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Triple-negative breast cancer (TNBC) poses a serious therapeutic challenge due to the occurrence of frequently aggressive, heterogenic, and metastatic tumours. The absence of therapeutic targets for traditional therapies is a hindrance to establishing a standardised therapy for TNBC. There is limited TNBCs epidemiological and real-world data about TNBC treatment regimens in Poland. We retrospectively analysed clinical data from our hospital registry from 2015 and 2020. A total of 8103 individuals with breast cancer were admitted to the MSCI, while 856 (10.6%) were diagnosed with TNBC. Most of the early-stage or locally advanced TNBC individuals had underlying conditions, presented mostly poorly differentiated (G3) stage II tumours and featured a bi-modal age distribution. On average, one-third of all tested TNBCs carried BRCA mutations and its identification impacted surgery preference. We observed a significant increase in the use of systemic therapy among TNBCs, whereas carboplatin and dose-dense regimens showed the most prominent upsurge in the neoadjuvant setting. Moreover, the use of neoadjuvants was positively correlated with less invasive breast and lymph node surgeries. The presented data align with general trends observed in other countries and will contribute to expanding knowledge in the planning of treatment regimens and their outcomes.

Introduction: Pembrolizumab combined with chemotherapy has become the standard of care for patients with non-small-cell lung cancer (NSCLC) and the expression of programmed death ligand 1 (PD-L1) in <50% of tumour cells (TC)., Methods: We evaluated the efficacy of the treatment in real-world practice, paying attention to the predictive factors, with a special focus on low level of PD-L1 expression. This study is a multicenter retrospective analysis of patients with stage IV NSCLC., Results: A group of 339 consecutive patients was analysed, among them 51% patients with low PD-L1 expression. In the overall population, the ORR was 40.6%, median PFS and OS were 13 months (95% CI 11.4-15) and 16.8 months (95% CI 13.3-20.3), respectively. In multivariate analysis for the entire study population, performance status - ECOG 1 vs. 0 (HR 2.2, 95%CI 1.1-4.6; p=0.02), neutrophil to lymphocyte ratio (NLR)>3 (HR 2.3, 95%CI 1.3-4.2; p=0.04), presence of liver (HR 2.0, 95%CI 1-3.7; p=0. 03) and bone metastases (HR 1.3, 95%CI 1-3; p=0.04), weight loss (HR 1.8, 95%CI 1.1-2.8; p=0.01) and sum of measurable lesions diameters >110 mm (HR 1.7, 95%CI 1-2.9, p=0.049) had a negative impact on OS., Conclusions: In the real world, patients can clinically benefit from immunochemotherapy, regardless of the expression of PD-L1 and the histological type. Other clinicopathological factors such as performance status, extent, and location of secondary lesions have prognostic significance., Competing Interests: MK-W: Honoraria: BMS, MSD, Roche, AstraZeneca, Pfizer, Janssen, Sanofi, Amgen, Takeda; RD: Roche, AstraZeneca, Pfizer, Bristol-Myers Squibb, GlaxoSmithKline, Novartis, Takeda, Amgen Lectures and advisory boards, compensated; TJ: Honoraria: Roche, BMS, MSD, Amgen, Pfizer, Takeda, Novartis, Astra Zeneca, Sanofi; PK: Advisory Board and Lectures: Roche, BMS, MSD, Amgen, Pfizer, Takeda, Novartis, Janssen, Astra Zeneca, Sanofi; JM: Lectures: BMS, MSD, Astra-Zeneca, Novartis; MB Advisory Board and Lectures: Roche, Boehringer-Ingelheim, AstraZeneca, MSD, BMS, Pfizer, Takeda, Amgen, Sanofi; KS: Honoraria: Roche, BMS, MSD, Amgen, Pfizer, Takeda, Janssen, Astra Zeneca; AW: Honoraria Pfizer, Roche, MSD, BMS, Astra Zeneca, Takeda.; KR: Honoraria BMS, MSD, Roche, Astra Zeneca, Amgen, Takeda; GC: Honoraria BMS, MSD, Astra-Zeneca, Roche, Amgen; EK: Honoraria- BMS, MSD, Roche, AstraZeneca, Novartis, GSK, Daiichi Sankyo, Regeneron, Nektar, Pfizer, Janssen, Amgen, Gilead; KS-Z: Honoraria BMS, Molteni, Merck; JR-K: Honoraria BMS, Molteni, Astra Zeneca, Merck; JS-K: Honoraria Novartis, Pierre Fabre, ROCHE; MoW: Honoraria: Amgen, Merck, MSD, Sanofi.; PW: Advisory Board and Consultancy: Roche-Genentech, BMS, MSD, MERCK, Amgen, Pfizer, Astra-Zeneca, Novartis, Johnson&Johnson, Sanofi-Aventis, Astellas, Lilly, GSK, Janssen, Immunicom Inc., GLG-Pharma,; DK: Advisory Board and Consultancy: Roche-Genentech, BMS, MSD, MERCK, Amgen, Pfizer, TAKEDA, Novartis, Johnson&Johnson, Astra-Zeneca, Sanofi-Aventis; MK: Advisory Board & Cosultancy – MERCK, ASTRA-ZENECA, TAKEDA, ROCHE, AMGEN. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Knetki-Wróblewska, Dziadziuszko, Jankowski, Krawczyk, Bryl, Stencel, Wrona, Bandura, Smok-Kalwat, Rok-Knapińska, Szydziak-Zwierzyńska, Rogoziewicz, Czyżewicz, Wójtowicz, Wojtukiewicz, Kalinka, Wysocki, Łobacz, Milanowski, Pawlik, Kowalski and Krzakowski.)

Background The implementation of next-generation sequencing (NGS) into daily practice allows for the identification of a greater number of molecular abnormalities. We aimed to confirm the benefits of immunotherapy in the group of patients with KRAS aberrations treated within clinical practice. Methods This study was a retrospective analysis of the patients (pts) treated in routine practice within the National Drug Programme in Poland. The NGS was performed using a FusionPlex Comprehensive Thyroid and Lung (CTL) kit (ArcherDx) and sequenced using a MiniSeq (Illumina). The analyses were performed with the R language environment, version 4.1.3. Results A total of 96 pts with chemotherapy-pre-treated advanced NSCLC (CS III−IV) were qualified for nivolumab or atezolizumab treatment following a molecular diagnosis by the NGS and the exclusion of EGFR and ALK gene abnormalities. A mutation in the KRAS gene was found in 26 patients (27%); among them, the variant p.Gly12Cyc (G12C) was the most common (42%). The median PFS and OS for the overall population were 2 months (95% CI: 1.8−2.75) and 10 months (95% CI: 6.9−16.2), respectively. No differences were observed in terms of the mPFS between the KRAS-mutated and KRAS wild-type (WT) patients. A trend toward a longer OS was observed in the group of patients with the KRAS mutation, but the difference was not statistically significant (p = 0.43). In the multivariate analysis, the presence of mutations in the KRAS gene had no prognostic significance, while the occurence of grade 3 toxicity and the neutrophil-to-lymphocyte ratio (NLR) > 3.5 were found as statistically significant factors. Conclusions Immunotherapy in the second-line treatment of advanced NSCLC allows for a benefit regardless of the KRAS gene mutation status. The treatment sequence, including molecularly targeted drugs such as sotorasib and adagrasib, is still discussed. The NGS is a valuable method to identify a variety of molecular abnormalities in patients with NSCLC in daily practice.

Due to increased lactate production during glucose metabolism, tumor cells heavily rely on efficient lactate transport to avoid intracellular lactate accumulation and acidification. Monocarboxylate transporter 4 (MCT4/SLC16A3) is a lactate transporter that plays a central role in tumor pH modulation. The discovery and optimization of a novel class of MCT4 inhibitors (hit 9a ), identified by a cellular screening in MDA-MB-231, is described. Direct target interaction of the optimized compound 18n with the cytosolic domain of MCT4 was shown after solubilization of the GFP-tagged transporter by fluorescence cross-correlation spectroscopy and microscopic studies. In vitro treatment with 18n resulted in lactate efflux inhibition and reduction of cellular viability in MCT4 high expressing cells. Moreover, pharmacokinetic properties of 18n allowed assessment of lactate modulation and antitumor activity in a mouse tumor model. Thus, 18n represents a valuable tool for investigating selective MCT4 inhibition and its effect on tumor biology.

In oncology, the "Warburg effect" describes the elevated production of energy by glycolysis in cancer cells. The ubiquitous and hypoxia-induced 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) plays a noteworthy role in the regulation of glycolysis by producing fructose-2,6-biphosphate (F-2,6-BP), a potent activator of the glycolysis rate-limiting phosphofructokinase PFK-1. Series of amides and sulfonamides derivatives based on a N-aryl 6-aminoquinoxaline scaffold were synthesized and tested for their inhibition of PFKFB3 in vitro in a biochemical assay as well as in HCT116 cells. The carboxamide series displayed satisfactory kinetic solubility and metabolic stability, and within this class, potent lead compounds with low nanomolar activity have been identified with a suitable profile for further in vivo evaluation., (Copyright © 2018. Published by Elsevier Ltd.)

Energy and biomass production in cancer cells are largely supported by aerobic glycolysis in what is called the Warburg effect. The process is regulated by key enzymes, among which phosphofructokinase PFK-2 plays a significant role by producing fructose-2,6-biphosphate; the most potent activator of the glycolysis rate-limiting step performed by phosphofructokinase PFK-1. Herein, the synthesis, biological evaluation and structure-activity relationship of novel inhibitors of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), which is the ubiquitous and hypoxia-induced isoform of PFK-2, are reported. X-ray crystallography and docking were instrumental in the design and optimisation of a series of N-aryl 6-aminoquinoxalines. The most potent representative, N-(4-methanesulfonylpyridin-3-yl)-8-(3-methyl-1-benzothiophen-5-yl)quinoxalin-6-amine, displayed an IC 50 of 14 nm for the target and an IC 50 of 0.49 μm for fructose-2,6-biphosphate production in human colon carcinoma HCT116 cells. This work provides a new entry in the field of PFKFB3 inhibitors with potential for development in oncology., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Each summer, the nuisance green alga Cladophora (mostly Cladophora glomerata) amasses along Lake Michigan beaches, creating nearshore anoxia and unsightly, malodorous mats that can attract problem animals and detract from visitor enjoyment. Traditionally, elevated counts of Escherichia coli are presumed to indicate the presence of sewage, mostly derived from nearby point sources. The relationship between fecal indicator bacteria and Cladophora remains essentially unstudied. This investigation describes the local and regional density of Escherichia coli and enterococci in Cladophora mats along beaches in the four states (Wisconsin, Illinois, Indiana, and Michigan) bordering Lake Michigan. Samples of Cladophora strands collected from 10 beaches (n = 41) were assayed for concentrations of E. coli and enterococci during the summer of 2002. Both E. coli and enterococci were ubiquitous (up to 97% occurrence), with overall log mean densities (+/- standard errors) of 5.3 (+/- 4.8) and 4.8 (+/- 4.5) per g (dry weight). E. coli and enterococci were strongly correlated in southern Lake Michigan beaches (P < 0.001, R(2) = 0.73, n = 17) but not in northern beaches (P = 0.892, n = 16). Both E. coli and enterococci survived for over 6 months in sun-dried Cladophora mats stored at 4 degrees C; the residual bacteria in the dried alga readily grew upon rehydration. These findings suggest that Cladophora amassing along the beaches of Lake Michigan may be an important environmental source of indicator bacteria and call into question the reliability of E. coli and enterococci as indicators of water quality for freshwater recreational beaches.

We present four cases with combined hypoplasia of the cerebellum and the ventral pons-pontocerebellar hypoplasia (PCH). PCH represents an autosomal recessive neurodegenerative disorder with fetal onset. The disease is rare, with less than 20 cases having been reported. The main findings of PCH and the inclusion criteria for our cases can be summarised as progressive microcephaly from birth, pontocerebellar hypoplasia documented by MRI and marked chorea, which may change, later in childhood, to more dystonic patterns. The cerebral cortex becomes progressively atrophic. Motor and mental development are delayed, and epilepsy, mainly tonic-clonic seizures, is frequent. The MRI features in all of our cases were: (1) Hypoplastic cerebellum situated close to the tentorium. The hypoplastic cerebellum has a reduced number of folia, in contrast to the normal number of thin folia in simple cerebellar atrophy. (2) The cerebellar hemispheres are reduced to bean-like or wing-like structures. The cerebellar hemispheres appear to 'float' in the posterior fossa. (3) Markedly hypoplastic ventral pons. (4) Slight atrophy of the supratentorial gyral pattern. (5) Dilated cerebromedullary cistern and fourth ventricle. (6) Delayed myelination of the white matter. (7) No significant disorganisation of brain architecture and no severe corpus callosum defect.

Purpose: To examine if RARE urography may replace conventional intravenous urography in patients with suspected urinary obstruction in pelvic tumours., Materials and Methods: In a prospective trial on 120 patients with pelvic tumours scheduled for operation, biplanar RARE urography was performed and compared to conventional intravenous urography and ultrasound findings., Results: In 30 out of 120 patients an ureteric obstruction was diagnosed by ultrasound. Sensitivity of RARE urography for obstruction was 98% as compared to 60% in conventional intravenous urography. In 12 patients additional retrograde cystoureterography showed a sensitivity of 83%. Specificity of RARE urography and intravenous urography was 100%. In combination with axial MR tomography RARE urography yielded a more precise localisation of the site of obstruction and the underlying cause (98%) as compared to conventional urography (60%) and ultrasound (56%)., Conclusion: By use of RARE urography urinary obstruction can be reliably demonstrated or ruled out. Combining RARE urography with tomographic MR imaging allows the precise depiction of the site of the obstruction and may demonstrate the underlying pathology.

Arthritis psoriatica has been known for over 160 years, however, not long ago it became a separate nosologic unit. In 1964 American Rheumatological Society introduced the name arthritis psoriatica, which is obligatory nowadays. It was thought in the beginning that the inflammation may coexist with psoriasis accidentally only, whereas epidemiological studies, clinical observations and serologic data excluded such a simple relation. Since the international diagnostic criteria were established and also the rheumatoid factor was discovered it has been clear there's a direct relation between arthritis psoriatica and dermatologic changes of a psoriasis type. Therefore it is a disease where rheumatology and dermatology meet with each other. The aim of our study was to collect the knowledge about the diagnosis of arthritis psoriatica.

Volumetric measurements have been performed in vitro to define permeability for water of different parts of peritoneum. The experiments were carried out on isolated fragments of rabbit mesentery, anterior abdominal wall, and diaphragm; mesothelial layer lining these membranes was retained in one group, whereas in another one it was intentionally desquamated. The membranes were mounted between two semichambers filled with Hanks solution; the volume on both sides of the membrane was strictly controlled by photo-gauges coupled with microdosi-meters. Transmembrane volume flow (Jv; nL/sec cm2) induced by hydrostatic pressure gradient (delta P; atm) was measured using an electronic device connected with the photo-gauges, and joined with a computer which monitored the values throughout the experiment. Hydraulic conductivity (Lp; in cm/sec atm) and index of impediment (Zp; in sec atm/cm) were calculated from the monitored values. Significant differences between the three types of peritoneal membrane were observed: the hydraulic conductivity of diaphragm was lowest, and the impediment highest (0.86 +/- 0.11 x 10(-2) and 116.3 +/- 12.2, respectively) contrasting with the corresponding values of mesentery which were highest, and lowest (38.9 +/- 3.7 x 10(-2), and 2.57 +/- 0.25, resp.); peritoneum taken from anterior abdominal wall showed intermediate values (6.3 +/- 0.56 x 10(-2), and 15.9 +/- 1.5, resp.). Removal of mesothelium induced significant increase of the permeability of diaphragm and anterior abdominal wall, however, no such effect was observed in mesentery. The obtained results seem to show that various parts of peritoneum may function qualitatively different during dialysis, however, any conclusion concerning clinical aspects of the dialysis should be drawn with all proper reserves.

Planimetric studies of peritoneal surface area were performed in 10 humans, 12 rabbits, and 15 rats. It was found that the total peritoneal surface area (TPSA) correlated in humans with body surface area (BSA) (r = 0.98, p < 0.0001) and body weight (r = 0.93, p < 0.001), and correlated in animals with body weight (r = 0.80, p < 0.005 in rabbits; and r = 0.88, p < 0.0001 in rats). The area of parietal peritoneum was 18.1 +/- 1.8% of TPSA in humans, 17.8 +/- 1.0% of TPSA in rabbits, and 22.6 +/- 2.1% of TPSA in rats (p < 0.001 vs humans and rabbits). Additionally, the area of peritoneum covering the individual organs (expressed as % of TPSA) was different in humans, rabbits, and rats: for example, the area of peritoneum covering the diaphragm was 6.4 +/- 1.5% of TPSA in humans, which was larger than in animals (3.0 +/- 0.3% in rats, p < 0.0001 vs humans and rabbits; and only 2.1 +/- 0.4% in rabbits, p < 0.0001 vs humans). Presented results show that interspecies variation in the topography of the peritoneum should be taken into account when the results from experimental studies done on animals are extrapolated to humans.

This work reports on the skin diseases which occur among the workers of the ceramic industry. The most frequently observed diseases were: dermatomycosis, eczema as a result of wear, and allergic diseases. Nickel, and also cobalt, turpentine, paraphenyldiamine and detergents were the main allergens. Mycotic infection was observed primarily among the workers using common bathrooms.

The authors evaluated 60 epidurographies performed in patients with suspected compressing lesions in the vertebral canal. It was demonstrated that epidurography may be a useful method for diagnosis of pathological conditions in the vertebral canal, particularly in its thoracolumbar part. In many cases this method is sufficient for establishing full diagnosis, not infrequently it should be applied as a supplementary procedure (e.g. for evaluating the structure of the vertebral canal or for accurate assessment of the size of the tumour situated in the canal) and in cases with high-grade stenosis of the canal it is the method of choice. Moreover, it was found that epidurography is a method of low invasiveness, not harmful and well tolerated by the patients.