Interactive enhancer hubs (iHUBs) mediate transcriptional reprogramming and adaptive resistance in pancreatic cancer.

OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) displays a remarkable propensity towards therapy resistance. However, molecular epigenetic and transcriptional mechanisms enabling this are poorly understood. In this study, we aimed to identify novel mechanistic approaches to overcome or prevent resistance in PDAC. DESIGN: We used in vitro and in vivo models of resistant PDAC and integrated epigenomic, transcriptomic, nascent RNA and chromatin topology data. We identified a JunD-driven subgroup of enhancers, called interactive hubs (iHUBs), which mediate transcriptional reprogramming and chemoresistance in PDAC. RESULTS: iHUBs display characteristics typical for active enhancers (H3K27ac enrichment) in both therapy sensitive and resistant states but exhibit increased interactions and production of enhancer RNA (eRNA) in the resistant state. Notably, deletion of individual iHUBs was sufficient to decrease transcription of target genes and sensitise resistant cells to chemotherapy. Overlapping motif analysis and transcriptional profiling identified the activator protein 1 (AP1) transcription factor JunD as a master transcription factor of these enhancers. JunD depletion decreased iHUB interaction frequency and transcription of target genes. Moreover, targeting either eRNA production or signaling pathways upstream of iHUB activation using clinically tested small molecule inhibitors decreased eRNA production and interaction frequency, and restored chemotherapy responsiveness in vitro and in vivo. Representative iHUB target genes were found to be more expressed in patients with poor response to chemotherapy compared with responsive patients. CONCLUSION: Our findings identify an important role for a subgroup of highly connected enhancers (iHUBs) in regulating chemotherapy response and demonstrate targetability in sensitisation to chemotherapy.

Synergistic combination of cytotoxic chemotherapy and cyclin-dependent kinase 4/6 inhibitors in biliary tract cancers.

BACKGROUND AND AIMS: Biliary tract cancers (BTCs) are uncommon, but highly lethal, gastrointestinal malignancies. Gemcitabine/cisplatin is a standard-of-care systemic therapy, but has a modest impact on survival and harbors toxicities, including myelosuppression, nephropathy, neuropathy, and ototoxicity. Whereas BTCs are characterized by aberrations activating the cyclinD1/cyclin-dependent kinase (CDK)4/6/CDK inhibitor 2a/retinoblastoma pathway, clinical use of CDK4/6 inhibitors as monotherapy is limited by lack of validated biomarkers, diffident preclinical efficacy, and development of acquired drug resistance. Emerging studies have explored therapeutic strategies to enhance the antitumor efficacy of CDK4/6 inhibitors by the combination with chemotherapy regimens, but their mechanism of action remains elusive. APPROACH AND RESULTS: Here, we report in vitro and in vivo synergy in BTC models, showing enhanced efficacy, reduced toxicity, and better survival with a combination comprising gemcitabine/cisplatin and CDK4/6 inhibitors. Furthermore, we demonstrated that abemaciclib monotherapy had only modest efficacy attributable to autophagy-induced resistance. Notably, triplet therapy was able to potentiate efficacy through elimination of the autophagic flux. Correspondingly, abemaciclib potentiated ribonucleotide reductase catalytic subunit M1 reduction, resulting in sensitization to gemcitabine. CONCLUSIONS: As such, these data provide robust preclinical mechanistic evidence of synergy between gemcitabine/cisplatin and CDK4/6 inhibitors and delineate a path forward for translation of these findings to preliminary clinical studies in advanced BTC patients.

Heparin-induced Anaphylaxis shock.

Introduction: Anaphylaxis is a fatal condition that can be easily managed if discovered early. Only a few examples of anaphylaxis-like reactions caused by heparin have been documented, and immediate-type hypersensitivity reactions to heparin are extremely uncommon. Case Presentation: We report a case of a 53-yearold gentleman known to have an End Stage Renal Disease (ESRD) on Hemodialysis for two years, who went to the dialysis facility in his usual state of health. After two hours of dialysis, a new lock of taurolidine/heparin was installed; one minute later, the patient started to vomit and became restless, blood pressure dropped to 60/47 mmHg, and urticarial hives and a reddish rash developed on his skin, covering his trunk and limbs. He was immediately given three doses of epinephrine intramuscularly, which he did not respond to. Therefore, an epinephrine infusion was started. IV hydrocortisone and diphenhydramine were given for symptomatic relief. The patient was shifted to the emergency department, where he became vitally stable and returned to baseline. Heparininduced anaphylaxis was assumed based on the quick response to the above medications. Conclusion: This case can be added to the growing literature regarding this rare reaction, and more studies should be done to understand the nature of the reaction better. We recommend that the healthcare team becomes vigilant of heparin as a possible cause of anaphylaxis.

Neoadjuvant Chemotherapy Switch in Borderline Resectable/Locally Advanced Pancreatic Cancer.

BACKGROUND: Neoadjuvant chemotherapy (NAC) is an integral part of preoperative treatment for patients with borderline resectable/locally advanced (BR/LA) pancreatic ductal adenocarcinoma (PDAC). The identification of a chemotherapeutic regimen that is both effective and tolerable is critical for NAC to be of oncologic benefit. After initial first-line (FL) NAC, some patients have lack of response or therapeutic toxicities precluding further treatment with the same regimen; optimal decision making regarding this patient population is unclear. Chemotherapy switch (CS) may allow for a larger proportion of patients to undergo curative-intent resection after NAC. METHODS: We reviewed our surgical database for patients undergoing combinatorial NAC for BR/LA PDAC. Variant histologic exocrine carcinomas, intraductal papillary mucinous neoplasm-associated PDAC, and patients without research consent were excluded. RESULTS: Overall, 468 patients with BR/LA PDAC receiving FL chemotherapy were reviewed, of whom 70% (329/468) continued with FL chemotherapy followed by surgical resection. The remaining 30% (139/468) underwent CS, with 72% (100/139) of CS patients going on to curative-intent surgical resection. Recurrence-free survival (RFS) and overall survival (OS) were not significantly different between the resected FL and CS cohorts (30.0 vs. 19.1 months, p = 0.13, and 41.4 vs. 36.4 months, p = 0.94, respectively) and OS was significantly worse in those undergoing CS without subsequent resection (19 months, p < 0.0001). On multivariable analysis, carbohydrate antigen (CA) 19-9 and pathologic treatment responses were predictors of RFS and OS. CONCLUSION: CS in patients undergoing NAC for BR/LA pancreatic cancer does not incur oncologic detriment. The incorporation of CS into NAC treatment sequencing may allow a greater proportion of patients to proceed to curative-intent surgery.

FDG-PET Predicts Neoadjuvant Therapy Response and Survival in Borderline Resectable/Locally Advanced Pancreatic Adenocarcinoma.

BACKGROUND: Neoadjuvant therapy (NAT) is used in borderline resectable/locally advanced (BR/LA) pancreatic ductal adenocarcinoma (PDAC). Anatomic imaging (CT/MRI) poorly predicts response, and biochemical (CA 19-9) markers are not useful (nonsecretors/nonelevated) in many patients. Pathologic response highly predicts survival post-NAT, but is only known postoperatively. Because metabolic imaging (FDG-PET) reveals primary tumor viability, this study aimed to evaluate our experience with preoperative FDG-PET in patients with BR/LA PDAC in predicting NAT response and survival. METHODS: We reviewed all patients with resected BR/LA PDAC who underwent NAT with FDG-PET within 60 days of resection. Pre- and post-NAT metabolic (FDG-PET) and biochemical (CA 19-9) responses were dichotomized in addition to pathologic responses. We compared post-NAT metabolic and biochemical responses as preoperative predictors of pathologic responses and recurrence-free survival (RFS) and overall survival (OS). RESULTS: We identified 202 eligible patients. Post-NAT, 58% of patients had optimization of CA 19-9 levels. Major metabolic and pathologic responses were present in 51% and 38% of patients, respectively. Median RFS and OS times were 21 and 48.7 months, respectively. Metabolic response was superior to biochemical response in predicting pathologic response (area under the curve, 0.86 vs 0.75; P<.001). Metabolic response was the only univariate preoperative predictor of OS (odds ratio, 0.25; 95% CI, 0.13-0.40), and was highly correlated (P=.001) with pathologic response as opposed to biochemical response alone. After multivariate adjustment, metabolic response was the single largest independent preoperative predictor (P<.001) for pathologic response (odds ratio, 43.2; 95% CI, 16.9-153.2), RFS (hazard ratio, 0.37; 95% CI, 0.2-0.6), and OS (hazard ratio, 0.21; 95% CI, 0.1-0.4). CONCLUSIONS: Among patients with post-NAT resected BR/LA PDAC, FDG-PET highly predicts pathologic response and survival, superior to biochemical responses alone. Given the poor ability of anatomic imaging or biochemical markers to assess NAT responses in these patients, FDG-PET is a preoperative metric of NAT efficacy, thereby allowing potential therapeutic alterations and surgical treatment decisions. We suggest that FDG-PET should be an adjunct and recommended modality during the NAT phase of care for these patients.

Patency rates of hepatic arterial resection and revascularization in locally advanced pancreatic cancer.

BACKGROUND: Arterial resection (AR) for pancreatic adenocarcinoma is increasingly considered at specialized centers. We aimed to examine the incidence, risk factors, and outcomes of hepatic artery (HA) occlusion after revascularization. METHODS: We included patients undergoing HA resection with interposition graft (IG) or primary end-to-end anastomoses (EE). Complete arterial occlusion (CAO) was defined as "early" (EO) or "late" (LO) before/after 90 days respectively. Kaplan-Meier and change-point analysis for CAO was performed. RESULTS: HA resection was performed in 108 patients, IG in 61% (66/108) and EE in 39% (42/108). An equal proportion (50%) underwent HA resection alone or in combination with celiac and/or superior mesenteric artery. CAO was identified in 18% of patients (19/108) with arterial IG least likely to occlude (p=0.019). Hepatic complications occurred in 42% (45/108) and correlated with CAO, symptomatic patients, venous resection, and postoperative portal venous patency. CAO-related operative mortality was 4.6% and significantly higher in EO vs LO (p = 0.046). Median CAO occlusion was 126 days. With change-point analysis, CAO was minimal beyond postoperative day 158. CONCLUSION: CAO can occur in up to 18% of patients and the first 5-month post-operative period is critical for surveillance. LO is associated with better outcomes compared to EO unless there is inadequate portal venous inflow.

The use of patient factors to improve the prediction of operative duration using laparoscopic cholecystectomy.

BACKGROUND: Reliable prediction of operative duration is essential for improving patient and care team satisfaction, optimizing resource utilization and reducing cost. Current operative scheduling systems are unreliable and contribute to costly over- and underestimation of operative time. We hypothesized that the inclusion of patient-specific factors would improve the accuracy in predicting operative duration. METHODS: We reviewed all elective laparoscopic cholecystectomies performed at a single institution between 01/2007 and 06/2013. Concurrent procedures were excluded. Univariate analysis evaluated the effect of age, gender, BMI, ASA, laboratory values, smoking, and comorbidities on operative duration. Multivariable linear regression models were constructed using the significant factors (p < 0.05). The patient factors model was compared to the traditional surgical scheduling system estimates, which uses historical surgeon-specific and procedure-specific operative duration. External validation was done using the ACS-NSQIP database (n = 11,842). RESULTS: A total of 1801 laparoscopic cholecystectomy patients met inclusion criteria. Female sex was associated with reduced operative duration (-7.5 min, p < 0.001 vs. male sex) while increasing BMI (+5.1 min BMI 25-29.9, +6.9 min BMI 30-34.9, +10.4 min BMI 35-39.9, +17.0 min BMI 40 + , all p < 0.05 vs. normal BMI), increasing ASA (+7.4 min ASA III, +38.3 min ASA IV, all p < 0.01 vs. ASA I), and elevated liver function tests (+7.9 min, p < 0.01 vs. normal) were predictive of increased operative duration on univariate analysis. A model was then constructed using these predictive factors. The traditional surgical scheduling system was poorly predictive of actual operative duration (R 2 = 0.001) compared to the patient factors model (R 2 = 0.08). The model remained predictive on external validation (R 2 = 0.14).The addition of surgeon as a variable in the institutional model further improved predictive ability of the model (R 2 = 0.18). CONCLUSION: The use of routinely available pre-operative patient factors improves the prediction of operative duration during cholecystectomy.

Impact of single-incision laparoscopic cholecystectomy (SILC) versus conventional laparoscopic cholecystectomy (CLC) procedures on surgeon stress and workload: a randomized controlled trial.

INTRODUCTION: Single-incision laparoscopic cholecystectomy (SILC) may lead to higher patient satisfaction; however, SILC may expose the surgeon to increased workload. The goal of this study was to compare surgeon stress and workload between SILC and conventional laparoscopic cholecystectomy (CLC). METHODS: During a double-blind randomized controlled trial comparing patient outcomes for SILC versus CLC (NCT0148943), surgeon workload was assessed by four measures: surgery task load index questionnaire (Surg-TLX), maximum heart rate, salivary cortisol level, and instruments usability survey. The maximum heart rate and salivary cortisol levels were sampled from the surgeon before the random assignment of the surgical procedure, intraoperatively after the cystic duct was clipped, and at skin closure. After each procedure, the surgeon completed the Surg-TLX and an instrument usability survey. Student's t tests, Wilcoxon rank sum test, and Kruskal-Wallis nonparametric ANOVAs on the dependent variables by the technique (SILC vs. CLC) were performed with α = 0.05. RESULTS: Twenty-three SILC and 25 CLC procedures were included in the intent-to-treat analysis. No significant differences were observed between SILC and CLC for patient demographics and procedure duration. SILC had significantly higher post-surgery surgeon maximum heart rates than CLC (p < 0.05). SILC also had significantly higher mean change in the maximum heart rate between during and post-procedure (p < 0.05) than CLC. Salivary cortisol level was significantly higher during SILC than CLC (p < 0.01). Awkward manipulation of the instruments and limited fine motions were reported significantly more frequently with SILC than CLC (p < 0.01). In the surgeon-reported Surg-TLX, subscale of physical demand was significantly more demanding for SILC than CLC (p < 0.05). CONCLUSIONS: Surgeon heart rate, salivary cortisol level, instrument usability, and Surg-TLX ratings indicate that SILC is significantly more stressful and physically demanding than the CLC. Surgeon stress and workload may impact patients' outcomes; thus, ergonomic improvement on SILC is necessary.

Quantifying Intraoperative Workloads Across the Surgical Team Roles: Room for Better Balance?

BACKGROUND: Surgical performance, provider health, and patient safety can be compromised when workload demands exceed individual capability on the surgical team. The purpose of this study is to quantify and compare intraoperative workload among surgical team members. METHODS: Observations were conducted for an entire surgical day for 33 participating surgeons and their surgical team at one medical institution. Workload (mental, physical, case complexity, distractions, and case difficulty) was measured for each surgical team member using questions from validated questionnaires. Statistical analyses were performed with a mixed effects model. RESULTS: A total of 192 surgical team members participated in 78 operative cases, and 344 questionnaires were collected. Procedures with high surgeon mental and physical workload included endovascular and gastric surgeries, respectively. Ratings did not differ significantly among surgeons and residents, but scrub nurses physical demand ratings were 14-22 (out of 100) points lower than the surgeons, residents, and surgical assistants. Residents reported the highest mental workload, averaging 19-24 points higher than surgical assistants, scrub nurses, and circulating nurses. Mental and physical demands exceeded 50 points 28-45 % of the time for surgeons and residents. Workload did not differ between minimally invasive and open techniques. CONCLUSION: The workload questionnaires are an effective tool for quantifying intraoperative workload across the surgical team to ensure mental and physical demands do not exceed thresholds where performance may decrease and injury risk increase. This tool has the potential to measure the safety of current procedures and drive design of workload interventions.

Acute massive posterior stroke with tonsillar herniation in a scuba diver.

A transient female passenger in her 40s presented to the emergency department (ED) exhibiting drowsiness post-scuba diving. Despite normal initial vitals, she reported dizziness, sleepiness, and occipital headache. A computed tomography (CT) scan showed a severe posterior circulation acute infarction affecting various brain regions, resulting in significant mass effects and complications like 4th ventricle compression, cerebellar tonsillar herniation, and hydrocephalus. Extensive diagnostic tests, blood workup, and stroke evaluations revealed normal findings, except for an incidental patent foramen ovale (PFO). Collaboration with neurosurgery led to her transfer for life-saving extraventricular drain (EVD) insertion and posterior fossa decompression. Treatment included right-side EVD insertion, suboccipital craniectomy, and foramen magnum decompression. Postoperatively, she was extubated the next day, alert, without focal neurological deficits. Upon EVD removal, a repeat CT head scan showed regression of mass effect. She was discharged home safely after 16 days, fully ambulating.

Lung adenocarcinoma presenting as miliary lung metastasis on imaging.

Intrapulmonary miliary metastasis is a rare presentation of adenocarcinoma of the lung, characterized by the dissemination of cancer cells throughout the lung parenchyma in different patterns. This case report highlights an unusual presentation of adenocarcinoma of the lung with intrapulmonary miliary metastasis, emphasizing the diagnostic challenges and management considerations. Here, we report a case of a 51-year-old female who presented to the emergency department (ED) with a 2-month history of dry cough, which started after a flu illness and was associated with mild shortness of breath, left-sided chest pain, and miliary nodules on chest imaging. During bronchoscopy, a transbronchial biopsy was taken for further pathological assessment. The results showed histopathological evidence of lung adenocarcinoma.

Atypical Presentation and Diagnostic Challenges of Appendicitis in an 85-Year-Old Male: A Case Report.

Acute appendicitis in elderly individuals is uncommon and poses a significant challenge due to atypical symptomatology. An 85-year-old male presented to the emergency department (ED) with abdominal pain associated with nausea and reduced oral intake. Physical examination revealed diffuse abdominal tenderness. He was initially treated for constipation with an enema and discharged. Two days later, the patient returned with worsened pain and a new onset of fever. Examination revealed guarding. Lab results showed significant elevation in C-reactive protein (CRP) and white blood count (WBC). A contrast-enhanced computed tomography (CT) scan showed evidence of a perforated appendix. He was admitted into the surgical ward and improved on conservative treatment. This case describes an atypical presentation of acute appendicitis in an elderly patient, emphasizing the importance of recognizing unusual presentations in this population. Early use of contrast-enhanced CT scans is crucial for accurate diagnosis and improving patients outcomes.

Case report: Dysphagia aortica.

Dysphagia, characterized by abnormal swallowing, presents as oropharyngeal or esophageal dysphagia. Dysphagia aortica, a rare manifestation, results from external aortic compression, leading to swallowing difficulties. Limited literature exists on this condition. We report a 22-year-old male with a complex surgical history, including aortic repairs, who presented with dysphagia and chest pain. Extensive evaluations ruled out other causes. Imaging revealed esophageal compression by an aortic graft. Endoscopy confirmed extrinsic compression. A barium swallow study was unremarkable. A diagnosis of dysphagia aortica was made, and conservative treatment was initiated. Dysphagia aortica remains a rare but noteworthy cause of dysphagia with this case highlighting the importance of considering vascular compression in patients with previous history of aortic surgery. Increased clinical awareness is essential for timely diagnosis and tailored treatment strategies. Further research is needed to establish guidelines for managing this condition, given its diverse causes.

Lhermitte-Duclos disease in a 51-year old patient.

Lhermitte-Duclos disease (LDD) is a rare, slow-growing neoplasm that develops in the brain's posterior fossa. It can appear as a single lesion or as part of Cowden's syndrome. We report the case of a 51-year-old female with a history of diabetes, hypertension, and a previously treated neuroendocrine tumor, who presented to the hospital after experiencing a generalized tonic-clonic seizure. Except for a tongue laceration, the neurological examination was unremarkable. Brain magnetic resonance imaging (MRI) showed a T2 left cerebellar hemisphere pseudomass lesion with iso-hyperintense signals suggestive of Lhermitte-Duclos disease. This case describes a unique presentation of LDD and its various radiological manifestations, emphasizing the importance of neuroimaging in its diagnosis. Additionally, it contributes to the expanding literature on the varied manifestations of LDD.

Baseline Characteristics and Use of Pretherapeutic 18 F-Fluorodeoxyglucose-PET for Pancreatic Cancer.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and lethal malignancy. Surgical resection is the only curative modality combined with neoadjuvant chemotherapy to improve survival. Given the limitations of traditional responses such as cross-sectional imaging (CT/MRI) or tumor markers, carbohydrate antigen 19-9 (CA19-9), the 2023 National Comprehensive Cancer Network guidelines included 18 F-fluorodeoxyglucose (FDG)-PET as an adjunct to assess response to neoadjuvant chemotherapy. There are common misconceptions on the metabolic activity (tumor avidity) in PDAC so we aimed to describe the baseline characteristics and use of FDG-PET in a cohort of treatment-naive patients with PDAC. STUDY DESIGN: A single-center retrospective study was conducted capturing all biopsy-proven, treatment-naive patients with PDAC who underwent either baseline FDG-PET/CT or FDG-PET/MRI imaging between 2008 and 2023. Baseline FDG-PET characteristics were collected, including primary tumors' maximum standardized uptake value defined as metabolic activity (FDG uptake) of tumor compared with surrounding pancreatic parenchymal background, and the identification of extrapancreatic metastatic disease. RESULTS: We identified 1,095 treatment-naive patients with PDAC who underwent baseline FDG-PET imaging at diagnosis. CA19-9 was elevated in 76% of patients. Overall, 96.3% (1,054) of patients had FDG-avid tumors with a median maximum standardized uptake value of 6.4. FDG-PET also identified suspicious extrapancreatic metastatic lesions in 50% of patients, with a higher proportion (p < 0.001) in PET/MRI (59.9%) vs PET/CT (44.3%). After controlling for CA19-9 elevation, PET/MRI was superior in detection of extrapancreatic lesions compared with PET/CT. CONCLUSIONS: FDG-PET has significant use in PDAC as a baseline imaging modality earlier neoadjuvant therapy given the majority of tumors are FDG-avid. FDG-PET can identify additional extrapancreatic suspicious lesions allowing for optimal initial staging, with PET/MRI having increased sensitivity over PET/CT.

Outcomes of Different Surgical Interventions for Treating Trigeminal Neuralgia: A Review.

Trigeminal neuralgia (TN) is a debilitating condition characterized by severe facial pain. Various surgical interventions are employed to manage this condition, including microvascular decompression (MVD), percutaneous radiofrequency rhizotomy (PRR), glycerol rhizotomy, percutaneous balloon compression (PBC), and stereotactic radiosurgery such as Gamma Knife radiosurgery (GKRS). This review synthesizes the outcomes of these interventions to provide an understanding of their efficacy and associated risks. MVD, known for its high initial relief rates, shows substantial long-term effectiveness, with recurrence rates varying based on patient demographics and comorbidities. GKRS offers significant pain relief with a favorable adverse event profile; however, recurrence rates increase over time, necessitating repeat procedures for sustained efficacy. PBC demonstrates high initial success, but pain recurrence is common, especially in patients with atypical TN. PRR provides immediate relief with a manageable recurrence rate and is particularly suitable for elderly patients and those with comorbidities. Glycerol rhizotomy, a cost-effective procedure, yields comparable outcomes to other interventions but requires careful patient selection. This review highlights the importance of tailored treatment approaches based on individual patient profiles, emphasizing the need for precise diagnostic criteria and careful patient selection to optimize outcomes. Long-term follow-up and the potential for repeat interventions are critical considerations in managing TN surgically.

YAP-TEAD inhibition is associated with upregulation of an androgen receptor mediated transcription program providing therapeutic escape.

Cholangiocarcinoma (CCA) is a highly aggressive form of liver cancer and is an increasing cause of cancer-related death worldwide. Despite its increasing incidence globally and alarming mortality, treatment options for CCA have largely remained unchanged, stressing the importance of developing new effective therapies. YAP activation is common in CCA, and its major transcriptional signaling partners are the TEAD proteins. CA3 is a small-molecule YAP-TEAD disrupter discovered utilizing a TEAD reporter assay. Utilizing CCA, gastric cancer cell lines, and patient-derived xenograft models (PDX), we demonstrate that CA3 is effective in inducing cell death and delaying tumor growth in both FGFR2 fusion and wild-type models. CA3 was associated with on-target decreases in YAP-TEAD target gene expression, TEAD reporter activity, and overall TEAD levels. Hippo pathway signaling was not altered as there was no change in YAP phosphorylation status in the cells exposed to CA3. RNA sequencing of gastric cancer and CCA models demonstrated upregulation of an androgen receptor-mediated transcriptional program following exposure to CA3 in five unique models tested. Consistent with this upstream regulator analysis, CA3 exposure in CCA cells was associated with increased AR protein levels, and combinatorial therapy with CA3 and androgen receptor blockade was associated with increased cancer cell death. CA3 behaves functionally as a YAP-TEAD disrupter in the models tested and demonstrated therapeutic efficacy. Exposure to CA3 was associated with compensatory androgen receptor signaling and dual inhibition improved the therapeutic effect.

Metabolome-wide association identifies altered metabolites and metabolic pathways in the serum of patients with cholangiocarcinoma.

Background & Aims: Metabolomic and lipidomic analyses provide an opportunity for novel biological insights. Cholangiocarcinoma (CCA) remains a highly lethal cancer with limited response to systemic, targeted, and immunotherapeutic approaches. Using a global metabolomics and lipidomics platform, this study aimed to discover and characterize metabolomic variations and associated pathway derangements in patients with CCA. Methods: Leveraging a biospecimen collection, including samples from patients with digestive diseases and normal controls, global serum metabolomic and lipidomic profiling was performed on 213 patients with CCA and 98 healthy controls. The CCA cohort of patients included representation of intrahepatic, perihilar, and distal CCA tumours. Metabolome-wide association studies utilizing multivariable linear regression were used to perform case-control comparisons, followed by pathway enrichment analysis, CCA subtype analysis, and disease stage analysis. The impact of biliary obstruction was evaluated by repeating analyses in subsets of patients only with normal bilirubin levels. Results: Of the 420 metabolites that discriminated patients with CCA from controls, decreased abundance of cysteine-glutathione disulfide was most closely associated with CCA. Additional conjugated bile acid species were found in increased abundance even in the absence of clinically relevant biliary obstruction denoted by elevated serum bilirubin levels. Pathway enrichment analysis also revealed alterations in caffeine metabolism and mitochondrial redox-associated pathways in the serum of patients with CCA. Conclusions: The presented metabolomic and lipidomic profiling demonstrated multiple alterations in the serum of patients with CCA. These exploratory data highlight novel metabolic pathways in CCA and support future work in therapeutic targeting of these pathways and the development of a precision biomarker panel for diagnosis. Impact and implications: Cholangiocarcinoma (CCA) is a highly lethal hepatobiliary cancer with limited treatment response, highlighting the need for a better understanding of the disease biology. Using a global metabolomics and lipidomics platform, we characterized distinct changes in the serum of 213 patients with CCA compared with healthy controls. The results of this study elucidate novel metabolic pathways in CCA. These findings benefit stakeholders in both the clinical and research realms by providing a foundation for improved disease diagnostics and identifying novel targets for therapeutic design.

Combined Antitumor Effect of the Serine Protease Urokinase Inhibitor Upamostat and the Sphingosine Kinase 2 Inhibitor Opaganib on Cholangiocarcinoma Patient-Derived Xenografts.

Upamostat is an orally available small-molecule serine protease inhibitor that is a highly potent inhibitor of trypsin 1, trypsin 2, trypsin 3 (PRSS1/2/3), and the urokinase-type plasminogen activator (uPA). These enzymes are expressed in many cancers, especially during tissue remodeling and subsequent tumor cell invasion. Opaganib (ABC294640), a novel, orally available small molecule is a selective inhibitor of the phosphorylation of sphingosine to sphingosine-1-phosphate (S-1-P) by sphingosine kinase 2 (SPHK2). Both sphingosine kinase 1 (SPHK1) and SPHK2 are known to regulate the proliferation-inducing compound S-1-P. However, SPHK2 is more critical in cancer pathogenesis. The goal of this project was to investigate the potential antitumor effects of upamostat and opaganib, individually and in combination, on cholangiocarcinoma (CCA) xenografts in nude mice. PAX165, a patient-derived xenograft (PDX) from a surgically resected CCA, expresses substantial levels of SPHK2, PRSS1, PRSS2, and PRSS3. Four groups of 18 mice each were treated with upamostat, opaganib, both, or vehicle. Mouse weights and PAX165 tumor volumes were measured. Tumor volumes in the upamostat, opaganib, and upamostat plus opaganib groups were significantly decreased compared to the control group.

Euglycemic diabetic ketoacidosis in a pregnant woman.

Background: Euglycemic diabetic ketoacidosis (EDKA) carries serious risks for mortality and morbidity for both the mother and the baby, and it is essential to recognize it early and start immediate treatment. Case Presentation: We present a case of EDKA in a 28-week pregnant woman known to have type 1 diabetes. She was found to have severe acidosis with a blood sugar level of 10.6 mmol/L (190.8 mg/dL) and normal anion gap. She was found to have EDKA, which was confirmed later with a depressed venous pH and bicarbonate level and an increased serum ketone level. The patient's acidosis was not improving significantly with 0.05 units/kg/h of insulin infusion, so a full dose of 0.1 unit/kg/h of insulin infusion was started following a full diabetic ketoacidosis (DKA) protocol regardless of her blood sugar level. The patient showed gradual improvement and was discharged home after 4 days, with follow-up with endocrinology and obstetrics. Conclusion: In conclusion, EDKA is a critical complication of diabetes, especially in pregnant women. Therefore, it is crucial to treat it early and potentially consider following a full DKA protocol using 0.1 unit/kg/h insulin infusion instead of 0.05 unit/kg/h.