Real-World Experience with Cemiplimab Treatment for Advanced Cutaneous Squamous Cell Carcinoma-A Retrospective Single-Center Study.

BACKGROUND: The systemic treatment of advanced cutaneous squamous cell carcinoma (cSCC) has seen significant developments in recent years. The anti-PD1 inhibitor cemiplimab has demonstrated efficacy in clinical trials, but real-world data are still limited. Here, we aimed to evaluate the efficacy and the safety of cemiplimab in a real-world clinical setting. METHODS: A retrospective analysis was carried out for all patients who received at least two doses of cemiplimab at our department between February 2020 and January 2023. Progression-free survival (PFS), overall survival (OS), the objective response rate (ORR), the disease control rate (DCR) and adverse events (AEs) were evaluated. RESULTS: Twenty-five patients were included with a median age of 78 (65-82) years. The median treatment duration was 48 (16-72) weeks. Five (20%) patients were immunocompromised. Sixteen patients (64%) developed AEs, including 36% serious AEs (SAEs) of grade ≥ 3. Six patients (24%) were withdrawn from treatment due to the occurrence of AEs. Among the 25 patients, 52% showed an objective response (3 complete and 10 partial responses), 76% had controlled disease and 24% experienced progression. Among the five immunocompromised patients, the ORR was 60%, while the DCR was 80%. CONCLUSIONS: This retrospective real-world study revealed that locally advanced or metastatic cSCC could be effectively treated with cemiplimab even in elderly, polymorbid and immunocompromised patients.

Downregulation of PACAP and the PAC1 Receptor in the Basal Ganglia, Substantia Nigra and Centrally Projecting Edinger-Westphal Nucleus in the Rotenone model of Parkinson's Disease.

Numerous in vitro and in vivo models of Parkinson's disease (PD) demonstrate that pituitary adenylate cyclase-activating polypeptide (PACAP) conveys its strong neuroprotective actions mainly via its specific PAC1 receptor (PAC1R) in models of PD. We recently described the decrease in PAC1R protein content in the basal ganglia of macaques in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD that was partially reversed by levodopa therapy. In this work, we tested whether these observations occur also in the rotenone model of PD in the rat. The rotarod test revealed motor skill deterioration upon rotenone administration, which was reversed by benserazide/levodopa (B/L) treatment. The sucrose preference test suggested increased depression level while the open field test showed increased anxiety in rats rendered parkinsonian, regardless of the received B/L therapy. Reduced dopaminergic cell count in the substantia nigra pars compacta (SNpc) diminished the dopaminergic fiber density in the caudate-putamen (CPu) and decreased the peptidergic cell count in the centrally projecting Edinger-Westphal nucleus (EWcp), supporting the efficacy of rotenone treatment. RNAscope in situ hybridization revealed decreased PACAP mRNA (Adcyap1) and PAC1R mRNA (Adcyap1r1) expression in the CPu, globus pallidus, dopaminergic SNpc and peptidergic EWcp of rotenone-treated rats, but no remarkable downregulation occurred in the insular cortex. In the entopeduncular nucleus, only the Adcyap1r1 mRNA was downregulated in parkinsonian animals. B/L therapy attenuated the downregulation of Adcyap1 in the CPu only. Our current results further support the evolutionarily conserved role of the PACAP/PAC1R system in neuroprotection and its recruitment in the development/progression of neurodegenerative states such as PD.

Anti-PD-1 Monotherapy in Advanced Melanoma-Real-World Data from a 77-Month-Long Retrospective Observational Study.

Real-world evidence plays an important role in the assessment of efficacy and safety of novel therapies. The increasing use of immune checkpoint inhibitors (ICIs) in patients with advanced melanoma has led to notably improved clinical outcomes, while they are also associated with immune-related adverse events (irAEs). The majority of the available data are based on clinical trials, where the investigated subjects often do not adequately represent the general patient population of the everyday practice. Although there is a niche of objective biomarkers for the future treatment response of ICIs, certain studies suggest that irAEs may be predictive. The aim of this study was to carry out a retrospective analysis of treatment data from patients with advanced melanoma, treated with a single anti-PD-1 agent (pembrolizumab or nivolumab) during a 77-month-long period. Treatment efficacy and occurrence of adverse events were analyzed to identify potential predictive markers. Primary and secondary endpoints were the overall survival (OS) and progression-free survival (PFS). In our cohort, we demonstrated that the occurrence of more than one irAE showed a correlation with response to PD-1 ICI therapy and improved the OS and PFS. Our study suggests, that the grade of toxicity of the irAE may affect the survival rate.

Anti-Interleukin-17 Therapy of Severe Psoriatic Patients Results in an Improvement of Serum Lipid and Inflammatory Parameters' Levels, but Has No Effect on Body Composition Parameters.

BACKGROUND: Psoriasis is frequently accompanied by metabolic syndrome. Effect of anti-tumor necrosis factor therapies on increases in body weight is well-known. Data on the effects of interleukin-17 inhibitors are limited. Authors determined the effect of anti-interleukin-17 therapies on the body composition and serum lipid and inflammatory parameters among severe psoriatic patients. METHODS: Thirty-five severe psoriatic patients were enrolled. Twenty-two received secukinumab and 13 received ixekizumab as their 2nd-or 3rd-line biological treatment. Before treatment initiation and 6 months later, laboratory examinations measuring metabolic and inflammatory panels and body composition analyses were performed. RESULTS: After 6 months, a significant reduction was observed in psoriasis area severity index (p < 0.001) from 18 to 0, in c-reactive protein (p < 0.001) from 6.6 to 4.00 mg/L, in low-density lipoprotein-cholesterol (p = 0.004) from 3.69 to 3.19 mmol/L, and an improvement in high-density lipoprotein-cholesterol (p = 0.022) from 1.31 to 1.40 mmol/L. Median baseline body mass index was 32.80 kg/m2. The body composition parameters did not show any significant changes. CONCLUSIONS: Anti-interleukin-17 therapy of severe psoriatic patients does not cause significant changes in body composition parameters. Improvements in the lipid and inflammatory parameters might have a beneficial effect on patients' cardiometabolic status. This effect might be detectable in high-risk obese psoriatic patients.

PEGylation of Superparamagnetic Iron Oxide Nanoparticles with Self-Organizing Polyacrylate-PEG Brushes for Contrast Enhancement in MRI Diagnosis.

For biomedical applications, superparamagnetic nanoparticles (MNPs) have to be coated with a stealth layer that provides colloidal stability in biological media, long enough persistence and circulation times for reaching the expected medical aims, and anchor sites for further attachment of bioactive agents. One of such stealth molecules designed and synthesized by us, poly(polyethylene glycol methacrylate-co-acrylic acid) referred to as P(PEGMA-AA), was demonstrated to make MNPs reasonably resistant to cell internalization, and be an excellent candidate for magnetic hyperthermia treatments in addition to possessing the necessary colloidal stability under physiological conditions (Illés et al. J. Magn. Magn. Mater. 2018, 451, 710⁻720). In the present work, we elaborated on the molecular background of the formation of the P(PEGMA-AA)-coated MNPs, and of their remarkable colloidal stability and salt tolerance by using potentiometric acid⁻base titration, adsorption isotherm determination, infrared spectroscopy (FT-IR ATR), dynamic light scattering, and electrokinetic potential determination methods. The P(PEGMA-AA)@MNPs have excellent blood compatibility as demonstrated in blood sedimentation, smears, and white blood cell viability experiments. In addition, blood serum proteins formed a protein corona, protecting the particles against aggregation (found in dynamic light scattering and electrokinetic potential measurements). Our novel particles also proved to be promising candidates for MRI diagnosis, exhibiting one of the highest values of r2 relaxivity (451 mM-1s-1) found in literature.

[Colon reconstruction after the Hartmann procedure. Laparoscopy or laparotomy?] / Colonrekonstrukció Hartmann-mutét után. Laparoszkópia vagy laparotomia?

The Hartmann procedure - primarily - was introduced for the treatment of cancerous diseases of sigmoid colon and rectum. In the last few years it was performed in cases with complicated inflammation of the left colon, colon cancers with bowel obstruction or perforation, or in the case of insufficiency of the anastomoses, or in urgent operations after traumatics bowel injuries, when making the anastomosis is at very high risk. Later on the restoration of the continuity of the GI tract can be done traditionally (by laparotomy) or laparoscopically. We present our experiences with the above technique, and also compare our results with traditional open surgeries in our patients.

S100P and HYAL2 as prognostic markers for patients with triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a group of very aggressive breast tumours, characterised by lack of expression of oestrogen receptor (ER), progesterone receptor (PR) and erb-b2 receptor tyrosine kinase 2 (ERBB2/HER2). Nevertheless, TNBCs show different clinical characteristics and are very diverse regarding prognostic outcome. So far, only a few prognostic markers for TNBC have been reported that could be helpful for therapeutic stratification. Here we have analysed the expression of S100P and HYAL2 using immunohistochemistry (IHC) in a TNBC cohort of 98 patients with a follow-up for recurrence and death. TNBC patients with high expression of both proteins showed significantly shorter progression-free survival (PFS) (mean PFS=35.9months, P=0.001) compared to TNBC patients with high expression levels of only one of the proteins (mean PFS=69.4months) and to TNBC patients with low expression of both proteins (mean PFS=83.3months). Moreover, multivariate Cox-regression model showed the combined expression of S100P and HYAL2 as independent prognostic factor for PFS (P=0.001). The expression of S100P and HYAL2 indicated similar prognostic effect to the overall survival (OS) of TNBC patients. In addition, high expression levels of both S100P and HYAL2 showed significant association with different clinicopathological characteristics, such as more recurrence events (P=0.004), and higher occurrence of metastasis (P=0.002). Our study proposes S100P and HYAL2 as potential prognostic markers for TNBC.

Influence of Intracranial Electrode Density and Spatial Configuration on Interictal Spike Localization: A Case Study.

PURPOSE: Poor seizure outcomes after epilepsy surgery often reflect an incorrect localization of the epileptic sources by standard intracranial EEG interpretation because of limited electrode coverage of the epileptogenic zone. This study investigates whether, in such conditions, source modeling is able to provide more accurate source localization than the standard clinical method that can be used prospectively to improve surgical resection planning. METHODS: Suboptimal epileptogenic zone sampling is simulated by subsets of the electrode configuration used to record intracranial EEG in a patient rendered seizure free after surgery. sLORETA and the clinical method solutions are applied to interictal spikes sampled with these electrode subsets and are compared for colocalization with the resection volume and displacement due to electrode downsampling. RESULTS: sLORETA provides often congruent and at times more accurate source localization when compared with the standard clinical method. However, with electrode downsampling, individual sLORETA solution locations can vary considerably and shift consistently toward the remaining electrodes. CONCLUSIONS: sLORETA application can improve source localization based on the clinical method but does not reliably compensate for suboptimal electrode placement. Incorporating sLORETA solutions based on intracranial EEG in surgical planning should proceed cautiously in cases where electrode repositioning is planned on clinical grounds.

Synthesis of poly(poly(ethylene glycol) methacrylate)-polyisobutylene ABA block copolymers by the combination of quasiliving carbocationic and atom transfer radical polymerizations.

Systematic investigations are carried out on the synthesis of a series of new, unique ABA-type triblock copolymers consisting of the hydrophobic and chemically inert polyisobutylene (PIB) inner and the hydrophilic comb-shaped poly(poly(ethylene glycol) methacrylate) (PPEGMA) polymacromonomer as an outer block. Telechelic PIB macroinitiators with narrow molecular weight distributions (MWD) are synthesized by quasiliving carbocationic polymerization of isobutylene with a bifunctional initiator followed by quantitative chain end derivatizations. Atom transfer radical polymerization (ATRP) of PEGMAs with various molecular weights is investigated by using these macroinitiators. It is found that CuBr is an inefficient ATRP catalyst, while CuCl leads to high, nearly complete conversions of the PEGMA macromonomers. Gel permeation chromatography (GPC) analyses reveal slow initiation of PEGMA at relatively high PIB/PEGMA ratios or with PEGMAs of higher molecular weights due to steric hindrance between the macroinitiator and macromonomer. The occurrence of slow initiation, and not permanent termination, is proven by highly efficient ATRP of a low-molecular-weight monomer, methyl methacrylate, with the block copolymers as macroinitiators. Successful synthesis of PPEGMA-PIB-PPEGMA ABA block copolymers is obtained by using either low-molecular-weight PEGMA or relatively low macroinitiator/macromonomer ratios. Differential scanning calorimetry (DSC) indicates phase separation and significant suppression of the crystallinity of the pendant poly(ethylene glycol) (PEG) chains in these new block copolymers.

Breast cancer mastectomy trends between 2006 and 2010: association with magnetic resonance imaging, immediate breast reconstruction, and hospital volume.

PURPOSE: Analysis of mastectomy rates in breast cancer patients diagnosed between 2006 and 2010 in Germany with focus on impact of breast magnetic resonance imaging (MRI), immediate breast reconstruction (IBR) rates, and hospital volume as possible influencing factors of mastectomy rates. METHODS: Data of a voluntary monitored benchmarking project were used to evaluate mastectomy trends across time in an unselected cohort of breast cancer patients. We used univariate and multivariate logistic regression analysis to identify predictive factors of mastectomy. RESULTS: A total of 142.863 cases were included into the analysis. There was an overall decrease of 5.9% (95% confidence interval 5.1-6.7) in mastectomy trend from 36.5% in 2006 to 30.6% in 2010 (P < 0.0001). Known predictive factors were confirmed. Breast MRI (odds ratio 1.42, 95% confidence interval 1.36-1.47) and small hospitals (<150 cases per year) seem to favor mastectomy. IBR was not associated with mastectomy rates. CONCLUSIONS: Mastectomy rates in comparable health systems differ. Performance of preoperative breast MRI and hospital volume seem to be independent influencing factors for mastectomy rates.

The CD44+ ALDH+ population of human keratinocytes is enriched for epidermal stem cells with long-term repopulating ability.

Like for other somatic tissues, isolation of a pure population of stem cells has been a primary goal in epidermal biology. We isolated discrete populations of freshly obtained human neonatal keratinocytes (HNKs) using previously untested candidate stem cell markers aldehyde dehydrogenase (ALDH) and CD44 as well as the previously studied combination of integrin α6 and CD71. An in vivo transplantation assay combined with limiting dilution analysis was used to quantify enrichment for long-term repopulating cells in the isolated populations. The ALDH(+) CD44(+) population was enriched 12.6-fold for long-term repopulating epidermal stem cells (EpiSCs) and the integrin α6(hi) CD71(lo) population was enriched 5.6-fold, over unfractionated cells. In addition to long-term repopulation, CD44(+) ALDH(+) keratinocytes exhibited other stem cell properties. CD44(+) ALDH(+) keratinocytes had self-renewal ability, demonstrated by increased numbers of cells expressing nuclear Bmi-1, serial transplantation of CD44(+) ALDH(+) cells, and holoclone formation in vitro. CD44(+) ALDH(+) cells were multipotent, producing greater numbers of hair follicle-like structures than CD44(-) ALDH(-) cells. Furthermore, 58% ± 7% of CD44(+) ALDH(+) cells exhibited label-retention. In vitro, CD44(+) ALDH(+) cells showed enhanced colony formation, in both keratinocyte and embryonic stem cell growth media. In summary, the CD44(+) ALDH(+) population exhibits stem cell properties including long-term epidermal regeneration, multipotency, label retention, and holoclone formation. This study shows that it is possible to quantify the relative number of EpiSCs in human keratinocyte populations using long-term repopulation as a functional test of stem cell nature. Future studies will combine isolation strategies as dictated by the results of quantitative transplantation assays, in order to achieve a nearly pure population of EpiSCs.

[Large-bowel necrosis following open-heart surgery]. / Colon necrosis halmozott elofordulása szívmutét után.

In the last 2 years 9 patients have been operated on in our surgical department because of colon necrosis which developed after open heart surgery. The symptoms--abdominal distension, circumscript peritonitis in the right lower part of the abdomen--developed 2-4 days after the heart operation. Laparotomies were carried out within 2 days from the onset of symptoms in all but one patient. In 7 patients the necrosis of the right colon, while in 2 other patients extreme dilatation of the colon was found. In 6 patients right hemicolectomy was carried out. One operation was finished without anastomosis with double stomas. In the 2 patients with no necrosis catheter-cecostomy was performed. All patients but one after hemicolectomy with reconstruction died after several reoperations because of suture leak. The other 3 patients were cured. We examined and analysed the pre-, intra- and postoperative circumstances of the heart operations, which lead to the severe complications. We think the cause of the problems was the liberal use of wide spectrum antibiotics with caused severe dysbacteriosis and Clostridium difficile toxicosis in the colon. This condition could lead to a pseudomembraneous colitis which resulted in the colon necrosis.

[Ileocecal intussusception caused by Burkitt lymphoma, cause of mechanical ileus]. / Ileocoecalis intussusceptiót elóidézó Burkitt-lymphoma, mint mechanikus ileus oka.

A 39-year-old man was admitted to our Medical Department, because of regular abdominal cramps. At physical examination a palpable mass was detected in the ileocoecal region with tenderness. Examinations proved ileocoecal intussusception. Emergency operation was performed. At histology the cause of small-bowel invagination was Burkitt-lymphoma. After the complex haematological examination chemotherapy was started. Six month after surgery the patient is symptomless.