Leistung eines mobilen Hand-Ultraschallgeräts zur Beurteilung artikulärer und periartikulärer entzündlicher Veränderungen bei Patienten mit Arthritis

1. Zusammenfassung der Publikation 1.1 Hintergrund und Ziele Der Einsatz mobiler Ultraschallgeräte in der klinischen Praxis nimmt stetig zu. Dies ist unter anderem auf ihre Handlichkeit und auf niedrige Anschaffungskosten zurückzuführen. (1) Die mobilen Ultraschallgeräte ermöglichen die Ultraschalldiagnostik in Bereichen, in denen konventionelle Ultraschallgeräte nicht zur Verfügung stehen. Das derzeitige Anwendungsspektrum liegt vor allem im Bereich des Point-of-Care-Ultraschalls, wie zum Beispiel in der prähospitalen Notfallmedizin, am Patientenbett oder bei der Durchführung von ultraschallgesteuerten Verfahren wie Punktionen. (2, 3 4, 5) Erste Daten zeigen eine adäquate Einsetzbarkeit dieser Geräte für die Untersuchung des Bewegungsapparates. (6, 7, 8, 9) Jedoch wurde bisher keine Evidenz geschaffen, die die Leistung dieser Geräte zur Erfassung von entzündlichen Veränderungen bei Patienten mit Arthritis überprüft. Ziel dieser Arbeit war es daher, (i) die Leistung eines mobilen Ultraschallgerätes bei der Beurteilung der Entzündungsaktivität und der post-entzündlichen Gelenkschäden bei Patienten mit Arthritis mit der eines konventionellen Ultraschallgerätes zu vergleichen und (ii) zu untersuchen, ob der Einsatz eines mobilen Ultraschallscanners zu einer Zeitersparnis bei der Durchführung muskuloskelettalen MSUS-Untersuchung führt. 1.2 Methoden Es wurden Patienten, die die Klassifikationskriterien für die rheumatoide Arthritis (RA) (10), Psoriasis-Arthritis (PsA) (11), systemischen Lupus erythematodes (SLE) (12) oder die Gichtarthropathie (13) erfüllten sowie mindestens ein arthritisches (geschwollenes und druckschmerzhaftes) Gelenk aufwiesen eingeschlossen. Um nicht-pathologische Befunde in die Auswertung einzuschließen, wurden gesunde Probanden rekrutiert. Demographische, krankheitsspezifische und laborchemische Daten wurden erhoben. Die arthritischen Gelenke und periartikulären Strukturen, wie Sehnen und Enthesen, wurden sowohl mit einem mobilen Ultraschallgerät („Butterfly iQ“ (Butterfly Network, Guilford, CT, USA)) als auch mit einem konventionellen Ultraschallgerät („Samsung HS40“ (Samsung Electronics, South Korea)) im B-Modus und Power Doppler (PD)-Modus untersucht. Die Bilder wurden für das Vorhandensein von Erosionen, Knochenneubildung, Synovitis, Gelenkerguss, Bursitis, Tenosynovitis und Enthesitis nach einem validierten Scoring-System ausgewertet (14). Bei der Ultraschall-Untersuchungan gesunden Probanden wurde die für die Untersuchung benötigte Messzeit mit beiden Geräten dokumentiert. 1.3 Ergebnisse Insgesamt wurden 34 Probanden (20 RA, 10 PsA, 1 SLE 1 Gicht, 2 gesunde Probanden) eingeschlossen, 186 Gelenke wurden insgesamt untersucht, 67 davon waren von gesunden Probanden. Im B-Modus zeigte sich eine Gesamtübereinstimmung von 97.1 % (Cohens Kappa 0.9, 95% Konfidenzintervall (KI) 0.89-0.94). Es gab keine signifikanten Unterschiede zwischen den verschiedenen untersuchten artikulären/periartikulären Regionen und dem Vorhandensein von pathologischen Veränderungen. In der Quantifizierung der Synovitis in B-Modus zeigte sich eine Konkordanz von 90.3 % (Cohens Kappa 0.84, 95% KI 0.76 – 0.91). Mit dem konventionellen Ultraschallgerät wurde in 61 Gelenken (33 %) ein PD-Signal festgestellt, während mit dem mobilen Ultraschallgerät in keinem dieser Gelenke ein PD-Signal nachweisbar war. Bei der Verwendung des mobilen Ultraschallgeräts wurde keine signifikante Zeitersparnis festgestellt (47,0 Sekunden/Gelenk (mobiles Gerät) vs. 46,3 Sekunden/Gelenk (konventionelles Gerät)). 1.4 Praktische Schlussfolgerungen Mittels mobilen Ultraschallgeräten können strukturelle und entzündliche Veränderungen bei Arthritis-Patienten genau erfasst werden, allerdings nur im B-Modus. Diese Daten sind ermutigend im Hinblick auf die breite Anwendung von tragbaren Ultraschallgeräten für muskuloskelettale Untersuchungen in der klinischen Praxis. Allerdings sind noch wesentliche Verbesserungen im PD-Modus erforderlich

Antitumor Efficacy of Dual Blockade with Encorafenib + Cetuximab in Combination with Chemotherapy in Human BRAFV600E-Mutant Colorectal Cancer

Antitumor efficacy; Chemotherapy; Colorectal cancerEficàcia antitumoral; Quimioteràpia; Càncer colorectalEficacia antitumoral; Quimioterapia; Cáncer colorrectalPurpose: Encorafenib + cetuximab (E+C) is an effective therapeutic option in chemorefractory BRAFV600E metastatic colorectal cancer (mCRC). However, there is a need to improve the efficacy of this molecular-targeted therapy and evaluate regimens suitable for untreated BRAFV600E in patients with mCRC. Experimental Design: We performed a series of in vivo studies using BRAFV600E mCRC tumor xenografts. Mice were randomized to receive 5-fluoruracil (5-FU), irinotecan, or oxaliplatin regimens (FOLFIRI or FOLFOX), (E+C) or the combination. Patients received long-term treatment until disease progression, with deescalation strategies used to mimic maintenance therapy. Transcriptomic changes after progression on cytotoxic chemotherapy or targeted therapy were assessed. Results: Antitumor activity of either FOLFIRI or E+C was better as first-line treatment as compared with second-line, with partial cross-resistance seen between a cytotoxic regimen and targeted therapy with an average 62% loss of efficacy for FOLFIRI after E+C and a 45% loss of efficacy of E+C after FOLFIRI (P < 0.001 for both). FOLFIRI-treated models had upregulation of epithelial–mesenchymal transition (EMT) and MAPK pathway activation, where E+C treated models had suppressed MAPK signaling. In contrast, with chemotherapy with E+C, EMT and MAPK signaling remained suppressed. FOLFOX or FOLFIRI, each in combination with E+C, were the most active first-line treatments as compared with E+C or to chemotherapy alone. Furthermore, FOLFOX in combination with E+C as first-line induction therapy, followed by E+C ± 5-FU as maintenance therapy, was the most effective strategy for long-term disease control. Conclusions: These results support the combination of cytotoxic chemotherapy and molecular-targeted therapy as a promising therapeutic approach in the first-line treatment of BRAFV600E mCRC.A research grant that partially covered the costs of the study was provided by Regione Campania (I-Cure Research Project, grant number: Cup 21C17000030007, to F. Ciardiello and L. Altucci). This work was also supported by Cancer Center Support Grant – Gastrointestinal Program (Project Number: 5P30 CA016672–46). O.E. Villarreal was supported by the CPRIT Training Program (RP210028)

Open-aqueduct LOVA, LIAS, iNPH: a comparative clinical-radiological study exploring the "grey zone" between different forms of chronic adulthood hydrocephalus

The definition of chronic adult hydrocephalus encompasses different pathological entities with overlapping characteristics, including long-standing overt ventriculomegaly in adults (LOVA), late-onset idiopathic aqueductal stenosis (LIAS) and idiopathic normal pressure hydrocephalus (iNPH). The aim of our study was to identify preoperative clinical and radiological features peculiar of these diseases providing some pathophysiology inferences on these forms of hydrocephalus

Scar-Free Laparoscopy in BRCA-Mutated Women

Background and Objectives: BRCA 1 and 2 mutations have a cumulative risk of developing ovarian cancer at 70 years of 41% and 15%, respectively, while a cumulative risk of breast cancer by 80 years of age was 72% for BRCA1 mutation carriers and 69% for BRCA2 mutation carriers. The NCCN recommends risk-reducing salpingo-oophorectomy (RRSO), typically between 35 and 40 years, and upon completion of childbearing in BRCA1 mutation, while it is reasonable to delay RRSO for management of ovarian cancer risk until age 40–45 years in patients with BRCA2. In recent years there have been two main lines of evolution in laparoscopy. The former concerning the development of a single-site laparoscopic and the latter concerning the miniaturisation of laparoscopic instruments (mini/micro-laparoscopy). Materials and Methods: In this case report, we show our experience in prophylactic adnexectomy, on a mutated-BRCA patient, using the MiniLap® percutaneous surgical system. Results: This type of technique is safe and effective and does not require a particular learning curve compared to single-port laparoscopy. Conclusions: The considerable aesthetic advantage of the scars, we believe, albeit to a lesser extent, is useful to find in these patients burdened by an important stress loa

Breast conserving treatment for ductal carcinoma in situ in the elderly: Can radiation therapy be avoided? Our experience

AbstractIntroduction: Ductal Carcinoma In Situ (DCIS) is a heterogeneous, pre-malignant disease accounting for 15–20% of all new breast cancers. If appropriately managed, DCIS has a small chance of impacting on patient life expectancy. Despite the possibility of a further recurrence or of a development in an invasive form, we are unable to select treatment of choice especially in the elderly. In particularly we risk an overtreatment of women at low risk of progression to invasive breast cancer. The aim of this study was to retrospectively evaluate the outcome of elderly patients affected by DCIS not undergoing Radiation Therapy (RT) after Breast Conserving Surgery (BCS). Material and methods: We reviewed our prospectively-maintained database from 1998 to 2013, selecting all women over 65 years old diagnosed with DCIS who did not receive RT for personal choice. We considered two groups, according to the risk of local recurrence (Low Risk (Group 1) vs. High Risk (Group 2)). Results: We identified 44 cases of DCIS treated with surgery alone or with surgery followed by adjuvant tamoxifen. 24 patients presented low risk of local recurrence (Group 1) and 20 had characteristics associated to high risk of local recurrence (Group 2). At a median follow-up of 66.3 months, no local recurrences have been described in group 1. No patients presented distant metastases, while 4 patients died for other causes. At a median follow-up of 72 months we observed 5 local recurrences in the second group (p < 0.05). Conclusion: Our results suggest that radiation therapy can be safely avoided in a selected group of elderly patients affected by DCIS

The Vulvar Immunohistochemical Panel (VIP) Project:Molecular Profiles of Vulvar Squamous Cell Carcinoma

Introduction: The study's aim was to investigate the immunohistochemical (IHC) expression of biological markers as potential prognostic/therapeutic factors in vulvar squamous cell carcinoma (VSCC). Methodology: A series of 101 patients surgically treated at our center from 2016 to 2020 were retrospectively enrolled: 53 node-negative (Group A) and 48 node-positive (Group B). A total of 146 samples, 101 from primary tumor (T) and 45 from nodal metastases (N), were investigated. The IHC panel included: p16, p53, MLH1, MSH2, MSH6, PMS2, PD-L1, CD3, HER2/neu, ER, PR, EGFR, VEGF, and CD31. The reactions were evaluated on qualitative and semi-quantitative scales. Generalized Linear Model (GLM) and cluster analysis were performed in R statistical environment. A distance plot compared the IHC panel of T with the correspondent N. Results: In Group A: p16-positive expression (surrogate of HPV-dependent pathway) was significantly higher (20.8% vs. 6.2%, p = 0.04). In Group B: PD-L1 positivity and high EGFR expression were found, respectively, in 77.1% and 97.9% patients (T and/or N). Overall, p16-negative tumors showed a higher PD-L1 expression (60.9% vs. 50.0%). In both groups: tumoral immune infiltration (CD3 expression) was mainly moderate/intense (80% vs. 95%); VEGF showed strong/moderate-diffuse expression in 13.9% of T samples; CD31, related to tumoral microvessel density (MVD), showed no difference between groups; a mutated p53 and over-expressed PD-L1 showed significant association with nodal metastasis, with Odds Ratios (OR) of 4.26 (CI 95% = 1.14-15.87, p = 0.03) and 2.68 (CI 95% = 1.0-7.19, p < 0.05), respectively; since all mismatch repair proteins (MMR) showed a retained expression and ER, PR, and HER2/neu were negative, they were excluded from further analysis. The cluster analysis identified three and four sub-groups of molecular profiles, respectively, in Group A and B, with no difference in prognosis. The molecular signature of each N and corresponding T diverged significantly in 18/41 (43.9%) cases. Conclusions: Our results support a potential role of immune checkpoint inhibitors and anti-VEGF and anti-EGFR drugs especially in patients with worse prognosis (metastatic, HPV-independent). A panel including EGFR, VEGF, PDL1, p16, and p53 might be performed routinely in primary tumor and repeated in case of lymph node metastases to identify changes in marker expressio

Receptor tyrosine kinase-dependent PI3K activation is an escape mechanism to vertical suppression of the EGFR/RAS/MAPK pathway in KRAS-mutated human colorectal cancer cell lines

Abstract BACKGROUND: Previous studies showed that the combination of an anti-Epidermal growth factor (EGFR) and a MEK-inhibitor is able to prevent the onset of resistance to anti-EGFR monoclonal antibodies in KRAS-wild type colorectal cancer (CRC), while the same combination reverts anti-EGFR primary resistance in KRAS mutated CRC cell lines. However, rapid onset of resistance is a limit to combination therapies in KRAS mutated CRC. METHODS: We generated four different KRAS mutated CRC cell lines resistant to a combination of cetuximab (an anti-EGFR antibody) and refametinib (a selective MEK-inhibitor) after continuous exposure to increasing concentration of the drugs. We characterized these resistant cell lines by evaluating the expression and activation status of a panel of receptor tyrosine kinases (RTKs) and intracellular transducers by immunoblot and qRT-PCR. Oncomine comprehensive assay and microarray analysis were carried out to investigate new acquired mutations or transcriptomic adaptation, respectively, in the resistant cell lines. Immunofluorescence assay was used to show the localization of RTKs in resistant and parental clones. RESULTS: We found that PI3K-AKT pathway activation acts as an escape mechanism in cell lines with acquired resistance to combined inhibition of EGFR and MEK. AKT pathway activation is coupled to the activation of multiple RTKs such as HER2, HER3 and IGF1R, though its pharmacological inhibition is not sufficient to revert the resistant phenotype. PI3K pathway activation is mediated by autocrine loops and by heterodimerization of multiple receptors. CONCLUSIONS: PI3K activation plays a central role in the acquired resistance to the combination of anti-EGFR and MEK-inhibitor in KRAS mutated colorectal cancer cell lines. PI3K activation is cooperatively achieved through the activation of multiple RTKs such as HER2, HER3 and IGF1R

Targeting BCL2 Overcomes Resistance and Augments Response to Aurora Kinase B Inhibition by AZD2811 in Small Cell Lung Cancer

PURPOSE: Therapeutic resistance to frontline therapy develops rapidly in small cell lung cancer (SCLC). Treatment options are also limited by the lack of targetable driver mutations. Therefore, there is an unmet need for developing better therapeutic strategies and biomarkers of response. Aurora kinase B (AURKB) inhibition exploits an inherent genomic vulnerability in SCLC and is a promising therapeutic approach. Here, we identify biomarkers of response and develop rational combinations with AURKB inhibition to improve treatment efficacy. EXPERIMENTAL DESIGN: Selective AURKB inhibitor AZD2811 was profiled in a large panel of SCLC cell lines (n = 57) and patient-derived xenograft (PDX) models. Proteomic and transcriptomic profiles were analyzed to identify candidate biomarkers of response and resistance. Effects on polyploidy, DNA damage, and apoptosis were measured by flow cytometry and Western blotting. Rational drug combinations were validated in SCLC cell lines and PDX models. RESULTS: AZD2811 showed potent growth inhibitory activity in a subset of SCLC, often characterized by, but not limited to, high cMYC expression. Importantly, high BCL2 expression predicted resistance to AURKB inhibitor response in SCLC, independent of cMYC status. AZD2811-induced DNA damage and apoptosis were suppressed by high BCL2 levels, while combining AZD2811 with a BCL2 inhibitor significantly sensitized resistant models. In vivo, sustained tumor growth reduction and regression was achieved even with intermittent dosing of AZD2811 and venetoclax, an FDA-approved BCL2 inhibitor. CONCLUSIONS: BCL2 inhibition overcomes intrinsic resistance and enhances sensitivity to AURKB inhibition in SCLC preclinical models

Sociality influences thermoregulation and roost switching in a forest bat using ephemeral roosts

In summer, many temperate bat species use daytime torpor, but breeding females do so less to avoid interferences with reproduction. In forest-roosting bats, deep tree cavities buffer roost microclimate from abrupt temperature oscillations and facilitate thermoregulation. Forest bats also switch roosts frequently, so thermally suitable cavities may be limiting. We tested how barbastelle bats (Barbastella barbastellus), often roosting beneath flaking bark in snags, may thermoregulate successfully despite the unstable microclimate of their preferred cavities. We assessed thermoregulation patterns of bats roosting in trees in a beech forest of central Italy. Although all bats used torpor, females were more often normothermic. Cavities were poorly insulated, but social thermoregulation probably overcomes this problem. A model incorporating the presence of roost mates and group size explained thermoregulation patterns better than others based, respectively, on the location and structural characteristics of tree roosts and cavities, weather, or sex, reproductive or body condition. Homeothermy was recorded for all subjects, including nonreproductive females: This probably ensures availability of a warm roosting environment for nonvolant juveniles. Homeothermy may also represent a lifesaver for bats roosting beneath loose bark, very exposed to predators, because homeothermic bats may react quickly in case of emergency. We also found that barbastelle bats maintain group cohesion when switching roosts: This may accelerate roost occupation at the end of a night, quickly securing a stable microclimate in the newly occupied cavity. Overall, both thermoregulation and roost-switching patterns were satisfactorily explained as adaptations to a structurally and thermally labile roosting environment