Skeletal muscle atrophy is a devastating and defining feature of cancer cachexia that reduces quality of life, treatment tolerance, and survival, but cannot be prevented or reversed by current management strategies. Ursolic acid is a natural dietary compound that has been shown to inhibit atrophy-associated changes in skeletal muscle mRNA expression in rodents and dogs, leading to beneficial changes in skeletal muscle structure and function. We hypothesized that dietary supplementation with ursolic acid might help support skeletal muscle mass and function during cancer. To test this hypothesis, we investigated ursolic acid's effects in five in vivo mouse models of cancer cachexia that are driven by pancreatic, colon, and lung cancer cells of mouse and human origin. We found that dietary supplementation with ursolic acid has broad-spectrum effects toward cancer-induced skeletal muscle atrophy, significantly preserving muscle mass in all five cancer cachexia models. Ursolic acid's positive effects on muscle mass and muscle fiber size led to significant improvements in grip strength and muscle tetanic force, persisted in the presence of chemotherapy, and were not associated with discernible changes in food intake or tumor growth. Ursolic acid appeared to generate its beneficial effects in skeletal muscle by acting directly on muscle cells, inhibiting catabolic effects of tumor-derived secreted factors, and inhibiting >90% of cancer-induced changes in skeletal muscle mRNA expression. These results strongly nominate ursolic acid as a promising potential nutritional approach for supporting muscle mass and function in individuals with cancer. NEW & NOTEWORTHY Cancer-induced muscle wasting affects many people with cancer, reducing treatment tolerance and survival. We identified a natural dietary compound, ursolic acid, that attenuates muscle atrophy across five preclinical cancer models spanning pancreatic, colon, and lung cancer. Ursolic acid inhibits cancer-induced changes in muscle mRNA expression, preserves muscle strength, and remains protective during chemotherapy, without affecting food intake or tumor burden. These results identify ursolic acid as a promising, translatable dietary supplement for supportive cancer care.

To the Editor: There have been many mentors on my academic journey, but I am writing today to express my gratitude for a rather unconventional guide: my undergraduate piano professor. My medical and scientific training has required a delicate balance between scientific rigor and clinical empathy, a balance I will continue to develop throughout life. Notwithstanding, my experiences at a conservatory-style music college provided an insightful framework with which to approach these challenges in a creative and penetrating manner. I worked with my piano professor for more than 3 years. Together, we studied countless cornerstones of the repertoire. Her mentorship went beyond mastering a musical piece: it involved dissecting a composition's heart and exploring its historical context, composer's perspective, and motifs. Her approach required me to scrutinize details, question common assumptions, and continuously strive for a deeper understanding. This culminated in art. Her reflective and critical approach significantly influenced my perspective in both medicine and research, fostering a culture of innovation, problem-solving, and patient-centered care.1 In my research, I found this ability to conceptualize a topic to be an invaluable asset. Through the lens of a pianist, I learned to appreciate the symphony of signaling in disease pathophysiology, with each element playing its part in the seeming cacophony of aberrant biology. Peering into the "score"—into the histology, the omics, the outcomes, etc.—has allowed me to approach complex medical issues with a multifaceted perspective that always raises more questions, hopefully pointing toward answers that guide patient care in new directions. The deep emotional connection formed with each musical piece has also translated into a unique approach toward patients. Just as the subtle black-and-white code of the eighth notes conveys feelings with interrogation, so does a metabolic panel or a computed tomography scan. The objective measures of our science and art need to be contextualized within the patient's emotions, struggles, and hopes to be provided with effective care. With the rise of interdisciplinary training in medicine, I believe that dynamic mentors from various fields can enrich our training. Their insight can help mold physicians and scientists to approach problems creatively and understand patients empathetically. I urge educators and mentors to broaden their horizons, but the greatest onus lies on learners: expect the unexpected and do not be afraid to look for guidance from novel sources. The piano bench may appear worlds removed from the laboratory bench or the bedside, but the lessons learned are universally applicable and profoundly impactful. Miles E. Cameron, PhDMD-PhD trainee, University of Florida College of Medicine, Gainesville, Florida; email: [email protected]; ORCID: https://orcid.org/0000-0003-0996-3754

BACKGROUND:Sixty percent of patients with esophageal cancer display signs of cachexia at diagnosis. Changes in body composition are common, and muscle mass and quality are measurable through imaging studies. Cachexia leads to functional impairments that complicate treatments, including surgery. We hypothesize that low muscle mass and quality associate with pulmonary function testing parameters, highlighting ventilatory deficits, and postoperative complications in patients receiving esophagectomy. STUDY DESIGN:We performed a retrospective review of patients receiving esophagectomy between 2012 and 2021 at our facility. PET/CT scans were used to quantify skeletal muscle at the L3 and T4 levels. Patient characteristics were recorded, including pulmonary function testing parameters. Regression models were created to characterize predictive associations. RESULTS:One hundred eight patients were identified. All were included in the final analysis. In linear regression adjusted for sex, age, and COPD status, low L3 muscle mass independently associated with low forced vital capacity (p < 0.005, β 0.354) and forced expiratory volume in 1 second (p < 0.001, β 0.392). Similarly, T4 muscle mass independently predicted forced vital capacity (p < 0.005, β 0.524) and forced expiratory volume in 1 second (p < 0.01, β 0.480). L3 muscle quality correlated with total lung capacity ( R 0.2463, p < 0.05). Twenty-six patients had pleural effusions postoperatively, associated with low muscle quality on L3 images (p < 0.05). Similarly, patients with hospitalization more than 2 weeks presented with lower muscle quality (p < 0.005). CONCLUSIONS:Cachexia and low muscle mass are common. Reduced muscle mass and quality independently associate with impaired forced vital capacity, forced expiratory volume in 1 second, and total lung capacity. We propose that respiratory muscle atrophy occurs with weight loss. Body composition analyses may aid in stratifying patients. Pulmonary function testing may also serve as a functional endpoint for clinical trials. These findings highlight the need to study mechanisms that lead to respiratory muscle pathology and dysfunction in tumor-bearing hosts.

Abstract Background Changes in body composition are common in esophageal cancer (EC). A majority of patients, regardless of stage, display signs of cachexia, including weight loss, skeletal and cardiac muscle atrophy and fat wasting. Bone loss is also common in cancer, secondary to shared signaling pathways that contribute to lean body loss. In this study, we hypothesized that bone density decreases progressively in patients with EC and that the continued loss of bone associated with oncologic outcomes. Methods We performed a retrospective review of all patients that received esophagectomy between 2012 and 2020 at our facility. Body composition was measured using PET/CT scans, and patients were classified by muscle mass according to sex- and BMI-dependent cutoffs. Bone density was measured by determining the radiation attenuation of the lumbar (L1-L5) vertebral bodies. The change in bone density was normalized by time and compared to tumor pathologic variables. A p-value less than 0.05 was considered statistically significant. Results Bone density was significantly reduced in patients with cachexia relative to those with appropriate muscle mass (108 ± 37.2 HU v. 146 ± 55.0 HU, p = 0.003). Furthermore, bone density correlated with muscle mass (p < 0.00001, R = 0.5055) and muscle quality/radiodensity (p = 0.0002, R = 0.4736). Mean rate of bone loss was −12.0 ± 27.9 HU/100d. Patients with regional lymph node metastases at surgery had more bone loss than those with N0 disease (−26.6 ± 30.8 HU/100d v. -2.71 ± 22.1 HU/100d, p = 0.03). Similarly, patients with positive lymphovascular invasion (−41.8 ± 32.6 HU/100d v. -3.53 ± 20.1 HU/100d, p = 0.005) and positive perineural invasion (−29.8 ± 32.4 HU/100d v. -3.12 ± 21.1 HU/100d, p = 0.01) progressively lost more bone. Conclusion Reduced bone mineral density is a key component of cachexia in patients with EC. We demonstrate herein that osteopenia in EC patients associates with several cachexia measures and that progressive loss of bone may predict early metastasis. Bone density may serve as a strong predictor of survival and stratification tool for clinical trials. These findings further highlight the need to study mechanisms that lead to bone wasting in tumor bearing hosts.

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Abstract Background Cachexia is a debilitating wasting syndrome affecting 60% of patients with esophageal cancer, regardless of stage. While cachexia is usually characterized by skeletal muscle atrophy, systemic inflammation and aberrant endocrine signaling is thought to also precipitate cardiac atrophy and dysfunction. Indeed, cachectic patients often display clinical signs of heart failure. In this initial study, we sought to characterize the relationships between weight loss, body composition and parameters of cardiac structure and function. Methods We performed a retrospective review of patients that received esophagectomy between 2015 and 2020 at our facility. Male patients with pre-operative transthoracic echocardiogram studies and no prior history of cardiac disease were included. Body composition was measured using PET/CT scans. Patients were classified as having cachexia if having more than 8% loss in body mass in the six months before surgery. Appropriate t-tests and correlational analyses were performed after assessing normality. A p-value less than 0.05 was considered statistically significant. Results Mean age was 65.8 ± 7.54 years. Mean six-month weight loss was 13.2%, and 65.4% of patients were classified as having cachexia. Patients with cachexia tended to have lower left ventricular mass (135 ± 7.38 g v. 148 ± 7.53 g, p = 0.2) and significantly lower left atrial diameter (3.32 ± 0.441 cm v. 4.47 ± 0.515 cm, p = 0.0261). Curiously, pre-operative weight loss positively correlated with left ventricular internal diameter end systole (R = 0.4521, p = 0.0204) and negatively correlated with diastolic blood pressure (R = -0.4102, p = 0.0417). When compared to segmented PET/CT scans, patients with increased deposition of adipose to muscle—a sign of pathologic remodeling—also had decreased left atrial diameter (R = 0.6497, p = 0.0222). Conclusions Various measures of heart structure and function are altered in cachectic patients with esophageal cancer. Patients were more weight loss have reduced left atrial and increased left ventricular diameters. These findings suggest that cardiac structure may dynamically change in response to cachexia. In summary, there is a profound need to better characterize the pathology of cardiac atrophy and dysfunction in patients with cachexia.

Pancreatic cancer is a deadly disease with limited diagnostic and treatment options. Not all populations are affected equally, as disparities exist in pancreatic cancer prevalence, treatment and outcomes. Recently, next-generation sequencing has facilitated a more comprehensive analysis of the human oral microbiome creating opportunity for its application in precision medicine. Oral microbial shifts occur in patients with pancreatic cancer, which may be appreciated years prior to their diagnosis. In addition, pathogenic bacteria common in the oral cavity have been found within pancreatic tumors. Despite these findings, much remains unknown about how or why the oral microbiome differs in patients with pancreatic cancer. As individuals develop, their oral microbiome reflects both their genotype and environmental influences. Genetics, race/ethnicity, smoking, socioeconomics and age affect the composition of the oral microbiota, which may ultimately play a role in pancreatic carcinogenesis. Multiple mechanisms have been proposed to explain the oral dysbiosis found in patients with pancreatic cancer though they have yet to be confirmed. With a better understanding of the interplay between the oral microbiome and pancreatic cancer, improved diagnostic and therapeutic approaches may be implemented to reduce healthcare disparities.

BACKGROUND Given the growing interest in using microRNAs (miRNAs) as biomarkers of early disease, establishment of robust protocols and platforms for miRNA quantification in biological fluids is critical. OBJECTIVE The goal of this multi-center pilot study was to evaluate the reproducibility of NanoString nCounter™ technology when analyzing the abundance of miRNAs in plasma and cystic fluid from patients with pancreatic lesions. METHODS Using sample triplicates analyzed across three study sites, we assessed potential sources of variability (RNA isolation, sample processing/ligation, hybridization, and lot-to-lot variability) that may contribute to suboptimal reproducibility of miRNA abundance when using nCounter™, and evaluated expression of positive and negative controls, housekeeping genes, spike-in genes, and miRNAs. RESULTS Positive controls showed a high correlation across samples from each site (median correlation coefficient, r> 0.9). Most negative control probes had expression levels below background. Housekeeping and spike-in genes each showed a similar distribution of expression and comparable pairwise correlation coefficients of replicate samples across sites. A total of 804 miRNAs showed a similar distribution of pairwise correlation coefficients between replicate samples (p= 0.93). After normalization and selecting miRNAs with expression levels above zero in 80% of samples, 55 miRNAs were identified; heatmap and principal component analysis revealed similar expression patterns and clustering in replicate samples. CONCLUSIONS Findings from this pilot investigation suggest the nCounter platform can yield reproducible results across study sites. This study underscores the importance of implementing quality control procedures when designing multi-center evaluations of miRNA abundance.

545 Background: Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of death in the United States. Treatment is difficult and often complicated by the presence of cachexia, a systemic wasting condition affecting most PDAC patients at diagnosis. Skeletal muscle atrophy is a hallmark of cachexia and predicts outcomes after surgery and chemotherapy. In this study, we sought to identify possible serum biomarkers of cachexia, which correlates with changes to lean body mass and survival, using an aptamer-based platform in patients with PDAC. We hypothesize that unique proteins associate with cachexia and survival measures. Methods: Using SomaScan we measured the serum levels of 4,006 proteins in 21 patients with PDAC undergoing curative surgery. Clinical data and anthropometric measurements derived from pre-operative CT imaging were compared to protein levels with Spearman correlational analyses and logistic regression. We then queried DAVID Bioinformatics database to identify enriched functional protein categories. Results: Mean age was 66.9 ± 8.91 years, and mean body-weight loss in the six months preceding diagnosis was 12.6 ± 8.80%. Using consensus guidelines considering percent weight loss and skeletal muscle mass and radiation attenuation, 10 subjects (46.7%) were defined as “cachectic.” We found 241 proteins significantly correlated to Cancer Weight Loss Grade (a composite measure of percent body weight loss and body mass index). High IDUA, CTLA4 and USE1, in particular, predicted the worst weight loss grade with 75% sensitivity and 92% specificity (AUC = 0.8894, odds ratio: 36, p = 0.0068). Four additional proteins significantly correlated with skeletal muscle index (CK-MM, CK-MB, PCOC2 and ADH4) while 13 proteins significantly correlated with muscle radiation attenuation. Lastly, we identified 18 proteins that significantly correlated with survival quartile. Of these, we found that elevated HS6ST2 and DEPP significantly predicted early recurrence and death compared to those with lower levels (medial survival: 177 days v. 850 days, p = 0.0049). Of the correlative proteins, enriched gene ontology terms included signal peptide (28.2), cytokine (6.86), negative regulation of endopeptidase activity (3.39), and immunoglobulin domain (3.24). Conclusions: Cancer cachexia in PDAC and various gastrointestinal malignancies remains a key clinical issue. While there are no definitive biomarkers currently in use to diagnose and manage cachexia preemptively, we present several potential candidates in a small cohort of patients. Ultimately, such assays may better elucidate common cachexia-inducing pathways, a shared spectrum of biomarkers and allow for the development of more specific therapies targeting cachexia.

Background:Curvularia is a ubiquitous fungus found in tropical climates and has been reported to grow on marijuana leaves. Rarely, it can infect humans and propagate from the nasal sinuses into the brain.Case:A 28-year-old immunocompetent patient presented with history of nasal polyps, headache, and subtle visual deficits on the right. Imaging revealed what appeared to be an invasive mass growing through the ethmoid and sphenoid sinuses into the anterior cranial fossa.Results:Otolaryngology performed an endoscopic nasal biopsy with pathology and cultures consistent for Curvularia (figure 6). A combination case with neurosurgery and otolaryngology was planned. Surgeons used a bifrontal craniotomy and endonasal approach for gross total resection. Following resection, the patient was placed on 4 weeks of amphotericin treatment followed by 12 months of voriconazole based on recommendations by infectious disease. The patient has been stable since surgery.Conclusion:Curvularia is a rare but potentially life threatening central nervous system infection that can be acquired from inhalational marijuana use. This illustrative case shows the importance of aggressive debridement followed by broad spectrum antifungal treatment to optimize outcome. With marijuana's increasing popularity, Curvalaria should be included on the differential diagnosis.

Abstract Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest of all common malignancies. Treatment is difficult and often complicated by the presence of cachexia. The clinical portrait of cachexia contributes to the poor prognosis experienced by PDAC patients and worsens therapeutic outcomes. We propose that low bone mineral density is a component of cachexia, which we explore herein through a retrospective review of all patients at our facility that underwent surgery for PDAC between 2011 and 2018 and compared to sex‐, age‐ and comorbidity‐matched control individuals. Data were abstracted from the medical record and pre‐operative computed tomography scans. Muscle mass and quality were measured at the L3 level and bone mineral density was measured as the radiation attenuation of the lumbar vertebral bodies. Patients with PDAC displayed typical signs of cachexia such as weight loss and radiologically appreciable deterioration of skeletal muscle. Critically, PDAC patients had significantly lower bone mineral density than controls, with 61.2% of PDAC patients categorized as osteopenic compared to 36.8% of controls. PDAC patients classified as osteopenic had significantly reduced survival (1.01 years) compared to patients without osteopenia (2.77 years). The presence of osteopenia was the strongest clinical predictor of 1‐ and 2‐year disease‐specific mortality, increasing the risk of death by 107% and 80%, respectively. Osteopenia serves as a test of 2‐year mortality with sensitivity of 76% and specificity of 58%. These data therefore identify impaired bone mineral density as a key component of cachexia and predictor of postoperative survival in patients with PDAC. The mechanisms that lead to bone wasting in tumor‐bearing hosts deserve further study.

Pancreatic neuroendocrine tumors (PNETs) represent a rare form of pancreatic cancer. Racial/ethnic disparities have been documented in pancreatic ductal adenocarcinoma, but health disparities have not been well described in patients with PNETs.

Background: Young patients with esophageal cancer (EC) are believed to have more aggressive disease, thus thought to have worse survival. Herein, we aim to study the impact of younger age on the short- and long-term outcomes of esophagectomy for EC. Methods: Patients who underwent esophagectomy for EC at our institution between 1994–2019 were included. Age 50 was defined as the cutoff for “young” vs . “old”. Patients from each age group were propensity-score matched 1:1 to compare postoperative and survival outcomes. Results: Our database reported 1,031 patients, 112 of whom were in the ‘young’ group. For the unmatched analysis, young patients were more likely to have squamous cell carcinoma, higher rates of locally advanced disease, and subsequently higher rates of neoadjuvant chemotherapy (79.5% vs . 68.3%; P=0.047). After matching for pre-treatment clinical factors, young patients were less likely to have pulmonary or cardiac complications after surgery, and three times more likely to receive AC despite matching for stage and response to treatment (26.7% vs . 7.9%; P=0.002). Then, we matched patients including receipt of AC to study survival. In the second match, median recurrence-free survival (RFS) for young patients was 49.0±26.0 vs . old 27.0±5.4 months (P=0.215). Median overall survival (OS) for young was 73.0±28.9 vs . old 31.0±6.3 months (P=0.073). Conclusions: Young EC patients tend to present with more advanced disease. However, when matched for stage and response to therapies, young patients were three-times more likely to be offered AC. After adjusting for receipt of adjuvant therapy no difference was detected in RFS.

LESSONS LEARNED:Preclinical studies have demonstrated that Src inhibition through dasatinib synergistically enhances the antitumor effects of oxaliplatin. In this phase II, single-arm study, FOLFOX with dasatinib in previously untreated patients with mPC only showed only modest clinical activity, with a progressive-free survival of 4 months and overall survival of 10.6 months. Continued investigation is ongoing to better understand the role of Src inhibition with concurrent 5-fluorouracil and oxaliplatin in a subset of exceptional responders.BACKGROUND:Src tyrosine kinase activity is overexpressed in many human cancers, including metastatic pancreatic cancer (mPC). Dasatinib is a potent inhibitor of Src family of tyrosine kinases. This study was designed to investigate whether dasatinib can synergistically enhance antitumor effects of FOLFOX regimen (FOLFOX-D).METHODS:In this single-arm, phase II study, previously untreated patients received dasatinib 150 mg oral daily on days 1-14, oxaliplatin 85 mg/m2 intravenous (IV) on day 1 every 14 days, leucovorin (LV) 400 mg/m2 IV on day 1 every 14 days, 5-fluorouracil (5-FU) bolus 400 mg/m2 on day 1 every 14 days, and 5-FU continuous infusion 2,400 mg/m2 on day 1 every 14 days. Primary endpoint was progression-free survival (PFS) with preplanned comparison to historical controls.RESULTS:Forty-four patients enrolled with an estimated median PFS of 4.0 (95% confidence interval [CI], 2.3-8.5) months and overall survival (OS) of 10.6 (95% CI, 6.9-12.7) months. Overall response rate (ORR) was 22.7% (n = 10): one patient (2.3%) with complete response (CR) and nine patients (20.5%) with partial response (PR). Fifteen patients (34.1%) had stable disease (SD). Nausea was the most common adverse event (AE) seen in 35 patients (79.5%).CONCLUSION:The addition of dasatinib did not appear to add incremental clinical benefit to FOLFOX in untreated patients with mPC.

Abstract Introduction: Pancreatic ductal adenocarcinoma (PDAC) is a devastating diagnosis with a five-year survival rate below 9%. Among various ethnic groups there are differing incidence and mortality rates that underpin a patient’s overall prognosis. Blacks have higher incidence and mortality rates and a worse prognosis compared to Whites. Conversely, Hispanic/Latino patients have the lowest recorded incidence and mortality rates. Though well recognized by experts, these discrepancies are poorly understood and unaccounted for by socioeconomic means. Therefore, we hypothesize that divergent biology drives the observed disparities in PDAC. Methods: Patients with PDAC that underwent surgery at our institution between 2010 and 2017 were included in this retrospective study. Surgical pathology reports were reviewed, and cases were matched by age, gender, and tumor grade. Psoas muscle indices (PMI) were measured from pre-operative CT scans. Baseline indices for respective ethnic groups were determined from healthy patients with non-oncologic pathology. Whole-exome sequencing was then performed on DNA from tumor and adjacent benign parenchyma. Results: Healthy Blacks have a significantly greater PMI than case-matched Whites (0.90 vs. 0.70, p < 0.005). Blacks and Whites with PDAC have a similar average pre-operative PMI (0.67 vs. 0.61, p = 0.3). However, when comparing pre-operative PMI to the baseline control PMI for the two racial groups, Blacks have a significantly greater percent decrease than Whites (29% vs. 14%, p < 0.05). By whole-exome sequencing, 22 new somatic mutations were identified in Black tumor samples compared to 7 new mutations in Whites. Among mutations exclusively present Blacks, ABCF1 and ANAPC1 were reported to be associated with chemoresponse and survival in colorectal and lung adenocarcinomas, respectively. Cytochrome p450 family member CYP2A7 mutations were associated with peritoneal metastasis. PHACTR4 mutations were associated with Stat3 signaling activation and IL-6 mediated phosphorylation in hepatocellular carcinoma. Lastly, Hispanic/Latino patients, while not part of our tumor molecular sequencing, more frequently sought surgical intervention for pre-malignant cystic pancreatic neoplasms when compared to Whites (28% vs. 7%, p < 0.05). Conclusion: Novel mutations and a strongly cachectic phenotype characterize Blacks with PDAC and may drive a particularly poor prognosis. While more research might define a molecular rationale for the better clinical outcomes in Latinos, Hispanic/Latino patients most frequently seek care for pre-malignant lesions. We conclude that recognizing the biological basis of cancer health disparities is essential for forming appropriate clinical decisions and defining specific therapeutic targets in ethnically diverse patients with PDAC. Citation Format: Miles E Cameron, Patrick W Underwood, Michael U Maduka, Steven J Hughes, Andrea N Riner, Jennifer B Permuth, Andrew R Judge, Jose G Trevino. Divergent biology in ethnically diverse populations is central to health disparities in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr D106.

Abstract Abstract Background Pancreatic cancer (PC) is one of the leading causes of cancer mortality and soon to be the second-leading cause of cancer death in the US by 2030. Patient derived xenografts (PDX) represent an opportunity to better understand the biology driving higher incidence and mortality. Racial disparities exist and Blacks have worse clinical outcomes than any other race. We hypothesize that the PDX tumors from the same patient will grow at differing rates including PDX development from patients of different races/ethnicities. Methods Under an IRB approved protocol, patients with the diagnosis of pancreatic adenocarcinoma (PDAC) were recruited for tissue donation. After surgical harvest of PC specimen, patient-derived xenograft (PDX) models were derived in NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice. After initial passage from operation room, tumors from each individual patient were allowed to grow and subsequently divided and passed into 5 NSG mice and tumor growth rates were assessed by digital caliper. Patient race/ethnicity were de-identified as G and number of passages (p) from initial implantation were considered. Growth was assessed from 41 to 56 days. Coefficient of variation was attained and demonstrated the variability in growth values within each graft. Results PDX grafts (GXpX) were measured from 41 to 56 days. G1p5 and G2p1 were from non-Hispanic White patients and G3p3 was from a Black patient with PDAC. G1p5 grew an average of 0.25 mm per day and tumor size at 55 days after implantation were 1.0 cm, 1.4 cm, and 1.7 cm with a coefficient of variation of 20.98%. G2p1 grew an average of 0.17 mm per day and tumor sizes at 56 days were 0.7 cm and 1.3 cm with a coefficient of variation of 42.42%. G3p3 grew an average of 0.16 mm per day and tumor size at 41 days were 1.3 cm, 1.3 cm, and 0.7 cm with a coefficient of variation of 31.49%. The growth rate of mice implanted with patient tumor G2p1 demonstrated more growth variation than G3p3 and G1p5. Conclusion PDX from the same patient and different races exhibit differing growth rates over time. Each PDX should be considered as a unique tumor given its gross heterogeneity and possible genetic drift within the same tumor. Recommendations for PDX model use should include tumor measurements of each individual xenograft throughout time intervals throughout experiments especially when considering therapeutics. These important observations will leverage our understanding of much needed preclinical tumor models in PDAC and help improve our understanding of the biology of racial disparities in pancreatic cancer. Citation Format: Michael U Maduka, Patrick W Underwood, Andrea N Riner, Miles E Cameron, Jose G Trevino. Same patient, different tumor. Does heterogeneity of pancreatic cancer matter? Differences in growth rates of patient-derived xenografts from individual patients [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr D110.

Smoking is highly associated with pancreatic cancer. Nicotine, the addictive component of tobacco, is involved in pancreatic cancer tumorigenesis, metastasis, and chemoresistance. This work aimed to describe the role of nicotine within the pancreatic cancer tumor microenvironment. Nicotine treatment was used in vitro to assess its effect on tumor-associated stromal cells and pancreatic cancer cells. Nicotine treatment was then used in a pancreatic cancer patient-derived xenograft model to study the effects in vivo. Nicotine induced secretion of interleukin 8 (IL-8) by tumor-associated stroma cells in an extracellular signal-regulated kinase (ERK)-dependent fashion. The secreted IL-8 and nicotine acted on the pancreatic cancer cell, resulting in upregulation of IL-8 receptor. Nicotine treatment of mice bearing pancreatic cancer patient-derived xenografts had significantly increased tumor mass, increased tumor-free weight loss, and decreased muscle mass. These represent important pathways through which nicotine acts within the tumor microenvironment and worsens pancreatic cancer-induced cachexia, potentially representing future therapeutic targets.

Abstract Skeletal muscle wasting is a devastating consequence of cancer that contributes to increased complications and poor survival, but is not well understood at the molecular level. Herein, we investigated the role of Myocilin (Myoc), a skeletal muscle hypertrophy-promoting protein that we showed is downregulated in multiple mouse models of cancer cachexia. Loss of Myoc alone was sufficient to induce phenotypes identified in mouse models of cancer cachexia, including muscle fiber atrophy, sarcolemmal fragility, and impaired muscle regeneration. By 18 months of age, mice deficient in Myoc showed significant skeletal muscle remodeling, characterized by increased fat and collagen deposition compared with wild-type mice, thus also supporting Myoc as a regulator of muscle quality. In cancer cachexia models, maintaining skeletal muscle expression of Myoc significantly attenuated muscle loss, while mice lacking Myoc showed enhanced muscle wasting. Furthermore, we identified the myocyte enhancer factor 2 C (MEF2C) transcription factor as a key upstream activator of Myoc whose gain of function significantly deterred cancer-induced muscle wasting and dysfunction in a preclinical model of pancreatic ductal adenocarcinoma (PDAC). Finally, compared with noncancer control patients, MYOC was significantly reduced in skeletal muscle of patients with PDAC defined as cachectic and correlated with MEF2c. These data therefore identify disruptions in MEF2c-dependent transcription of Myoc as a novel mechanism of cancer-associated muscle wasting that is similarly disrupted in muscle of patients with cachectic cancer. Significance: This work identifies a novel transcriptional mechanism that mediates skeletal muscle wasting in murine models of cancer cachexia that is disrupted in skeletal muscle of patients with cancer exhibiting cachexia.