertaken using dose-rate measurements at 1 cm and 30 cm from Tc-99m sources to simulate the processing of samples. The study has shown that radiation doses arising from a zero delay in sample handling represent a negligible radiation risk to pathologists and are well within relevant limits specified in the Ionising Radiations Regulations 1999. CONCLUSIONS: This study supports adoption of a zero-delay SLN histopathology protocol. Centres must, however, complete a risk assessment that accounts for local practice and adopt simple precautions to keep doses to pathologists as low as reasonably achievable.

Hepatocyte growth factor in saliva of patients with renal failure and periodontal disease.

BACKGROUND: Hepatocyte growth factor (HGF), endogenous cytokine with pleiotropic repairing and regeneration properties in relation to most tissues and organs, contributes to the progression of periodontal disease (PD). Furthermore, PD is a significant health problem in patients with chronic renal failure (CRF). The role of HGF in the development of PD in this specific population was not a subject of research so far. MATERIAL AND METHODS: The following groups were enrolled in the study: (1) 26 chronic hemodialysis (HD) subjects, (2) 26 patients treated by continuous ambulatory peritoneal dialysis (CAPD), (3) 28 predialysis CRF patients, (4) 26 subjects with advanced PD (without coexisting diseases), and (5) 20 healthy subjects without PDs. HGF level in saliva was measured using the immunoenzymatic method. Gingival index, papillary bleeding index, plaque index, and the loss of clinical attachment level were evaluated. RESULTS: The HGF level in saliva of HD patients was twice higher than in that of subjects with healthy periodontium. Direct relationships between proper HGF level in saliva and the indices GI, PBI, and PI in CAPD-treated patients and with more severe PD were shown. It was found that PD is most advanced in HD patients, moderately in CAPD-treated patients and to the smallest extent in predialysis CRF patients. CONCLUSIONS: The HGF level in mixed saliva is the index of PD progression in subjects without renal failure and in CAPD-treated patients. PD is common in renal failure patients and is a significant problem concerning general health status.

Knowledge of nurses working at schools in Bialystok, Poland, of tooth avulsion and its management.

AIM: The purpose of this study was to evaluate the knowledge of first aid in tooth avulsion among nurses working at schools in Bialystok, Poland. A part of this population attended a lecture on the management of dental trauma 2 years before. METHODS: The survey was conducted in September 2010 and covered 50 (96.15%) school nurses from Bialystok. Thirty-eight of them attended the dental trauma lecture conducted 2 years before the survey. They were asked to fill in an anonymous questionnaire consisting of 20 closed questions referring to demographic data, previous dental trauma experience, and training. Seven questions referred directly to the knowledge of management of dental avulsion and on that basis, the level of nurses' knowledge was evaluated. The data were analyzed statistically using the Mann-Withney U-test with P < 0.05 to find factors influencing the level of knowledge. RESULTS: The study showed that nurses' knowledge about tooth avulsion was at an appropriate level. 86% of the participants chose the correct definition of the term of replantation, 92% understood that the time is crucial for the result of a replantation, 94% knew that an avulsed tooth should be held by the crown, and 96% pointed the proper transport medium. A half of the surveyed nurses declared that they would provide tooth replantation and another 16% would consult the procedures by calling a dentist. One statistically significant correlation between the level of knowledge and previous dental trauma training was revealed (P < 0.01). CONCLUSIONS: The lay knowledge of tooth avulsion in the population of nurses working at schools in Bialystok, Poland, was at an appropriate level. There was a strong correlation between this level and the participation in the lecture on the management of dental trauma conducted 2 years before.