Does a postmortem redistribution affect the concentrations of the 7 azaindole-derived synthetic cannabinoid 5F-MDMB-P7AICA in tissues and body fluids following pulmonary administration to pigs?

Many fatal intoxications have been reported in connection with the consumption of newer, highly potent synthetic cannabinoids. Yet, a possible postmortem redistribution (PMR) might complicate reliable interpretation of analytical results. Thus, it is necessary to investigate the PMR-potential of new synthetic cannabinoids. The pig model has already proven to be suitable for this purpose. Hence, the aim of this study was to study the PMR of the synthetic cannabinoid 5F-MDMB-P7AICA and its main metabolite 5F-MDMB-P7AICA-dimethylbutanoic acid (DBA). 5F-MDMB-P7AICA (200 µg/kg body weight) was administered by inhalation to anesthetized and ventilated pigs. At the end of the experiment, the animals were euthanized and stored at room temperature for 3 days. Tissue and body fluid samples were taken daily. Specimens were analyzed after solid phase extraction using a standard addition method and LC-MS/MS, blood was quantified after protein precipitation using a validated method. In perimortem samples, 5F-MDMB-P7AICA was found mainly in adipose tissue, bile fluid, and duodenum contents. Small amounts of 5F-MDMB-P7AICA were found in blood, muscle, brain, liver, and lung. High concentrations of DBA were found primarily in bile fluid, duodenum contents, urine, and kidney/perirenal fat tissue. In the remaining tissues, rather low amounts could be found. In comparison to older synthetic cannabinoids, PMR of 5F-MDMB-P7AICA was less pronounced. Concentrations in blood also appear to remain relatively stable at a low level postmortem. Muscle, kidney, fat, and duodenum content are suitable alternative matrices for the detection of 5F-MDMB-P7AICA and DBA, if blood specimens are not available. In conclusion, concentrations of 5F-MDMB-P7AICA and its main metabolite DBA are not relevantly affected by PMR.

Short-term cryoprotectant-free cryopreservation at -20°C does not affect the viability and regenerative capacity of nanofat.

Nanofat is an autologous fat derivative with high regenerative activity, which is usually administered immediately after its generation by mechanical emulsification of adipose tissue. For its potential repeated use over longer time, we herein tested whether cryopreservation of nanofat is feasible. For this purpose, the inguinal fat pads of donor mice were processed to nanofat, which was i) frozen and stored in a freezer at -20°C, ii) shock frozen in liquid nitrogen with subsequent storage at -80°C or iii) gradually frozen and stored at -80°C. After 7 days, the cryopreserved nanofat samples were thawed and immunohistochemically compared with freshly generated nanofat (control). Nanofat frozen and stored at -20°C exhibited the lowest apoptotic rate and highest densities of blood and lymph vessels, which were comparable to those of control. Accordingly, nanofat cryopreserved at -20°C or control nanofat were subsequently fixed with platelet-rich plasma in full-thickness skin defects within dorsal skinfold chambers of recipient mice to assess vascularization, formation of granulation tissue and wound closure by means of stereomicroscopy, intravital fluorescence microscopy, histology and immunohistochemistry over 14 days. These analyses revealed no marked differences between the healing capacity of wounds filled with cryopreserved or control nanofat. Therefore, it can be concluded that cryopreservation of nanofat is simply feasible without affecting its viability and regenerative potential. This may broaden the range of future nanofat applications, which would particularly benefit from repeated administration of this autologous biological product.

Effect of a comprehensive lifestyle intervention program on body weight and health behavior in women with breast cancer: Results from a randomized controlled trial.

BACKGROUND: Both overweight/obesity and a Western lifestyle are associated with a poorer prognosis in women with breast cancer. The primary aim of this analysis was to examine the effect of a telephone-delivered lifestyle intervention program on reducing body weight and waist circumference, decreasing cardiovascular risk factors and improving lifestyle. DESIGN: Data is derived from an open-label, randomized, controlled phase III study that evaluated two chemotherapy regimens and the impact of a 2-year lifestyle intervention on disease-free survival and secondary outcomes in women with intermediate-risk to high-risk breast cancer. Initially, 2292 women with a body mass index (BMI) between 24 and 40 kg/m2 were randomized into one of two arms of the lifestyle intervention study. After accounting for dropout, 1785 participants remained: 776 in the intervention group (IG) who received a telephone-delivered lifestyle intervention supported by mailed materials, and 1009 in the low-level intervention group (LLIG) who received only mailed educational materials with general recommendations for a healthy lifestyle. Body weight, waist circumference, dietary intake, physical activity, and cardiovascular disease risk parameters were measured repeatedly throughout the intervention and a subsequent 2-year follow-up period. Linear mixed models for repeated measures were used to assess differences in study outcomes between the LLIG and IG at each measured time point. RESULTS: IG participants showed a mean weight loss of -2.7 kg (kg) (versus +0.4 kg, LLIG) at 6 months, -2.8 kg (vs. +0.8 kg, LLIG) at 12 months and -1.8 kg at 24 months (versus +0.9 kg, LLIG). Significant between-group differences for weight loss and reduced waist circumference were observed at all time points until the end of the lifestyle intervention (all p-values < 0.0001), including post-intervention. Reduced energy intake and a higher alternate healthy eating index (AHEI) score in the IG was detected during the lifestyle intervention (AHEI at 24 months: IG 49.1% versus LLIG 42.0%, p < 0.001). Modest significant improvements in several cardiovascular risk factors were observed during the intervention, including fasting plasma glucose, HbA1c, systolic and diastolic blood pressure, and lipids. CONCLUSIONS: A mainly telephone-delivered lifestyle intervention program can reduce body weight and waist circumference, improve diet quality, and decrease cardiometabolic risk in women with overweight/obesity and newly diagnosed, human epidermal growth factor receptor 2 (HER2)/neu-negative, intermediate-risk to high-risk breast cancer. Weight loss, reduced waist circumference and improved dietary patterns were maintained for up to two years post-intervention. TRIAL REGISTRATION: The protocol was registered under the EU Clinical Trials Register, https://www.clinicaltrialsregister.eu/, identifier: 2008-005453-38.

Susceptibility gene mutations in germline and tumors of patients with HER2-negative advanced breast cancer.

Germline mutations in BRCA1 and BRCA2 (gBRCA1/2) are required for a PARP inhibitor therapy in patients with HER2-negative (HER2-) advanced breast cancer (aBC). However, little is known about the prognostic impact of gBRCA1/2 mutations in aBC patients treated with chemotherapy. This study aimed to investigate the frequencies and prognosis of germline and somatic BRCA1/2 mutations in HER2- aBC patients receiving the first chemotherapy in the advanced setting. Patients receiving their first chemotherapy for HER2- aBC were retrospectively selected from the prospective PRAEGNANT registry (NCT02338167). Genotyping of 26 cancer predisposition genes was performed with germline DNA of 471 patients and somatic tumor DNA of 94 patients. Mutation frequencies, progression-free and overall survival (PFS, OS) according to germline mutation status were assessed. gBRCA1/2 mutations were present in 23 patients (4.9%), and 33 patients (7.0%) had mutations in other cancer risk genes. Patients with a gBRCA1/2 mutation had a better OS compared to non-mutation carriers (HR: 0.38; 95%CI: 0.17-0.86). PFS comparison was not statistically significant. Mutations in other risk genes did not affect prognosis. Two somatic BRCA2 mutations were found in 94 patients without gBRCA1/2 mutations. Most frequently somatic mutated genes were TP53 (44.7%), CDH1 (10.6%) and PTEN (6.4%). In conclusion, aBC patients with gBRCA1/2 mutations had a more favorable prognosis under chemotherapy compared to non-mutation carriers. The mutation frequency of ~5% with gBRCA1/2 mutations together with improved outcome indicates that germline genotyping of all metastatic patients for whom a PARP inhibitor therapy is indicated should be considered.

Pediatric-type diffuse low-grade gliomas.

The World Health Organization's 5th edition classification of Central Nervous System (CNS) tumors differentiates diffuse gliomas into adult and pediatric variants. Pediatric-type diffuse low-grade gliomas (pDLGGs) are distinct from adult gliomas in their molecular characteristics, biological behavior, clinical progression, and prognosis. Various molecular alterations identified in pDLGGs are crucial for treatment. There are four distinct entities of pDLGGs. All four of these tumor subtypes exhibit diffuse growth and share overlapping histopathological and imaging characteristics. Molecular analysis is essential for differentiating these lesions.

Myotonometry and extended field-of-view ultrasound imaging allow reliable quantification of patellar tendon stiffness and length at rest and during maximal load, whereas several restrictions exist for the Achilles tendon.

Introduction: Stiffness and length are well-established tendon parameters in sports and medicine. Myotonometry and ultrasound imaging are the commonly used methods to quantify these parameters. However, further studies are needed to clarify the reliability of these methods, especially when assessing maximally loaded tendons and when conducted by different experienced investigators. This study aimed to determine the intra- and interrater reliabilities of measuring the stiffness and length of the patellar tendon (PT) and Achilles tendon (AT) using the myotonometry method and the extended field-of-view ultrasound (EFOV-US) technique at rest and maximal load performed by different experienced investigators. Methods: Twenty-seven participants were examined on three different days by one experienced investigator and one novice investigator. Primary outcomes were the intraclass correlation coefficient (ICC) and associated 95% confidence interval (95% CI), coefficient of variation (CV), standard error of measurement (SEM), and minimal detectable change (MDC) across the measurement days and investigators. Results: For PT measurements at rest and maximal load, the estimated ICCs for stiffness and length were ≥.867 and ≥.970, respectively, with 95% CIs ranging from poor (.306) to excellent (.973) and good (.897) to excellent (.999). The CV, SEM, and MDC for PT stiffness and length were ≤5.2% and ≤2.0%, ≤39.3 N/m and ≤0.9 mm, and ≤108.9 N/m and ≤2.6 mm, respectively. For AT measurements, some restrictions were evident for stiffness at rest and both parameters at maximal load. However, regarding AT length at rest, the estimated ICC was ≥.996, with an excellent 95% CI (.987-.999). The CV, SEM, and MDC for AT length at rest were 2.8%, ≤1.1 mm, and ≤2.9 mm, respectively. Conclusion: The estimated ICCs show good to excellent reliability for the myotonometry method and the EFOV-US technique for measuring PT stiffness and length at rest and maximal load for experienced and novice investigators. However, some restrictions are evident for the AT, especially for measurements at maximal load.

Evaluation of ChatGPT's Potential in Tailoring Gynecological Cancer Therapies.

BACKGROUND/AIM: Demographic change and increasing complexity of therapy decisions lead to a growing burden on the healthcare system, necessitating efforts to simplify and enhance the efficiency of patient care. The present study evaluates ChatGPT's ability to provide therapy recommendations for gynecological malignancies that are both in line with the local guidelines and individually tailored to the patient. PATIENTS AND METHODS: Sixteen patients with endometrial, cervical, and ovarian cancer who were treated in the gynecological clinic of the University Hospital Erlangen from January 2022 to August 2023 were included in the analysis. Data collected within clinical routine care were communicated to the chat-based AI model ChatGPT (version 3.5). ChatGPT's performance generating treatment plans were evaluated using an answer scoring system and descriptive analysis. RESULTS: According to the answer scoring system [range: -1 point (minimum) to 2 points (maximum)], ChatGPT demonstrated a good potential in generating therapy recommendations with an average score of 0.75 points for patients with ovarian cancer, 0.7 points for cervical and 1.5 points for endometrial cancer patients. The most common deductions in points were about incomplete therapy recommendations, whereas contraindicated treatment modalities were rarely suggested. Individual patient characteristics were regularly considered by ChatGPT. ChatGPT reliably indicated aftercare and provided detailed information on preventive measures as well as supportive treatment. CONCLUSION: ChatGPT is a promising tool for the generation of therapy suggestions for gynecological carcinomas with high flexibility in response to individual patient differences. At the current state, however, ChatGPT is not suitable for replacing expert panels.

Skin treatment with non-thermal plasma modulates the immune system through miR-223-3p and its target genes.

Non-thermal plasma, a partially ionized gas, holds significant potential for clinical applications, including wound-healing support, oral therapies, and anti-tumour treatments. While its applications showed promising outcomes, the underlying molecular mechanisms remain incompletely understood. We thus apply non-thermal plasma to mouse auricular skin and conducted non-coding RNA sequencing, as well as single-cell blood sequencing. In a time-series analysis (five timepoints spanning 2 hours), we compare the expression of microRNAs in the plasma-treated left ears to the unexposed right ears of the same mice as well as to the ears of unexposed control mice. Our findings indicate specific effects in the treated ears for a set of five miRNAs: mmu-miR-144-5p, mmu-miR-144-3p, mmu-miR-142a-5p, mmu-miR-223-3p, and mmu-miR-451a. Interestingly, mmu-miR-223-3p also exhibits an increase over time in the right non-treated ear of the exposed mice, suggesting systemic effects. Notably, this miRNA, along with mmu-miR-142a-5p and mmu-miR-144-3p, regulates genes and pathways associated with wound healing and tissue regeneration (namely ErbB, FoxO, Hippo, and PI3K-Akt signalling). This co-regulation is particularly remarkable considering the significant seed dissimilarities among the miRNAs. Finally, single-cell sequencing of PBMCs reveals the downregulation of 12 from 15 target genes in B-cells, Cd4+ and Cd8+ T-cells. Collectively, our data provide evidence for a systemic effect of non-thermal plasma.

The WERA cancer center matrix: Strategic management of patient access to precision oncology in a large and mostly rural area of Germany.

PURPOSE: Providing patient access to precision oncology (PO) is a major challenge of clinical oncologists. Here, we provide an easily transferable model from strategic management science to assess the outreach of a cancer center. METHODS: As members of the German WERA alliance, the cancer centers in Würzburg, Erlangen, Regensburg and Augsburg merged care data regarding their geographical impact. Specifically, we examined the provenance of patients from WERA´s molecular tumor boards (MTBs) between 2020 and 2022 (n = 2243). As second dimension, we added the provenance of patients receiving general cancer care by WERA. Clustering our catchment area along these two dimensions set up a four-quadrant matrix consisting of postal code areas with referrals towards WERA. These areas were re-identified on a map of the Federal State of Bavaria. RESULTS: The WERA matrix overlooked an active screening area of 821 postal code areas - representing about 50 % of Bavaria´s spatial expansion and more than six million inhabitants. The WERA matrix identified regions successfully connected to our outreach structures in terms of subsidiarity - with general cancer care mainly performed locally but PO performed in collaboration with WERA. We also detected postal code areas with a potential PO backlog - characterized by high levels of cancer care performed by WERA and low levels or no MTB representation. CONCLUSIONS: The WERA matrix provided a transparent portfolio of postal code areas, which helped assessing the geographical impact of our PO program. We believe that its intuitive principle can easily be transferred to other cancer centers.

Correlation of RANK and RANKL with mammographic density in primary breast cancer patients.

PURPOSE: The receptor activator of nuclear factor kappa B (RANK) and its ligand (RANKL) have been shown to promote proliferation of the breast and breast carcinogenesis. The objective of this analysis was to investigate whether tumor-specific RANK and RANKL expression in patients with primary breast cancer is associated with high percentage mammographic density (PMD), which is a known breast cancer risk factor. METHODS: Immunohistochemical staining of RANK and RANKL was performed in tissue microarrays (TMAs) from primary breast cancer samples of the Bavarian Breast Cancer Cases and Controls (BBCC) study. For RANK and RANKL expression, histochemical scores (H scores) with a cut-off value of > 0 vs 0 were established. PMD was measured in the contralateral, non-diseased breast. Linear regression models with PMD as outcome were calculated using common predictors of PMD (age at breast cancer diagnosis, body mass index (BMI) and parity) and RANK and RANKL H scores. Additionally, Spearman rank correlations (ρ) between PMD and RANK and RANKL H score were performed. RESULTS: In the final cohort of 412 patients, breast cancer-specific RANK and RANKL expression was not associated with PMD (P = 0.68). There was no correlation between PMD and RANK H score (Spearman's ρ = 0.01, P = 0.87) or RANKL H score (Spearman's ρ = 0.04, P = 0.41). RANK expression was highest in triple-negative tumors, followed by HER2-positive, luminal B-like and luminal A-like tumors, while no subtype-specific expression of RANKL was found. CONCLUSION: Results do not provide evidence for an association of RANK and RANKL expression in primary breast cancer with PMD.

The Hallmarks of Endometriosis.

A heuristic tool called "the hallmarks of cancer" helps to reduce the enormous complexity of cancer phenotypes and genotypes to a preliminary set of guiding principles. Other aspects of cancer have surfaced as possible improvements in our understanding of the disease's mechanisms. Endometriosis is a gynecological disease condition negatively impacting the quality of life of many women. To date, there is no curative treatment for endometriosis. Therapy is aimed at treating the symptoms using hormone therapy, pain therapy and complementary therapy. Chronic pain and overlapping pain syndromes and illnesses can also be treated with multimodal pain therapy and psychosomatic therapy. Endometriosis is, however, a chronic and complex entity which, in this regard, resembles cancer. The present work investigates the hallmarks of endometriosis with a view to summarizing the current research status and paving new ways for future research projects.

Statement of the Uterus Commission of the Gynecological Oncology Working Group (AGO) on Neoadjuvant Chemotherapy Prior to Definitive Radiochemotherapy in Patients with Locally Advanced Cervical Cancer.

The presentation of the results of the prospective randomized international multicenter GCIG INTERLACE trial at the 2023 congress of the European Society of Medical Oncology (ESMO) is likely to change the therapy for locally advanced cervical cancer. In the GCIG INTERLACE trial, six cycles of neoadjuvant chemotherapy administered weekly and consisting of carboplatin AUC2 and paclitaxel 80 mg/m 2 followed by definitive radiochemotherapy with pelvic radiotherapy (40 - 50.4 Gray) and cisplatin (40 mg/m 2 once a week for 5 weeks) and brachytherapy (total dose EQD2 at least 78 Gy at point A) (experimental arm) were compared with definitive radiochemotherapy alone (standard arm) in patients with locally advanced cervical cancer (Fédération Internationale de Gynécologie et d'Obstétrique [FIGO] 2008 stage IB1/node positive, IB2, II, IIIB and IVA) and was found to be significantly superior with significantly longer recurrence-free survival (hazard ratio [HR] 0.65; 95% confidence interval [CI] 0.64 - 0.91; p = 0.013) and significantly longer overall survival rates (HR 0.61; 95% CI: 0.40 - 0.91; p = 0.04) after 5 years' follow-up. After considering the results of the GCIG INTERLACE trial published at the congress, the Uterus Commission of the AGO is of the opinion that neoadjuvant chemotherapy with carboplatin AUC2 and paclitaxel 80 mg/m 2 d1, q7, x6 may be offered to patients with locally advanced cervical cancer (FIGO stage IB1/node positive, IB2, II, IIIB and IVA) in addition to the current standard therapy after the patient has been informed about the risks, with the decision taken on a case-by-case basis. However, before this approach can be discussed at guideline level or defined as the new therapy standard, it will be necessary to wait until the data from the full publication are available.

Cytotoxic impact of nicotine products on periodontal ligament cells.

OBJECTIVES: The primary objective of this in vitro experiment was an assessment of proliferative capacity, metabolic activity, and potential cellular detriment of human periodontal ligament cells (hPDL) exposed to cigarette smoke (CS), electronic cigarette vapor (eCV), and heated tobacco product aerosol (HTP), or air (control). MATERIALS AND METHODS: Using a CAD/CAM-designed exposition chamber, hPDL were exposed to CS, eCV, HTP, or air (control) based on the Health Canada Intense Smoking Regime. Cell proliferation, metabolic activity, and cellular detriment were assessed at various time points. RESULTS: Compared to the control, hPDL exposed to CS exhibited significantly decreased cell numbers at all time points. HTP exposure led to reduced cell numbers 48 h and 72 h post-exposure, while eCV-exposed cells showed no significant decrease. The metabolic activity of eCV-treated hPDL was slightly reduced at 7 h but recovered at 24 h and 48 h. In contrast, CS-treated cells exhibited significantly decreased metabolic activity at 24 h and 48 h, and HTP-exposed cells showed a significant decrease after 48 h. Flow cytometry indicated both apoptotic and necrotic cell death following CS exposure, with necrotic cell death being more pronounced. CONCLUSIONS: eCV and HTP demonstrated comparatively reduced detrimental effects on hPDL compared to CS. CLINICAL RELEVANCE: The findings suggest that conventional cigarette smoke poses a substantial risk to periodontal health by significantly impairing cell proliferation and metabolic activity. However, alternatives such as eCV and HTP may offer a comparatively reduced risk.

Concurrent RB1 Loss and BRCA-Deficiency Predicts Enhanced Immunological Response and Long-Term Survival in Tubo-Ovarian High-Grade Serous Carcinoma.

PURPOSE: To evaluate RB1 expression and survival across ovarian carcinoma histotypes, and how co-occurrence of BRCA1 or BRCA2 (BRCA) alterations and RB1 loss influences survival in tubo-ovarian high-grade serous carcinoma (HGSC). EXPERIMENTAL DESIGN: RB1 protein expression was classified by immunohistochemistry in ovarian carcinomas of 7436 patients from the Ovarian Tumor Tissue Analysis consortium. We examined RB1 expression and germline BRCA status in a subset of 1134 HGSC, and related genotype to overall survival (OS), tumor-infiltrating CD8+ lymphocytes and transcriptomic subtypes. Using CRISPR-Cas9, we deleted RB1 in HGSC cells with and without BRCA1 alterations to model co-loss with treatment response. We performed whole-genome and transcriptome data analyses on 126 primary HGSC to characterize tumors with concurrent BRCA-deficiency and RB1 loss. RESULTS: RB1 loss was associated with longer OS in HGSC, but with poorer prognosis in endometrioid ovarian carcinoma. Patients with HGSC harboring both RB1 loss and pathogenic germline BRCA variants had superior OS compared to patients with either alteration alone, and their median OS was three times longer than those without pathogenic BRCA variants and retained RB1 expression (9.3 vs. 3.1 years). Enhanced sensitivity to cisplatin and paclitaxel was seen in BRCA1-altered cells with RB1 knockout. Combined RB1 loss and BRCA-deficiency correlated with transcriptional markers of enhanced interferon response, cell-cycle deregulation, and reduced epithelial-mesenchymal transition. CD8+ lymphocytes were most prevalent in BRCA-deficient HGSC with co-loss of RB1. CONCLUSIONS: Co-occurrence of RB1 loss and BRCA-deficiency was associated with exceptionally long survival in patients with HGSC, potentially due to better treatment response and immune stimulation.

A Hybrid Type III Effectiveness-Implementation Trial to Optimize Medication Safety With Oral Antitumor Therapy in Real-World: The AMBORA Competence and Consultation Center.

PURPOSE: Implementation science endeavors to facilitate the translation of evidence-based research into clinical routine. The clinical pharmacological/pharmaceutical care program evaluated in the randomized AMBORA trial on medication safety with oral antitumor therapeutics (OAT) optimizes care delivery and provides significant benefits for patients, treatment teams, and health care systems. Thus, we aimed to investigate the implementation of this care program within the AMBORA Competence and Consultation Center (AMBORA Center). METHODS: The AMBORA Center within a University Comprehensive Cancer Center offered several services (eg, patient consultations) and was evaluated according to the RE-AIM framework. This multicenter hybrid type III trial focused on implementation outcomes (eg, patient recruitment, referring units, evaluation of services) while concurrently investigating effectiveness (eg, side effects, medication errors). Quantitative and qualitative assessments were combined. RESULTS: The AMBORA Center conducted over 800 consultations with 420 patients in seven institutions. The primary end point of counseling 70% of patients treated with OAT was not reached. Patients were referred by 15 treatment units compared with 11 units in the AMBORA trial. On the basis of heterogeneous referral rates and characteristics across the institutions, barriers and facilitators of the implementation process were derived. Several survey results (eg, stakeholder interviews, online/paper-based questionnaires) reflected a high appreciation of services by patients and health care professionals. The severity of 60.1% (178 of 296) of detected side effects improved, and 86.3% (297 of 344) of medication errors were resolved. CONCLUSION: Despite not reaching the primary implementation outcome, the AMBORA Center included more treatment units and demonstrated patient benefit of the AMBORA care program by meeting all effectiveness outcomes. We outlined quantitative and qualitative implementation characteristics to enhance outreach and foster further dissemination of centers to optimize medication safety with OAT.

Preconditioning Strategies for Improving the Outcome of Fat Grafting.

Autologous fat grafting is a common procedure in plastic, reconstructive, and aesthetic surgery. However, it is frequently associated with an unpredictable resorption rate of the graft depending on the engraftment kinetics. This, in turn, is determined by the interaction of the grafted adipose tissue with the tissue at the recipient site. Accordingly, preconditioning strategies have been developed following the principle of exposing these tissues in the pretransplantation phase to stimuli inducing endogenous protective and regenerative cellular adaptations, such as the upregulation of stress-response genes or the release of cytokines and growth factors. As summarized in the present review, these stimuli include hypoxia, dietary restriction, local mechanical stress, heat, and exposure to fractional carbon dioxide laser. Preclinical studies show that they promote cell viability, adipogenesis, and angiogenesis, while reducing inflammation, fibrosis, and cyst formation, resulting in a higher survival rate and quality of fat grafts in different experimental settings. Hence, preconditioning represents a promising approach to improve the outcome of fat grafting in future clinical practice. For this purpose, it is necessary to establish standardized preconditioning protocols for specific clinical applications that are efficient, safe, and easy to implement into routine procedures.

Implementation of quality indicators for vulvar cancer in gynaecological cancer centres certified by the German Cancer Society (DKG).

PURPOSE: In 2018, the first guideline-based quality indicators (QI) for vulvar cancer were implemented in the data-sheets of certified gynaecological cancer centres. The certification process includes guideline-based QIs as a fundamental component. These indicators are specifically designed to evaluate the level of care provided within the centres. This article aims to give an overview of the developing process of guideline based-QIs for women with vulvar cancer and presents the QIs results from the certified gynaecological cancer centres. METHODS: The QIs were derived in a standardized multiple step process during the update of the 2015 S2k guideline "Diagnosis, Therapy, and Follow-Up Care of Vulvar Cancer and its Precursors" (registry-number: no. 015/059) and are based on strong recommendations. RESULTS: In total, there are eight guideline-based QIs for vulvar cancer. Four QIs are part of the certification process. In the treatment year 2021, 2.466 cases of vulvar cancer were treated in 177 centres. The target values in the centres for pathology reports on tumour resection and lymphadenectomy as well as sentinel lymph nodes have increased since the beginning of the certification process and have been above 90% over the past three treatment years (2019-2021). DISCUSSION: QIs based on strong guideline recommendations, play a crucial role in measuring and allowing to quantify essential aspects of patient care. By utilizing QIs, centres are able to identify areas for process optimization and draw informed conclusions. Over the years the quality of treatment of vulvar cancer patients measured by the QIs was improved. The certification system is continuously reviewed to enhance patient care even further by using the outcomes from QIs revaluation.

Quality-Assured Analysis of PIK3CA Mutations in Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer Tissue.

In precision oncology, reliable testing of predictive molecular biomarkers is a prerequisite for optimal patient treatment. Interlaboratory comparisons are a crucial tool to verify diagnostic performance and reproducibility of one's approach. Herein is described the design and results of the first recurrent, internationally performed PIK3CA (phosphatidylinositol-4,5-bisphosphate 3 kinase catalytic subunit α) breast cancer tissue external quality assessment (EQA), organized by German Quality in Pathology GmbH and started in 2021. After the internal pretesting phase performed by the (lead) panel institutes, in both 2021 and 2022, each EQA test set comprised n = 10 tissue samples of hormone receptor-positive, human epidermal growth factor receptor 2-negative invasive breast cancer that had to be analyzed and reported by the participants. In 2021, the results were evaluated separately for German-speaking countries (part 1) and international laboratories (part 2). In 2022, the EQA was performed across the European Union. The EQA success rates were 84.6% (n = 11/13), 88.6% (n = 39/44), and 87.9% (n = 29/33) for EQA 2021 part 1, part 2, and EQA 2022, respectively. The most commonly used methods were next-generation sequencing and mutation-/allele-specific qualitative PCR-based assays. In summary, this recurrent PIK3CA EQA proved to be a suitable approach to obtain an international overview of methods used for PIK3CA mutation analysis, to evaluate them qualitatively, and identify the strengths and weaknesses of individual methods.

Integrative multi-omics analyses to identify the genetic and functional mechanisms underlying ovarian cancer risk regions.

To identify credible causal risk variants (CCVs) associated with different histotypes of epithelial ovarian cancer (EOC), we performed genome-wide association analysis for 470,825 genotyped and 10,163,797 imputed SNPs in 25,981 EOC cases and 105,724 controls of European origin. We identified five histotype-specific EOC risk regions (p value <5 × 10-8) and confirmed previously reported associations for 27 risk regions. Conditional analyses identified an additional 11 signals independent of the primary signal at six risk regions (p value <10-5). Fine mapping identified 4,008 CCVs in these regions, of which 1,452 CCVs were located in ovarian cancer-related chromatin marks with significant enrichment in active enhancers, active promoters, and active regions for CCVs from each EOC histotype. Transcriptome-wide association and colocalization analyses across histotypes using tissue-specific and cross-tissue datasets identified 86 candidate susceptibility genes in known EOC risk regions and 32 genes in 23 additional genomic regions that may represent novel EOC risk loci (false discovery rate <0.05). Finally, by integrating genome-wide HiChIP interactome analysis with transcriptome-wide association study (TWAS), variant effect predictor, transcription factor ChIP-seq, and motifbreakR data, we identified candidate gene-CCV interactions at each locus. This included risk loci where TWAS identified one or more candidate susceptibility genes (e.g., HOXD-AS2, HOXD8, and HOXD3 at 2q31) and other loci where no candidate gene was identified (e.g., MYC and PVT1 at 8q24) by TWAS. In summary, this study describes a functional framework and provides a greater understanding of the biological significance of risk alleles and candidate gene targets at EOC susceptibility loci identified by a genome-wide association study.

The role of peroxisome proliferator-activated receptors in endometriosis.

Endometriosis constitutes the most common cause of chronic pelvic pain in female patients and is associated with infertility. Although there is no known cause for the disease, it is a heritable condition that is determined by numerous genetic, epigenetic, and environmental aspects. Peroxisome proliferator-activated receptors (PPARs) represent nuclear receptor proteins that control gene expression. By using the MEDLINE and LIVIVO databases we conducted a literature review in order to look into the role of PPARs in the endometriosis pathophysiology and succeeded in revealing 36 pertinent publications between 2001 and 2022. In regards to PPAR expression in endometriosis, PPARγ seems to represent the most studied PPAR isoform in endometriosis and to influence various pathways involved in the disease onset and progression. It's interesting to note that diverse treatment agents targeting the PPAR system have been identified as innovative, effective therapeutic alternatives in the context of endometriosis treatment. In conclusion, PPARs appear to contribute an important role in both endometriosis pathophysiology and therapy.