Cervical orthosis does not improve postoperative pain following posterior cervical fusion: a randomized controlled trial.

PURPOSE: To determine whether postoperative neck pain in the first 4 weeks following multi-level posterior cervical fusion (PCF) with orthosis is equivalent to multi-level PCF without orthosis. METHODS: Patients were randomly assigned in a 1:1 ratio to postoperative orthosis (CO) for 6 weeks or no orthosis (NO). Randomization was stratified by indication (traumatic vs. degenerative), and preoperative opioid use. A model of longitudinal regression for repeated measures was used. The two-sided 95% confidence interval (CI) was used to test equivalence. If the CI lay between the pre-determined margin of equivalence (-2.0 to + 2.0 pain score) the two groups were considered equivalent. A multiple imputation procedure was used to replace missing data. RESULTS: Thirty-one patients were enrolled in each group. At baseline, the CO group had more neck pain (5.3 vs. 3.2, p = 0.013). The Four week post-operative neck pain intensity score was 4.6 ± 0.3 for the CO group vs. 4.9 ± 0.3 for the NO group. The 95% confidence interval (-1.2 to 0.6) was within the pre-determined equivalence margin. Neck Disability Index, quality-of-life scores, and arm pain were similar. Eleven patients in the CO group and 12 patients in the NO group had an adverse event. The CO group had reduced range of motion at 6 weeks. CONCLUSION: Pain scores over the first 4 weeks after surgery were equivalent for patients undergoing multi-level PCF treated with or without a cervical orthosis. Our findings do not support the routine use of a postoperative cervical orthosis for postoperative pain control. Clinical Trials Registration Number NCT04308122, April 22, 2020.

Circadian disruption, clock genes, and metabolic health.

A growing body of research has identified circadian-rhythm disruption as a risk factor for metabolic health. However, the underlying biological basis remains complex, and complete molecular mechanisms are unknown. There is emerging evidence from animal and human research to suggest that the expression of core circadian genes, such as circadian locomotor output cycles kaput gene (CLOCK), brain and muscle ARNT-Like 1 gene (BMAL1), period (PER), and cyptochrome (CRY), and the consequent expression of hundreds of circadian output genes are integral to the regulation of cellular metabolism. These circadian mechanisms represent potential pathophysiological pathways linking circadian disruption to adverse metabolic health outcomes, including obesity, metabolic syndrome, and type 2 diabetes. Here, we aim to summarize select evidence from in vivo animal models and compare these results with epidemiologic research findings to advance understanding of existing foundational evidence and potential mechanistic links between circadian disruption and altered clock gene expression contributions to metabolic health-related pathologies. Findings have important implications for the treatment, prevention, and control of metabolic pathologies underlying leading causes of death and disability, including diabetes, cardiovascular disease, and cancer.

Understanding futility in pancreaticoduodenectomy: Insights from a national cohort.

BACKGROUND AND OBJECTIVES: Pancreaticoduodenectomy (PD), the only surgical option for right-sided pancreatic ductal adenocarcinoma (PDAC), carries significant morbidity. Not all patients may be deriving a survival benefit from this operation. We sought to identify the rate of futile PD and its associated factors in a large national cohort. METHODS: We performed a retrospective analysis using the National Cancer Database (2004-2020), including all patients who underwent PD for non-metastatic PDAC. The primary outcome was operative futility, which was defined as death within 12 months of diagnosis despite PD. Multivariable regression was used to identify factors associated with futility. We performed a subgroup analysis on patients who received neoadjuvant systemic therapy. RESULTS: Data from 66 326 patients were analyzed, and 16 772 (25.3%) underwent PD that met criteria for futility. Macroscopically positive margins (odds ratio [OR]: 2.87; 95% confidence interval [CI]: 2.36-3.48), poor tumor differentiation (OR: 2.44; 95% CI: 2.25-2.65), and N2 nodal stage (OR: 2.09; 95% CI: 1.98-2.20) were associated with the greatest odds of futility. Meanwhile, receipt of any systemic therapy (OR: 0.33; 95% CI: 0.31-0.34), receipt of any radiation (OR: 0.60; 95% CI: 0.57-0.63), and receipt of neoadjuvant systemic therapy (OR: 0.62; 95% CI: 0.57-0.66) were associated with the lowest odds of futility. In the neoadjuvant subgroup, a longer diagnosis-to-surgery interval was associated with lower odds of futility. CONCLUSION: PD was futile in about one quarter of patients. Futility was associated with higher age and worse tumor biology. Receipt of neoadjuvant therapy resulted in fewer futile operations.

Diverse mechanisms by which chemical pollutant exposure alters gut microbiota metabolism and inflammation.

The human gut microbiome, the host, and the environment are inextricably linked across the life course with significant health impacts. Consisting of trillions of bacteria, fungi, viruses, and other micro-organisms, microbiota living within our gut are particularly dynamic and responsible for digestion and metabolism of diverse classes of ingested chemical pollutants. Exposure to chemical pollutants not only in early life but throughout growth and into adulthood can alter human hosts' ability to absorb and metabolize xenobiotics, nutrients, and other components critical to health and longevity. Inflammation is a common mechanism underlying multiple environmentally related chronic conditions, including cardiovascular disease, multiple cancer types, and mental health. While growing research supports complex interactions between pollutants and the gut microbiome, significant gaps exist. Few reviews provide descriptions of the complex mechanisms by which chemical pollutants interact with the host microbiome through either direct or indirect pathways to alter disease risk, with a particular focus on inflammatory pathways. This review focuses on examples of several classes of pollutants commonly ingested by humans, including (i) heavy metals, (ii) persistent organic pollutants (POPs), and (iii) nitrates. Digestive enzymes and gut microbes are the first line of absorption and metabolism of these chemicals, and gut microbes have been shown to alter compounds from a less to more toxic state influencing subsequent distribution and excretion. In addition, chemical pollutants may interact with or alter the selection of more harmful and less commensal microbiota, leading to gut dysbiosis, and changes in receptor-mediated signaling pathways that alter the integrity and function of the gut intestinal tract. Arsenic, cadmium, and lead (heavy metals), influence the microbiome directly by altering different classes of bacteria, and subsequently driving inflammation through metabolite production and different signaling pathways (LPS/TLR4 or proteoglycan/TLR2 pathways). POPs can alter gut microbial composition either directly or indirectly depending on their ability to activate key signaling pathways within the intestine (e.g., PCB-126 and AHR). Nitrates and nitrites' effect on the gut and host may depend on their ability to be transformed to secondary and tertiary metabolites by gut bacteria. Future research should continue to support foundational research both in vitro, in vivo, and longitudinal population-based research to better identify opportunities for prevention, gain additional mechanistic insights into the complex interactions between environmental pollutants and the microbiome and support additional translational science.

Aryl Hydrocarbon Receptor Knockout Accelerates PanIN Formation and Fibro-Inflammation in a Mutant Kras -Driven Pancreatic Cancer Model.

OBJECTIVES: The pathogenesis of pancreas cancer (PDAC) remains poorly understood, hindering efforts to develop a more effective therapy for PDAC. Recent discoveries show the aryl hydrocarbon receptor (AHR) plays a crucial role in the development of several cancers and can be targeted for therapeutic effect. However, its involvement in the pathogenesis of PDAC remains unclear. To address this gap, we evaluated the role of AHR in the development of PDAC precancerous lesions in vivo . MATERIALS AND METHODS: We created a global AHR-null, mutant Kras -driven PDAC mouse model (A -/- KC) and evaluated the changes in PDAC precursor lesion formation (PanIN-1, 2, and 3) and associated fibro-inflammation between KC and A -/- KC at 5 months of age. We then examined the changes in the immune microenvironment followed by single-cell RNA-sequencing analysis to evaluate concomitant transcriptomic changes. RESULTS: We identified a significant increase in PanIN-1 lesion formation and PanIN-1 associated fibro-inflammatory infiltrate in A -/- KC versus KC mice. This was associated with significant changes in the adaptive immune system, particularly a decrease in the CD4+/CD8+ T-cell ratio, as well as a decrease in the T-regulatory/Th17 T-cell ratio suggesting unregulated inflammation. CONCLUSIONS: These findings show the loss of AHR results in heightened Kras -induced PanIN formation, through modulation of immune cells within the pancreatic tumor microenvironment.

DNAJB1-PRKACA fusion protein-regulated LINC00473 promotes tumor growth and alters mitochondrial fitness in fibrolamellar carcinoma.

Fibrolamellar carcinoma (FLC) is a rare liver cancer that disproportionately affects adolescents and young adults. Currently, no standard of care is available and there remains a dire need for new therapeutics. Most patients harbor the fusion oncogene DNAJB1-PRKACA (DP fusion), but clinical inhibitors are not yet developed and it is critical to identify downstream mediators of FLC pathogenesis. Here, we identify long noncoding RNA LINC00473 among the most highly upregulated genes in FLC tumors and determine that it is strongly suppressed by RNAi-mediated inhibition of the DP fusion in FLC tumor epithelial cells. We show by loss- and gain-of-function studies that LINC00473 suppresses apoptosis, increases the expression of FLC marker genes, and promotes FLC growth in cell-based and in vivo disease models. Mechanistically, LINC00473 plays an important role in promoting glycolysis and altering mitochondrial activity. Specifically, LINC00473 knockdown leads to increased spare respiratory capacity, which indicates mitochondrial fitness. Overall, we propose that LINC00473 could be a viable target for this devastating disease.

Nanodrug-bacteria conjugates-mediated oncogenic collagen depletion enhances immune checkpoint blockade therapy against pancreatic cancer.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) cancer cells specifically produce abnormal oncogenic collagen to bind with integrin α3ß1 receptor and activate the downstream focal adhesion kinase (FAK), protein kinase B (AKT), and mitogen-activated protein kinase (MAPK) signaling pathway. Collectively, this promotes immunosuppression and tumor proliferation and restricts the response rate of clinical cancer immunotherapies. METHODS: Here, by leveraging the hypoxia tropism and excellent motility of the probiotic Escherichia coli strain Nissle 1917 (ECN), we developed nanodrug-bacteria conjugates to penetrate the extracellular matrix (ECM) and shuttle the surface-conjugated protein cages composed of collagenases and anti-programmed death-ligand 1 (PD-L1) antibodies to PDAC tumor parenchyma. FINDINGS: We found the oncogenic collagen expression in human pancreatic cancer patients and demonstrated its interaction with integrin α3ß1. We proved that reactive oxygen species (ROS) in the microenvironment of PDAC triggered collagenase release to degrade oncogenic collagen and block integrin α3ß1-FAK signaling pathway, thus overcoming the immunosuppression and synergizing with anti-PD-L1 immunotherapy. CONCLUSIONS: Collectively, our study highlights the significance of oncogenic collagen in PDAC immunotherapy, and consequently, we developed a therapeutic strategy that can deplete oncogenic collagen to synergize with immune checkpoint blockade for enhanced PDAC treatment efficacy. FUNDING: This work was supported by the University of Wisconsin Carbone Cancer Center Research Collaborative and Pancreas Cancer Research Task Force, UWCCC Transdisciplinary Cancer Immunology-Immunotherapy Pilot Project, and the start-up package from the University of Wisconsin-Madison (to Q.H.).

Hidroadenocarcinoma Mimicking Epidermal Inclusion Cyst of the Palm.

Hidradenocarcinoma is a rare malignant tumor of sweat glands of the skin that has been reported several times in the hand. We report a case of hidradenocarcinoma of the palm in a 55-year-old woman that presented as a painless volar hand mass. A staged rotational forearm flap was used after resection.

Single-cell RNA sequencing of neurofibromas reveals a tumor microenvironment favorable for neural regeneration and immune suppression in a neurofibromatosis type 1 porcine model.

Neurofibromatosis Type 1 (NF1) is one of the most common genetically inherited disorders that affects 1 in 3000 children annually. Clinical manifestations vary widely but nearly always include the development of cutaneous, plexiform and diffuse neurofibromas that are managed over many years. Recent single-cell transcriptomics profiling efforts of neurofibromas have begun to reveal cell signaling processes. However, the cell signaling networks in mature, non-cutaneous neurofibromas remain unexplored. Here, we present insights into the cellular composition and signaling within mature neurofibromas, contrasting with normal adjacent tissue, in a porcine model of NF1 using single-cell RNA sequencing (scRNA-seq) analysis and histopathological characterization. These neurofibromas exhibited classic diffuse-type histologic morphology and expected patterns of S100, SOX10, GFAP, and CD34 immunohistochemistry. The porcine mature neurofibromas closely resemble human neurofibromas histologically and contain all known cellular components of their human counterparts. The scRNA-seq confirmed the presence of all expected cell types within these neurofibromas and identified novel populations of fibroblasts and immune cells, which may contribute to the tumor microenvironment by suppressing inflammation, promoting M2 macrophage polarization, increasing fibrosis, and driving the proliferation of Schwann cells. Notably, we identified tumor-associated IDO1 +/CD274+ (PD-L1) + dendritic cells, which represent the first such observation in any NF1 animal model and suggest the role of the upregulation of immune checkpoints in mature neurofibromas. Finally, we observed that cell types in the tumor microenvironment are poised to promote immune evasion, extracellular matrix reconstruction, and nerve regeneration.

Management of limb length discrepancy after bone sarcoma resection about the knee in the skeletally immature.

Patients with bone sarcomas increasingly choose limb salvage. This can lead to issues with limb length discrepancy (LLD) for the skeletally immature. We synthesize management options into an algorithm and report our results. Patients with bone sarcomas involving any location from the femoral diaphysis to the tibial diaphysis 12 years or younger were reviewed. Our clinical pathway prescribed patients with metadiaphyseal lesions to intercalary allograft reconstruction, epiphyseal lesions and less than 5 cm expected LLD to osteoarticular allograft and patients with more than 5 cm expected LLD to extendable prosthesis. Twenty patients met inclusion criteria: 11 with osteoarticular allografts, 5 with extendable prostheses and 4 with intercalary allografts; median age 11.5 years; median follow-up 8.2 years; and final median LLD 1.6 cm. Five patients had contralateral epiphysiodesis, two patients underwent contralateral femoral shortening and a median of 6 (range 4-8) lengthenings were performed for extendable prostheses. Four patients had residual LLD over 3 cm. There were 13 revisions in 8 patients and 2 amputations. Limb-salvage in paediatric bone sarcoma of the knee can be managed with multiple techniques producing satisfactory results in regards to LLD. Careful pre-operative planning and shared decision making is a requisite given the high rate of secondary procedures for both LLD and reconstructive failures. Level of evidence: Level III Retrospective Comparative Study.

Occipital Nocardia Abscess Presenting With Positive Visual Phenomenon and Quadrantanopsia.

ABSTRACT: A 74-year-old man with chronic obstructive pulmonary disease, glaucoma, and Stage IIIB squamous cell lung cancer experienced several minutes of flashing lights in his right visual hemifield, followed by onset of a right visual field defect. On examination, the patient had a right homonymous hemianopsia that was most dense inferiorly by confrontation testing. Emergent CT scan of the head revealed a 2.5 × 3 cm hypodensity in the left occipital lobe, which was interpreted as an acute stroke. Continuous EEG monitoring captured left posterior quadrant seizures that were temporally correlated to the positive visual phenomena. Subsequent MRI of the brain with and without contrast revealed a conglomerate of centrally necrotic and peripherally enhancing mass lesions. On biopsy, a thick purulent material was drained and Gram stain of the sample revealed gram-positive beaded rods, which speciated to Nocardia farcinica . The patient was treated with a six-week course of intravenous meropenem and a one-year course of oral trimethroprim-sulfamethoxazole. On follow-up, the patient experienced resolution of the right visual field deficit.

NCCN Guidelines® Insights: Biliary Tract Cancers, Version 2.2023.

In 2023, the NCCN Guidelines for Hepatobiliary Cancers were divided into 2 separate guidelines: Hepatocellular Carcinoma and Biliary Tract Cancers. The NCCN Guidelines for Biliary Tract Cancers provide recommendations for the evaluation and comprehensive care of patients with gallbladder cancer, intrahepatic cholangiocarcinoma, and extrahepatic cholangiocarcinoma. The multidisciplinary panel of experts meets at least on an annual basis to review requests from internal and external entities as well as to evaluate new data on current and emerging therapies. These Guidelines Insights focus on some of the recent updates to the NCCN Guidelines for Biliary Tract Cancers as well as the newly published section on principles of molecular testing.

The circadian clock is disrupted in pancreatic cancer.

Disruption of the circadian clock is linked to cancer development and progression. Establishing this connection has proven beneficial for understanding cancer pathogenesis, determining prognosis, and uncovering novel therapeutic targets. However, barriers to characterizing the circadian clock in human pancreas and human pancreatic cancer-one of the deadliest malignancies-have hindered an appreciation of its role in this cancer. Here, we employed normalized coefficient of variation (nCV) and clock correlation analysis in human population-level data to determine the functioning of the circadian clock in pancreas cancer and adjacent normal tissue. We found a substantially attenuated clock in the pancreatic cancer tissue. Then we exploited our existing mouse pancreatic transcriptome data to perform an analysis of the human normal and pancreas cancer samples using a machine learning method, cyclic ordering by periodic structure (CYCLOPS). Through CYCLOPS ordering, we confirmed the nCV and clock correlation findings of an intact circadian clock in normal pancreas with robust cycling of several core clock genes. However, in pancreas cancer, there was a loss of rhythmicity of many core clock genes with an inability to effectively order the cancer samples, providing substantive evidence of a dysregulated clock. The implications of clock disruption were further assessed with a Bmal1 knockout pancreas cancer model, which revealed that an arrhythmic clock caused accelerated cancer growth and worse survival, accompanied by chemoresistance and enrichment of key cancer-related pathways. These findings provide strong evidence for clock disruption in human pancreas cancer and demonstrate a link between circadian disruption and pancreas cancer progression.

Titanium vs. carbon fiber-reinforced intramedullary nailing for humeral bone tumors.

BACKGROUND: Multiple techniques have been described to treat humeral diaphyseal bone tumors requiring curettage or excision. Recent studies have suggested that carbon fiber-reinforced polyetheretherketone (CFR-PEEK) intramedullary nails (IMNs) may be preferable to titanium IMNs for patients with musculoskeletal tumors due to CFR-PEEK's high tensile strength, radiolucency, a modulus of elasticity closer to native bone, and improved postoperative surveillance/radiation dosing. In this study, we describe the rate of fixation failure for both CFR-PEEK and titanium humeral IMNs when used for humeral diaphyseal bone tumors requiring curettage or excision. METHODS: This was a single-institution retrospective cohort study including 81 patients (27 CFR-PEEK and 54 titanium) treated for a humeral diaphyseal bone tumor using an IMN ± methylmethacrylate between January 2017 and December 2022. Primary outcome was revision surgery due to soft tissue complications, nonunions, structural complications such as periprosthetic fracture or IMN breakage, periprosthetic infection, tumor progression, and implant failure due to rejection or fatigue. RESULTS: No failures were observed in either patients treated with titanium nails or patients treated with CFR-PEEK not requiring curettage. Fixation failure due to implant failure was observed in 2 cases-at 214 days and 469 days after surgery-where CFR-PEEK IMN was used for stabilization after a wide segmental resection for oncologic control with a cement spacer reconstruction. In both cases, the resection was larger than 6 cm, the remaining distal humerus was less than 5 cm, and failures occurred at the interface of the residual bone and spacer. Both patients were revised using a titanium distal posterolateral humeral plate fixed with screws and cables without any subsequent complications. One additional CFR-PEEK IMN required revision surgery after 744 days due to progression of the tumor and subsequent nonunion. One revision surgery was observed after 63 days for the titanium IMN because of nonunion and tumor progression. CONCLUSIONS: Humeral diaphyseal bone tumors requiring large segmental resection with small residual bone and a large cement spacer may fail via tension due to bending forces at the distal portion. In this clinical scenario, the use of larger-diameter CFR-PEEK IMNs may be indicated when available. In the interim, use of intercalary allografts instead of cement spacers, additional fixation with a titanium plate distally, or the use of a titanium nail when using a cement spacer may be considered.

Critical Review of Oncologic Medical Malpractice Claims Against Orthopaedic Surgeons.

INTRODUCTION: The purpose of this study was to determine the most common allegations for malpractice litigation brought against orthopaedic surgeons for oncologic matters and the resulting verdicts. METHODS: The Westlaw Legal research database was queried for malpractice cases filed against orthopaedic surgeons for oncologic matters in the United States after 1980. Plaintiff demographics, state of filing, allegations, and outcomes of lawsuits were recorded and reported accordingly. RESULTS: A total of 36 cases met the inclusion and exclusion criteria and were subsequently included in the final analysis. The overall rate of cases filed remained consistent through the past four decades and was primarily related to a primary sarcoma diagnosis in adult women. The primary reason for litigation was failure to diagnose a primary malignant sarcoma (42%) followed by failure to diagnose unrelated carcinoma (19%). The most common states of filing were primarily located in the Northeast (47%), where a plaintiff verdict was also more commonly encountered as compared with other regions. Damages awarded averaged $1,672,500 with a range of $134, 231 to $6,250,000 and a median of $918,750. CONCLUSION: Failure to diagnose primary malignant sarcoma and unrelated carcinoma was the most common reason for oncologic litigation brought against orthopaedic surgeons. Although most of the cases ruled in favor of the defendant surgeon, it is important for orthopaedic surgeons to be aware of the potential errors that not only prevent litigation but also improve patient care.

Pdx1 expression in hematopoietic cells activates Kras-mutation to drive leukemia in KC (Pdx1-Cre; LSL-KrasG12D/+) mice.

The highly utilized KC model has a reported lethality rate of about 30%, which has been attributed to pancreas cancer. However, a competing cause of lethality in KC mice is due to the activation of mutant-Kras gene (KrasG12D/+) in the multipotent progenitor cells (MPP), and subsequent development of Kras-mutant T-cell acute lymphoblastic leukemia (T-ALL). Overall, 20% (5/25) of KC mice developed T-ALL by 9 months of age. Transplantation of pooled bone marrow from KC mice into CD45 congenic mice caused T-ALL in 100% of recipient mice, confirming that mutant-Kras expression in the hematologic compartment is driving the development of T-ALL in the KC mouse model. These results are an essential consideration for investigators using this model. Further, the lower penetrance of T-ALL in KC mice (versus existing leukemia models) suggests this model could be considered as an alternative research model to evaluate onset and factors that exacerbate the development of T-ALL.

Soluble TNF mediates amyloid-independent, diet-induced alterations to immune and neuronal functions in an Alzheimer's disease mouse model.

Introduction: Increasing evidence indicates that neurodegenerative diseases, including Alzheimer's disease (AD), are a product of gene-by-environment interplay. The immune system is a major contributor mediating these interactions. Signaling between peripheral immune cells and those within the microvasculature and meninges of the central nervous system (CNS), at the blood-brain barrier, and in the gut likely plays an important role in AD. The cytokine tumor necrosis factor (TNF) is elevated in AD patients, regulates brain and gut barrier permeability, and is produced by central and peripheral immune cells. Our group previously reported that soluble TNF (sTNF) modulates cytokine and chemokine cascades that regulate peripheral immune cell traffic to the brain in young 5xFAD female mice, and in separate studies that a diet high in fat and sugar (HFHS) dysregulates signaling pathways that trigger sTNF-dependent immune and metabolic responses that can result in metabolic syndrome, which is a risk factor for AD. We hypothesized that sTNF is a key mediator of peripheral immune cell contributions to gene-by-environment interactions to AD-like pathology, metabolic dysfunction, and diet-induced gut dysbiosis. Methods: Female 5xFAD mice were subjected to HFHS diet for 2 months and then given XPro1595 to inhibit sTNF for the last month or saline vehicle. We quantified immune cell profiles by multi-color flow cytometry on cells isolated from brain and blood; metabolic, immune, and inflammatory mRNA and protein marker biochemical and immunhistological analyses, gut microbiome, and electrophysiology in brain slices were also performed. Results: Here, we show that selective inhibition of sTNF signaling via the biologic XPro1595 modulates the effects of an HFHS diet in 5xFAD mice on peripheral and central immune profiles including CNS-associated CD8+ T cells, the composition of gut microbiota, and long-term potentiation deficits. Discussion: Obesogenic diet induces immune and neuronal dysfunction in 5xFAD mice and sTNF inhibition mitigates its effects. A clinical trial in subjects at risk for AD due to genetic predisposition and underlying inflammation associated with peripheral inflammatory co-morbidities will be needed to investigate the extent to which these findings translate to the clinic.

Chronic jetlag accelerates pancreatic neoplasia in conditional Kras-mutant mice.

Misalignment of the circadian clock compared to environmental cues causes circadian desynchrony, which is pervasive in humans. Clock misalignment can lead to various pathologies including obesity and diabetes, both of which are associated with pancreatic ductal adenocarcinoma - a devastating cancer with an 80% five-year mortality rate. Although circadian desynchrony is associated with an increased risk of several solid-organ cancers, the correlation between clock misalignment and pancreas cancer is unclear. Using a chronic jetlag model, we investigated the impact of clock misalignment on pancreas cancer initiation in mice harboring a pancreas-specific activated Kras mutation. We found that chronic jetlag accelerated the development of pancreatic cancer precursor lesions, with a concomitant increase in precursor lesion grade. Cell-autonomous knock-out of the clock in pancreatic epithelial cells of Kras-mutant mice demonstrated no acceleration of precursor lesion formation, indicating non-cell-autonomous clock dysfunction was responsible for the expedited tumor development. Therefore, we applied single-cell RNA sequencing over time and identified fibroblasts as the cell population manifesting the greatest clock-dependent changes, with enrichment of specific cancer-associated fibroblast pathways due to circadian misalignment.