Ensemble feature selection and tabular data augmentation with generative adversarial networks to enhance cutaneous melanoma identification and interpretability.

BACKGROUND: Cutaneous melanoma is the most aggressive form of skin cancer, responsible for most skin cancer-related deaths. Recent advances in artificial intelligence, jointly with the availability of public dermoscopy image datasets, have allowed to assist dermatologists in melanoma identification. While image feature extraction holds potential for melanoma detection, it often leads to high-dimensional data. Furthermore, most image datasets present the class imbalance problem, where a few classes have numerous samples, whereas others are under-represented. METHODS: In this paper, we propose to combine ensemble feature selection (FS) methods and data augmentation with the conditional tabular generative adversarial networks (CTGAN) to enhance melanoma identification in imbalanced datasets. We employed dermoscopy images from two public datasets, PH2 and Derm7pt, which contain melanoma and not-melanoma lesions. To capture intrinsic information from skin lesions, we conduct two feature extraction (FE) approaches, including handcrafted and embedding features. For the former, color, geometric and first-, second-, and higher-order texture features were extracted, whereas for the latter, embeddings were obtained using ResNet-based models. To alleviate the high-dimensionality in the FE, ensemble FS with filter methods were used and evaluated. For data augmentation, we conducted a progressive analysis of the imbalance ratio (IR), related to the amount of synthetic samples created, and evaluated the impact on the predictive results. To gain interpretability on predictive models, we used SHAP, bootstrap resampling statistical tests and UMAP visualizations. RESULTS: The combination of ensemble FS, CTGAN, and linear models achieved the best predictive results, achieving AUCROC values of 87% (with support vector machine and IR=0.9) and 76% (with LASSO and IR=1.0) for the PH2 and Derm7pt, respectively. We also identified that melanoma lesions were mainly characterized by features related to color, while not-melanoma lesions were characterized by texture features. CONCLUSIONS: Our results demonstrate the effectiveness of ensemble FS and synthetic data in the development of models that accurately identify melanoma. This research advances skin lesion analysis, contributing to both melanoma detection and the interpretation of main features for its identification.

Relationship between the Presence of Human Papillomavirus in the Female Urethra and Recurrent Urinary Tract Infections.

Introduction: Recurrent urinary tract infections (rUTIs) are highly prevalent health issues among women, significantly impacting their quality of life. Urethral pain or urethritis can arise from infectious or non-infectious origins. The presence of Human Papillomavirus (HPV) in the urogenital tract has been associated with high-risk sexual behaviors, but its presence in the female urethra without such behaviors has not been thoroughly investigated. Objectives: The study aims to determine the presence of HPV in the urethra of women with recurrent urinary tract infections (rUTIs) and concomitant urethral syndrome and to compare the clinical and microbiological characteristics of women with and without urethral HPV, specifically focusing on those without high-risk sexual behaviors. Methods: This prospective multicenter study included 138 women over 18 years old with rUTIs and concomitant urethral pain syndrome. High-risk sexual behaviors, sexually transmitted infections, and vaginitis were set as exclusion criteria. Participants were divided into two groups: NHPV (n = 72) with no urethral HPV and HPV (n = 66) with urethral HPV presence. Variables analyzed included age, body mass index (BMI), follow-up duration, comorbidities, treatments, toxic habits, surgical history, main symptoms, urine sediment findings, and cultures from urine and vaginal exudate. HPV genotyping was also performed. Descriptive statistics were used, along with Student's t-test, Chi-square, Fisher's exact test, ANOVA, and multivariate cluster analysis. Results: The NHPV group was older on average (48.75 years) compared to the HPV group (39.09 years). The HPV group had a longer follow-up period (2634 days vs. 1975 days in NHPV). Urinary incontinence was significantly more common in NHPV (63.89%) compared to HPV (18.18%) (p = 0.001). HPV-positive women had a higher prevalence of verrucous lesions in the vaginal introitus (64% vs. 8% in NHPV). Additionally, the HPV group showed higher rates of pyuria (27.27%), vaginal Candida albicans (36.26%), and positive urine cultures for Escherichia coli (47.83%), Enterococcus faecalis (36.36%), and Klebsiella pneumoniae (21.74%). No significant differences were observed between the groups concerning BMI, smoking habits, diabetes, or the main symptom at consultation. The most common HPV genotypes identified were G35, G42, and G66 (each 27%). Multivariate analysis revealed that sensitivity to nitrofurantoin was the most significant variable in the HPV group (importance of 0.96), followed by fosfomycin (0.79), trimethoprim (0.79), and amoxicillin (0.71). Conclusions: HPV was present in the urethra of 47.8% of women with rUTIs and concomitant urethral syndrome who did not exhibit high-risk sexual behaviors. These women were younger and had a longer duration of symptoms compared to those without urethral HPV. The identification of Enterococcus faecalis, Escherichia coli, and Klebsiella pneumoniae was more common in the HPV group. The sensitivity of bacteria to nitrofurantoin and fosfomycin is crucial for the clinical management of these patients. The presence of urethral HPV should be considered in the evaluation and treatment of women with rUTIs and urethral syndrome.

Early outcomes of robotic modified retromuscular Sugarbaker technique for end colostomy parastomal hernia repair.

AIM: The modified retromuscular Sugarbaker or Pauli technique is a technique for parastomal hernia repair, which requires the dissection of the retromuscular space and a transversus abdominis release for stoma lateralization and placement of a retromuscular mesh. Given the limited evidence regarding the robotic approach to this technique, this study aims to evaluate the outcomes of this newly introduced procedure, focusing on the rate of 30-day complications and recurrence rates. METHODS: Retrospective case series report. Patients included underwent an elective robotic modified retromuscular Sugarbaker technique for the repair of a parastomal hernia associated with an end colostomy. All surgeries were performed at a tertiary referral center from September 2020 to December 2023. RESULTS: A total of 21 patients underwent a robotic modified retromuscular Sugarbaker in our study. The parastomal hernias operated on were classified according to the European Hernia Society as 9.5% (2/21) type I, 52.4% (11/21) type II, 23.8% (5/21) type III, 14.3% (3/21) type IV. Early complications observed included 14.3% (3/21) seroma, 9.5% (2/21) surgical site infection, 19% (4/21) postoperative ileus, and one case of large bowel obstruction due to colitis (4.8%), which was managed conservatively. No Clavien-Dindo grade III complications were reported. The overall recurrence rate was 9.5% (2/21) with a median follow-up of 12.5 months (IQR: 3.9-21.3). Both recurrences occurred during the early phases of the learning curve and were possibly attributed to insufficient lateralization of the stoma. CONCLUSION: Robotic modified retromuscular Sugarbaker for parastomal hernia repair is a challenging procedure with promising early outcomes.

Orpinolide disrupts a leukemic dependency on cholesterol transport by inhibiting OSBP.

Metabolic alterations in cancer precipitate in associated dependencies that can be therapeutically exploited. To meet this goal, natural product-inspired small molecules can provide a resource of invaluable chemotypes. Here, we identify orpinolide, a synthetic withanolide analog with pronounced antileukemic properties, via orthogonal chemical screening. Through multiomics profiling and genome-scale CRISPR-Cas9 screens, we identify that orpinolide disrupts Golgi homeostasis via a mechanism that requires active phosphatidylinositol 4-phosphate signaling at the endoplasmic reticulum-Golgi membrane interface. Thermal proteome profiling and genetic validation studies reveal the oxysterol-binding protein OSBP as the direct and phenotypically relevant target of orpinolide. Collectively, these data reaffirm sterol transport as a therapeutically actionable dependency in leukemia and motivate ensuing translational investigation via the probe-like compound orpinolide.

Discovery and Mechanistic Elucidation of NQO1-Bioactivatable Small Molecules That Overcome Resistance to Degraders.

Degraders hold the promise to efficiently inactivate previously intractable disease-relevant targets. Unlike traditional inhibitors, degraders act substoichiometrically and rely on the hijacked proteolysis machinery, which can also act as an entry point for resistance. To fully harness the potential of targeted protein degradation, it is crucial to comprehend resistance mechanisms and formulate effective strategies to overcome them. We conducted a chemical screening to identify synthetic lethal vulnerabilities of cancer cells that exhibit widespread resistance to degraders. Comparative profiling followed by tailored optimization delivered the small molecule RBS-10, which shows preferential cytotoxicity against cells pan-resistant to degraders. Multiomics deconvolution of the mechanism of action revealed that RBS-10 acts as a prodrug bioactivated by the oxidoreductase enzyme NQO1, which is highly overexpressed in our resistance models. Collectively, our work informs on NQO1 as an actionable vulnerability to overcome resistance to degraders and as a biomarker to selectively exploit bioactivatable prodrugs in cancer.

Delay in the residents' choice for General and Digestive Surgery: Analysis of the period 2018-2022.

INTRODUCTION: Every year hundreds of medical residents choose their specialization in various surgical fields. However, these numbers have been poorly analyzed. The objective of this study was to evaluate the selection of General and Digestive Surgery by medical residents and compare these results with the selection of other surgical specialties. METHODS: Cross-sectional observational study. The data from the selection of the medical residents from surgical specialties and the top 10 most demanded specialties between the years 2018 and 2022 were included. An analysis of adjusted ranking numbers based on the number of available positions was also conducted. RESULTS: The number of available positions in General and Digestive Surgery increased by 17.7% during the study period. However, the selection of our specialty has been delayed, with a median ranking number of 2419 (IQR: 1621-3284) in 2018, and 3484 (IQR: 2306-4156) in 2022 (p: .000). These differences remained significant after adjusting for the number of available positions (p: .000). The choice of Urology, Thoracic Surgery, Cardiovascular Surgery, Gastroenterology, and Paediatrics also declined during this period, while Plastic Surgery, Dermatology, Ophthalmology, Anesthesiology, and Endocrinology improved their numbers. CONCLUSION: The choice of General and Digestive Surgery has been delayed according to the data from the MIR selection of 2018-2022. The increase in the number of available positions has not been associated with a proportional increase in demand.

Analysis of recurrence and risk factors in laparoscopic sandwich technique for parastomal hernia repair.

INTRODUCTION: Parastomal hernias are frequent and highly recurrent. The sandwich technique is a combination of the keyhole and Sugarbaker techniques, using a double intraperitoneal mesh. The objective of this study was to assess the outcomes of the sandwich technique, specifically focusing on recurrence rates. MATERIALS AND METHODS: Observational retrospective study conducted in two tertiary referral centers in Catalonia, Spain. All consecutive patients who underwent parastomal hernia repair using the sandwich technique between 1st January 2016 and 31st December 2021 were included. RESULTS: A total of 38 patients underwent the laparoscopic sandwich technique for parastomal hernia repair. The overall recurrence rate was 7.9% (3/38), with a median follow-up of 39 months (IQR: 12.3-56.5). According to the EHS classification for parastomal hernia, there were 47.4% (18/38) type I defects, 10.5% (4/38) type II defects, 28.9% (11/38) type III defects, and 13.2% (5/38) type IV defects. The used mesh was predominantly TiMesh® (76.3%; 29/38), followed by DynaMesh® IPOM (23.7%; 9/38). Patients with recurrence exhibited higher rates of seroma, hematoma, surgical site infection, and one case of early recurrence attributed to mesh retraction. Consequently, postoperative complications emerged as the primary risk factor for hernia recurrence. CONCLUSION: The sandwich technique demonstrated recurrence rates consistent with those reported in the existing literature.

Podcast 3. Lessons learned: managing financial costs and where you can go for more information.

The patient authors with over 48 years of combined real-world experience with chronic myeloid leukemia, and a healthcare professional, use their own personal experiences to describe the factors that may affect the patien-doctor relationship, patient care and outcomes. The authors believe that this podcast series and associated manuscript will aid both patients and healthcare professionals to improve their patient-doctor relationships and communication through diagnosis, treatment decision-making and learning to live with CML (or another disease). In this episode, they discuss managing financial costs and where to find resources and support groups.

The beginning: diagnosis and selecting your doctor.

The patient authors with over 48 years of combined real-world experience with chronic myeloid leukemia, and a healthcare professional, use their own personal experiences to describe the factors that may affect the patient-doctor relationship, patient care and outcomes. The authors believe that this podcast series and associated manuscript will aid both patients and healthcare professionals to improve their patient-doctor relationships and communication through diagnosis, treatment decision-making and learning to live with CML (or another disease). In this episode, they discuss the importance of the patient-doctor relationship, the patient authors' own diagnosis experiences and considerations when selecting a health care team.

Podcast 2. The journey: staying on top of your cancer.

The patient authors with over 48 years of combined real-world experience with chronic myeloid leukemia, and a healthcare professional, use their own personal experiences to describe the factors that may affect the patient-doctor relationship, patient care and outcomes. The authors believe that this podcast series and associated manuscript will aid both patients and healthcare professionals to improve their patient-doctor relationships and communication through diagnosis, treatment decision-making and learning to live with CML (or another disease). In this episode, they discuss communication between a patient and their healthcare team and establishing a treatment protocol.

Characterization of p38α autophosphorylation inhibitors that target the non-canonical activation pathway.

p38α is a versatile protein kinase that can control numerous processes and plays important roles in the cellular responses to stress. Dysregulation of p38α signaling has been linked to several diseases including inflammation, immune disorders and cancer, suggesting that targeting p38α could be therapeutically beneficial. Over the last two decades, numerous p38α inhibitors have been developed, which showed promising effects in pre-clinical studies but results from clinical trials have been disappointing, fueling the interest in the generation of alternative mechanisms of p38α modulation. Here, we report the in silico identification of compounds that we refer to as non-canonical p38α inhibitors (NC-p38i). By combining biochemical and structural analyses, we show that NC-p38i efficiently inhibit p38α autophosphorylation but weakly affect the activity of the canonical pathway. Our results demonstrate how the structural plasticity of p38α can be leveraged to develop therapeutic opportunities targeting a subset of the functions regulated by this pathway.

Bladder Capacity in Women With Overactive Bladder Syndrome: A Cross-sectional Study.

OBJECTIVE: To evaluate bladder capacity in women with idiopathic overactive bladder syndrome (OAB) through bladder diary, cystomanometry, and uroflowmetry and assess the concordance of the different measures of bladder capacity. A secondary objective is to describe the relationship between bladder capacity and urinary frequency in OAB patients. METHODS: An observational cross-sectional multicentric study was conducted, including female patients diagnosed with idiopathic OAB. All participants underwent a urodynamic study and completed a 3-day bladder diary (3dBD). Different parameters were used to calculate bladder capacity: maximum cystometric capacity (MCC) assessed at the end of filling cystometry, voided volume (VV) during the uroflowmetry, maximum voided volume (VVmax), and average voided volume (VVmed), both assessed through the 3dBD. Reproducibility analysis was performed to assess the agreement among the different bladder capacity measures. Intraclass correlation coefficient (ICC) and weighted Kappa index were used. Bladder capacity parameters were also assessed in relation to urinary frequency. RESULTS: Bladder capacity measures were diminished in this population, except for VVmax. Poor correlation was found between the different bladder capacity variables (ICC and weighted Kappa index <0.4). Twenty-four-hour frequency and average VV present a weak negative linear relationship (Pearson coefficient -0.344). CONCLUSION: MCC and average VV are reduced in OAB patients. MCC does not correlate well with functional bladder volumes determined by voiding diary in the OAB population.

The importance of developing open communication and a professional, long-term relationship between patients with chronic myeloid leukemia and their oncologist.

A good patient-doctor relationship and positive communication strongly influence patient quality of life and clinical outcomes. Demonstrating the importance of communication in the patient-doctor relationship are three patient authors who have 48 years of combined real-world experience with chronic myeloid leukemia (CML) in the USA. Using their own personal experiences, these patient authors and a healthcare professional provide suggestions related to improving patient-doctor relationships and communication at each stage of the journey from diagnosis to learning to live with CML. The authors believe these recommendations are applicable to patients with CML and with other diseases, their caregivers and healthcare professionals.

Exploring the role of mitochondria transfer/transplant and their long-non-coding RNAs in regenerative therapies for skin aging.

Advancing age and environmental stressors lead to mitochondrial dysfunction in the skin, inducing premature aging, impaired regeneration, and greater risk of cancer. Cells rely on the communication between the mitochondria and the nucleus by tight regulation of long non-coding RNAs (lncRNAs) to avoid premature aging and maintain healthy skin. LncRNAs act as key regulators of cell proliferation, differentiation, survival, and maintenance of skin structure. However, research on how the lncRNAs are dysregulated during aging and due to stressors is needed to develop therapies to regenerate skin's function and structure. In this article, we discuss how age and environmental stressors may alter lncRNA homeodynamics, compromising cell survival and skin health, and how these factors may become inducers of skin aging. We describe skin cell types and how they depend on mitochondrial function and lncRNAs. We also provide a list of mitochondria localized and nuclear lncRNAs that can serve to better understand skin aging. Using bioinformatic prediction tools, we predict possible functions of lncRNAs based on their subcellular localization. We also search for experimentally determined protein interactions and the biological processes involved. Finally, we provide therapeutic strategies based on gene editing and mitochondria transfer/transplant (AMT/T) to restore lncRNA regulation and skin health. This article offers a unique perspective in understanding and defining the therapeutic potential of mitochondria localized lncRNAs (mt-lncRNAs) and AMT/T to treat skin aging and related diseases.

Maximum tumor-absorbed dose measured by voxel-based multicompartmental dosimetry as a response predictor in yttrium-90 radiation segmentectomy for hepatocellular carcinoma.

OBJECTIVE: Advances in hepatic radioembolization are based on a selective approach with radical intent and the use of multicompartment dosimetric analysis. The objective of this study is to assess the utility of voxel-based dosimetry in the quantification of actual absorbed doses in radiation segmentectomy procedures and to establish cutoff values predictive of response. METHODS: Ambispective study in hepatocarcinoma patients treated with radiation segmentectomy. Calculated dosimetric parameters were mean tumor-absorbed dose, maximum tumor AD, minimal tumor AD in 30, 50, and 70% of tumor volume and mean AD in non-tumor liver. The actual absorbed dose (aAD) was calculated on the Y-90-PET/CT image using 3D voxel-based dosimetry software. To assess radiological response, localized mRECIST criteria were used. The objective response rate (ORR) was defined as CR or PR. RESULTS: Twenty-four HCC patients, BCLC 0 (5), A (17) and B (2) were included. The mean yttrium-90 administered activity was 1.38 GBq in a mean angiosome volume of 206.9 cc and tumor volume 56.01 cc. The mean theoretical AD was 306.3 Gy and aAD 352 Gy. A very low concordance was observed between both parameters (rho_c 0.027). ORR at 3 and 6 m was 84.21% and 92.31%, respectively. Statistically significant relationship was observed between the maximum tumor-absorbed dose and complete radiological response at 3 m (p 0.022). CONCLUSION: A segmental approach with radical intention leads to response rates greater than 90%, being the tumor maximum absorbed dose the dosimetric parameter that best predicts radiological response in voxel-based dosimetry.

External validation of yonsei nomogram predicting chronic kidney disease development after partial nephrectomy: An international, multicenter study.

OBJECTIVE: To externally validate Yonsei nomogram. METHODS: From 2000 through 2018, 3526 consecutive patients underwent on-clamp PN for cT1 renal masses at 23 centers were included. All patients had two kidneys, preoperative eGFR ≥60 ml/min/1.73 m2, and a minimum follow-up of 12 months. New-onset CKD was defined as upgrading from CKD stage I or II into CKD stage ≥III. We obtained the CKD-free progression probabilities at 1, 3, 5, and 10 years for all patients by applying the nomogram found at https://eservices.ksmc.med.sa/ckd/. Thereafter, external validation of Yonsei nomogram for estimating new-onset CKD stage ≥III was assessed by calibration and discrimination analysis. RESULTS AND LIMITATION: Median values of patients' age, tumor size, eGFR and follow-up period were 47 years (IQR: 47-62), 3.3 cm (IQR: 2.5-4.2), 90.5 ml/min/1.73 m2 (IQR: 82.8-98), and 47 months (IQR: 27-65), respectively. A total of 683 patients (19.4%) developed new-onset CKD. The 5-year CKD-free progression rate was 77.9%. Yonsei nomogram demonstrated an AUC of 0.69, 0.72, 0.77, and 0.78 for the prediction of CKD stage ≥III at 1, 3, 5, and 10 years, respectively. The calibration plots at 1, 3, 5, and 10 years showed that the model was well calibrated with calibration slope values of 0.77, 0.83, 0.76, and 0.75, respectively. Retrospective database collection is a limitation of our study. CONCLUSIONS: The largest external validation of Yonsei nomogram showed good calibration properties. The nomogram can provide an accurate estimate of the individual risk of CKD-free progression on long-term follow-up.

Project Confirm: Accelerated Drug Approvals for Chronic Myeloid Leukemia.

The FDA has an accelerated approval program for drugs that have been identified as promising treatments for serious conditions when the available data suggest that the benefits outweigh the foreseeable risks. All of the currently available treatment options for chronic myeloid leukemia (CML) initially went through the accelerated approval program. Here, a group of academic CML experts, patient panelists, and members from the FDA convened to discuss the utility of the accelerated approval program as it pertains to CML, and the utility of this program in future drug development in this disease. The results of that discussion are summarized here.

Accuracy and prognostic impact of FDG PET/CT and biopsy in bone marrow assessment of follicular lymphoma at diagnosis: A Nation-Wide cohort study.

BACKGOUND: In the workup of follicular lymphoma (FL), bone marrow biopsy (BMB) assessment is a key component of FLIPI and FLIPI2, the most widely used outcome scores. During the previous decade, several studies explored the role of FDG-PET/CT for detecting nodal and extranodal disease, with only one large study comparing both techniques. METHODS: The aim of our study was to evaluate the diagnostic accuracy and the prognostic impact of both procedures in a retrospective cohort of 299 FL patients with both tests performed at diagnosis. In order to avoid a collinearity bias, FLIPI2 was deconstructed in its founding parameters, and the bone marrow involvement (BMI) parameter separately included as: a positive BMB, a positive PET/CT, the combined "PET/CT and BMB positive" or "PET/CT or BMB positive". These variables were also confronted independently with the POD24 in 233 patients treated with intensive regimens. RESULTS: In the total cohort, bone marrow was involved in 124 and 60 patients by BMB and PET/CT, respectively. In terms of overall survival, age > 60 y.o. and the combined "PET/CT or BMB positive" achieved statistical independence as a prognostic factor. In patients treated with an intensive regimen, only the combined "PET/CT or BMB positive" added prognostic value for a shorter overall survival, when confronted with the POD24. CONCLUSION: Our results show that in FL both BMB and PET/CT should be considered at diagnosis, as their combined assessment provides independent prognostic value in the context of the most widely use clinical scores.