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Simple Summary: Forkhead-box M1 (FOXM1) is a proliferation-associated transcription factor, overexpressed in almost all the cancers, making its regulation worth investigating. FOXM1 is known to bind to the promoters of certain microRNAs, a class of biomolecules involved in post-transcriptional gene regulation. Database mining followed by Venn analysis led us to the shortlisting of seven microRNAs, among which microRNA-532-3p showed the strongest interaction with FOXM1 3'UTR. The ectopic overexpression of miR-532-3p in colorectal cancer (CRC) cells led to decreased FOXM1 levels which resulted in the alteration of CRC functionalities. These altered phenotypes were supported by a change in the expression of proliferation and EMT markers. In conclusion, the present study suggested that the regulation of FOXM1 by microRNA-532-3p via its interaction with FOXM1 3'UTR inhibited CRC proliferation, migration, and invasion. Colorectal cancer (CRC) is a heterogeneous disease and classified into various subtypes, among which transcriptional alterations result in CRC progression, metastasis, and drug resistance. Forkhead-box M1 (FOXM1) is a proliferation-associated transcription factor which is overexpressed in CRC and the mechanisms of FOXM1 regulation have been under investigation. Previously, we showed that FOXM1 binds to promoters of certain microRNAs. Database mining led to several microRNAs that might interact with FOXM1 3'UTR. The interactions between shortlisted microRNAs and FOXM1 3'UTR were quantitated by a dual-luciferase reporter assay. MicroRNA-532-3p interacted with the 3'UTR of the FOXM1 mRNA transcript most efficiently. MicroRNA-532-3p was ectopically overexpressed in colorectal cancer (CRC) cell lines, leading to reduced transcript and protein levels of FOXM1 and cyclin B1, a direct transcriptional target of FOXM1. Further, a clonogenic assay was conducted in overexpressed miR-532-3p CRC cells that revealed a decline in the ability of cells to form colonies and a reduction in migratory and invading potential. These alterations were reinforced at molecular levels by the altered transcript and protein levels of the conventional EMT markers E-cadherin and vimentin. Overall, this study identifies the regulation of FOXM1 by microRNA-532-3p via its interaction with FOXM1 3'UTR, resulting in the suppression of proliferation, migration, and invasion, suggesting its role as a tumor suppressor in CRC. [ABSTRACT FROM AUTHOR]

Simple Summary: Viral infection poses cancer risk and the PD-1/PD-L1 immune check point plays a critical role in this process. Despite the success of the existing anti-PD-1 and PD-L1 antibodies, significant challenges remain due to drug resistance and serious side effects. We have developed a novel anti-PD-1 antibody P1801 which has significant PD-1 blocking and antitumor activities. It displayed unique binding properties distinctive from pembrolizumab and nivolumab with limited ADCC- and CDC-mediated lysis of normal immune cells. We are initiating a Phase 1 clinical study to test its combination use with ropeginterferon alfa-2b, a new-generation interferon-alfa-based therapy which also has antiviral and antitumor activities, for the treatment of cancer. Programmed cell death 1 (PD-1) and programmed death-ligand 1 (PD-L1) interact to form an immune checkpoint fostering viral infection and viral oncogene-induced tumorigenesis. We generated a novel anti-human PD-1, humanized monoclonal antibody P1801 and investigated its pharmacologic, pharmacokinetic (PK), and pharmacodynamic properties. In vitro binding assays revealed that P1801 uniquely binds to human PD-1 and inhibits its interaction with PD-L1/2. It showed a minor effect on the induction of antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). P1801 significantly induced the release of IL-2 from activated T-cells but not from nonactivated T-cells. A dose-dependent linear PK profile was observed for the cynomolgus monkeys treated with repeated doses of P1801 at 5 mg/kg to 200 mg/kg once weekly. A four-week repeat-dose toxicity study revealed that P1801 given weekly was safe and well tolerated at doses ranging from 5 to 200 mg/kg/dose. No pathological abnormalities were noted. In humanized PD-1 mice harboring human PD-L1-expressing colon tumor cells, P1801 administered intraperitoneally twice per week at 12 mg/kg significantly inhibited tumor growth and prolonged mouse survival. P1801 displayed unique binding properties different from pembrolizumab and nivolumab. Therefore, it showed distinctive immunological reactions and significant antitumor activities. We are initiating a Phase 1 clinical study to test its combination use with ropeginterferon alfa-2b, which also has antiviral and antitumor activities, for the treatment of cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Pancreatic cancer is one of the most deadly forms of cancer. Current treatment options often fail because too little of the chemotherapy gets into the cancer. Hyperthermia, or heat treatment, has shown some promise in treating pancreatic cancer and may make it more likely for the chemotherapy to enter into the cancer. This study aims to design liposomes that can increase the amount of chemotherapy reaching pancreatic cancer by targeting the liposomes with hyperthermia. Treatment of pancreatic ductal adenocarcinoma with gemcitabine is limited by an increased desmoplasia, poor vascularization, and short plasma half-life. Heat-sensitive liposomes modified by polyethylene glycol (PEG; PEGylated liposomes) can increase plasma stability, reduce clearance, and decrease side effects. Nevertheless, translation of heat-sensitive liposomes to the clinic has been hindered by the low loading efficiency of gemcitabine and by the difficulty of inducing hyperthermia in vivo. This study was designed to investigate the effect of phospholipid content on the stability of liposomes at 37 °C and their release under hyperthermia conditions; this was accomplished by employing a two-stage heating approach. First the liposomes were heated at a fast rate, then they were transferred to a holding bath. Thermosensitive liposomes formulated with DPPC: DSPC: PEG2k (80:15:5, mole%) exhibited minimal release of carboxyfluorescein at 37 °C over 30 min, indicating stability under physiological conditions. However, upon exposure to hyperthermic conditions (43 °C and 45 °C), these liposomes demonstrated a rapid and significant release of their encapsulated content. The encapsulation efficiency for gemcitabine was calculated at 16.9%. Additionally, fluorescent analysis during the removal of unencapsulated gemcitabine revealed an increase in pH. In vitro tests with BxPC3 and KPC cell models showed that these thermosensitive liposomes induced a heat-dependent cytotoxic effect comparable to free gemcitabine at temperatures above 41 °C. This study highlights the effectiveness of the heating mechanism and cell models in understanding the current challenges in developing gemcitabine-loaded heat-sensitive liposomes. [ABSTRACT FROM AUTHOR]

Simple Summary: Immune checkpoint inhibitors (ICIs) are a common and growing type of cancer treatment, but they can cause side effects. This study aims to understand these side effects in patients with kidney cancer and bladder cancer. We compared the types and severity of side effects between these two groups to determine if there are differences. We also compared them to other tumor types to see if there is a unique pattern. The findings will help doctors better predict and manage side effects. This will hopefully lead to improving patient care for those receiving ICI treatment. Background: Immune checkpoint inhibitors (ICIs) have become common lines of therapy for genitourinary cancers (GUcs). Given their widespread use, understanding the risk factors, comparative profiles, and timing of immune-related adverse events (irAEs) is essential. Methods: We created an IRB-approved retrospective registry of all patients who received at least one dose of an ICI for any indication between 1 February 2011 and 7 April 2022 at a comprehensive cancer center and its outreach clinics. Dichotomous outcomes were modeled using multivariable logistic regression. Survival outcomes were compared using multivariable Cox regression. Results: Among 3101 patients, 196 had renal cell carcinoma (RCC) and 170 had urothelial tumors. RCC patients were more likely to experience irAEs (OR 1.78; 95% CI 1.32–2.39), whereas urothelial carcinoma patients were not (OR 1.22; 95% CI 0.88–1.67). RCC patients were more prone to dermatitis, thyroiditis, acute kidney injury, and myocarditis, compared to other tumors, while urothelial carcinoma patients were not. The impact of irAEs on survival was not significantly different for GUcs compared to other tumors. Conclusions: RCC primaries have a significantly different irAE profile than most tumors, as opposed to urothelial primaries. Further, RCC was more likely to experience any irAEs. Heterogeneity of survival benefits by irAEs was not seen. [ABSTRACT FROM AUTHOR]

Simple Summary: Immune checkpoint inhibitors (ICIs) have been experimentally used in refractory pituitary neuroendocrine tumours (PitNETs). We reviewed the published data on PitNETs treated with PD-1/PD-L1 inhibitors. Demographics, clinical–pathological features, treatment details, radiological and biochemical responses, and survival were evaluated. Among twenty-nine ICI-treated PitNETs, eighteen secreted adrenocorticotropic hormone (ACTH) (62.1%), seven were prolactinomas (24.1%), and four were non-functioning PitNETs. All patients underwent various therapies prior to ICI treatment. A positive radiological response (i.e., partial/complete radiological response and stable disease) was observed in eighteen cases (62.1%), of which ten and four were ACTH- and prolactin-secreting PitNETs, respectively. Hormonal levels reduced or stabilised after using ICIs in 11 cases (64.7%). The median survival after using ICIs was 13 months. These data suggest a promising role of ICIs in patients with PitNETs refractory to other treatment modalities. Therapeutic options for pituitary neuroendocrine tumours (PitNETs) refractory to temozolomide are scarce. Immune checkpoint inhibitors (ICIs), particularly inhibitors of the programmed cell death-1 (PD-1) pathway and its ligand (PD-L1), have been experimentally used in aggressive or metastatic PitNETs. We aimed to study the therapeutic usefulness of anti-PD-1 drugs in patients with aggressive or metastatic PitNETs. Published cases and case series involving patients with PitNETs treated with PD-1/PD-L1 inhibitors were reviewed. Demographic data, clinical–pathological features, previous therapies, drug dosage and posology, and the best radiological and biochemical responses, as well as survival data, were evaluated. We identified 29 cases of aggressive (n = 13) or metastatic (n = 16) PitNETs treated with PD-1/PD-L1 inhibitors. The hypersecretion of adrenocorticotropic hormone (ACTH) was documented in eighteen cases (62.1%), seven were prolactinomas (24.1%), and four were non-functioning PitNETs. All patients underwent various therapies prior to using ICIs. Overall, a positive radiological response (i.e., partial/complete radiological response and stable disease) was observed in eighteen of twenty-nine cases (62.1%), of which ten and four were ACTH- and prolactin-secreting PitNETs, respectively. Hormonal levels reduced or stabilised after using ICIs in 11 of the 17 functioning PitNET cases with available data (64.7%). The median survival of patients treated with ICIs was 13 months, with a maximum of 42 months in two ACTH-secreting tumours. Among 29 patients with PitNETs treated with PD-1/PD-L1 inhibitors, the positive radiological and biochemical response rates were 62.1% and 64.7%, respectively. Altogether, these data suggest a promising role of ICIs in patients with aggressive or metastatic PitNETs refractory to other treatment modalities. [ABSTRACT FROM AUTHOR]

Simple Summary: In recent years, cancer has gradually become a terrible killer of human health. Due to various factors such as tumor heterogeneity and the complexity of the microenvironment, completely conquering cancer has always been a major problem in the scientific research community. Therefore, more detailed research and individualized treatment are essential. Everyone knows that tumor cells in the process of rapid proliferation need replenishing nutrients to sustain their energy supply. Intervention of tumor cell metabolism is gradually becoming a way to treat cancer. As an important transporter of glutamine, ASCT2 can uptake glutamine from the tumor microenvironment to support the growth and metabolism of cancer cells. Deficiency of ASCT2 can significantly inhibit tumor progression. However, not all patients benefit from this treatment. Our study aims to explore the metabolic heterogeneity of breast cancer and its related mechanisms, as well as to find metabolic-sensitive populations for further precision treatment. As a crucial amino acid, glutamine can provide the nitrogen and carbon sources needed to support cancer cell proliferation, invasion, and metastasis. Interestingly, different types of breast cancer have different dependences on glutamine. This research shows that basal-like breast cancer depends on glutamine, while the other types of breast cancer may be more dependent on glucose. Glutamine transporter ASCT2 is highly expressed in various cancers and significantly promotes the growth of breast cancer. However, the key regulatory mechanism of ASCT2 in promoting basal-like breast cancer progression remains unclear. Our research demonstrates the significant change in fatty acid levels caused by ASCT2, which may be a key factor in glutamine sensitivity. This phenomenon results from the mutual activation between ASCT2-mediated glutamine transport and lipid metabolism via the nuclear receptor PPARα. ASCT2 cooperatively promoted PPARα expression, leading to the upregulation of lipid metabolism. Moreover, we also found that C118P could inhibit lipid metabolism by targeting ASCT2. More importantly, this research identifies a potential avenue of evidence for the prevention and early intervention of basal-like breast cancer by blocking the glutamine–lipid feedback loop. [ABSTRACT FROM AUTHOR]

Simple Summary: In metastatic estrogen-receptor (ER)-positive HER2-negative breast cancer, resistance to endocrine therapy can be caused by ER loss and the mutation of ESR1, the gene coding for ERs. These mechanisms have been studied in isolation but not in the same population. Here, we studied both mechanisms and their interaction. We found that, in a population of 136 patients, one of these mechanisms was responsible for endocrine resistance in 30% of the patients. ESR1 mutation was associated with endocrine therapy. ER loss and ESR1 mutation were mutually exclusive, so testing for ESR1 mutations can be limited to ER-positive metastases. Furthermore, we demonstrated that ER loss has a negative effect on overall survival, while we did not observe this effect for ESR1 mutation. In patients with metastatic estrogen-receptor (ER)-positive HER2-negative breast cancer, the loss of ER expression and the mutation of ESR1—the gene encoding the ER receptor—are mechanisms for resistance to endocrine therapy. We aimed to determine the frequency of these mechanisms and their interaction. Metastases were retrieved from our pathology files. ESR1 hotspot mutations resulting in p.(D538G), p.(Y537S), and p.(L536H) were determined by means of pyrosequencing. Clinical data were retrieved from electronic medical records. A total of 136 metastases were available for analysis. ER loss was found in 23 metastases (17%). ESR1 mutations were found in 18 metastases (13%), including p.(D538G) in 9, p.(Y537S) in 7, and p.(L536H) in 2. ESR1 mutation and ER loss were mutually exclusive (p = 0.042), and ESR1 mutation was associated with endocrine therapy (p = 0.002). ESR1 mutation was found in two primary breast cancers. ESR1 mutations are rare in primary breast cancer and develop in metastases during endocrine therapy. Furthermore, ER loss had a statistically significant negative effect on overall survival when compared to patients without ER loss, with a rate ratio of 3.21 (confidence interval 1.95–5.26). No such effect was observed for ESR1 mutations, with a rate ratio of 1.15 (confidence interval 0.67–1.95). We conclude that ER loss and ESR1 mutation together account for 30% of the resistance to endocrine therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: In this retrospective study of 61 patients with diffuse gliomas, APT-weighted imaging in the solid tumor component provided quantitative metrics associated with WHO grade and survival. Mean APT values of the necrotic component showed high variability between subjects, warranting further investigation. These results highlight the importance of assessing the different tumor components with APT-weighted imaging, to provide useful diagnostic and prognostic information for the management of patients with gliomas. Amide Proton Transfer-weighted (APTw) imaging is a molecular MRI technique used to quantify protein concentrations in gliomas, which have heterogeneous components with varying cellularity and metabolic activity. This study aimed to assess the correlation between the component-specific APT signal of the neoplasm and WHO grade, molecular profile and survival status. Sixty-one patients with adult-type diffuse gliomas were retrospectively analyzed. APT values were semi-automatically extracted from tumor solid and, whenever present, necrotic components. APT values were compared between groups stratified by WHO grade, IDH-mutation, MGMT promoter methylation and 1- and 2-year survival status using Wilcoxon rank-sum test, adjusting for multiple comparisons. Overall survival (OS) was analyzed in the subgroup of 48 patients with grade 4 tumors using Cox proportional-hazards models. Random-effects models were used to assess inter-subject heterogeneity of the mean APT values in each tumor component. APT values of the solid component significantly differed between patients with grades 2–3 and 4 tumors (mean 1.58 ± 0.50 vs. 2.04 ± 0.56, p = 0.028) and correlated with OS after 1 year (1.81 ± 0.58 in survivors vs. 2.17 ± 0.51 in deceased patients, p = 0.030). APT values did not differ by IDH-mutation, MGMT methylation, and 2-year survival status. Within grade 4 glioma patients, higher APT kurtosis of the solid component was a negative prognostic factor (hazard ratio = 1.60, p = 0.040). Mean APT values of the necrosis showed high inter-subject variability, although most necrotic tumors were grade 4 and IDH wildtype. In conclusion, APTw imaging in the solid component provided metrics associated with glioma grade and survival status but showed weak correlation with IDH-mutation and MGMT promoter methylation status, in contrast to previous works. Further research is needed to understand APT signal variability within the necrotic component of high-grade gliomas. [ABSTRACT FROM AUTHOR]

Simple Summary: Single small primary liver cancers are curable with treatments such as surgical resection, ablation, and liver transplant; however, many patients initially receive trans-arterial chemo-embolisation (TACE), which is generally not considered a curative treatment in itself, and often go on to receive further follow-up treatments. Little is known regarding the outcomes of such patients compared to those who receive upfront ablation. Our real-world multi-centre study demonstrates that key survival outcomes are similar between those initially undergoing TACE and those receiving ablation after controlling for other key clinical variables and allowing for subsequent individualised treatment selection. Percutaneous ablation is recommended in Barcelona Clinic Liver Cancer (BCLC) stage 0/A patients with HCC ≤3 cm as a curative treatment modality alongside surgical resection and liver transplantation. However, trans-arterial chemo-embolisation (TACE) is commonly used in the real-world as an initial treatment in patients with single small HCC in contrast to widely accepted clinical practice guidelines which typically describe TACE as a treatment for intermediate-stage HCC. We performed this real-world propensity-matched multi-centre cohort study in patients with single HCC ≤ 3 cm to assess for differences in survival outcomes between those undergoing initial TACE and those receiving upfront ablation. Patients with a new diagnosis of BCLC 0/A HCC with a single tumour ≤3 cm first diagnosed between 1 January 2016 and 31 December 2020 who received initial TACE or ablation were included in the study. A total of 348 patients were included in the study, with 147 patients receiving initial TACE and 201 patients undergoing upfront ablation. After propensity score matching using key covariates, 230 patients were available for analysis with 115 in each group. There were no significant differences in overall survival (log-rank test p = 0.652) or liver-related survival (log-rank test p = 0.495) over a median follow-up of 43 months. While rates of CR were superior after ablation compared to TACE as a first treatment (74% vs. 56%, p < 0.004), there was no significant difference in CR rates when allowing for further subsequent treatments (86% vs. 80% p = 0.219). In those who achieved CR, recurrence-free survival and local recurrence-free survival were similar (log rank test p = 0.355 and p = 0.390, respectively). Our study provides valuable real-world evidence that TACE when offered with appropriate follow-up treatment is a reasonable initial management strategy in very early/early-stage HCC, with similar survival outcomes as compared to those managed with upfront ablation. Further work is needed to better define the role for TACE in BCLC 0/A HCC. [ABSTRACT FROM AUTHOR]

Simple Summary: Intratumoral hypoxia is associated with poor prognosis and therapeutic resistance by modifying the tumor microenvironment in several cancers. MTH1, a member of the Nudix family, maintains the genomic integrity and viability of tumor cells under hypoxic conditions. This study aimed to investigate whether the antitumor activity of immune cells is effective under hypoxia and whether hypoxia-induced MTH1 could be a target for immunotherapy. We found that MTH1 expression is elevated in hypoxic head and neck cancer cell lines and tissues. A novel MTH1 epitope peptide activates CD4+ helper T cells with cytotoxic activity, and is effective even under hypoxic conditions. Combining MTH1-targeted immunotherapy with PD-1 blockade enhances cytotoxicity. These results suggest that MTH1-targeted immunotherapy combined with checkpoint blockade could effectively treat hypoxic tumors by maintaining T-cell activity and increasing cytotoxicity under hypoxic conditions. Intratumoral hypoxia is associated with tumor progression, aggressiveness, and therapeutic resistance in several cancers. Hypoxia causes cancer cells to experience replication stress, thereby activating DNA damage and repair pathways. MutT homologue-1 (MTH1, also known as NUDT1), a member of the Nudix family, maintains the genomic integrity and viability of tumor cells in the hypoxic tumor microenvironment. Although hypoxia is associated with poor prognosis and can cause therapeutic resistance by regulating the microenvironment, it has not been considered a treatable target in cancer. This study aimed to investigate whether hypoxia-induced MTH1 is a useful target for immunotherapy and whether hypoxic conditions influence the antitumor activity of immune cells. Our results showed that MTH1 expression was elevated under hypoxic conditions in head and neck cancer cell lines. Furthermore, we identified a novel MTH1-targeting epitope peptide that can activate peptide-specific CD4+ helper T cells with cytotoxic activity. The proliferation and cytotoxic activity of T cells were maintained under hypoxic conditions, and PD-1 blockade further augmented the cytotoxicity. These results indicate that MTH1-targeted immunotherapy combined with checkpoint blockade can be an effective strategy for the treatment of hypoxic tumors. [ABSTRACT FROM AUTHOR]

Simple Summary: Diffuse large B cell lymphoma (DLBCL) is the most diagnosed, aggressive non-Hodgkin lymphoma, a type of blood cancer. In this study, we developed new DLBCL cell-derived xenograft mouse models. We found that our models show consistent tumor burden with unformal disease progression and organ-specific infiltration. Diffuse large B cell lymphoma (DLBCL) is the most diagnosed, aggressive non-Hodgkin lymphoma, with ~40% of patients experiencing refractory or relapsed disease. Given the low response rates to current therapy, alternative treatment strategies are necessary to improve patient outcomes. Here, we sought to develop an easily accessible new xenograft mouse model that better recapitulates the human disease for preclinical studies. We generated two Luciferase (Luc)-EGFP-expressing human DLBCL cell lines representing the different DLBCL cell-of-origin subtypes. After intravenous injection of these cells into humanized NSG mice, we monitored the tumor growth and evaluated the organ-specific engraftment/progression period. Our results showed that human IL6-expressing NSG (NSG-IL6) mice were highly permissive for DLBCL cell growth. In NSG-IL6 mice, systemic engraftments of both U2932 activated B cell-like- and VAL germinal B cell-like-DLBCL (engraftment rate; 75% and 82%, respectively) were detected within 2nd-week post-injection. In the organ-specific ex vivo evaluation, both U2932-Luc and VAL-Luc cells were initially engrafted and expanded in the spleen, liver, and lung and subsequently in the skeleton, ovary, and brain. Consistent with the dual BCL2/MYC translocation association with poor patient outcomes, VAL cells showed heightened proliferation in human IL6-conditioned media and caused rapid tumor expansion and early death in the engrafted mice. We concluded that the U2932 and VAL cell-derived human IL6-expressing mouse models reproduced the clinical features of an aggressive DLBCL with a highly consistent pattern of tumor development. Based on these findings, NSG mice expressing human IL6 have the potential to serve as a new tool to develop DLBCL xenograft models to overcome the limitations of standard subcutaneous DLBCL xenografts. [ABSTRACT FROM AUTHOR]

Simple Summary: Head and Neck Cancer is often diagnosed at an advanced stage, resulting in poor long-term prognosis. Additionally, this cancer is resistant to chemotherapy. This systematic review article aims to examine the literature on published methods to overcome resistance to chemotherapy for head and neck cancer. According to the "cancer stem cell" (CSCs) theory, tumors are a diverse and expanding group of malignant cells that originate from a small number of CSCs. Despite treatment, these cells can still become active and proliferate, which can result in distant metastasis and local recurrences. A new paradigm in cancer treatment involves targeting both CSCs and the cancer cells in a tumor. This review aims to examine the literature on methods published to overcome chemoresistance due to the presence of CSCs in head and neck cancers. The review was registered with PROSPERO (ID# CRD42024512809). After Pub Med, Scopus, and WoS database searches, 31 relevant articles on oral squamous cell carcinoma (OSCC) were selected. Compounds that increased chemosensitivity by targeting CSCs in head and neck squamous cell carcinoma (HNSCC) were divided into (1) natural products, (2) adjuvant molecules to traditional chemotherapy, and (3) CSCs targeting patient-specific fresh biopsies for functional precision medicine. [ABSTRACT FROM AUTHOR]

Simple Summary: Preoperative risk prediction prior to oncologic esophagectomy is crucial for assisting surgeons in accurate patient selection and patients in their informed decision making. A new risk stratification tool, the IESG prediction model, was recently introduced, categorizing patients into different risk levelsMachine learning is a subfield of artificial intelligence and may allow for a more accurate identification of patients at risk. Therefore, we evaluated the IESG risk model and compared its performance with ML models. We found that the IESG risk model provided an overall adequate risk estimation. However, ML showed better results in the accurate risk stratification of patients, demonstrating its potential as a novel and powerful approach for future patient assessment. Risk prediction prior to oncologic esophagectomy is crucial for assisting surgeons and patients in their joint informed decision making. Recently, a new risk prediction model for 90-day mortality after esophagectomy using the International Esodata Study Group (IESG) database was proposed, allowing for the preoperative assignment of patients into different risk categories. However, given the non-linear dependencies between patient- and tumor-related risk factors contributing to cumulative surgical risk, machine learning (ML) may evolve as a novel and more integrated approach for mortality prediction. We evaluated the IESG risk model and compared its performance to ML models. Multiple classifiers were trained and validated on 552 patients from two independent centers undergoing oncologic esophagectomies. The discrimination performance of each model was assessed utilizing the area under the receiver operating characteristics curve (AUROC), the area under the precision–recall curve (AUPRC), and the Matthews correlation coefficient (MCC). The 90-day mortality rate was 5.8%. We found that IESG categorization allowed for adequate group-based risk prediction. However, ML models provided better discrimination performance, reaching superior AUROCs (0.64 [0.63–0.65] vs. 0.44 [0.32–0.56]), AUPRCs (0.25 [0.24–0.27] vs. 0.11 [0.05–0.21]), and MCCs (0.27 ([0.25–0.28] vs. 0.15 [0.03–0.27]). Conclusively, ML shows promising potential to identify patients at risk prior to surgery, surpassing conventional statistics. Still, larger datasets are needed to achieve higher discrimination performances for large-scale clinical implementation in the future. [ABSTRACT FROM AUTHOR]

Simple Summary: Studies of genetic predisposition to renal cell carcinoma (RCC) have been highly variable in design and have reported similarly highly variable rates of cases identified as carrying pathogenic variants in cancer susceptibility genes (4–26%). The aim of our study was to conduct a population-based study of genetic predisposition to RCC. We conducted a 21-gene panel sequencing study and identified that 18/1029 participants (1.7%) carried a pathogenic or likely pathogenic (PLP) variant. Genes with PLP variants included BAP1, FH, FLCN, MITF, MSH6, SDHB, TSC1, and VHL. This study provides further evidence that family history alone may not be sufficient for identifying all individuals who are at increased genetic risk of renal cell carcinoma, and further research is urgently needed to understand how to target genetic testing to identify those at high genetic risk of kidney cancer. Renal cell carcinoma (RCC) has been associated with germline pathogenic or likely pathogenic (PLP) variants in recognised cancer susceptibility genes. Studies of RCC using gene panel sequencing have been highly variable in terms of study design, genes included, and reported prevalence of PLP variant carriers (4–26%). Studies that restricted their analysis to established RCC predisposition genes identified variants in 1–6% of cases. This work assessed the prevalence of clinically actionable PLP variants in renal cancer predisposition genes in an Australian population-based sample of RCC cases. Germline DNA from 1029 individuals diagnosed with RCC who were recruited through the Victoria and Queensland cancer registries were screened using a custom amplicon-based panel of 21 genes. Mean age at cancer diagnosis was 60 ± 10 years, and two-thirds (690, 67%) of the participants were men. Eighteen participants (1.7%) were found to carry a PLP variant. Genes with PLP variants included BAP1, FH, FLCN, MITF, MSH6, SDHB, TSC1, and VHL. Most carriers of PLP variants did not report a family history of the disease. Further exploration of the clinical utility of gene panel susceptibility testing for all RCCs is warranted. [ABSTRACT FROM AUTHOR]

Simple Summary: Survivors of childhood cancer are predisposed to a range of late effects of treatment, including high symptom burden. Symptom burden may vary over time. The aim of this prospective pilot study was to assess the feasibility of collecting daily symptoms from adult survivors of childhood cancer using mobile health (mHealth) technology to evaluate symptom fluctuation and associations with future health-related quality of life (HRQOL). The 41 survivors included in this study had high adherence to symptom reporting (83%) and HRQOL reporting (95%). Variability of daily symptom burden differed from person-to-person (74%), day-to-day (18%), and month-to-month (8%). Additionally, a higher symptom burden was associated with poorer HRQOL in the future. Daily assessment of symptoms using mHealth technology revealed fluctuations in symptomology and the association between symptom burden and HRQOL. This method of symptom assessment is valuable for improving our understanding of symptom dynamics and sources of variability. Background: Cancer therapies predispose survivors to a high symptom burden. This study utilized mobile health (mHealth) technology to assess the feasibility of collecting daily symptoms from adult survivors of childhood cancer to evaluate symptom fluctuation and associations with future health-related quality-of-life (HRQOL). Methods: This prospective study used an mHealth platform to distribute a 20-item cancer-related symptom survey (5 consecutive days each month) and an HRQOL survey (the day after the symptom survey) over 3 consecutive months to participants from the Childhood Cancer Survivor Study. These surveys comprised a PROMIS-29 Profile and Neuro-QOL assessed HRQOL. Daily symptom burden was calculated by summing the severity (mild, moderate, or severe) of 20 symptoms. Univariate linear mixed-effects models were used to analyze total, person-to-person, day-to-day, and month-to-month variability for the burden of 20 individual symptoms. Multivariable linear regression was used to analyze the association between daily symptom burden in the first month and HRQOL in the third month, adjusted for covariates. Results: Out of the 60 survivors invited, 41 participated in this study (68% enrollment rate); 83% reported their symptoms ≥3 times and 95% reported HRQOL in each study week across 3 months. Variability of daily symptom burden differed from person-to-person (74%), day-to-day (18%), and month-to-month (8%). Higher first-month symptom burden was associated with poorer HRQOL related to anxiety (regression coefficient: 6.56; 95% CI: 4.10–9.02), depression (6.32; 95% CI: 3.18–9.47), fatigue (7.93; 95% CI: 5.11–10.80), sleep (6.07; 95% CI: 3.43–8.70), pain (5.16; 95% CI: 2.11–8.22), and cognitive function (–6.89; 95% CI: –10.00 to –3.79) in the third month. Conclusions: Daily assessment revealed fluctuations in symptomology, and higher symptom burden was associated with poorer HRQOL in the future. Utilizing mHealth technology for daily symptom assessment improves our understanding of symptom dynamics and sources of variability. [ABSTRACT FROM AUTHOR]

Simple Summary: Radiotherapy is the main local treatment for head and neck cancer. Radiation oncologists and patients should be alert to late carotid artery stenosis and brain necrosis after treatment. Objective: This study aims to examine whether radiation therapy doses are related to incidences of carotid artery stenosis and brain necrosis in a large-scale real-world database. Methods: We identified a cohort of HNC patients from the catastrophic illness patient dataset using ICD-9 or ICD-10 to compare the incidence and risks of carotid artery stenosis (CAS) and brain necrosis (RIBN) in patients who received a radiation therapy dose of ≥5400 cGy/30 fractions (group A) with those who received a radiation therapy dose of <5400 cGy/30 fractions (group B). The incidence and hazard ratios were quantified using Cox proportional hazards models. Results: A total of 19,964 patients were identified in group A and group B. Among them, 965 and 863 cases of CAS and 435 and 359 cases of RIBN were identified in group A and group B, respectively. There was no statistically significant association between the two groups for CAS risk, whereas there was a statistically significant association between the two groups for RIBN risk. The most common primary site of head and neck cancers was the nasopharynx (1144 of 19,964, 5.73%). Conclusions: Our study suggests that RT may increase the risk of carotid stenosis and brain necrosis in patients with NPC. To ensure patient safety during treatment, the optimal balance between tumor control and toxicity prevention in individual patients through minimization of the radiation dose to all relevant OARs must be properly understood. [ABSTRACT FROM AUTHOR]

Simple Summary: Studies analyzing specific treatment-related prognostic factors can provide important information about disease biology and improve the use of biomarkers to optimize treatment decisions. The aim of our retrospective study was to determine the prognostic performance of clinicopathological factors and blood biomarkers in patients with unresectable metastatic melanoma treated with BRAF and MEK inhibitors. A total of 199 patients were included in the multivariate analysis of the risk of progression and death. We found that primary tumor localization on the limbs, Clark invasion level V, M1c stage or M1d stage at the start of therapy, and elevated baseline serum S100B level were independently and significantly associated with poor outcomes. The present study suggests that clinicopathological factors, including primary tumor characteristics and stage of metastatic disease, as well as serum markers may provide information on the probability of survival in patients with advanced melanoma treated with BRAF and MEK inhibitors. Prognostic studies can provide important information about disease biology and improve the use of biomarkers to optimize treatment decisions. Methods: A total of 199 patients with advanced melanoma treated with BRAF + MEK inhibitors were included in our single-center retrospective study. We analyzed the risk of progression and death using multivariate Cox proportional hazard models. The predictive effect of prognostic factors on progression-free survival (PFS) was evaluated in ROC analysis. Results: We found that primary tumor localization, Clark level, pT category, baseline M stage and baseline serum S100B are independent and significant prognostic factors for PFS. The discriminative power of the combination of these factors was excellent for predicting 18 month PFS (AUC 0.822 [95% CI 0.727; 0.916], p < 0.001). Primary tumor localization on the extremities, Clark level V, baseline M1c stage or M1d stage, and elevated baseline serum S100B and LDH levels were independently and significantly associated with unfavorable overall survival (OS). Conclusion: Baseline M stage and serum S100B appear to be independent prognostic factors for both PFS and OS in melanoma patients treated with BRAF + MEK inhibitors. We newly identified significant and independent prognostic effects of primary tumor localization and Clark level on survival that warrant further investigation. [ABSTRACT FROM AUTHOR]

Simple Summary: Colorectal cancer (CRC) is one of the most common causes of death worldwide. Today, this disease does not have an effective treatment, leading to the exploration of novel pharmacological molecules. In this paper, we design and synthesize with a new synthetic route the lipophilic cation derived from gallic acid (TPP+C10) and gentisic acid (GA-TPP+C10), both able to reach mitochondria and uncouple the electron transport chain. Our results show that combining 5-fluorouracil with GA-TPP+C10 has a synergistic cytotoxic effect on CRC cells. Both compounds show antimigratory effects, decreasing signaling pathways and biomarkers. Our results show that mitochondrial agents could be an alternative to standard CRC drugs against this disease. Colorectal cancer (CRC) is the third leading cause of cancer deaths in the world. Standard drugs currently used for the treatment of advanced CRC—such as 5-fluorouracil (5FU)—remain unsatisfactory in their results due to their high toxicity, high resistance, and adverse effects. In recent years, mitochondria have become an attractive target for cancer therapy due to higher transmembrane mitochondrial potential. We synthesized gallic acid derivatives linked to a ten-carbon aliphatic chain associated with triphenylphosphonium (TPP+C10), a lipophilic cationic molecule that induces the uncoupling of the electron transport chain (ETC). Other derivatives, such as gentisic acid (GA-TPP+C10), have the same effects on colorectal cancer cells. Although part of our group had previously reported preparing these structures by a convergent synthesis route, including their application via flow chemistry, there was no precedent for a new methodology for preparing these compounds. In this scenario, this study aims to develop a new linear synthesis strategy involving an essential step of Steglich esterification under mild conditions (open flask) and a high degree of reproducibility. Moreover, the study seeks to associate GA-TPP+C10 with 5FU to evaluate synergistic antineoplastic effects. In addition, we assess the antimigratory effect of GA-TPP+C10 and TPP+C10 using human and mouse metastatic CRC cell lines. The results show a new and efficient synthesis route of these compounds, having synergistic effects in combination with 5FU, increasing apoptosis and enhancing cytotoxic properties. Additionally, the results show a robust antimigratory effect of GATPP+C10 and TPP+C10, reducing the activation pathways linked to tumor progression and reducing the expression of VEGF and MMP-2 and MMP-9, common biomarkers of advanced CRC. Moreover, TPP+C10 and GA-TPP+C10 increase the activity of metabolic signaling pathways through AMPK activation. The data allow us to conclude that these compounds can be used for in vivo evaluations and are a promising alternative associated with conventional therapies for advanced colorectal cancer. Additionally, the reported intermediates of the new synthesis route could give rise to analog compounds with improved therapeutic activity. [ABSTRACT FROM AUTHOR]

Simple Summary: Understanding the inflammatory interplay between cancer and COVID-19 infection is essential for improving patient care. Our study bridges a vital knowledge gap by exploring how a pre-existing tumor-induced inflammatory state can exacerbate the inflammatory response to COVID-19, adversely impacting COVID-19 outcomes. We introduce the FLARE score, a robust predictor derived from circulating inflammatory markers, that provides clinicians a practical tool for early identification of patients with cancer at higher risk of severe COVID-19 complications who might benefit most from immediate and intensive treatment strategies. Additionally, our study also underscore the role of immature neutrophils in the progression of COVID-19 in patients with cancer, advocating for further investigation into how these cells contribute to both cancer and COVID-19 disease. Purpose: Inflammation and neutrophils play a central role in both COVID-19 disease and cancer. We aimed to assess the impact of pre-existing tumor-related inflammation on COVID-19 outcomes in patients with cancer and to elucidate the role of circulating neutrophil subpopulations. Methods: We conducted a multicenter retrospective analysis of 524 patients with cancer and SARS-CoV-2 infection, assessing the relationship between clinical outcomes and circulating inflammatory biomarkers collected before and during COVID-19 infection. Additionally, a single-center prospective cohort study provided data for an exploratory analysis, assessing the immunophenotype of circulating neutrophils and inflammatory cytokines. The primary endpoints were 30-day mortality and the severity of COVID-19 disease. Results: Prior to COVID-19, 25% of patients with cancer exhibited elevated dNLR, which increased to 55% at the time of COVID-19 diagnosis. We developed the FLARE score, incorporating both tumor- and infection-induced inflammation, which categorized patients into four prognostic groups. The poor prognostic group had a 30-day mortality rate of 68%, significantly higher than the 23% in the favorable group (p < 0.0001). This score proved to be an independent predictor of early mortality. This prospective analysis revealed a shift towards immature forms of neutrophils and higher IL-6 levels in patients with cancer and severe COVID-19 infection. Conclusions: A pre-existing tumor-induced pro-inflammatory state significantly impacts COVID-19 outcomes in patients with cancer. The FLARE score, derived from circulating inflammatory markers, emerges as an easy-to-use, globally accessible, effective tool for clinicians to identify patients with cancer at heightened risk of severe COVID-19 complications and early mortality who might benefit most from immediate and intensive treatment strategies. Furthermore, our findings underscore the significance of immature neutrophils in the progression of COVID-19 in patients with cancer, advocating for further investigation into how these cells contribute to both cancer and COVID-19 disease. [ABSTRACT FROM AUTHOR]

Simple Summary: Placental allograft tissue has been extensively used in wound healing. It can also be placed along the neurovascular bundles during radical prostatectomy to improve post-operative continence and erectile function recovery. The existing literature shows how placental allografts lead to improved functional recovery after radical prostatectomy. It is unknown whether these allografts have an impact on biochemical recurrence (BCR). Our study was a single surgeon retrospective review of 362 radical prostatectomy cases. The subgroups were the negative control group and two brands of cryopreserved amniotic membrane (CAM). Our data show improved continence recovery using CAM allografts. At a median follow-up of 41 months, there was no observed impact of BCR. Interestingly, in vitro analysis also revealed decreased cell viability of prostate cancer cell lines when incubated with the CAM allograft. Although further investigation is required, our data do not support a need for oncologic concern while using CAM allografts during radical prostatectomy. Background: Human placental allografts are widely used to promote wound healing. Placental (or amniotic membrane/umbilical cord) allografts are placed along the neurovascular bundles during radical prostatectomy to improve continence and erectile function recovery. It is unknown whether placental allografts impact biochemical recurrence (BCR). Methods: This was a single-surgeon retrospective study of 566 robotic radical prostatectomies performed from April 2015 to March 2021. The patients were divided into three groups: the negative control, Brand A, and Brand B. Brand A and Brand B were both cryopreserved amniotic membrane (CAM) allografts. A total of 324 cases were included for BCR Kaplan–Meier and risk-adjusted multivariate analyses (362 for continence analysis). In vitro analyses were performed to determine the effect of CAM allografts on prostate cancer (PCa) cell line growth. Results: For propensity score-matched analysis (adjusting for pre-operative PSA, tumor stage, Gleason Grade, and margin status), (1) the allograft groups did not show differences in time to BCR vs. the negative control group (p = 0.7), and (2) combined allograft treatment groups showed better continence recovery vs. the negative controls (p = 0.01). In vitro, placental allografts reduced PCa cell line growth in co-culture assays. Conclusions: cryopreserved AM allografts (combined or individual brands) did not show a significant effect on BCR but improved continence recovery for PCa patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Previous studies have reported the gene mutational landscapes and PD-L1 expression levels of thymic epithelial tumors. However, due to the rarity of the disease, heterogeneity, whether from the different sequencing methods or the patients, does exist across these studies, hampering the large-scale application of targeted therapy and immunotherapy. Thus, we conducted a meta-analysis on the genetic alterations and molecular landscapes of TETs and obtained the pooled estimated mutation rates of the most frequently mutated genes in TETs, as well as the PD-L1 expression levels in TETs. Confounding factors that may contribute to the heterogeneity are also discussed in our manuscript. Our efforts have provided a more accurate overview of the gene mutation landscape and PD-L1 expression levels in TETs, which may contribute to the cure of TETs, advanced TETs, or metastatic TETs in particular. Thymic epithelial tumors (TETs), consisting of thymomas, thymic carcinomas (TCs), and thymic neuroendocrine tumors, are rare diseases. Surgery remains the prime option in resectable and early-stage TETs, while chemotherapy, targeted therapy, and immunotherapy are also potential treatment modalities. However, the inadequate comprehension of the molecular landscape of TETs impedes the exploitation of such therapies. Hence, we conducted a meta-analysis which includes 21 studies reporting on genomic alterations in TETs and 14 studies reporting on PD-L1 expression levels, respectively. The pooled estimated rates of the most frequently mutated genes and PD-L1 expression levels were analyzed using the R software. We uncovered that the pooled estimated overall mutation rate is 0.65 ([0.49; 0.81]), and the top three genes with highest mutation frequency in thymomas and TCs are GTF2I (0.4263 [0.3590; 0.4936]), TP53 (0.1101 [0.0000; 0.2586]), and RAS (0.0341 [0.0104; 0.0710]), and TP53 (0.1797 [0.0732; 0.3203]), CDKN2A (0.0608 [0.0139; 0.1378]), and TET2 (0.0318 [0.0087; 0.0639]), respectively. A uniform GTF2I mutational rate in thymomas and TP53 mutational rate in thymic squamous cell carcinomas (TSCCs) are also observed. The pooled estimated expression level of PD-L1 is 0.71 ([0.59–0.81]). This systematic review provides an overview of the gene alteration landscape and PD-L1 expression levels in TETs, discovers several potential confounding factors that may contribute to the high heterogeneity, and facilitates deeper investigations into the elucidation of the molecular landscape of TETs. [ABSTRACT FROM AUTHOR]

Simple Summary: It is unknown whether different types of exercise effect physical function, quality of life, mental wellbeing, and symptoms in older patients with blood cancers. No studies specifically focusing on patients over 65 years were identified. However, across adult age groups, we found that exercise has small to moderate positive effects on physical function, aerobic capacity, muscle strength, quality of life, fatigue, pain, anxiety, and depression. These benefits were generally consistent regardless of age, except for physical function and pain, which favored younger adults. Overall, exercise improves physical function and quality of life and reduces symptoms in adults with blood cancers undergoing treatment, but the role of age remains uncertain. Older patients receiving antineoplastic treatment face challenges such as frailty and reduced physical capacity and function. This systematic review and meta-analysis aimed to evaluate the effects of exercise interventions on physical function outcomes, health-related quality of life (QoL), and symptom burden in older patients above 65 years with hematological malignancies undergoing antineoplastic treatment. This review adheres to Cochrane guidelines, with the literature searches last updated on 27 March 2024, including studies with patients above 18 years. Screening of identified studies, data extraction, risk of bias, and GRADE assessments were performed independently by two authors. Meta-analyses evaluated the impact of exercise, considering advancing age. Forty-nine studies contributed data to the meta-analyses. Five studies included patients with a mean age above 60 years, and none included only patients above 60. Exercise interventions had moderate to small positive effects on QoL global (SMD 0.34, 95% CI [0.04–0.64]) and physical function (SMD 0.29, 95% CI [0.12–0.45]). Age did not explain the variability in exercise effects, except for physical function (slope 0.0401, 95% CI [0.0118–0.0683]) and pain (slope 0.0472, 95% CI [0.01–0.09]), which favored younger patients. Exercise interventions improve physical function and QoL and reduce symptoms in adults with hematological malignancies undergoing antineoplastic treatment; however, the influence of age remains inconclusive. [ABSTRACT FROM AUTHOR]

Simple Summary: Skin diseases can be serious, and early detection is key to effective treatment. Unfortunately, the quality of images used to diagnose these diseases often suffers due to interference from hair, making accurate diagnosis challenging. This research introduces a novel technology, the DM–AHR, a self-supervised conditional diffusion model designed specifically to generate clear, hairless images for better skin disease diagnosis. Our work not only presents a new, advanced model that expertly identifies and removes hair from dermoscopic images but also introduces a specialized dataset, DERMAHAIR, to further research and improve diagnostic processes. The enhancements in image quality provided by DM–AHR significantly improve the accuracy of skin disease diagnoses, and it promises to be a valuable tool in medical imaging. Accurate skin diagnosis through end-user applications is important for early detection and cure of severe skin diseases. However, the low quality of dermoscopic images hampers this mission, especially with the presence of hair on these kinds of images. This paper introduces DM–AHR, a novel, self-supervised conditional diffusion model designed specifically for the automatic generation of hairless dermoscopic images to improve the quality of skin diagnosis applications. The current research contributes in three significant ways to the field of dermatologic imaging. First, we develop a customized diffusion model that adeptly differentiates between hair and skin features. Second, we pioneer a novel self-supervised learning strategy that is specifically tailored to optimize performance for hairless imaging. Third, we introduce a new dataset, named DERMAHAIR (DERMatologic Automatic HAIR Removal Dataset), that is designed to advance and benchmark research in this specialized domain. These contributions significantly enhance the clarity of dermoscopic images, improving the accuracy of skin diagnosis procedures. We elaborate on the architecture of DM–AHR and demonstrate its effective performance in removing hair while preserving critical details of skin lesions. Our results show an enhancement in the accuracy of skin lesion analysis when compared to existing techniques. Given its robust performance, DM–AHR holds considerable promise for broader application in medical image enhancement. [ABSTRACT FROM AUTHOR]

Simple Summary: Obesity is a clear risk factor for future colorectal cancer (CRC), but its impact on mortality remains to be fully elucidated. Prior studies have had methodologic limitations, and key variables remain under-investigated. In this study of prospectively collected data from the Multiethnic Cohort, pre-diagnosis BMI trajectories were not associated with CRC-specific or all-cause mortality. Factors associated with mortality included African American race or Hawaiian ethnicity, smoking, and diabetes. Accounting for long-term BMI trajectories before diagnosis and other relevant factors demonstrates that obesity is not protective of mortality after CRC diagnosis. Background: Prior studies are inconclusive regarding the effect of obesity on mortality in persons with colorectal cancer (CRC). We sought to determine the association of pre-diagnosis body mass index (BMI) trajectories on mortality after CRC diagnosis. Methods: Utilizing the Multiethnic Cohort, we included adults aged 18–75 between 1 January 1993 and 1 January 2019 with a diagnosis of CRC and at least three available BMIs. The primary exposure, BMI, was subjected to group-based trajectory modeling (GBTM). We evaluated all-cause and CRC-specific mortality, using Cox proportional hazard (PH) models. Results: Of 924 persons, the median age was 60 years, and 54% were female. There was no statistically significant association between pre-cancer BMI trajectory and either all-cause or cancer-specific mortality. In competing risk analysis, the risk of CRC-specific mortality was higher for African Americans (HR = 1.56, 95% CI [1.00–2.43], p = 0.048) and smokers (HR = 1.59, 95% CI [1.10–2.32], p = 0.015). Risk of all-cause mortality was higher for Hawaiian persons (HR = 2.85, 95% CI [1.31–6.21], p = 0.009) and persons with diabetes (HR = 1.83, 95% CI [1.08–3.10], p = 0.026). Conclusions: Pre-diagnosis BMI trajectories were not associated with mortality after CRC diagnosis, whereas race/ethnicity, diabetes, and smoking were associated with an increased risk of death. Our findings suggest the obesity paradox alone does not account for mortality after CRC diagnosis. [ABSTRACT FROM AUTHOR]

Simple Summary: T regulatory cells are specialized lymphocytes that prevent excessive immune responses, yet they can suppress beneficial anti-tumor immunity when infiltrating malignant tumors. Osteopontin, a versatile protein produced by various cells, including T lymphocytes, influences both inflammation-related diseases and cancer immunity. Its role in T regulatory cells, however, remains less explored. Our study examined the impact of osteopontin deficiency on T regulatory cells. We generated mice lacking osteopontin in these cells and observed impaired immune suppression capabilities, which resulted in increased tumor-fighting activity against melanoma. These findings emphasize osteopontin's crucial role in T regulatory cell stability and functionality within the tumor microenvironment, providing valuable insights for developing new immunotherapeutic strategies. Foxp3-expressing regulatory T (Treg) cells represent the most highly immunosuppressive cell in the tumor microenvironment (TME) that halts effective anti-tumor immunity. Osteopontin (Opn), an extracellular matrix (ECM) glycophosphoprotein, plays key roles in many types of immune-related diseases and is associated with cancer aggressiveness when expressed by tumor cells. However, its role in Foxp3Treg heterogeneity, function, and stability in the TME is poorly defined. We generated mice with a Foxp3-specific deletion of Opn and assessed the ability of Opn-deficient Tregs to suppress inflammation. As these mice aged, they developed a scurfy-like syndrome characterized by aberrant and excessive activation of effector T cells. We evaluated and further confirmed the reduced suppressive capacity of Opn-deficient Tregs in an in vivo suppression assay of colitis. We also found that mice with Opn-deficient Foxp3+ Tregs have enhanced anti-tumor immunity and reduced tumor burden, associated with an unstable Treg phenotype, paralleled by reduced Foxp3 expression in tumor-infiltrating lymphocytes. Finally, we observed reduced Foxp3 and Helios expression in Opn-deficient Tregs compared to wild-type controls after in vitro activation. Our findings indicate that targeting Opn in Tregs reveals vigorous and effective ways of promoting Treg instability and dysfunction in the TME, facilitating anti-tumor immunity. [ABSTRACT FROM AUTHOR]

Simple Summary: Targeted therapies with BRAF- and MEK-inhibitors have significantly improved outcomes for patients with metastatic melanoma, but they come with a risk of heart-related side effects. This study included 108 real-world patients with metastatic melanoma from Eastern Denmark from 2019–2022 treated with encorafenib and binimetinib. Heart function was monitored with MUGA scans at baseline and every three months. While 18% of the patients experienced minor heart issues without symptoms, only 6% faced major problems, some needing medical intervention. However, no severe heart issues occurred beyond six months of starting the treatment. This suggests that it might be safe to reduce heart monitoring after six to nine months if no issues appear early on. Modern therapies targeting the BRAF gene mutation in advanced melanoma have significantly improved patient outcomes but pose cardiovascular risks. This retrospective study in Eastern Denmark (2019–2022) assessed 108 melanoma patients treated with encorafenib and binimetinib. Patients were monitored for heart function using multigated acquisition (MUGA) scans. The study defined major cardiotoxicity as a decline in left ventricular ejection fraction (LVEF) by more than 10 percentage points to below 50%, and minor cardiotoxicity as a decrease in LVEF by more than 15 points but remaining above 50%. Results showed that 19 patients (18%) developed minor cardiotoxicity and were asymptomatic, while 7 (6%) experienced major cardiotoxicity, with two requiring intervention. Notably, no significant declines in LVEF were observed after six months of treatment. The study concluded that significant cardiotoxicity occurred in 6% of cases, mostly asymptomatic and reversible, and suggests that monitoring LVEF could potentially be reduced after 6–9 months if no early signs of cardiotoxicity are detected. This provides valuable insights into the cardiac safety of these treatments in real-world settings. [ABSTRACT FROM AUTHOR]

Simple Summary: Prostate mpMRI is currently the most widely used image diagnosis approach to detect prostate cancer, while the PI-RADS system was developed to standardize and improve the accuracy of suspicious lesion identification on MRI. However, there still remain several limitations including inter-individual inconsistencies and naked-eye insufficiency. This study aims to apply AI technology to image interpretation to enhance diagnostic efficiency and explore the use of T2-weighted image-based stimulated biopsy in predicting prostate cancer (PCa). Using 820 lesions from The Cancer Imaging Archive database and 83 lesions from Hong Kong Queen Mary Hospital, we constructed 18 machine-learning models based on three algorithms and conducted both internal and external validation. We found that the logistic regression-based model provides additional diagnostic value to the PI-RADS in predicting PCa. Background: Currently, prostate cancer (PCa) prebiopsy medical image diagnosis mainly relies on mpMRI and PI-RADS scores. However, PI-RADS has its limitations, such as inter- and intra-radiologist variability and the potential for imperceptible features. The primary objective of this study is to evaluate the effectiveness of a machine learning model based on radiomics analysis of MRI T2-weighted (T2w) images for predicting PCa in prebiopsy cases. Method: A retrospective analysis was conducted using 820 lesions (363 cases, 457 controls) from The Cancer Imaging Archive (TCIA) Database for model development and validation. An additional 83 lesions (30 cases, 53 controls) from Hong Kong Queen Mary Hospital were used for independent external validation. The MRI T2w images were preprocessed, and radiomic features were extracted. Feature selection was performed using Cross Validation Least Angle Regression (CV-LARS). Using three different machine learning algorithms, a total of 18 prediction models and 3 shape control models were developed. The performance of the models, including the area under the curve (AUC) and diagnostic values such as sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), were compared to the PI-RADS scoring system for both internal and external validation. Results: All the models showed significant differences compared to the shape control model (all p < 0.001, except SVM model PI-RADS+2 Features p = 0.004, SVM model PI-RADS+3 Features p = 0.002). In internal validation, the best model, based on the LR algorithm, incorporated 3 radiomic features (AUC = 0.838, sensitivity = 76.85%, specificity = 77.36%). In external validation, the LR (3 features) model outperformed PI-RADS in predictive value with AUC 0.870 vs. 0.658, sensitivity 56.67% vs. 46.67%, specificity 92.45% vs. 84.91%, PPV 80.95% vs. 63.64%, and NPV 79.03% vs. 73.77%. Conclusions: The machine learning model based on radiomics analysis of MRI T2w images, along with simulated biopsy, provides additional diagnostic value to the PI-RADS scoring system in predicting PCa. [ABSTRACT FROM AUTHOR]

Simple Summary: Immune checkpoint inhibitors (ICIs) are cancer immunotherapeutics that reinvigorate immune cells' ability to attack tumor cells. Despite remarkable results in some patients, ICIs do not demonstrate the same efficacy across all individuals. In this study, we present the first side-by-side comparison of an agent-based model (ABM) with an ordinary differential equation (ODE) model for ICIs targeting the PD-1/PD-L1 immune checkpoint. We consider tumor cells of high and low antigenicity and two distinct immune-cell kill mechanisms. Using key parameters calibrated from mouse bladder cancer studies, we simulate virtual tumors using both models. Our research identifies crucial tumor-immune characteristics that influence the efficacy of ICIs. By exploring the unique spatial insights provided by the ABM, we underscore the importance of considering the spatial complexity of the tumor microenvironment in mathematical models of ICIs, potentially paving the way for more effective cancer treatments. Since the introduction of the first immune checkpoint inhibitor (ICI), immunotherapy has changed the landscape of molecular therapeutics for cancers. However, ICIs do not work equally well on all cancers and for all patients. There has been a growing interest in using mathematical and computational models to optimize clinical responses. Ordinary differential equations (ODEs) have been widely used for mechanistic modeling in immuno-oncology and immunotherapy. They allow rapid simulations of temporal changes in the cellular and molecular populations involved. Nonetheless, ODEs cannot describe the spatial structure in the tumor microenvironment or quantify the influence of spatially-dependent characteristics of tumor-immune dynamics. For these reasons, agent-based models (ABMs) have gained popularity because they can model more detailed phenotypic and spatial heterogeneity that better reflect the complexity seen in vivo. In the context of anti-PD-1 ICIs, we compare treatment outcomes simulated from an ODE model and an ABM to show the importance of including spatial components in computational models of cancer immunotherapy. We consider tumor cells of high and low antigenicity and two distinct cytotoxic T lymphocyte (CTL) killing mechanisms. The preferred mechanism differs based on the antigenicity of tumor cells. Our ABM reveals varied phenotypic shifts within the tumor and spatial organization of tumor and CTLs despite similarities in key immune parameters, initial simulation conditions, and early temporal trajectories of the cell populations. [ABSTRACT FROM AUTHOR]

Simple Summary: The naturally occurring derivative of estrogen, 2-methoxyestradiol (2-ME), has been shown to have good anti-cancer properties. However, it is broken down too quickly within the blood to be clinically useful. We designed 2-ME analogs with modifications which could avoid rapid metabolism, would preferably stay in the tumor, and were more toxic to cancer cells. Here, we looked more closely at how these compounds work within cancer cells, and how they communicate within themselves and with their environment. ESE-15-one and ESE-16 interfere with the functioning of the intracellular cytoskeleton (actin and microtubules), sending messages that stop cell division, intracellular transport of proteins, and cell migration and invasion, eventually inducing cell suicide. They also inhibited the movement of cells that make blood vessels that would support tumor growth. Using eggs with chicken embryos, we could show that the compounds reduced the tumor size and diminished the spread of cancer cells in a living system. The microtubule-disrupting agent 2-methoxyestradiol (2-ME) displays anti-tumor and anti-angiogenic properties, but its clinical development is halted due to poor pharmacokinetics. We therefore designed two 2-ME analogs in silico—an ESE-15-one and an ESE-16 one—with improved pharmacological properties. We investigated the effects of these compounds on the cytoskeleton in vitro, and their anti-angiogenic and anti-metastatic properties in ovo. Time-lapse fluorescent microscopy revealed that sub-lethal doses of the compounds disrupted microtubule dynamics. Phalloidin fluorescent staining of treated cervical (HeLa), metastatic breast (MDA-MB-231) cancer, and human umbilical vein endothelial cells (HUVECs) displayed thickened, stabilized actin stress fibers after 2 h, which rearranged into a peripheral radial pattern by 24 h. Cofilin phosphorylation and phosphorylated ezrin/radixin/moesin complexes appeared to regulate this actin response. These signaling pathways overlap with anti-angiogenic, extra-cellular communication and adhesion pathways. Sub-lethal concentrations of the compounds retarded both cellular migration and invasion. Anti-angiogenic and extra-cellular matrix signaling was evident with TIMP2 and P-VEGF receptor-2 upregulation. ESE-15-one and ESE-16 exhibited anti-tumor and anti-metastatic properties in vivo, using the chick chorioallantoic membrane assay. In conclusion, the sulfamoylated 2-ME analogs displayed promising anti-tumor, anti-metastatic, and anti-angiogenic properties. Future studies will assess the compounds for myeloproliferative effects, as seen in clinical applications of other drugs in this class. [ABSTRACT FROM AUTHOR]

Simple Summary: Inflammatory bowel disease (IBD) increases the risk of developing colitis-associated colorectal cancer (CAC) compared to the general population. The specific genetic alterations associated with the onset of CAC are largely unknown. In this study, we investigated the role of vitamin D3 upregulated protein 1 (VDUP1) in a CAC mouse model. VDUP1 knockout (KO) increased the severity of colitis and CAC development. Our data suggest that VDUP1 may be explored as a potential therapeutic approach for CAC prevention. VDUP1 acts as a tumor suppressor gene in various cancers. VDUP1 is expressed at low levels in sporadic and ulcerative-colitis-associated colorectal cancer. However, the effects of VDUP1 deficiency on CAC remain unclear. In this study, we found that VDUP1 deficiency promoted CAC development in mice. Wild-type (WT) and VDUP1 KO mice were used to investigate the role of VDUP1 in the development of azoxymethane (AOM)- and dextran sulfate sodium (DSS)-induced CAC. VDUP1 levels significantly decreased in the colonic tumor and adjacent nontumoral tissues of WT mice after AOM/DSS treatment. Moreover, AOM/DSS-treated VDUP1 KO mice exhibited a worse survival rate, disease activity index, and tumor burden than WT mice. VDUP1 deficiency significantly induced cell proliferation and anti-apoptosis in tumor tissues of VDUP1 KO mice compared to WT littermates. Additionally, mRNA levels of interleukin-6 and tumor necrosis factor-alpha and active forms of signal transducer and activator of transcription 3 and nuclear factor-kappa B p65 were significantly increased in the tumor tissues of VDUP1 KO mice. Overall, this study demonstrated that the loss of VDUP1 promoted AOM/DSS-induced colon tumorigenesis in mice, highlighting the potential of VDUP1-targeting strategies for colon cancer prevention and treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: Postoperative adjuvant chemotherapy generally improves survival in patients with breast cancer. However, adjuvant chemotherapy does not benefit all patients. There are considerations and guidelines that guide us as to whether or not chemotherapy is recommended to a particular patient. The decision is based on clinicopathologic features and may be aided by multigene assays. The Oncotype DX test is used worldwide. It makes the recommendation more accurate; however, there are possibilities to refine the process to make a more accurate decision. We investigated how we could move forward in recommending adjuvant chemotherapy. Background: The use of the Oncotype DX test reduces the rate of adjuvant chemotherapy recommendations. Few in-depth analyses have been performed on this decision-making process. Methods: We retrospectively analyzed patient data based on available Oncotype DX test results (RS) irrespective of nodal status at a single center. We collected recommendations from six oncologists, first without RS (pre-RS) and then with RS results (post-RS). We investigated changes in recommendations, agreement between oncologist decisions, and the effect of different National Comprehensive Cancer Network (NCCN) recommendation categories (for, against, and considering chemotherapy). Results: Data from 201 patients were included in the analysis. Recommendation of chemotherapy decreased by an average of 39.5%. Agreement improved substantially with RS, with a kappa value pre-RS of 0.37 (fair agreement) and post-RS of 0.75 (substantial agreement). Discordance remained substantial in cases where the NCCN recommendations considered chemotherapy only (32%). Pre-RS consensus against chemotherapy predicted low RS results (50 out of 51 patients). Post-RS consensus was highest in the NCCN chemotherapy recommendation group. Conclusions: The Oncotype DX test substantially improves decision accuracy in recommending adjuvant chemotherapy. It may be further improved with a consensus decision. In the case of pre-RS consensus against chemotherapy, the test can be spared. [ABSTRACT FROM AUTHOR]

Simple Summary: Advanced urinary bladder cancer (BCa) is characterized by rapid progression and development of therapy resistance. Despite all the available therapies, the five-year survival of metastatic BCa is a dismal 8% or lower. Many conjugates and additives of the natural polyphenol curcumin were developed and tested for potential therapeutic for cancers, with little success in vivo due to their rapid elimination and poor tissue penetrance. We tested a novel molecular hybrid CMC-2 composed of a curcumin scaffold conjugated to two dichloroacetate and glycine molecules. CMC-2 showed significantly higher antiproliferative and anti-survival activities against BCa than its parent compounds. Further, it was equally effective against chemotherapy-naïve and multidrug-resistant BCas (MDR-BCa). When tested in vivo using BCa xenograft in athymic mice, CMC-2 significantly delayed tumor growth without systemic toxicity. The mechanism of anticancer activity of CMC-2 was the induction of excessive oxidative stress in the cancer cells, leading to apoptotic cell death. These results show the potential of CMC-2 as a nontoxic oral treatment for high-grade bladder cancers. Tumor cells produce excessive reactive oxygen species (ROS) but cannot detoxify ROS if they are due to an external agent. An agent that produces toxic levels of ROS, specifically in tumor cells, could be an effective anticancer drug. CMC-2 is a molecular hybrid of the bioactive polyphenol curcumin conjugated to dichloroacetate (DCA) via a glycine bridge. The CMC-2 was tested for its cytotoxic antitumor activities and killed both naïve and multidrug-resistant (MDR) bladder cancer (BCa) cells with equal potency (<1.0 µM); CMC-2 was about 10–15 folds more potent than curcumin or DCA. Growth of human BCa xenograft in mice was reduced by >50% by oral gavage of 50 mg/kg of CMC-2 without recognizable systemic toxicity. Doses that used curcumin or DCA showed minimum antitumor effects. In vitro, the toxicity of CMC-2 in both naïve and MDR cells depended on increased intracellular ROS in tumor cells but not in normal cells at comparable doses. Increased ROS caused the permeabilization of mitochondria and induced apoptosis. Further, adding N-Acetyl cysteine (NAC), a hydroxyl radical scavenger, abolished excessive ROS production and CMC-2's cytotoxicity. The lack of systemic toxicity, equal potency against chemotherapy -naïve and resistant tumors, and oral bioavailability establish the potential of CMC-2 as a potent drug against bladder cancers. [ABSTRACT FROM AUTHOR]

Simple Summary: Somatostatin analogs like lanreotide are considered first-line agents for the treatment of gastroenteropancreatic neuroendocrine tumors (NET). Although its effects on tumor proliferation and hormonal regulation are somewhat understood, its influence on the immune system has not been well elucidated. We used a double-pronged approach to understand the role of lanreotide in immune system regulation in healthy donor T cells in vitro as well as in vivo in cells obtained from 17 NET patients. We looked at cytokine signaling and differential gene expression to elucidate lanreotide's role in the treatment of NET through additional novel immune pathways. The CLARINET trial led to the approval of lanreotide for the treatment of patients with gastroenteropancreatic neuroendocrine tumors (NETs). It is hypothesized that lanreotide regulates proliferation, hormone synthesis, and other cellular functions via binding to somatostatin receptors (SSTR1–5) present in NETs. However, our knowledge of how lanreotide affects the immune system is limited. In vitro studies have investigated functional immune response parameters with lanreotide treatment in healthy donor T cell subsets, encompassing the breadth of SSTR expression, apoptosis induction, cytokine production, and activity of transcription factor signaling pathways. In our study, we characterized in vitro immune mechanisms in healthy donor T cells in response to lanreotide. We also studied the in vivo effects by looking at differential gene expression pre- and post-lanreotide therapy in patients with NET. Immune-focused gene and protein expression profiling was performed on peripheral blood samples from 17 NET patients and correlated with clinical response. In vivo, lanreotide therapy showed reduced effects on wnt, T cell receptor (TCR), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) signaling in CD8+ T cells in responders compared to non-responders. Compared to non-responders, responders showed reduced effects on cytokine and chemokine signaling but greater effects on ubiquitination and proteasome degradation genes. Our results suggest significant lanreotide pharmacodynamic effects on immune function in vivo, which correlate with responses in NET patients. This is not evident from experimental in vitro settings. [ABSTRACT FROM AUTHOR]

Simple Summary: Treatment personalization is essential in the era of precision medicine. Biomarkers are necessary to predict clinical outcomes and guide treatment selection to improve efficacy and reduce toxicity. Genomic human leukocyte antigen-class I (HLA-I) has been shown to correlate with outcomes among non-small cell lung cancer (NSCLC) patients treated with immunotherapy. Here, we investigate whether the HLA genotype is predictive of outcomes in regard to the combination of immunotherapy with chemotherapy. We found that the HLA-I supertypes HLA-A01 and -A03, but not HLA homozygosity, overall correlated with survival in NSCLC patients treated with immunochemotherapy. While further validation is needed, these results highlight the potential and variability of the HLA genotyping as a biomarker for immunotherapy delivery. Introduction: Maximal heterozygosity on the human leukocyte antigen (HLA) loci has been found to be associated with improved survival and development of immune-related adverse events (irAEs) among NSCLC patients treated with immunotherapy. Here, we investigated the effect of germline HLA-I/-II on clinical outcomes among NSCLC patients treated with first-line pembrolizumab in combination with chemotherapy. Method: We prospectively recruited patients with NSCLC who were commencing first-line pembrolizumab in combination with chemotherapy. DNA from white blood cells was used for high-resolution HLA-I/II typing. Results: Of the 65 patients recruited, 53 complied with the inclusion criteria. We did not find an association between HLA-I/-II homozygosity and clinical outcome among the studied population. However, the presence of HLA-A01 was associated with unfavourable PFS (HR = 2.32, 95%CI 1.13–4.77, p = 0.022) and worsening OS (HR = 2.86, 95%CI 1.06–7.70, p = 0.038). The presence of HLA-B27 was associated with improved PFS (HR = 0.35, 95%CI 0.18–0.71, p = 0.004) and trends toward improving OS. None of the HLA-I supertypes were associated with the development or worsening of irAEs. Conclusions: The absence of association between genomic HLA-I/-II homozygosity and clinical outcome among patients with advanced NSCLC treated with pembrolizumab in combination with chemotherapy might reflect a diminished role for HLA molecules among patients with low or no PD-L1. HLA-A01 and HLA-B27 might have a role in predicting clinical outcomes among this cohort of patients. Further studies are needed to explore biomarkers for this group of patients. [ABSTRACT FROM AUTHOR]

Simple Summary: This study introduces a deep learning model designed to predict the 5-year recurrence risk of lung adenocarcinoma based on histopathology images. Using a dataset of 189 patients with 455 histopathology slides, our model demonstrated superior performance in risk stratification, achieving a hazard ratio of 2.29 (95% CI: 1.69–3.09, p < 0.005). This outperforms several existing deep learning methods, showcasing the potential of deep learning in automatically predicting lung adenocarcinoma recurrence risk. The superior performance of this model underscores the potential for deep learning models to be integrated into clinical workflows for more accurate and automated risk assessment in lung adenocarcinoma. This could lead to more personalized treatment strategies and better patient outcomes. Lung cancer is the leading cause of cancer-related death in the United States. Lung adenocarcinoma (LUAD) is one of the most common subtypes of lung cancer that can be treated with resection. While resection can be curative, there is a significant risk of recurrence, which necessitates close monitoring and additional treatment planning. Traditionally, microscopic evaluation of tumor grading in resected specimens is a standard pathologic practice that informs subsequent therapy and patient management. However, this approach is labor-intensive and subject to inter-observer variability. To address the challenge of accurately predicting recurrence, we propose a deep learning-based model to predict the 5-year recurrence of LUAD in patients following surgical resection. In our model, we introduce an innovative dual-attention architecture that significantly enhances computational efficiency. Our model demonstrates excellent performance in recurrent risk stratification, achieving a hazard ratio of 2.29 (95% CI: 1.69–3.09, p < 0.005), which outperforms several existing deep learning methods. This study contributes to ongoing efforts to use deep learning models for automatically learning histologic patterns from whole slide images (WSIs) and predicting LUAD recurrence risk, thereby improving the accuracy and efficiency of treatment decision making. [ABSTRACT FROM AUTHOR]

Simple Summary: Adjuvant therapy with targeted therapy or immunotherapy has become the standard of care for fully resected stage III–IV melanoma. In this scenario, real-world data are needed to relate the actual effectiveness and safety of these regimens with the evidence provided in the clinical trials. This study provides clinicians and researchers with the results of an Italian single-center real-world experience on the use of adjuvant therapy in resected stage III–IV melanoma patients. Our findings confirm the real-world effectiveness and safety of adjuvant regimens, yet underscores the need for further research to explore biomarker-based predictors for relapse and to assess the translation of improved relapse-free survival into long-term overall survival benefit. This study was carried out at the Dermatologic Clinic of the University of Turin, Italy, to assess the effectiveness and safety of adjuvant therapy in patients who received either targeted therapy (TT: dabrafenib + trametinib) or immunotherapy (IT: nivolumab or pembrolizumab) for up to 12 months. A total of 163 patients participated, including 147 with stage III and 19 with stage IV with no evidence of disease. The primary outcomes were relapse-free survival (RFS), distant metastasis-free survival (DMFS), and overall survival (OS). At 48 months, both TT and IT approaches yielded comparable outcomes in terms of RFS (55.6–55.4%, p = 0.532), DMFS (58.2–59.8%, p = 0.761), and OS (62.4–69.5%, p = 0.889). Whilst temporary therapy suspension was more common among TT-treated patients compared to IT-treated individuals, therapy discontinuation due to adverse events occurred at comparable rates in both groups. Predictors of relapse included mitoses, lymphovascular invasion, ulceration, and positive sentinel lymph nodes. Overall, the proportion of BRAF-mutated patients receiving IT stood at 7.4%, lower than what was observed in clinical trials. [ABSTRACT FROM AUTHOR]

Simple Summary: Skin cancer rates in Canada are rising quickly, with about one-third of Canadians likely to be affected in their lifetime. Despite this alarming trend, government actions to reduce skin cancer are limited. Our study, conducted in Manitoba, found that many residents have risky sun exposure habits and lack awareness about skin cancer. Over 65% reported a history of sunburns, more than half had used tanning beds, and a large majority recently tanned for pleasure. Misconceptions are common, with over 50% believing that tans are healthy or a sign of beauty. Moreover, sun protection practices are inadequate, with less than 60% using protective clothing and under 50% using sunscreen. These findings highlight the need for targeted public health campaigns to improve awareness and promote better sun protection behaviors to prevent future skin cancers in Manitoba. The rapidly increasing skin cancer rates in Canada are alarming, with current data estimating that 1/3 of Canadians will be affected in their lifetime. Thus, deeper understanding of high-risk sun exposure behaviors is needed to help counter this trend. Only limited action has been taken by federal/provincial governments to reduce skin cancer incidence. A cross-sectional survey study was conducted in Manitoba, with frequency counts, means, and percentages used to encapsulate responses. Age- and gender-adjusted odds ratios were calculated using logistic regression analyses. Our study identified worrying inadequacies in sun protective behaviors and attitudes, with the threat of such high-risk behaviors amplified by a lack of skin cancer awareness. Alarming elements were noted in participants' sun exposure history (>65% reported a history of sunburns, >50% previously used a tanning bed, and >75% recently tanned for pleasure), beliefs and attitudes (>50% believe that they look better/healthier with a tan, and >40% believe that having a base tan is protective against further sun damage), and sun protection efforts (sun protective clothing was used <60% of the time, sunscreen was used by <50%, and there was a lack of knowledge about sunscreen characteristics in ~30% of respondents), in addition to significant differences being established between demographic subgroups (based on gender, age, skin phototype, income, and education attained). This study provides worrisome insight onto the grim landscape of sun protective behaviors and attitudes in Manitoba, which will inevitably translate into higher skin cancer rates and should serve as a call to action to promote targeted public health messaging in this jurisdiction and beyond. [ABSTRACT FROM AUTHOR]

Simple Summary: The inactivation of apoptotic signaling by inhibitors of apoptosis proteins (IAPs) is one of the important hallmarks of cancer cells. Survivin, a 16.5 kDa member of the IAP family, is commonly enriched in many cancers and is a potential therapeutic target. We investigated the Survivin-targeting potential of Withaferin-A (Wi-A) and Withanone (Wi-N), two major withanolides from Withania somnifera (Ashwagandha), using computational assays. The results were validated in various in vitro experimental assays using Wi-A-rich extracts from Ashwagandha leaves, suggesting their use as an important bioresource for cancer drug development. Survivin, a member of the IAP family, functions as a homodimer and inhibits caspases, the key enzymes involved in apoptosis. Several Survivin inhibitors, including YM-155, Debio1143, EM1421, LQZ-7I, and TL32711, have emerged as potential anticancer drugs awaiting validation in clinical trials. Due to the high cost and adverse side effects of synthetic drugs, natural compounds with similar activity have also been in demand. In this study, we conducted molecular docking assays to evaluate the ability of Wi-A and Wi-N to block Survivin dimerization. We found that Wi-A, but not Wi-N, can bind to and prevent the homodimerization of Survivin, similar to YM-155. Therefore, we prepared a Wi-A-rich extract from Ashwagandha leaves (Wi-AREAL). Experimental analyses of human cervical carcinoma cells (HeLa and ME-180) treated with Wi-AREAL (0.05–0.1%) included assessments of viability, apoptosis, cell cycle, migration, invasion, and the expression levels (mRNA and protein) of molecular markers associated with these phenotypes. We found that Wi-AREAL led to growth arrest mediated by the upregulation of p21WAF1 and the downregulation of several proteins (CDK1, Cyclin B, pRb) involved in cell cycle progression. Furthermore, Wi-AREAL treatment activated apoptosis signaling, as evidenced by reduced PARP-1 and Bcl-2 levels, increased procaspase-3, and elevated Cytochrome C. Additionally, treating cells with a nontoxic low concentration (0.01%) of Wi-AREAL inhibited migration and invasion, as well as EMT (epithelial–mesenchymal transition) signaling. By combining computational and experimental approaches, we demonstrate the potential of Wi-A and Wi-AREAL as natural inhibitors of Survivin, which may be helpful in cancer treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: Robotic-assisted thoracic surgery (RATS) has gained popularity worldwide; however, its use in large-sized non-small cell lung cancer (NSCLC) is controversial. Our study evaluates the feasibility of single-port RATS lobectomy in patients with large-sized NSCLC (larger than 5 cm) and compares its perioperative outcomes with those of two-port RATS lobectomy. This study demonstrated that single-port RATS is comparable to two-port RATS for large-sized NSCLC. Our findings suggest that single-port RATS is feasible and can be an alternative surgical option for large-sized tumors. Single-port robotic-assisted thoracic surgery (SP-RATS) lobectomy using the da Vinci Xi system has been performed by several pioneers. However, due to the severe collisions and the steep learning curve, this approach is not yet widely used. This study aimed to evaluate the feasibility of SP-RATS lobectomy for large-sized non-small cell lung cancer (NSCLC). As we believe that for large-sized tumors it is reasonable to make a slightly larger incision, we performed SP-RATS lobectomy for large-sized NSCLC (greater than 5 cm) through a single incision (6–8 cm). Eleven patients underwent SP-RATS lobectomy using the da Vinci Xi system at our institution from April 2022 to May 2024. The median tumor size on computed tomography and on pathology was 6.6 cm [interquartile range (IQR), 6.1–7.5 cm] and 6 cm [IQR, 5.1–7.1], respectively. The median total operative time was 198 min [IQR, 159–260 min], and the median postoperative length of stay was 4 days [IQR, 4–10 days], with no major postoperative complications (≥grade III on the Clavien–Dindo classification). Our approach may combine the benefits of single-port surgery with those of robotic surgery and is safe, feasible, and may promote better outcomes in patients with large-sized NSCLC. [ABSTRACT FROM AUTHOR]

Simple Summary: This pilot study aims to identify the physical, mental, social, psychological, and health needs encountered by cancer survivors in order to propose and facilitate appropriate and tailored responses. To the best of our knowledge, this is one of the first multidimensional studies investigating this topic in Italy. Data show that the quality of life of cancer survivors is affected by cancer and its treatment, reporting more frailties than the general population, especially those over 65 years old. These findings could help develop multidisciplinary planning of survivorship care for the transition of patients from oncological management to primary healthcare. Background: Understanding the specific needs of cancer survivors is essential for healthcare policy. In Italy, dedicated studies are lacking, so we aimed to investigate the physical, mental, social, and health difficulties encountered by these patients. Methods: We conducted a cross-sectional study on breast or colorectal cancer survivors (people 5+ years free from it and its treatments) using an ad hoc survey including validated questionnaires (Grauer–Palombi, SF-36, PREDIMED). Participants were recruited within the Oncology Unit of the "Policlinico Tor Vergata", Italy. Results: A total of 62 patients (80.6% females; years range: 37–87) agreed to be interviewed. A profile of cancer survivors was drafted: an overaged person with multiple co-morbidities, not well-nourished, adhering to the Mediterranean diet, reporting critical conditions as for physical and functional status. The mean number of co-morbidities was 3.6 ± 2.4 SD, with a statistically significant difference between age groups (under and over 65). Compared to the general population, the sample showed more frailties, especially when >65. The risk of having multimorbidity (four or more co-morbidities) significantly increased in those over 65 (OR: 4.72; CI: 1.43–15.59). Conclusion: There is an urgent need for survivorship care planning for the patient-centered continuum of care. Assessing and monitoring their specific needs will help propose appropriate and tailored responses. [ABSTRACT FROM AUTHOR]

Simple Summary: Circulating tumor cells (CTCs) play an important role in the formation of metastases in the body. Various approaches have been proposed to cleanse the blood of these CTCs and thus prevent the formation of metastases. However, the efficiency of non-implantable blood purification devices for CTC removal has not yet been clearly demonstrated. Here, we have attempted to evaluate, with a simple computer simulation, whether the use of a non-implantable device for CTC excision can be effective and lead to a significant reduction in metastases. We show that non-implantable devices for CTC removal are de facto ineffective in terms of reducing metastases due to various factors. The results of this work argue that only implantable devices can successfully deplete metastasis-relevant CTCs and potentially reduce the metastatic burden of cancer patients. Circulating tumor cells (CTCs) are cells that have separated from a solid cancerous lesion and entered the bloodstream. They play a crucial role in driving the metastatic spread to distant organs, which is the leading cause of cancer-related deaths. Various concepts for blood purification devices aiming to remove CTCs from the blood and prevent metastases have been developed. Until now, it is not clear if such devices can indeed reduce new metastasis formation in a significant way. Here, we present a simple theoretical model of CTCs in the bloodstream that can be used to predict a reduction in metastatic burden using an extracorporeal or intracorporeal blood purification device. The model consists of a system of ordinary differential equations that was numerically solved and simulated. Various simulations with different parameter settings of extracorporeal and intracorporeal devices revealed that only devices implanted directly in tumor-draining vessels can reduce the metastatic burden significantly. Even if an extracorporeal device is used permanently, the reduction in metastases is only 82%, while a permanently operating implanted device in the tumor-draining vessel would achieve a reduction of 99.8%. These results are mainly due to the fact that only a small fraction of CTCs reaches peripheral circulation, resulting in a proportionally small amount of purified blood in extracorporeal devices. [ABSTRACT FROM AUTHOR]

Simple Summary: Early detection of melanoma and differentiation from benign nevi can be challenging even for the most experienced dermatologists. To improve melanoma detection, artificial intelligence algorithms incorporating dermoscopy have been developed, but lack transparency and therefore have limited training value for healthcare providers. To address this, an automated approach utilizing imaging biomarker cues (IBCs), logical features extracted from images that mimic expert dermatologists' dermoscopic pattern recognition skills, was developed. This study excluded deep learning approaches to which IBCs are complementary or alternative. Ten participants assessed 78 dermoscopic images (39 melanomas and 39 nevi) first without IBCs and then with IBCs. Using IBCs significantly improved diagnostic accuracy: sensitivity increased significantly from 73.69% to 81.57% (p = 0.0051) and specificity increased from 60.50% to 67.25% (p = 0.059). These results indicate that incorporating IBCs can significantly enhance melanoma diagnosis, with potential implications for improved screening practices. Further research is needed to confirm these findings across a variety of healthcare providers. Incorporation of dermoscopy and artificial intelligence (AI) is improving healthcare professionals' ability to diagnose melanoma earlier, but these algorithms often suffer from a "black box" issue, where decision-making processes are not transparent, limiting their utility for training healthcare providers. To address this, an automated approach for generating melanoma imaging biomarker cues (IBCs), which mimics the screening cues used by expert dermoscopists, was developed. This study created a one-minute learning environment where dermatologists adopted a sensory cue integration algorithm to combine a single IBC with a risk score built on many IBCs, then immediately tested their performance in differentiating melanoma from benign nevi. Ten participants evaluated 78 dermoscopic images, comprised of 39 melanomas and 39 nevi, first without IBCs and then with IBCs. Participants classified each image as melanoma or nevus in both experimental conditions, enabling direct comparative analysis through paired data. With IBCs, average sensitivity improved significantly from 73.69% to 81.57% (p = 0.0051), and the average specificity improved from 60.50% to 67.25% (p = 0.059) for the diagnosis of melanoma. The index of discriminability (d′) increased significantly by 0.47 (p = 0.002). Therefore, the incorporation of IBCs can significantly improve physicians' sensitivity in melanoma diagnosis. While more research is needed to validate this approach across other healthcare providers, its use may positively impact melanoma screening practices. [ABSTRACT FROM AUTHOR]

Simple Summary: Germline mutation rates and spectra across three cohorts of Chinese patients: a high-risk breast cancer cohort, an unselected breast cancer cohort, and a benign breast lesion cohort were compared. The high-risk cohort had the highest mutation rate at 11.9%, while the unselected cancer and benign lesion cohorts had rates of 6.5% and 8.1%, respectively. Notably, 29.3% of the unselected breast cancer patients met genetic testing criteria, and this subgroup had a mutation rate similar to the high-risk cohort. High-penetrance gene mutations were only found in the high-risk and unselected cancer cohorts. Unexpectedly, a 2% mutation rate was observed in the benign lesion cohort. These findings highlight the need for broader genetic testing of all breast cancer patients, not just those deemed high-risk, to identify more individuals harboring clinically relevant germline mutations. Mutation study for high-risk breast and ovarian cancer (HBOC) has been extensively studied in patients of different ethnicities. Here we compared the germline mutation rate and mutation spectrum of patients (n = 4341) with benign breast diseases or breast cancers, with and without other risk factors. Three cohorts of Chinese patients were recruited. The first cohort, high-risk cohort (HR, n = 3935) included high-risk breast cancer patients fulfilling high-risk HBOC criteria and who are recruited at our genetics clinic. The second cohort, unselected cancer cohort (CC, n = 307) was from general recruitment of patients with breast cancer at breast surgery clinics. The third cohort, benign breast lesion cohort (NC, n = 99) comprised 99 patients with benign breast diseases such as fibroadenoma, fibroadenomatoid hyperplasia, and intraductal papilloma. Thirty HBOC related genes were sequenced on the above-mentioned patient cohorts. The germline mutation rates of HR, CC, and NC cohort were 11.9%, 6.5%, and 8.1%, respectively. In the CC cohort, 29.3% (90/307) of patients fulfilled the National Comprehensive Cancer Network (NCCN) high-risk genetic test criteria 2022 v.2. The mutation rate for this group of patients was 11.1%, similar to that of the HR cohort, while the mutation rate for those not fulfilling testing criteria was 4.6%, like that of the NC cohort. High penetrance genes (BRCA1/2, CDH1, PALB2, PTEN, and TP53) mutations were only found in the HR (10.6%) and CC (3.3%) cohorts but were not found in the NC cohort. ATM, BRIP1, RAD51C, and RAD51D mutations were identified in all cohorts. RAD51C and RAD51D mutations showed conflicting penetrance. An unexpectedly high mutation rate of total 2% was found in the NC cohort but it was only 0.3% and 0.5% in the HR cohort and CC cohort, respectively. Our results show a clinical need to enhance genetic testing of unselected breast cancer patients to identify the high-risk patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Squamous cell carcinoma of the anus or anal cancer is increasing in prevalence, and the standard treatment of mitomycin and 5-fluorouracil is too toxic for many patients. Unfortunately, there is currently no standard of care for what to do for this disease when someone is not a candidate for this aggressive treatment. Here, we demonstrate the promising preliminary toxicity profile and efficacy of the combination of weekly carboplatin and paclitaxel chemotherapy for patients with localized anal cancer. This regimen was able to complete 80% of the intended treatments with anticipated toxicities, and 89% achieved a complete clinical response. This combination is a promising regimen and is already being investigated further in a clinical trial. Background: Although squamous cell carcinoma of the anus (SCCA) is a relatively uncommon malignancy in the United States, it continues to increase in incidence. Treatment for locoregional disease includes mitomycin and 5-fluorouracil with radiation. This combination is associated with significant toxicity, limiting its use in patients who are older or have certain comorbidities. Carboplatin and paclitaxel (C/P) is an accepted treatment regimen for metastatic SCCA. We aim to evaluate the efficacy and toxicity of weekly C/P given with radiation for patients unable to receive standard chemoradiation for SCCA. Methods: From our cancer registry, adult patients who received weekly intravenous C/P concurrent with standard-dose radiation for localized SCCA were included in this study. Clinical response was determined based on the evidence of disease on imaging and/or anoscopy. Toxicities were graded according to the CTCAE v5. Results: Ten patients were included; eight were female, and the median age was 75.5 years (54–87). Six had T2 disease, and four had T3 tumors. Four had node-positive disease. The majority (70%) of patients were dosed at standard C (AUC 2) and P (50 mg/m2), with a limited subset requiring dose reduction for baseline performance status. Patients completed a mean of 78.3% (40–100%) of the intended treatments. A total of 89% of the patients achieved a complete clinical response. With a median follow-up of 25.8 months (3.4–50.4 months), 67% of the patients are alive and without recurrence. Two patients have had local recurrence, and one patient had metastatic progression. The most common toxicities of any grade included leukopenia (100%), anemia (100%), radiation dermatitis (100%), diarrhea (100%), and fatigue (100%). Grade 3 or higher toxicities included neutropenic fever (20%), neutropenia (30%), and anemia (30%). Conclusions: This study demonstrates promising tolerability and efficacy for weekly C/P chemoradiation for patients with anal cancer unable to receive mitomycin and 5-fluorouracil. This regimen merits further investigation in prospective clinical trials. [ABSTRACT FROM AUTHOR]

Persons with disabilities experience numerous barriers to healthcare access including vaccine accessibility. The purpose of this study was to determine COVID-19 vaccine uptake in the spinal cord injury and disease (SCI/D) population of Ontario and identify potential factors influencing C OVID-19 vaccine uptake. This was a retrospective closed-cohort study using administrative health data on individuals with SCI/D of traumatic and non-traumatic causes to examine the monthly number of COVID-19 vaccine doses received between December 2020 and December 2023. Logistic regression analysis was used to examine the potential association between socio-demographic, clinical, and neighbourhood characteristics with initial COVID-19 vaccine receipt and booster dose uptake. By the end of the observation period in December 2023, 82.9% received the full two-dose coverage and 65.6% received at least one additional booster dose in a cohort of 3574 individuals with SCI/D. SCI/D individuals showed a comparable COVID-19 vaccine uptake percentage to the general population. Sociodemographic, clinical, and neighbourhood characteristics were associated with COVID-19 vaccine uptake in the SCI/D population, including age, type of injury, number of comorbidities, mental health history, and neighbourhood characteristics such as income. Further investigation is necessary to determine the causation effects of these relationships with vaccine uptake to address health equity concerns. [ABSTRACT FROM AUTHOR]

Background: The disparities in healthcare access due to varying insurance coverage significantly impact hospital outcomes, yet what is unclear is the role of insurance in providing care once the patient is in the hospital for a preventable admission, particularly in a weak gatekeeping environment. This study aimed to investigate the association between insurance types and readmission rates, healthcare expenditures, and length of hospital stay among patients with chronic ambulatory care sensitive conditions (ACSCs) in China. Methods: This retrospective observational study utilized hospitalization data collected from the Nanhai District, Foshan City, between 2016 and 2020. Generalized linear models (GLMs) were employed to analyze the relationship between medical insurance types and readmission rates, lengths of hospital stay, total medical expenses, out-of-pocket expenses, and insurance-covered expenses. Results: A total of 185,384 records were included. Among these, the participants covered by urban employee basic medical insurance (UEBMI) with 44,415 records and urban and rural resident basic medical insurance (URRBMI) with 80,752 records generally experienced more favorable outcomes compared to self-pay patients. Specifically, they had lower readmission rates (OR = 0.57, 95% CI: 0.36 to 0.90; OR = 0.59, 95% CI: 0.42 to 0.84) and reduced out-of-pocket expenses (β = −0.54, 95% CI: −0.94 to −0.14; β = −0.41, 95% CI: −0.78 to −0.05). However, they also experienced slightly longer lengths of hospital stay (IRR = 1.08, 95% CI: 1.03 to 1.14; IRR = 1.11, 95% CI: 1.04 to 1.18) and higher total medical expenses (β = 0.26, 95% CI: 0.09 to 0.44; β = 0.25, 95% CI: 0.10 to 0.40). Conclusions: This study found that different types of health insurance were associated with varying clinical outcomes among patients with chronic ambulatory care sensitive conditions (ACSCs) in China. Since the hospitalization of these patients was initially avoidable, disparities in readmission rates, lengths of hospital stay, and medical expenses among avoidable inpatient cases exacerbated the health gap between different insurance types. Addressing the disparities among different types of insurance can help reduce unplanned hospitalizations and promote health equity. [ABSTRACT FROM AUTHOR]

Climate change threatens environmental stability and human health, with limited research on younger children's perceptions. This study examines Italian primary school children's views on climate change to guide educational and policy strategies. Surveying 973 children (5–11 years) from different regions, findings showed high awareness (93%) and concern (63%) about climate change. Regional differences indicated greater concern in the south. Gender disparities revealed females were more concerned and experienced more sleep difficulties. Younger children had stronger emotional responses, while older ones showed increased pro-environmental behaviors. Despite moderate self-confidence in effecting change, a strong sense of responsibility and trust in adults was prevalent. These results highlight the need for early, continuous climate education tailored to regional, age, and gender-specific needs. Addressing children's views on climate change can help educators and policymakers foster resilience and proactive attitudes, supporting the development of informed and engaged future stewards of the planet. [ABSTRACT FROM AUTHOR]

Background: Healthcare professionals frequently encounter various forms of aggression, ranging from verbal abuse to physical assaults, which can compromise both their occupational well-being and patient-care quality. Despite its prevalence and serious consequences, workplace aggression is often underreported due to a lack of standardized assessment tools. This study aims to develop a valid Italian version of the Hospital Aggressive Behaviour Scale-Users. Methods: The scale's structure was evaluated using exploratory (EFA) and confirmatory (CFA) factor analyses on two samples of healthcare professionals during and after the pandemic. Reliability, measurement invariance, and nomological validity were examined. Results: EFA revealed a two-factor structure comprising eight items (χ2 = 59.651, df = 13, p = 0.00; CFI = 0.98; TLI = 0.95; RMSEA = 0.07; SRMR = 0.02), distinguishing non-physical and physical aggression, and meeting all recommended criteria. CFA confirmed this structure, demonstrating good reliability and outperforming alternative models. The same factor structure was confirmed in standard (χ2 = 35.01, df = 19, p = 0.00; CFI = 0.99; TLI = 0.99; RMSEA = 0.03; SRMR = 0.02) and emergency (χ2 = 30.65, df = 19, p = 0.04; CFI = 0.98; TLI = 0.97; RMSEA = 0.06; SRMR = 0.04) contexts. Full residual invariance was found across job tenure groups. Aggression was positively associated with emotional exhaustion, psychological distance, psychosomatic symptoms, post-traumatic stress symptoms, and turnover intentions while negatively related to job satisfaction. Nurses and healthcare assistants reported higher levels of aggression than doctors. Conclusions: This study provides a reliable, context-specific instrument for documenting and analysing outsider aggression. The insights can inform targeted interventions, contributing to a healthier hospital environment. [ABSTRACT FROM AUTHOR]

Background: Acupuncture is frequently used to manage pediatric cerebral palsy (CP), yet updated evidence is needed to guide future research and clinical practice. Methods: Seven databases were searched from 1994 to 26 June 2023. Randomized controlled trials (RCTs) involving body, scalp, or ear acupuncture for managing CP, excluding acupoint injection, catgut embedding, electro-acupuncture, or laser acupuncture, were included. Results: Twenty RCTs with 1797 participants were analyzed. Acupuncture groups had better improvements in gross motor function measure (GMFM) scores by 5% (mean difference: 5.93, 95% CI: 3.67–8.19, p < 0.001, I2 = 57%); a 16% higher probability to yield prominent improvement in effectiveness rate (ER) (risk ratio: 1.16, 95% CI: 1.08–1.25, p < 0.001, I2 = 0%); and better outcomes in the Modified Ashworth Scale (MAS) (standardized mean difference [SMD]: 0.3, 95%, CI: 0.11–0.49, p < 0.001, I2 = 0%), the Berg Balance Scale (BBS) (SMD: 2.48; 95% CI: 2.00–2.97, p < 0.001, I2 = 72%) and ADL (SMD: 1.66; 95% CI: 1.23–2.08, p < 0.001, I2 = 91%). Studies with eight core acupoints identified from all ninety-five acupoints had better ER. Conclusions: Acupuncture, especially using core acupoints, may be effective for managing symptoms in children with CP. [ABSTRACT FROM AUTHOR]

This study aimed to confirm the mediating effects of symptom experiences on the relationship between the body image and quality of life of hemodialysis patients. Data were collected from 153 patients who were diagnosed with ESRD at a tertiary general hospital and receiving regular hemodialysis in Korea. The data were collected between 20 July and 11 August 2023. The following statistical analyses were conducted: t-test, ANOVA, Scheffé test, Pearson's correlation coefficient analysis, and Hayes' Process Macro Model 4 (to test the mediating effect). The factors influencing quality of life were body image (β = 0.46, p < 0.001), monthly family income (over KRW 3 million) (β = 0.22, p = 0.002), and symptom experiences (β = −0.20, p = 0.001). The mediation analysis indicated that the symptom experiences mediated the relationship between body image and quality of life. Based on the results, education, counseling, and symptom management programs that can improve body image and reduce symptom experience should be developed, and customized programs that reflect the characteristics of a target population, such as economic level, should be developed and provided. [ABSTRACT FROM AUTHOR]