Evaluating Combinations of Biological and Clinicopathologic Factors Linked to Poor Outcomes in Resected Colorectal Liver Metastasis: An External Validation Study.

BACKGROUND: Recent studies have suggested that certain combinations of KRAS or BRAF biomarkers with clinical factors are associated with poor outcomes and may indicate that surgery could be "biologically" futile in otherwise technically resectable colorectal liver metastasis (CRLM). However, these combinations have yet to be validated through external studies. PATIENTS AND METHODS: We conducted a systematic search to identify these studies. The overall survival (OS) of patients with these combinations was evaluated in a cohort of patients treated at 11 tertiary centers. Additionally, the study investigated whether using high-risk KRAS point mutations in these combinations could be associated with particularly poor outcomes. RESULTS: The recommendations of four studies were validated in 1661 patients. The first three studies utilized KRAS, and their validation showed the following median and 5-year OS: (1) 30 months and 16.9%, (2) 24.3 months and 21.6%, and (3) 46.8 months and 44.4%, respectively. When analyzing only patients with high-risk KRAS mutations, median and 5-year OS decreased to: (1) 26.2 months and 0%, (2) 22.3 months and 15.1%, and (3) not reached and 44.9%, respectively. The fourth study utilized BRAF, and its validation showed a median OS of 10.4 months, with no survivors beyond 21 months. CONCLUSION: The combinations of biomarkers and clinical factors proposed to render surgery for CRLM futile, as presented in studies 1 (KRAS high-risk mutations) and 4, appear justified. In these studies, there were no long-term survivors, and survival was similar to that of historic cohorts with similar mutational profiles that received systemic therapies alone for unresectable disease.

[Metabolic, clinical and body composition changes in Mexican adults undergoing bariatric surgery]. / Cambios metabólicos, clínicos y de composición corporal en adultos mexicanos sometidos a cirugía bariátrica.

BACKGROUND: morbid obesity is a major public health problem that is increasing. Currently, there are a limited number of studies carried out in the Mexican population that describe the effects of bariatric surgery. OBJECTIVE: to establish in people undergoing a bariatric procedure the metabolic and body composition difference before and after bariatric surgery. MATERIAL AND METHODS: an observational, analytical, and longitudinal study was carried out in 50 patients with morbid obesity who underwent laparoscopic Sleeve Gastrectomy (LSG) and Laparoscopic Roux-en-Y gastric bypass (LRYGB). Body composition and metabolic markers in blood were measured. Differences in the metabolic profile before and after surgery were analyzed in the entire study group and a subanalysis was performed by bariatric surgical technique, determining the percentage of remission of comorbidities. RESULTS: after the intervention, there is a significant decrease in all metabolic and body composition markers, except HDL cholesterol, which showed a tendency to increase without being significant. Women with LRYGB have a greater decrease in fat-free mass. LRYGB decreased the prevalence of fatty liver, gastroesophageal reflux, insulin resistance, and hypercholesterolemia more, while LSG decreased the prevalence of hypertension, osteoarthritis, hypothyroidism, and hypertriglyceridemia more. CONCLUSION: bariatric surgery induces metabolic changes that could contribute to improving comorbidities associated with obesity. In general, metabolic improvement is greater in LRYGB compared to LSG.

Incidental Pulmonary Nodules: Differential Diagnosis and Clinical Management.

BACKGROUND: According to data from the USA, the incidence of incidentally discovered pulmonary nodules is 5.8 per 100 000 person-years for women and 5.2 per 100 000 person-years for men. Their management as recommended in the pertinent guidelines can substantially improve clinical outcomes. More than 95% of all pulmonary nodules revealed by computed tomography (CT) are benign, but many cases are not managed in conformity with the guidelines. In this article, we summarize the appropriate clinical approach and provide an overview of the pertinent diagnostic studies and when they should be performed. METHODS: This review is based on relevant publications retrieved by a selective search in PubMed. The authors examined English-language recommendations issued since 2010 for the management of pulmonary nodules, supplemented by comments from the German lung cancer guideline. RESULTS: In general, the risk that an incidentally discovered pulmonary nodule is malignant is low but rises markedly with increasing size and the presence of risk factors. When such a nodule is detected, the further recommendation, depending on size, is either for follow-up examinations with chest CT or else for an extended evaluation with positron emission tomography-CT and biopsy for histology. The diagnostic evaluation should include consideration of any earlier imaging studies that may be available as an indication of possible growth over time. Single nodules measuring less than 6 mm, in patients with few or no risk factors, do not require any follow-up. Lung cancer is diagnosed in just under 10% of patients with a nodule measuring more than 8 mm. CONCLUSION: The recommendations of the guidelines for the management of incidentally discovered pulmonary nodules are intended to prevent both over- and undertreatment. If a tumor is suspected, further care should be provided by an interdisciplinary team.

Cine-MRI and T1TSE Sequence for Mediastinal Mass.

Background/Objectives: Contrast-enhanced computed tomography (CT) is the standard radiologic examination for evaluating the extent of mediastinal tumors. If tumor infiltration into the large central thoracic vessels, the pericardium, or the myocardium is suspected, cine magnetic resonance imaging (cine-MRI) can provide additional valuable information. Methods: We conducted a retrospective study of patients with mediastinal tumors who were staged with CT, cine-MRI, and a T1-weighted turbo spin echo (T1TSE) prior to surgical resection. Imaging was re-evaluated regarding tumor infiltration into the pericardium, myocardium, superior vena cava, aorta, pulmonary arteries, and atria and compared with intraoperative findings and postoperative histopathological reports (gold standard). Unclear CT findings were further investigated. Results: Forty-seven patients (29 female and 18 male patients; median age: 58 years) met the inclusion criteria. Cine-MRI was able to predict infiltration of the aorta in 86%, pulmonary arteries in 85%, and atria in 80% of unclear CT cases. Aortic tumor infiltration in unclear CT cases was significantly more often correctly diagnosed with cine-MRI than with T1TSE sequence. Conclusions: Additional cine-MRI is of crucial benefit in unclear CT cases. We recommend performing cine-MRI if infiltration into the large central vessels and atria is suspected. T1TSE sequence is of very limited additional value.

The third symposium on treatment-induced neuroendocrine prostate cancer: insights and future directions.

Neuroendocrine prostate cancer (NEPC) is a rare and aggressive subtype of prostate cancer (PCa), emerging from advanced treatments and characterized by loss of androgen receptor (AR) signaling and neuroendocrine features, leading to rapid progression and treatment resistance. The third symposium on treatment-induced NEPC, held from 21 to 23 June 2024, at Harrison Hot Springs Resort, BC, Canada, united leading global researchers and clinicians. Sponsored by the Vancouver Prostate Centre (VPC), Canadian Institute of Health Research, Prostate Cancer Foundation Canada and Pharma Planter Inc, the event focused on the latest NEPC research and innovative treatment strategies. Co-chaired by Drs. Yuzhuo Wang and Martin Gleave, the symposium featured sessions on NEPC's historical context, molecular pathways, epigenetic regulation and the role of the tumor microenvironment and metabolism in its progression. Keynotes from experts like Dr. Himisha Beltran and Dr. Martin Gleave highlighted the complexity of NEPC. The Emerging Talent session showcased new research, pointing to the future of NEPC treatment. The symposium concluded with a consensus on the need for early detection, targeted therapies and personalized medicine to effectively combat NEPC, emphasizing the importance of global collaboration in advancing NEPC understanding and treatment.

Community assessment of methods to deconvolve cellular composition from bulk gene expression.

We evaluate deconvolution methods, which infer levels of immune infiltration from bulk expression of tumor samples, through a community-wide DREAM Challenge. We assess six published and 22 community-contributed methods using in vitro and in silico transcriptional profiles of admixed cancer and healthy immune cells. Several published methods predict most cell types well, though they either were not trained to evaluate all functional CD8+ T cell states or do so with low accuracy. Several community-contributed methods address this gap, including a deep learning-based approach, whose strong performance establishes the applicability of this paradigm to deconvolution. Despite being developed largely using immune cells from healthy tissues, deconvolution methods predict levels of tumor-derived immune cells well. Our admixed and purified transcriptional profiles will be a valuable resource for developing deconvolution methods, including in response to common challenges we observe across methods, such as sensitive identification of functional CD4+ T cell states.

Tumor-derived GLI1 promotes remodeling of the immune tumor microenvironment in melanoma.

BACKGROUND: Melanoma progression is based on a close interaction between cancer cells and immune cells in the tumor microenvironment (TME). Thus, a better understanding of the mechanisms controlling TME dynamics and composition will help improve the management of this dismal disease. Work from our and other groups has reported the requirement of an active Hedgehog-GLI (HH-GLI) signaling for melanoma growth and stemness. However, the role of the downstream GLI1 transcription factor in melanoma TME remains largely unexplored. METHODS: The immune-modulatory activity of GLI1 was evaluated in a syngeneic B16F10 melanoma mouse model assessing immune populations by flow cytometry. Murine polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) were differentiated from bone marrow cells and their immunosuppressive ability was assessed by inhibition of T cells. Conditioned media (CM) from GLI1-overexpressing mouse melanoma cells was used to culture PMN-MDSCs, and the effects of CM were evaluated by Transwell invasion assay and T cell inhibition. Cytokine array analysis, qPCR and chromatin immunoprecipitation were performed to explore the regulation of CX3CL1 expression by GLI1. Human monocyte-derived dendritic cells (moDCs) were cultured in CM from GLI1-silenced patient-derived melanoma cells to assess their activation and recruitment. Blocking antibodies anti-CX3CL1, anti-CCL7 and anti-CXCL8 were used for in vitro functional assays. RESULTS: Melanoma cell-intrinsic activation of GLI1 promotes changes in the infiltration of immune cells, leading to accumulation of immunosuppressive PMN-MDSCs and regulatory T cells, and to decreased infiltration of dendric cells (DCs), CD8 + and CD4 + T cells in the TME. In addition, we show that ectopic expression of GLI1 in melanoma cells enables PMN-MDSC expansion and recruitment, and increases their ability to inhibit T cells. The chemokine CX3CL1, a direct transcriptional target of GLI1, contributes to PMN-MDSC expansion and recruitment. Finally, silencing of GLI1 in patient-derived melanoma cells promotes the activation of human monocyte-derived dendritic cells (moDCs), increasing cytoskeleton remodeling and invasion ability. This phenotype is partially prevented by blocking the chemokine CCL7, but not CXCL8. CONCLUSION: Our findings highlight the relevance of tumor-derived GLI1 in promoting an immune-suppressive TME, which allows melanoma cells to evade the immune system, and pave the way for the design of new combination treatments targeting GLI1.

Cryo-EM structure of the CDK2-cyclin A-CDC25A complex.

The cell division cycle 25 phosphatases CDC25A, B and C regulate cell cycle transitions by dephosphorylating residues in the conserved glycine-rich loop of CDKs to activate their activity. Here, we present the cryo-EM structure of CDK2-cyclin A in complex with CDC25A at 2.7 Å resolution, providing a detailed structural analysis of the overall complex architecture and key protein-protein interactions that underpin this 86 kDa complex. We further identify a CDC25A C-terminal helix that is critical for complex formation. Sequence conservation analysis suggests CDK1/2-cyclin A, CDK1-cyclin B and CDK2/3-cyclin E are suitable binding partners for CDC25A, whilst CDK4/6-cyclin D complexes appear unlikely substrates. A comparative structural analysis of CDK-containing complexes also confirms the functional importance of the conserved CDK1/2 GDSEID motif. This structure improves our understanding of the roles of CDC25 phosphatases in CDK regulation and may inform the development of CDC25-targeting anticancer strategies.

Epigenetic regulation of the tumor microenvironment: A leading force driving pancreatic cancer.

Dysregulation of the epigenomic landscape of tumor cells has been implicated in the pathogenesis of pancreatic cancer. However, these alterations are not only restricted to neoplastic cells. The behavior of other cell populations in the tumor stroma such as cancer-associated fibroblasts, immune cells, and others are mostly regulated by epigenetic pathways. Here, we present an overview of the main cellular and acellular components of the pancreatic cancer tumor microenvironment and discuss how the epigenetic mechanisms operate at different levels in the stroma to establish a differential gene expression to regulate distinct cellular phenotypes contributing to pancreatic tumorigenesis.

The Pharmacokinetics, Metabolism, and Clearance Mechanisms of Ritlecitinib, a Janus Kinase 3 and Tyrosine-Protein Kinase Family Inhibitor, in Humans.

Ritlecitinib is an oral once-daily irreversible inhibitor of Janus kinase 3 and tyrosine-protein kinase family being developed for the treatment of moderate-to-severe alopecia areata. This study examined the disposition of ritlecitinib in male participants following oral and intravenous administration using accelerator mass spectroscopy methodology to estimate pharmacokinetic parameters and characterize metabolite profiles. The results indicated ritlecitinib had a systemic clearance of 43.7 L/h, a steady state volume of distribution of 73.8 L, extent of absorption of 89%, time to maximum plasma concentration of ∼0.5 hours, and absolute oral bioavailability of 64%. An observed long terminal half-life of total radioactivity was primarily attributed to ritlecitinib binding to plasma albumin. Ritlecitinib was the main circulating drug species in plasma (∼30%), with one major pharmacologically inactive cysteine conjugated metabolite (M2) at >10%. Oxidative metabolism (fractional clearance 0.47) and glutathione-related conjugation (fractional clearance 0.24) were the primary routes of elimination for ritlecitinib with the greatest disposition of radioactivity shown in the urine (∼71%). In vitro phenotyping indicated ritlecitinib cytochrome P450 (CYP) fraction of metabolism assignments of 0.29 for CYP3A, 0.09 for CYP2C8, 0.07 for CYP1A2, and 0.02 for CYP2C9. In vitro phenotyping in recombinant human glutathione S-transferases indicated ritlecitinib was turned over by a number of cytosolic and microsomal enzyme isoforms. SIGNIFICANCE STATEMENT: This study provides a detailed understanding of the disposition and metabolism of ritlecitinib, a JAK3 and TEC family kinase inhibitor for alopecia areata in humans, as well as characterization of clearance pathways and pharmacokinetics of ritlecitinib and its metabolites. As an AMS-based ADME study design, we have expanded on reporting the standard ADME endpoints, providing key pharmacokinetic parameters, such as clearance, volume of distribution, and bioavailability, allowing for a more comprehensive understanding of drug disposition.

Influence of Neoadjuvant Therapy on Success of Endoscopic Vacuum Therapy in Anastomotic Leakage after Rectal Resection Because of Rectal Cancer.

Background: For locally advanced rectal cancer, neoadjuvant therapy (NT) is an established element of therapy. Endoscopic vacuum therapy (EVT) has been a relevant treatment option for anastomotic leakage after rectal resection since 2008. The aim was to evaluate the influence of NT on the duration and success of EVT in anastomotic leakage after rectal resection for rectal cancer. Methods: This was a monocentric, retrospective cohort study including patients who underwent rectal resection with primary anastomosis because of histologically proven carcinoma of the rectum in the Department for General and Visceral Surgery of Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin over a period of ten years (2012 to 2022). Results: Overall, 243 patients were included, of which 47 patients (19.3%) suffered from anastomotic leakage grade B with consecutive EVT. A total of 29 (61.7%) patients received NT and 18 patients (38.3%) did not. The median duration of EVT until the removal of the sponge did not differ between patients with and without NT: 24.0 days (95% CI 6.44-41.56) versus 20.0 days (95% CI 17.03-22.97); p = 0.273. The median duration from insertion of EVT until complete healing was 74.0 days with NT (95% CI 10.07-137.93) versus 62.0 days without NT (95% CI 45.99-78.01); p = 0.490. Treatment failure-including early persistence and late onset of recurrent anastomotic leakage-was evident in 27.6% of patients with NT versus 27.8% without NT; p = 0.989. Ostomy was reversed in 19 patients (79.2%) with NT compared to 11 patients (68.8%) without NT; p = 0.456. Overall, continuity was restored in 75% of patients in the long term after EVT. Conclusion: This trial comprised-to our knowledge-the largest study cohort to analyze the outcome of EVT in anastomotic leakage after rectal resection for rectal cancer. We conclude that neoadjuvant therapy neither prolongs EVT nor the time to healing from anastomotic leakage. The rates of treatment failure of EVT and permanent ostomy were not higher when neoadjuvant therapy was used.

Interpretable artificial intelligence to optimise use of imatinib after resection in patients with localised gastrointestinal stromal tumours: an observational cohort study.

BACKGROUND: Current guidelines recommend use of adjuvant imatinib therapy for many patients with gastrointestinal stromal tumours (GISTs); however, its optimal treatment duration is unknown and some patient groups do not benefit from the therapy. We aimed to apply state-of-the-art, interpretable artificial intelligence (ie, predictions or prescription logic that can be easily understood) methods on real-world data to establish which groups of patients with GISTs should receive adjuvant imatinib, its optimal treatment duration, and the benefits conferred by this therapy. METHODS: In this observational cohort study, we considered for inclusion all patients who underwent resection of primary, non-metastatic GISTs at the Memorial Sloan Kettering Cancer Center (MSKCC; New York, NY, USA) between Oct 1, 1982, and Dec 31, 2017, and who were classified as intermediate or high risk according to the Armed Forces Institute of Pathology Miettinen criteria and had complete follow-up data with no missing entries. A counterfactual random forest model, which used predictors of recurrence (mitotic count, tumour size, and tumour site) and imatinib duration to infer the probability of recurrence at 7 years for a given patient under each duration of imatinib treatment, was trained in the MSKCC cohort. Optimal policy trees (OPTs), a state-of-the-art interpretable AI-based method, were used to read the counterfactual random forest model by training a decision tree with the counterfactual predictions. The OPT recommendations were externally validated in two cohorts of patients from Poland (the Polish Clinical GIST Registry), who underwent GIST resection between Dec 1, 1981, and Dec 31, 2011, and from Spain (the Spanish Group for Research in Sarcomas), who underwent resection between Oct 1, 1987, and Jan 30, 2011. FINDINGS: Among 1007 patients who underwent GIST surgery in MSKCC, 117 were included in the internal cohort; for the external cohorts, the Polish cohort comprised 363 patients and the Spanish cohort comprised 239 patients. The OPT did not recommend imatinib for patients with GISTs of gastric origin measuring less than 15·9 cm with a mitotic count of less than 11·5 mitoses per 5 mm2 or for those with small GISTs (<5·4 cm) of any site with a count of less than 11·5 mitoses per 5 mm2. In this cohort, the OPT cutoffs had a sensitivity of 92·7% (95% CI 82·4-98·0) and a specificity of 33·9% (22·3-47·0). The application of these cutoffs in the two external cohorts would have spared 38 (29%) of 131 patients in the Spanish cohort and 44 (35%) of 126 patients in the Polish cohort from unnecessary treatment with imatinib. Meanwhile, the risk of undertreating patients in these cohorts was minimal (sensitivity 95·4% [95% CI 89·5-98·5] in the Spanish cohort and 92·4% [88·3-95·4] in the Polish cohort). The OPT tested 33 different durations of imatinib treatment (<5 years) and found that 5 years of treatment conferred the most benefit. INTERPRETATION: If the identified patient subgroups were applied in clinical practice, as many as a third of the current cohort of candidates who do not benefit from adjuvant imatinib would be encouraged to not receive imatinib, subsequently avoiding unnecessary toxicity on patients and financial strain on health-care systems. Our finding that 5 years is the optimal duration of imatinib treatment could be the best source of evidence to inform clinical practice until 2028, when a randomised controlled trial with the same aims is expected to report its findings. FUNDING: National Cancer Institute.

Hepatectomy versus systemic therapy for liver-limited BRAF V600E-mutated colorectal liver metastases: multicentre retrospective study.

BACKGROUND: To date, only two studies have compared the outcomes of patients with liver-limited BRAF V600E-mutated colorectal liver metastases (CRLMs) managed with resection versus systemic therapy alone, and these have reported contradictory findings. METHODS: In this observational, international, multicentre study, patients with liver-limited BRAF V600E-mutated CRLMs treated with resection or systemic therapy alone were identified from institutional databases. Patterns of recurrence/progression and overall survival were compared using multivariable analyses of the entire cohort and a propensity score-matched cohort. RESULTS: Of 170 patients included, 119 underwent hepatectomy and 51 received systemic treatment. Surgically treated patients had a more favourable pattern of recurrence with most recurrences limited to a single site, whereas diffuse progression was more common among patients who received systemic treatment (19 versus 44%; P = 0.002). Surgically treated patients had longer median overall survival (35 versus 20 months; P < 0.001). Hepatectomy was independently associated with better OS than systemic treatment alone (HR 0.37, 95% c.i. 0.21 to 0.65). In the propensity score-matched cohort, surgically treated patients had longer median overall survival (28 versus 20 months; P < 0.001); hepatectomy was independently associated with better overall survival (HR 0.47, 0.25 to 0.88). CONCLUSION: BRAF V600E mutation should not be considered a contraindication to surgery for patients with resectable, liver-only CRLMs.

CT-guided needle biopsy is not associated with increased ipsilateral pleural metastasis.

INTRODUCTION: Histological confirmation of a lung tumor is the prerequisite for treatment planning. It has been suspected that CT-guided needle biopsy (CTGNB) exposes the patient to a higher risk of pleural recurrence. However, the distance between tumor and pleura has largely been neglected as a possible confounder when comparing CTGNB to bronchoscopy. METHODS: All patients with lung cancer histologically confirmed by bronchoscopy or CTGNB between 2010 and 2020 were enrolled and studied. Patients' medical histories, radiologic and pathologic findings and surgical records were reviewed. Pleural recurrence was diagnosed by pleural biopsy, fluid cytology, or by CT chest imaging showing progressive pleural nodules. RESULTS: In this retrospective unicenter analysis, 844 patients underwent curative resection for early-stage lung cancer between 2010 and 2020. Median follow-up was 47.5 months (3-137). 27 patients (3.2 %) with ipsilateral pleural recurrence (IPR) were identified. The distance of the tumor to the pleura was significantly smaller in patients who underwent CTGNB. A tendency of increased risk of IPR was observed in tumors located in the lower lobe (HR: 2.18 [±0.43], p = 0.068), but only microscopic pleural invasion was a significant independent predictive factor for increased risk of IPR (HR: 5.33 [± 0.51], p = 0.001) by multivariate cox analysis. Biopsy by CTGNB did not affect IPR (HR: 1.298 [± 0.39], p = 0.504). CONCLUSION: CTGNB is safe and not associated with an increased incidence of IPR in our cohort of patients. This observation remains to be validated in a larger multicenter patient cohort.

ReFerm®: a postbiotic fermented oat gruel composition is reducing mast cell degranulation in the colon of patients with irritable bowel syndrome.

Background: Irritable bowel syndrome (IBS) is a highly prevalent gastrointestinal disorder that affects ~4% of the global population. ReFerm® is a postbiotic product derived from oat gruel fermented with Lactobacillus plantarum 299v, and it has been shown to have beneficial effects on intestinal permeability in patients with IBS. In this study, we investigated the effects of ReFerm® on regulators of intestinal permeability, namely mast cells and enteric glial cells. Materials and methods: A total of 30 patients with moderate to severe IBS were treated with an enema containing ReFerm® or a placebo twice daily. The patients underwent sigmoidoscopy with biopsies obtained from the distal colon at baseline and after 14 days of treatment. These biopsies were processed in two ways: some were fixed, embedded in paraffin, sectioned, and stained for mast cells and enteric glial cells; others were cryopreserved, lysed, and subjected to Western blotting to analyze the same markers. Results: Treatment with ReFerm®, but not the placebo, significantly reduced mast cell tryptase protein levels in the biopsy lysates. Although the number of mast cells remained unchanged in colonic biopsies, ReFerm® treatment significantly reduced mast cell degranulation, a result not observed in the placebo group. Neither ReFerm® or placebo treatment had an impact on total protein levels or the number of enteric glial cells in the biopsies. Conclusion: ReFerm® treatment significantly reduced both total mast cell tryptase levels and the degranulation of mast cells in colonic biopsies from patients with IBS, suggesting a decrease in mast cell activity as a potential mechanism underlying the beneficial effects of ReFerm®. However, further research is required to assess the molecular mechanisms through which ReFerm® operates in the colons of patients with IBS. Clinical trial registration: https://clinicaltrials.gov, identifier: NCT05475314.

Insights into the mechanisms driven by H3K4 KMTs in pancreatic cancer.

Pancreatic cancer is a malignancy arising from the endocrine or exocrine compartment of this organ. Tumors from exocrine origin comprise over 90% of all pancreatic cancers diagnosed. Of these, pancreatic ductal adenocarcinoma (PDAC) is the most common histological subtype. The five-year survival rate for PDAC ranged between 5 and 9% for over four decades, and only recently saw a modest increase to ∼12-13%, making this a severe and lethal disease. Like other cancers, PDAC initiation stems from genetic changes. However, therapeutic targeting of PDAC genetic drivers has remained relatively unsuccessful, thus the focus in recent years has expanded to the non-genetic factors underlying the disease pathogenesis. Specifically, it has been proposed that dynamic changes in the epigenetic landscape promote tumor growth and metastasis. Emphasis has been given to the re-organization of enhancers, essential regulatory elements controlling oncogenic gene expression, commonly marked my histone 3 lysine 4 monomethylation (H3K4me1). H3K4me1 is typically deposited by histone lysine methyltransferases (KMTs). While well characterized as oncogenes in other cancer types, recent work has expanded the role of KMTs as tumor suppressor in pancreatic cancer. Here, we review the role and translational significance for PDAC development and therapeutics of KMTs.

KRAS Promotes GLI2-Dependent Transcription during Pancreatic Carcinogenesis.

Aberrant activation of GLI transcription factors has been implicated in the pathogenesis of different tumor types including pancreatic ductal adenocarcinoma. However, the mechanistic link with established drivers of this disease remains in part elusive. In this study, using a new genetically engineered mouse model overexpressing constitutively active mouse form of GLI2 and a combination of genome-wide assays, we provide evidence of a novel mechanism underlying the interplay between KRAS, a major driver of pancreatic ductal adenocarcinoma development, and GLI2 to control oncogenic gene expression. These mice, also expressing KrasG12D, show significantly reduced median survival rate and accelerated tumorigenesis compared with the KrasG12D only expressing mice. Analysis of the mechanism using RNA sequencing demonstrate higher levels of GLI2 targets, particularly tumor growth-promoting genes, including Ccnd1, N-Myc, and Bcl2, in KrasG12D mutant cells. Furthermore, chromatin immunoprecipitation sequencing studies showed that in these cells KrasG12D increases the levels of trimethylation of lysine 4 of the histone 3 (H3K4me3) at the promoter of GLI2 targets without affecting significantly the levels of other major active chromatin marks. Importantly, Gli2 knockdown reduces H3K4me3 enrichment and gene expression induced by mutant Kras. In summary, we demonstrate that Gli2 plays a significant role in pancreatic carcinogenesis by acting as a downstream effector of KrasG12D to control gene expression.

Prostate Cancer Risk Stratification by Digital Histopathology and Deep Learning.

PURPOSE: Prostate cancer (PCa) represents a highly heterogeneous disease that requires tools to assess oncologic risk and guide patient management and treatment planning. Current models are based on various clinical and pathologic parameters including Gleason grading, which suffers from a high interobserver variability. In this study, we determine whether objective machine learning (ML)-driven histopathology image analysis would aid us in better risk stratification of PCa. MATERIALS AND METHODS: We propose a deep learning, histopathology image-based risk stratification model that combines clinicopathologic data along with hematoxylin and eosin- and Ki-67-stained histopathology images. We train and test our model, using a five-fold cross-validation strategy, on a data set from 502 treatment-naïve PCa patients who underwent radical prostatectomy (RP) between 2000 and 2012. RESULTS: We used the concordance index as a measure to evaluate the performance of various risk stratification models. Our risk stratification model on the basis of convolutional neural networks demonstrated superior performance compared with Gleason grading and the Cancer of the Prostate Risk Assessment Post-Surgical risk stratification models. Using our model, 3.9% of the low-risk patients were correctly reclassified to be high-risk and 21.3% of the high-risk patients were correctly reclassified as low-risk. CONCLUSION: These findings highlight the importance of ML as an objective tool for histopathology image assessment and patient risk stratification. With further validation on large cohorts, the digital pathology risk classification we propose may be helpful in guiding administration of adjuvant therapy including radiotherapy after RP.

A critical appraisal of the current landscape of resectable BRAF mutated colorectal liver metastases: a systematic review.

BACKGROUND: Patients with surgically resectable BRAF-mutated colorectal liver metastases (CRLM) or limited extrahepatic disease constitute a highly selective subgroup among BRAF-mutated patients, characterized by a more indolent disease biology. This is evident in their suitability for surgical resection. However, initial studies from a decade ago presented a discouraging outlook for these patients, citing early, frequent, multifocal recurrences and a very limited median overall survival (OS) of less than two years. Our objective was to provide an updated, comprehensive, and critically assessed review of the current literature on the prognostic impact of BRAF variants in CRLM, as well as to explore optimal treatment strategies for these patients through a systematic search. METHODS: A systematic literature search of the Medline, Scopus, and CENTRAL databases for studies reporting long-term outcomes of patients with a known BRAF status was performed. RESULTS: A total of 386 unique studies were screened during the study selection process. After applying the exclusion criteria, a total of 18 studies published between 2012 and 2023 were deemed eligible for inclusion. CONCLUSIONS: In contrast to older studies, more recent studies, with larger sample sizes, have revealed that the rate of extrahepatic recurrence is comparable between BRAF-mutated and wild-type patients. Furthermore, they have reported significantly improved survival outcomes, with OS extending up to 52 months. Notably, patients with non-V600E BRAF mutations may even achieve outcomes comparable to those with wild-type BRAF CRLM. Additionally, a few recent studies have compared surgery and systemic therapies, indicating that surgery is associated with improved survival rates, even for patients with the V600E mutation. This challenges the previous belief that BRAF mutations are absolute contraindications to surgical treatment. Surgical denial for technically resectable patients may now be reserved for specific clinical scenarios, such as the presence of a BRAF V600E mutation and concurrent extrahepatic disease.

Deciphering the Transcription Factor Landscape in Neuroendocrine Prostate Cancer Progression: A Novel Approach to Understand NE Transdifferentiation.

Background and Objective: Prostate cancer (PCa) is a leading cause of cancer mortality in men, with neuroendocrine prostate cancer (NEPC) representing a particularly resistant subtype. The role of transcription factors (TFs) in the progression from prostatic adenocarcinoma (PRAD) to NEPC is poorly understood. This study aims to identify and analyze lineage-specific TF profiles in PRAD and NEPC and illustrate their dynamic shifts during NE transdifferentiation. Methods: A novel algorithmic approach was developed to evaluate the weighted expression of TFs within patient samples, enabling a nuanced understanding of TF landscapes in PCa progression and TF dynamic shifts during NE transdifferentiation. Results: unveiled TF profiles for PRAD and NEPC, identifying 126 shared TFs, 46 adenocarcinoma-TFs, and 56 NEPC-TFs. Enrichment analysis across multiple clinical cohorts confirmed the lineage specificity and clinical relevance of these lineage-TFs signatures. Functional analysis revealed that lineage-TFs are implicated in pathways critical to cell development, differentiation, and lineage determination. Novel lineage-TF candidates were identified, offering potential targets for therapeutic intervention. Furthermore, our longitudinal study on NE transdifferentiation highlighted dynamic TF expression shifts and delineated a three-phase hypothesis for the process comprised of de-differentiation, dormancy, and re-differentiation. and proposing novel insights into the mechanisms of PCa progression. Conclusion: The lineage-specific TF profiles in PRAD and NEPC reveal a dynamic shift in the TF landscape during PCa progression, highlighting three distinct phases of NE transdifferentiation.