Thoracic sarcopenia measured by Hounsfield unit average calculation predicts morbidity and mortality in coronary artery bypass grafting.

OBJECTIVES: The aim of the study was to investigate the potential prognostic role of preoperative measurement of erector spinae myosteatosis with Hounsfield unit average calculation as a marker for sarcopenia and frailty in patients undergoing coronary bypass surgery. METHODS: Preoperative computer tomography-derived measurements of 479 consecutive patients undergoing coronary bypass surgery between January 2017 and December 2019 were retrospectively performed. The erector spinae muscle at the level of the 12th vertebra was manually outlined bilaterally on the axial computer tomography slices and Hounsfield unit average calculation was performed. The lower quartile of muscle density values was defined as myosteatotic and thus sarcopenic. Sarcopenic (n = 121) versus non-sarcopenic patients (n = 358) were compared regarding postoperative morbidity and short- and long-term mortality. Results were adjusted for age, body mass index, atrial fibrillation and hypertension using inverse probability weighting. RESULTS: Sarcopenia was associated with higher 30-day mortality (4.1% vs 0.8%; P = 0.012), mid-term mortality after 1 year (9.3% vs 3.1%; P = 0.047) and 2 years (10.8% vs 4.2%; P = 0.047). Long-term mortality (5 years) was 20.8% for sarcopenic and 13.0% for non-sarcopenic patients but was not found to be significantly different (P = 0.089). Sarcopenia was associated with higher rates of reintubation (7.5% vs 1.1%; P < 0.001), sternal wound infections (7.5% vs 2.8%; P = 0.039) and acute kidney injury requiring haemodialysis (2.5% vs 0.4%; P = 0.021). CONCLUSIONS: In patients undergoing coronary bypass surgery, sarcopenia was associated with increased short-term mortality, mid-term mortality and morbidity. The measurement of erector spinae myosteatosis could be an easy and useful parameter in preoperative risk assessment.

Discriminating Malignant from Benign Testicular Masses Using Multiparametric Magnetic Resonance Imaging-A Prospective Single-Center Study.

Objective: The objective of this study was to prospectively assess the extent to which magnetic resonance imaging (MRI) can differentiate malignant from benign lesions of the testis. Materials and Methods: All included patients underwent multiparametric testicular MRI, including diffusion-weighted imaging (DWI) and subtraction dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI). Subsequently, all patients underwent a histopathological examination via orchiectomy or testicular biopsy/partial resection. The Kolmogorov-Smirnov test, t-test, Mann-Whitney U test, Fisher's exact test, and logistic regression were applied for statistical analysis. Results: We included 48 male patients (median age 37.5 years [range 18-69]) with testicular tumors. The median tumor size on MRI was 2.0 cm for malignant tumors and 1.1 cm for benign tumors (p < 0.05). A statistically significant difference was observed for the type (type 0-III curve, p < 0.05) and pattern of enhancement (homogeneous, heterogeneous, or rim-like, p < 0.01) between malignant and benign tumors. The minimum apparent diffusion coefficient (ADC) value was 0.9 for benign tumors and 0.7 for malignant tumors (each ×103 mm2/s, p < 0.05), while the mean ADC was 0.05. The mean ADC value was significantly lower for malignant tumors; the mean ADC value was 1.1 for benign tumors and 0.9 for malignant tumors (each ×103 mm2/s, p < 0.05). The sensitivity, specificity, positive predictive value, and negative predictive value of multiparametric MRI for differentiating malignant from benign testicular lesions were 94.3%, 76.9%, 91.7%, and 83.3%, respectively. The surgical procedures performed included orchiectomy (n = 33; 71.7%) and partial testicular resection (n = 11; 23.9%). Histopathology (HP) revealed malignancy in 35 patients (72.9%), including 26 with seminomas and 9 with non-seminomatous germ cell tumors (NSGCTs). The HP was benign in 13 (27.1%) patients, including 5 with Leydig cell tumors. Conclusions: Malignant and benign tumors differ in MRI characteristics in terms of the type and pattern of enhancement and the extent of diffusion restriction, indicating that MRI can be an important imaging modality for the accurate diagnosis of testicular lesions.

Large Bouncing Mass in the Right Atrium: Metastasis of Malignant Melanoma.

This paper presents a rare case of malignant melanoma metastasizing to the heart, highlighting the diagnostic journey, therapeutic considerations, and clinical implications. Enhanced awareness of atypical metastases aids early recognition and treatment strategies for improved patient care. Comprehensive understanding of cardiac involvement in melanoma contributes to better outcomes and clinical decision making. (Level of Difficulty: Beginner.).

Generation and Characterization of Iduronidase-Cleavable ADCs.

A crucial design feature for the therapeutic success of antibody-drug conjugates (ADCs) is the linker that connects the antibody with the drug. Linkers must be stable in circulation and efficiently release the drug inside the target cell, thereby having a fundamental impact on ADC pharmacokinetics and efficacy. The variety of enzymatically cleavable linkers applied in ADCs is limited, and some are believed to be associated with unwanted side effects due to the expression of cleavage-mediating enzymes in nonmalignant cells. Based on a bioinformatic screen of lysosomal enzymes, we identified α-l-iduronidase (IduA) as an interesting candidate for ADC linker cleavage because of its low expression in normal tissues and its overexpression in several tumor types. In the present study, we report a novel IduA-cleavable ADC linker using exatecan and duocarmycin as payloads. We showed the functionality of our linker system in cleavage assays using recombinant IduA or cell lysates and compared it to established ADC linkers. Subsequently, we coupled iduronide-exatecan via interchain cysteines or iduronide-duocarmycin via microbial transglutaminase (mTG) to an anti-CEACAM5 (aCEA5) antibody. The generated iduronide-exatecan ADC showed high serum stability and similar target-dependent tumor cell killing in the subnanomolar range but reduced toxicity on nonmalignant cells compared to an analogous cathepsin B-activatable valine-citrulline-exatecan ADC. Finally, in vivo antitumor activity could be demonstrated for an IduA-cleavable duocarmycin ADC. The presented results emphasize the potential of iduronide linkers for ADC development and represent a tool for further balancing out tumor selectivity and safety.

Manufacturing flexible vascular models for cardiovascular surgery planning and endovascular procedure simulations: An approach to segmentation and post-processing with open-source software and end-user 3D printers.

306Three-dimensional (3D)-printed vascular models for cardiovascular surgery planning and endovascular procedure simulations often lack realistic biological tissues mimicking material properties, including flexibility or transparency, or both. Transparent silicone or silicone-like vascular models were not available for end-user 3D printers and had to be fabricated using complex and cost-intensive workarounds. This limitation has now been overcome by novel liquid resins with biological tissue properties. These new materials enable simple and low-cost fabrication of transparent and flexible vascular models using end-user stereolithography 3D printers and are promising technological advances toward more realistic patient-specific, radiation-free procedure simulations and planning in cardiovascular surgery and interventional radiology. This paper presents our patient-specific manufacturing process of fabricating transparent and flexible vascular models using freely available open-source software for segmentation and 3D post-processing, aiming to facilitate the integration of 3D printing into clinical care.

The Presence of Ascending Aortic Dilatation in Patients Undergoing Transcatheter Aortic Valve Replacement Is Negatively Correlated with the Presence of Diabetes Mellitus and Does Not Impair Post-Procedural Outcomes.

Both relevant aortic valve stenosis (AS) and aortic valve insufficiency significantly contribute to structural changes in the ascending aorta (AA) and thus to its dilatation. In patients with severe AS undergoing transcatheter aortic valve replacement (TAVR), survival data regarding aortic changes and laboratory biomarker analyses are scarce. METHODS: A total of 179 patients with severe AS and an available computed tomography were included in this retrospective study. AA was measured, and dilatation was defined as a diameter ≥ 40 mm. Thirty-two patients had dilatation of the AA. A further 32 patients from the present population with a normal AA were matched to the aortic dilatation group with respect to gender, age, body mass index and body surface area, and the resulting study groups were compared with each other. In addition to echocardiographic and clinical characteristics, the expression of cardiovascular biomarkers such as brain natriuretic peptide (BNP), soluble suppression of tumorigenicity-2 (sST2), growth/differentiation of factor-15 (GDF-15), heart-type fatty-acid binding protein (H-FABP), insulin-like growth factor binding protein 2 (IGF-BP2) and soluble urokinase-type plasminogen activator receptor (suPAR) was analyzed. Kaplan-Meier curves for short- and long-term survival were obtained, and Pearson's and Spearman's correlations were calculated to identify the predictors between the diameter of the AA and clinical parameters. RESULTS: A total of 19% of the total cohort had dilatation of the AA. The study group with an AA diameter ≥ 40 mm showed a significantly low comorbidity with respect to diabetes mellitus in contrast to the comparison cohort with an AA diameter < 40 mm (p = 0.010). This result continued in the correlation analyses performed, as the presence of diabetes mellitus correlated negatively not only with the diameter of the AA (r = -0.404; p = 0.001) but also with the presence of aortic dilatation (r = -0.320; p = 0.010). In addition, the presence of AA dilatation after TAVR was shown to have no differences in terms of patient survival at 1, 3 and 5 years. There were no relevant differences in the cardiovascular biomarkers studied between the patients with dilated and normal AAs. CONCLUSION: The presence of AA dilatation before successful TAVR was not associated with a survival disadvantage at the respective follow-up intervals of 1, 3 and 5 years. Diabetes mellitus in general seemed to have a protective effect against the development of AA dilatation or aneurysm in patients with severe AS.

A Story of PA/BSA and Biomarkers to Diagnose Pulmonary Hypertension in Patients with Severe Aortic Valve Stenosis-The Rise of IGF-BP2 and GDF-15.

(1) Background: Currently, echocardiography is the primary non-invasive diagnostic method used to screen patients with severe aortic valve stenosis (AS) for pulmonary hypertension (PH) by estimating systolic pulmonary artery pressure (sPAP). Other radiological methods have been a focus of research in the past couple of years, as it was shown that by determining the pulmonary artery (PA) diameter, prognostic statements concerning overall mortality could be made in these patients. This study compared established and novel cardiovascular biomarkers with the PA/BSA value to detect PH in patients with severe AS. (2) Methods: The study cohort comprised 188 patients with severe AS undergoing transcatheter aortic valve replacement (TAVR), who were then divided into two groups based on PA/BSA values obtained through CT-angiography. The presence of PH was defined as a PA/BSA ≥ 16.6 mm/m2 (n = 81), and absence as a PA/BSA < 16.6 mm/m2 (n = 107). Blood samples were taken before TAVR to assess cardiovascular biomarkers used in this study, namely brain natriuretic peptide (BNP), cardiac troponin I (cTnI), high-sensitive troponin (hsTN), soluble suppression of tumorigenesis-2 (sST2), growth/differentiation factor 15 (GDF-15), heart-type fatty acid-binding protein (H-FABP), insulin-like growth factor binding protein 2 (IGF-BP2), and soluble urokinase-type plasminogen activator receptor (suPAR). (3) Results: Patients with a PA/BSA ≥ 16.6 mm/m2 showed significantly higher levels of BNP (p = <0.001), GDF-15 (p = 0.040), and H-FABP (p = 0.007). The other investigated cardiovascular biomarkers did not significantly differ between the two groups. To predict a PA/BSA ≥ 16.6 mm/m2, cut-off values for the biomarkers were calculated. Here, GDF-15 (p = 0.029; cut-off 1172.0 pg/mL) and BNP (p < 0.001; cut-off 2194.0 pg/mL) showed significant results. Consequently, analyses of combined biomarkers were performed, which yielded IGF-BP2 + BNP (AUC = 0.721; 95%CI = 0.585−0.857; p = 0.004) as the best result of the two-way analyses and GDF-15 + IGF-BP2 + BNP (AUC = 0.727; 95%CI = 0.590−0.864; p = 0.004) as the best result of the three-way analyses. No significant difference regarding the 1-year survival between patients with PA/BSA < 16.6 mm/m2 and patients with PA/BSA ≥ 16.6 mm/m2 was found (log-rank test: p = 0.452). (4) Conclusions: Although PA/BSA aims to reduce the bias of the PA value caused by different body compositions and sizes, it is still a controversial parameter for diagnosing PH. Combining the parameter with different cardiovascular biomarkers did not lead to a significant increase in the diagnostic precision for detecting PH in patients with severe AS.

Body composition dynamics and impact on clinical outcome in gastric and gastro-esophageal junction cancer patients undergoing perioperative chemotherapy with the FLOT protocol.

PURPOSE: Perioperative chemotherapy with FLOT constitutes a standard of care approach for locally advanced, resectable gastric or gastro-esophageal junction (GEJ) cancer. We aimed at investigating anthropometric, CT-based and FDG-PET-based body composition parameters and dynamics during this multidisciplinary approach and the impact on clinical outcomes. METHODS: This retrospective, single-center study was based on medical records and (FDG-PET)-CT images among gastric/GEJ cancer patients undergoing perioperative FLOT chemotherapy. RESULTS: Between 2016 and 2021, 46 gastric/GEJ cancer patients started perioperative FLOT at our tertiary cancer center (Salzburg, Austria). At a median follow-up of 32 months median PFS was 47.4 months and median OS was not reached. The skeletal muscle index (SMI, cm2/m2) turned out to be the only body composition parameter with a statistically significant decrease during pre-operative FLOT (51.3 versus 48.8 cm2/m2, p = 0.02). Neither pre-FLOT body mass index (BMI), nor SMI had an impact on the duration of pre-operative FLOT, the time interval from pre-operative FLOT initiation to surgery, the necessity of pre-operative or post-operative FLOT de-escalation or the likelihood of the start of postoperative chemotherapy. Pre-FLOT BMI (overweight versus normal, HR: 0.11, 95% CI: 0.02-0.65, p = 0.02) and pre-FLOT SMI (sarcopenia versus no sarcopenia, HR: 5.08, 95% CI: 1.27-20.31, p = 0.02) were statistically significantly associated with PFS in the multivariable analysis. CONCLUSION: The statistically significant SMI loss during pre-operative FLOT and the meaningful impact of baseline SMI and BMI on PFS argue for the implementation of a nutritional screening and support program prior to the initiation of pre-operative FLOT in clinical routine.

How We Treat Localized Rectal Cancer-An Institutional Paradigm for Total Neoadjuvant Therapy.

Total neoadjuvant therapy (TNT)-the neoadjuvant employment of radiotherapy (RT) or chemoradiation (CRT) as well as chemotherapy (CHT) before surgery-may lead to increased pathological complete response (pCR) rates as well as a reduction in the risk of distant metastases in locally advanced rectal cancer. Furthermore, increased response rates may allow organ-sparing strategies in a growing number of patients with low rectal cancer and upfront immunotherapy has shown very promising early results in patients with microsatellite instability (MSI)-high/mismatch-repair-deficient (dMMR) tumors. Despite the lack of a generally accepted treatment standard, we strongly believe that existing data is sufficient to adopt the concept of TNT and immunotherapy in clinical practice. The treatment algorithm presented in the following is based on our interpretation of the current data and should serve as a practical guide for treating physicians-without any claim to general validity.

CT-Diagnosed Sarcopenia and Cardiovascular Biomarkers in Patients Undergoing Transcatheter Aortic Valve Replacement: Is It Possible to Predict Muscle Loss Based on Laboratory Tests?-A Multicentric Retrospective Analysis.

BACKGROUND: Patients with severe aortic valve stenosis (AS) often present with heart failure and sarcopenia. Sarcopenia, described as progressive degradation of skeletal muscle mass, has frequently been implicated as a cause of increased mortality, prolonged hospitalization and generalized poor outcome after transcatheter aortic valve replacement (TAVR). At present, sarcopenia is defined by the European Working Group on Sarcopenia in Older People (EWGSOP) based on clinical examination criteria and radiological imaging. The aim of the present study was to compare patients with Computed Tomography (CT)-diagnosed sarcopenia with regard to the expression of cardiovascular biomarkers in order to obtain additional, laboratory-chemical information. METHODS: A total of 179 patients with severe AS were included in this retrospective study. Sarcopenia was determined via CT by measurement of the psoas muscle area (PMA), which was indexed to body surface area (PMAi). According to previous studies, the lowest tertile was defined as sarcopenic. Patients with (59/179) and without sarcopenia (120/179) in the overall cohort were compared by gender-specific cut-offs with regard to the expression of cardiovascular biomarkers such as brain natriuretic peptide (BNP), soluble suppression of tumorigenicity-2 (sST2), growth/differentiation of factor-15 (GDF-15), heart-type fatty-acid binding protein (H-FABP), insulin like growth factor binding protein 2 (IGF-BP2) and soluble urokinase-type plasminogen activator receptor (suPAR). Additionally, binary logistic regression analyses were calculated to detect possible predictors of the presence of sarcopenia. RESULTS: No statistical differences regarding one-year survival could be detected between sarcopenic and non-sarcopenic patients in survival curves (log rank test p = 0.179). In the entire cohort, only BNP and hemoglobin (HB) showed a statistically significant difference, with only HB emerging as a relevant predictor for the presence of sarcopenia after binary logistic regression analysis (p = 0.015). No relevant difference in biomarker expression could be found in the male cohort. Regarding the female cohort, statistically significant differences were found in BNP, HB and hematocrit (HK). In binary logistic regression, however, none of the investigated criteria could be related to sarcopenia. CONCLUSION: Regardless of gender, patients with imaging-based muscle degradation did not demonstrate significantly different cardiovascular biomarker expression compared to those without it.

The Diagnostic Value of the Added MR Imaging of the Scrotum in the Preoperative Workup of Sonographically Indeterminate Testicular Lesions-A Retrospective Multicenter Analysis.

BACKGROUND: The purpose of this study was to retrospectively analyze the diagnostic accuracy of magnetic resonance imaging (MRI) examinations of the scrotum in comparison with standard ultrasound (US) and histopathology. METHODS: A retrospective multi-center analysis of MRI examinations of the scrotum performed between 06/2008 and 04/2021 was conducted. RESULTS: A total of n = 113 patients were included. A total of 53 histopathologies were available, with 52.8% malignant and 50.9% benign findings. Related to histopathology, imaging was true negative, false negative, false positive, and true positive in 4.1%, 2.1%, 25.0% and 37.5% for standard ultrasound (US) and 9.1%, 1.8%, 25.5% and 43.6% for MRI. Sensitivity, specificity, positive predictive value and negative predictive value were 94.7%, 20.0%, 36.0% and 88.9% for US and 85.7%, 72.8%, 52.1% and 93.7% for MRI, respectively. Benign lesions were significantly smaller than malignant ones in standard US (p = 0.001), histopathology (p = 0.001) and MRI (p = 0.004). The size of malignant tumors did not differ significantly between histopathology and standard US (0.72) and between histopathology and MRI (p = 0.88). CONCLUSIONS: MRI shows good sensitivity and specificity for the estimation of testicular tumors in this collective. Benign lesions are significantly smaller than malignant ones. Both MRI and US can estimate the size of malignant tumors adequately.

EGFR binding Fc domain-drug conjugates: stable and highly potent cytotoxic molecules mediate selective cell killing.

The exposition of cancer cells to cytotoxic doses of payload is fundamental for the therapeutic efficacy of antibody drug conjugates (ADCs) in solid cancers. To maximize payload exposure, tissue penetration can be increased by utilizing smaller-sized drug conjugates which distribute deeper into the tumor. Our group recently explored small human epidermal growth factor receptor 2 (HER2) targeting Fc antigen binding fragments (Fcabs) for ADC applications in a feasibility study. Here, we expand this concept using epidermal growth factor receptor (EGFR) targeting Fcabs for the generation of site-specific auristatin-based drug conjugates. In contrast to HER2-targeting Fcabs, we identified novel conjugation sites in the EGFR-targeting Fcab scaffold that allowed for higher DAR enzymatic conjugation. We demonstrate feasibility of resultant EGFR-targeting Fcab-drug conjugates that retain binding to half-life prolonging neonatal Fc receptor (FcRn) and EGFR and show high serum stability as well as target receptor mediated cell killing at sub-nanomolar concentrations. Our results emphasize the applicability of the Fcab format for the generation of drug conjugates designed for increased penetration of solid tumors and potential FcRn-driven antibody-like pharmacokinetics.

Effect of Conjugation Site and Technique on the Stability and Pharmacokinetics of Antibody-Drug Conjugates.

Appropriate selection of conjugation sites and conjugation technologies is now widely accepted as crucial for the success of antibody-drug conjugates (ADCs). Herein, we present ADCs conjugated by different conjugation methods to different conjugation positions being systematically characterized by multiple in vitro assays as well as in vivo pharmacokinetic (PK) analyses in transgenic Tg276 mice. Conjugation to cysteines, genetically introduced at positions N325, L328, S239, D265, and S442, was compared to enzymatic conjugation via microbial transglutaminase (mTG) either to C-terminal light (LC) or heavy chain (HC) recognition motifs or to endogenous position Q295 of a native antibody. All conjugations yielded homogeneous DAR 2 ADCs with similar hydrophobicity, thermal stability, human neonatal Fc receptor (huFcRn) binding, and serum stability properties, but with pronounced differences in their PK profiles. mTG-conjugated ADC variants conjugated either to Q295 or to LC recognition motifs showed superior PK behavior. Within the panel of engineered cysteine variants L328 showed a similar PK profile compared to previously described S239 but superior PK compared to S442, D265, and N325. While all positions were first tested with trastuzumab, L328 and mTG LC were further evaluated with additional antibody scaffolds derived from clinically evaluated monoclonal antibodies (mAb). Based on PK analyses, this study confirms the newly described position L328 as favorable site for cysteine conjugation, comparable to the well-established engineered cysteine position S239, and emphasizes the favorable position Q295 of native antibodies and the tagged LC antibody variant for enzymatic conjugations via mTG. In addition, hemizygous Tg276 mice are evaluated as an adequate model for ADC pharmacokinetics, facilitating the selection of suitable ADC candidates early in the drug discovery process.

Generation and Biological Evaluation of Fc Antigen Binding Fragment-Drug Conjugates as a Novel Antibody-Based Format for Targeted Drug Delivery.

Fragment crystallizable (Fc) antigen binding fragments (Fcabs) represent a novel antibody format comprising a homodimeric Fc region with an engineered antigen binding site. In contrast to their full-length antibody offspring, Fcabs combine Fc-domain-mediated and antigen binding functions at only one-third of the size. Their reduced size is accompanied by elevated tissue penetration capabilities, which is an attractive feature for the treatment of solid tumors. In the present study, we explored for the first time Fcabs as a novel scaffold for antibody-drug conjugates (ADCs). As model, various HER2-targeting Fcab variants coupled to a pH-sensitive dye were used in internalization experiments. A selective binding on HER2-expressing tumor cells and receptor-mediated endocytosis could be confirmed for selected variants, indicating that these Fcabs meet the basic prerequisite for an ADC approach. Subsequently, Fcabs were site-specifically coupled to cytotoxic monomethyl auristatin E yielding homogeneous conjugates. The conjugates retained HER2 and FcRn binding behavior of the parent Fcabs, showed a selective in vitro cell killing and conjugation site-dependent serum stability. Moreover, Fcab conjugates showed elevated penetration in a spheroid model, compared to their full-length antibody and Trastuzumab counterparts. Altogether, the presented results emphasize the potential of Fcabs as a novel scaffold for targeted drug delivery in solid cancers and pave the way for future in vivo translation.

Regorafenib Is Associated With Increased Skeletal Muscle Loss Compared to TAS-102 in Metastatic Colorectal Cancer.

BACKGROUND: Current guidelines of the National Comprehensive Cancer Network and the European Society of Medical Oncology recommend regorafenib or trifluridine/tipiracil (TAS-102) for third-line therapy of metastatic colorectal cancer (mCRC). We evaluated the impact of regorafenib and TAS-102 treatment on skeletal muscle dynamics and sarcopenia. PATIENTS AND METHODS: This retrospective analysis was based on unselected, consecutive mCRC patients treated with regorafenib and/or TAS-102 during third or later line of therapy at our tertiary-care cancer center in Salzburg, Austria. The skeletal muscle index (SMI, cm2/m2) and sarcopenia were evaluated from cross-sectional computed tomographic images at the level of the third lumbar vertebra. RESULTS: Between January 2013 and April 2018, a total of 45 patients had received regorafenib and/or TAS-102. At initial mCRC diagnosis and at initiation of third-line therapy, 24% and 54% of patients presented with sarcopenia. A statistically significant skeletal muscle loss was observed during regorafenib treatment (median SMI change: -2.75 cm2/m2 [-6.3%]; P < .0001), which was not the case during TAS-102 therapy (-1.5 cm2/m2 [-3.5%]; P = .575). Furthermore, subclassification of patients into 3 groups-normal muscle mass, stable sarcopenia, and new-onset sarcopenia-at initiation of third-line therapy permitted discrimination of overall survival, with 1-year overall survival rates of 61%, 29%, and 16%, respectively (P = .04). CONCLUSION: The frequency of sarcopenia increases during the course of mCRC and negatively affects survival. In contrast to TAS-102, regorafenib is associated with increased skeletal muscle loss during mCRC treatment and should therefore be used with caution in mCRC patients with preexisting sarcopenia or a history of recent weight loss.

[Acute Pelvic pain in women-gynecological causes]. / Akutes Abdomen der Frau: gynäkologische Ursachen.

BACKGROUND: Acute pelvic pain in women may be due to gynecological, gastrointestinal, and urinary tract disorders. Ectopic pregnancy (EP), pelvic inflammatory disease (PID), and ruptured ovarian cysts are the most common gynecological causes for acute pelvic pain and their diagnosis can be challenging. METHODS: Patient history, clinical examination, and blood tests as well as patient age and potential pregnancy status help to establish the correct diagnosis. While sonography (US) remains the primary imaging modality of choice, computed tomography (CT) plays an important role in patients with indeterminate US evaluation and for treatment planning. CONCLUSION: Diagnostic imaging is pivotal to differentiate potentially life- and fertility-threatening conditions from those that can be treated conservatively. Profound knowledge of the most common gynecological pathologies allows prompt and correct radiological diagnosis and assists in proper treatment planning.

Assessing the mechanism and therapeutic potential of modulators of the human Mediator complex-associated protein kinases.

Mediator-associated kinases CDK8/19 are context-dependent drivers or suppressors of tumorigenesis. Their inhibition is predicted to have pleiotropic effects, but it is unclear whether this will impact on the clinical utility of CDK8/19 inhibitors. We discovered two series of potent chemical probes with high selectivity for CDK8/19. Despite pharmacodynamic evidence for robust on-target activity, the compounds exhibited modest, though significant, efficacy against human tumor lines and patient-derived xenografts. Altered gene expression was consistent with CDK8/19 inhibition, including profiles associated with super-enhancers, immune and inflammatory responses and stem cell function. In a mouse model expressing oncogenic beta-catenin, treatment shifted cells within hyperplastic intestinal crypts from a stem cell to a transit amplifying phenotype. In two species, neither probe was tolerated at therapeutically-relevant exposures. The complex nature of the toxicity observed with two structurally-differentiated chemical series is consistent with on-target effects posing significant challenges to the clinical development of CDK8/19 inhibitors.