Oncogenic Fatty Acid Metabolism Rewires Energy Supply Chain in Gastric Carcinogenesis.

BACKGROUND & AIMS: Gastric carcinogenesis develops within a sequential carcinogenic cascade from precancerous metaplasia to dysplasia and adenocarcinoma, and oncogenic gene activation can drive the process. Metabolic reprogramming is considered a key mechanism for cancer cell growth and proliferation. However, how metabolic changes contribute to the progression of metaplasia to dysplasia remains unclear. We have examined metabolic dynamics during gastric carcinogenesis using a novel mouse model that induces Kras activation in zymogen-secreting chief cells. METHODS: We generated a Gif-rtTA;TetO-Cre;KrasG12D (GCK) mouse model that continuously induces active Kras expression in chief cells after doxycycline treatment. Histologic examination and imaging mass spectrometry were performed in the GCK mouse stomachs at 2 to 14 weeks after doxycycline treatment. Mouse and human gastric organoids were used for metabolic enzyme inhibitor treatment. The GCK mice were treated with a stearoyl- coenzyme A desaturase (SCD) inhibitor to inhibit the fatty acid desaturation. Tissue microarrays were used to assess the SCD expression in human gastrointestinal cancers. RESULTS: The GCK mice developed metaplasia and high-grade dysplasia within 4 months. Metabolic reprogramming from glycolysis to fatty acid metabolism occurred during metaplasia progression to dysplasia. Altered fatty acid desaturation through SCD produces a novel eicosenoic acid, which fuels dysplastic cell hyperproliferation and survival. The SCD inhibitor killed both mouse and human dysplastic organoids and selectively targeted dysplastic cells in vivo. SCD was up-regulated during carcinogenesis in human gastrointestinal cancers. CONCLUSIONS: Active Kras expression only in gastric chief cells drives the full spectrum of gastric carcinogenesis. Also, oncogenic metabolic rewiring is an essential adaptation for high-energy demand in dysplastic cells.

Single-Cell Transcriptomics Reveals a Conserved Metaplasia Program in Pancreatic Injury.

BACKGROUND & AIMS: Acinar to ductal metaplasia (ADM) occurs in the pancreas in response to tissue injury and is a potential precursor for adenocarcinoma. The goal of these studies was to define the populations arising from ADM, the associated transcriptional changes, and markers of disease progression. METHODS: Acinar cells were lineage-traced with enhanced yellow fluorescent protein (EYFP) to follow their fate post-injury. Transcripts of more than 13,000 EYFP+ cells were determined using single-cell RNA sequencing (scRNA-seq). Developmental trajectories were generated. Data were compared with gastric metaplasia, KrasG12D-induced neoplasia, and human pancreatitis. Results were confirmed by immunostaining and electron microscopy. KrasG12D was expressed in injury-induced ADM using several inducible Cre drivers. Surgical specimens of chronic pancreatitis from 15 patients were evaluated by immunostaining. RESULTS: scRNA-seq of ADM revealed emergence of a mucin/ductal population resembling gastric pyloric metaplasia. Lineage trajectories suggest that some pyloric metaplasia cells can generate tuft and enteroendocrine cells (EECs). Comparison with KrasG12D-induced ADM identifies populations associated with disease progression. Activation of KrasG12D expression in HNF1B+ or POU2F3+ ADM populations leads to neoplastic transformation and formation of MUC5AC+ gastric-pit-like cells. Human pancreatitis samples also harbor pyloric metaplasia with a similar transcriptional phenotype. CONCLUSIONS: Under conditions of chronic injury, acinar cells undergo a pyloric-type metaplasia to mucinous progenitor-like populations, which seed disparate tuft cell and EEC lineages. ADM-derived EEC subtypes are diverse. KrasG12D expression is sufficient to drive neoplasia when targeted to injury-induced ADM populations and offers an alternative origin for tumorigenesis. This program is conserved in human pancreatitis, providing insight into early events in pancreas diseases.

Intentional tanning behaviors among undergraduates on the United States' Gulf Coast.

BACKGROUND: Rates of melanoma have dramatically increased among adolescents and young adults in recent years, particularly among young women. Exposure to ultraviolet radiation from intentional tanning practices is likely a major contributor to this epidemic. Southern and coastal regions have higher melanoma mortality rates among non-Hispanic whites in other parts of the U.S., yet little is known about tanning practices of adolescents and young adults in these regions. This study determines the prevalence and methods of intentional tanning utilized by an undergraduate population located on the United States' Gulf Coast. METHODS: Undergraduate students enrolled at a university on the Gulf Coast completed an online survey from March-April 2016, self-reporting their engagement, knowledge, and attitudes regarding outdoor tanning (OT), indoor tanning (IT) and spray tanning (ST). Univariate and multivariate analyses were performed to identify factors associated with tanning behaviors. RESULTS: 2668 undergraduates completed the survey. Of these, 64.9% reported OT tanning, 50.7% reported ever IT, and 21.2% reported ever ST. CONCLUSIONS: In the largest study to date of intentional tanning behaviors of adolescents and young adults from coastal regions, we found high rates of intentional tanning behaviors. There was also significant engagement in spray tanning by this population, not previously reported for adolescents and young adults in a sample of this size. We also identified a high association between different tanning methods, indicating this population engages in multiple tanning behaviors, a phenomenon whose health consequences are not yet known.

Dihydroxyacetone induces G2/M arrest and apoptotic cell death in A375P melanoma cells.

The active ingredient in sunless tanning products (STPs) is a simple sugar, dihydroxyacetone (DHA). Several studies have demonstrated that DHA is absorbed within the viable layers of skin and not fully contained within the stratum corneum. Additionally, spray tanning and other aerosolized application methods have increased the risk of internal exposure through mucous membranes and inhalation. Beyond its presence in STPs, DHA also occurs as an endogenous by-product of fructose metabolism, and an excess of DHA in cells can induce advanced glycation end (AGE) products and oxidative stress. Therefore, exogenous and endogenous exposures to DHA may be harmful to cells, and it has already been demonstrated that exogenous exposure to DHA is cytotoxic in immortalized keratinocytes. Still, little is known about the exogenous DHA exposure effects on other skin components. In this study, we explore the effects of exogenous DHA exposure in a human melanoma cell line, A375P. Melanoma cells were sensitive to DHA and displayed a transient burst of reactive oxygen species within an hour of exposure. Cell cycle arrest at G2/M was observed within 24 h of exposure, and apoptosis, monitored by the cleavage of PARP-1 and Caspase-3, was detected within 72 h of exposure to DHA. Together, these demonstrate that exogenous exposure to DHA has cytotoxic effects in our selected cell model and indicates the need to further investigate the exogenous exposure effects of DHA in other relevant exposure models.

College tanning behaviors, attitudes, beliefs, and intentions: A systematic review of the literature.

Despite well-established links between exposure to ultraviolet radiation (UVR) and skin cancer, UVR-based tanning behaviors persist among college students. Understanding tanning motivations, perceptions, barriers, and demographic characteristics of this population is critical to modifying these behaviors, but is limited by variability in study design, sample size, and outcomes measured in the current literature. To help clarify the tanning behaviors of this population and provide a concise reference for future studies, this review examines existing reports to determine the comparability of tanning behaviors across multiple U.S. college populations. A systematic review of the literature was performed in July 2016 to identify studies investigating tanning behaviors among U.S. college students. Twenty-three studies met inclusion criteria. High rates of indoor tanning (IT) and outdoor tanning (OT) were found among college students. Key motivators included appearance, emotion, health perceptions, and the influence of parents, peers, and the media. Misconceptions regarding skin protection, low rates of sun protective behaviors, and tanning dependence were barriers against safe UVR exposure. Understudied demographic factors may account for variance in observed tanning behaviors, emphasizing the need for standardization efforts to consistently identify trends associated with geographical region, age, year in college, and sex. The findings presented in this review reaffirm that college students are at high risk for tanning-associated skin cancer, emphasizing the critical need for effective, targeted interventions. Improved interventions will reduce the burden of skin cancer within this group, ultimately contributing to longer, healthier lives.

Histology-based Classification Predicts Pattern of Recurrence and Improves Risk Stratification in Primary Retroperitoneal Sarcoma.

OBJECTIVE: To determine the prognostic significance of histologic type/subtype in a large series of patients with primary resected retroperitoneal sarcoma. BACKGROUND: The histologic diversity and rarity of retroperitoneal sarcoma has hampered the ability to predict patient outcome. METHODS: From a single-institution, prospective database, 675 patients treated surgically for primary, nonmetastatic retroperitoneal sarcoma during 1982 to 2010 were identified and histologic type/subtype was reviewed. Clinicopathologic variables were analyzed for association with disease-specific death (DSD), local recurrence (LR), and distant recurrence (DR). RESULTS: Median follow-up for survivors was 7.5 years. The predominant histologies were well-differentiated liposarcoma, dedifferentiated liposarcoma, and leiomyosarcoma. Five-year cumulative incidence of DSD was 31%, and factors independently associated with DSD were R2 resection, resection of 3 or more contiguous organs, and histologic type. Five-year cumulative incidence for LR was 39% and for DR was 24%. R1 resection, age, tumor size, and histologic type were independently associated with LR; size, resection of 3 or more organs, and histologic type were independently associated with DR. Liposarcoma and leiomyosarcoma were associated with late recurrence and DSD (as long as 15 years from diagnosis). For solitary fibrous tumor, LR was uncommon (<10%), but early distant recurrence was common (36% at 5 years). Nomograms were developed to predict DSD, LR, and DR. CONCLUSIONS: Histologic type/subtype is the most important independent predictor of DSD, LR, and DR in primary retroperitoneal sarcoma. Histology predicts the pattern and incidence of LR and DR and will aid in more accurate patient counseling and selection of patients for adjuvant therapy trials.

Surgical management of retroperitoneal and pelvic sarcomas.

Management of retroperitoneal sarcomas presents technical and oncological challenges. Imaging is crucial for diagnosis and to define local tumor extent. Complete gross resection at initial presentation is the best chance for cure, but there is controversy as to how this can be best achieved. There is a long-term risk of local recurrence, which is best treated with repeat resection if feasible. The roles of radiation and chemotherapy remain undefined.

Surgical management of non-colorectal hepatic metastasis.

Isolated hepatic metastases from non-colorectal primary tumors are rare. Patients with neuroendocrine tumors have an indolent biology compared with other non-colorectal histologies. This article discusses the surgical management options for patients with neuroendocrine liver metastases and, separately, for those with non-colorectal, non-neuroendocrine metastases. Emphasis is placed on the importance of patient selection, understanding the tumor biology and response to systemic therapy.

Oncogenic GNAS drives a gastric pylorus program in intraductal papillary mucinous neoplasms of the pancreas.

OBJECTIVE: Intraductal Papillary Mucinous Neoplasms (IPMNs) are cystic lesions and bona fide precursors for pancreatic ductal adenocarcinoma (PDAC). Recently, we showed that acinar to ductal metaplasia, an injury repair program, is characterized by a transcriptomic program similar to gastric spasmolytic polypeptide expressing metaplasia (SPEM), suggesting common mechanisms of reprogramming between the stomach and pancreas. The aims of this study were to assay IPMN for pyloric markers and to identify molecular drivers of this program. DESIGN: We analyzed RNA-seq studies of IPMN for pyloric markers, which were validated by immunostaining in patient samples. Cell lines expressing Kras G12D +/- GNAS R201C were manipulated to identify distinct and overlapping transcriptomic programs driven by each oncogene. A PyScenic-based regulon analysis was performed to identify molecular drivers in the pancreas. Expression of candidate drivers was evaluated by RNA-seq and immunostaining. RESULTS: Pyloric markers were identified in human IPMN. GNAS R201C drove expression of these markers in cell lines and siRNA targeting of GNAS R201C or Kras G12D demonstrates that GNAS R201C amplifies a mucinous, pyloric phenotype. Regulon analysis identified a role for transcription factors SPDEF, CREB3L1, and CREB3L4, which are expressed in patient samples. siRNA-targeting of Spdef inhibited mucin production. CONCLUSION: De novo expression of a SPEM phenotype has been identified in pancreatitis and a pyloric phenotype in Kras G12D -driven PanIN and Kras G12D ;GNAS R201C -driven IPMN, suggesting common mechanisms of reprogramming between these lesions and the stomach. A transition from a SPEM to pyloric phenotype may reflect disease progression and/or oncogenic mutation. IPMN-specific GNAS R201C amplifies a mucinous phenotype, in part, through SPDEF.

Prognostic significance of early recurrence: a conditional survival analysis in patients with resected colorectal liver metastasis.

BACKGROUND: For patients undergoing liver resection for colorectal metastases, specific clinico-pathological variables have been shown to be prognostic at baseline. This study analyses how the prognostic capability of these variables changes in a conditional survival model. METHODS: Retrospective review of a prospectively maintained database of patients who underwent an R0 resection of colorectal liver metastases from 1994 to 2004 at a single institution. RESULTS: In total, 807 patients were identified, with an 87-month median follow-up for survivors. Five- and 10-year disease-specific survivals (DSS) were 68% and 55%, respectively. The probability of further survival increased as the survival time increased. For 3-year survivors (n = 504), DSS were no longer significantly different between patients with a low (0-2) or high (3-5) clinical risk score (CRS, P = 0.19). On multivariate analysis, independent predictors of DSS for 3-year survivors were recurrence within the first 3 years after a liver resection, a pre-operative carcinoembryonic antigen (CEA) >200 ng/ml and disease-free interval <12 months prior to the diagnosis of liver metastasis. However, for those patients who were recurrence free at 1 year, no clinico-pathological variables retained prognostic significance. DISCUSSION: After 3 years of DSS and 1 year of recurrence-free survival, baseline clinico-pathological variables have a limited ability to predict future survival. Early post-operative recurrence appears to be the most useful single clinical feature in estimating conditional DSS.

Margin-Negative en Bloc Resection of a Large Retroperitoneal Melanoma Including Reconstruction of the Infra-renal Inferior Vena Cava.

The management and outcomes for patients with metastatic melanoma have been revolutionized by immunotherapy. This case report highlights the role of surgery as an adjuvant to systemic therapies when there is oligoprogressive disease. We describe a 74-year-old man with metastatic melanoma who initially had a complete radiographic response after dual agent immunotherapy but subsequently developed a large metastasis in the retroperitoneum. After multidisciplinary discussion, he underwent margin negative resection that required en bloc segmental resection of the infra-renal inferior vena cava. To our knowledge, this is the first reported resection of a melanoma metastasis in this location.

Effects of Specialist Palliative Care for Patients Undergoing Major Abdominal Surgery for Cancer: A Randomized Clinical Trial.

Importance: Specialist palliative care benefits patients undergoing medical treatment of cancer; however, data are lacking on whether patients undergoing surgery for cancer similarly benefit from specialist palliative care. Objective: To determine the effect of a specialist palliative care intervention on patients undergoing surgery for cure or durable control of cancer. Design, Setting, and Participants: This was a single-center randomized clinical trial conducted from March 1, 2018, to October 28, 2021. Patients scheduled for specified intra-abdominal cancer operations were recruited from an academic urban referral center in the Southeastern US. Intervention: Preoperative consultation with palliative care specialists and postoperative inpatient and outpatient palliative care follow-up for 90 days. Main Outcomes and Measures: The prespecified primary end point was physical and functional quality of life (QoL) at postoperative day (POD) 90, measured by the Functional Assessment of Cancer Therapy-General (FACT-G) Trial Outcome Index (TOI), which is scored on a range of 0 to 56 with higher scores representing higher physical and functional QoL. Prespecified secondary end points included overall QoL at POD 90 measured by FACT-G, days alive at home until POD 90, and 1-year overall survival. Multivariable proportional odds logistic regression and Cox proportional hazards regression models were used to test the hypothesis that the intervention improved each of these end points relative to usual care in an intention-to-treat analysis. Results: A total of 235 eligible patients (median [IQR] age, 65.0 [56.8-71.1] years; 141 male [60.0%]) were randomly assigned to the intervention or usual care group in a 1:1 ratio. Specialist palliative care was received by 114 patients (97%) in the intervention group and 1 patient (1%) in the usual care group. Adjusted median scores on the FACT-G TOI measure of physical and functional QoL did not differ between groups (intervention score, 46.77; 95% CI, 44.18-49.04; usual care score, 46.23; 95% CI, 43.08-48.14; P = .46). Intervention vs usual care group odds ratio (OR) was 1.17 (95% CI, 0.77-1.80). Palliative care did not improve overall QoL measured by the FACT-G score (intervention vs usual care OR, 1.09; 95% CI, 0.75-1.58), days alive at home (OR, 0.87; 95% CI, 0.69-1.11), or 1-year overall survival (hazard ratio, 0.97; 95% CI, 0.50-1.88). Conclusions and Relevance: This randomized clinical trial showed no evidence that early specialist palliative care improves the QoL of patients undergoing nonpalliative cancer operations. Trial Registration: ClinicalTrials.gov Identifier: NCT03436290.

Small Bowel Obstruction Caused by Bezoar Formation Around Intraluminal Hernia Mesh.

We present a case report wherein a 55-year-old female presented to our clinic with chronic nausea, vomiting, and dehydration in the setting of a complex past surgical history, including laparoscopic incisional hernia repair in 2007 with intraperitoneal TiMeshTM. She then developed chronic nausea and vomiting and was hospitalized numerous times for dehydration. Due to her ongoing symptoms, she was taken to the operating room for exploration. A large, firm, mobile mass was identified within a loop of small bowel and was found to be a large bezoar firmly attached to a piece of intraluminal mesh. She progressed well postoperatively and, on outpatient follow-up, her pre-operative abdominal symptoms had completely resolved. To our knowledge, this is the first reported case of gallstone-like bezoar formation around an intraluminal hernia mesh causing small bowel obstruction and chronic abdominal pain.

Surgical Resection of Colorectal Liver Metastases: Attitudes and Practice Patterns in the Deep South.

BACKGROUND: Metastatic disease is the leading cause of mortality in colorectal cancer. Resection of colorectal liver metastases, when possible, is associated with improved long-term survival and the possibility of cure. However, nationwide studies suggest that liver resection is under-utilized in the treatment of colorectal liver metastases. This study was undertaken to understand attitudes and practice patterns among medical oncologists in the Deep South. METHODS: A survey of medical oncologists in the states of Alabama, Mississippi, and the Florida panhandle was performed. Respondents were queried regarding perceptions of resectability and attitudes towards surgical referral. RESULTS: We received 63 responses (32% response rate). Fifty percent of respondents reported no liver surgeons in their practice area. Commonly perceived contraindications to liver resection included extrahepatic metastatic disease (72%), presence of > 4 metastases (72%), bilobar metastases (61%), and metastases > 5 cm (46%). Bilobar metastatic disease was perceived as a contraindication more frequently by non-academic medical oncologists (70% vs. 33%, p = 0.03). CONCLUSIONS: Wide variations exist in perceptions of resectability and referral patterns for colorectal liver metastases among surveyed medical oncologists. There is a need for wider dissemination of resectability criteria and more liver surgeon involvement in the management of patients with colorectal liver metastases.

Enteroendocrine Cell Formation Is an Early Event in Pancreatic Tumorigenesis.

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a 5-year survival rate of only 11%, due, in part, to late diagnosis, making the need to understand early events in tumorigenesis critical. Acinar-to-ductal metaplasia (ADM), when not resolved, is a PDAC precursor. Recently, we showed that ADM is constituted by a heterogenous population of cells, including hormone-producing enteroendocrine cells (EECs: gamma, delta, epsilon, and enterochromaffin cells). In this study, we employed histopathological techniques to identify and quantify the abundance of EEC subtypes throughout pancreatic tumorigenesis in mouse models and human disease. We found that EECs are most abundant in ADM and significantly decrease with lesion progression. Co-immunofluorescence identifies distinct lineages and bihormonal populations. Evaluation of EEC abundance in mice lacking Pou2f3 demonstrates that the tuft cell master regulator transcription factor is not required for EEC formation. We compared these data to human neoplasia and PDAC and observed similar trends. Lastly, we confirm that EECs are a normal cellular compartment within the murine and human pancreatic ductal trees. Altogether, these data identify EECs as a cellular compartment of the normal pancreas, which expands early in tumorigenesis and is largely lost with disease progression.

Complex Surgical Management of Radiation-Associated Left Retroperitoneal Sarcoma.

Radiation-associated sarcomas (RASs) are rare entities that tend to have an aggressive course and poor prognosis. Criteria for diagnosis of radiation-associated sarcoma include therapeutic radiation preceding the development of sarcoma, sarcoma arising within or near the irradiated field, and tumor histology that is distinct from the primary tumor necessitating radiation. Despite their relatively uncommon occurrence, RASs are a well-established complication of radiation therapy. We present the complex, multidisciplinary surgical management of a patient with multi-compartmental radiation-associated sarcoma of the left retroperitoneum occurring nearly 25 years after undergoing whole trunk radiation for Hodgkin's lymphoma.

Eicosanoids in the pancreatic tumor microenvironment - a multicellular, multifaceted progression.

Background and Aims: Eicosanoids, oxidized fatty acids that serve as cell-signaling molecules, have been broadly implicated in tumorigenesis. Here, we aimed to identify eicosanoids associated with pancreatic tumorigenesis and the cell types responsible for their synthesis. Methods: We profiled normal pancreas and pancreatic ductal adenocarcinoma (PDAC) in mouse models and patient samples using mass spectrometry. We interrogated RNA sequencing datasets for eicosanoid synthase or receptor expression. Findings were confirmed by immunostaining. Results: In murine models, we identified elevated levels of PGD2, prostacyclin, and thromboxanes in neoplasia while PGE2, 12-HHTre, HETEs, and HDoHEs are elevated specifically in tumors. Analysis of scRNA-seq datasets suggests that PGE2 and prostacyclins are derived from fibroblasts, PGD2 and thromboxanes from myeloid cells, and PGD2 and 5-HETE from tuft cells. In patient samples, we identified a transition from PGD2 to PGE2-producing enzymes in the epithelium during the transition to PDAC, fibroblast/tumor expression of PTGIS, and myeloid/tumor cell expression of TBXAS1. Conclusions: Our analyses identify key changes in eicosanoid species during pancreatic tumorigenesis and the cell types that contribute to their synthesis. Thromboxane and prostacyclin expression is conserved between animal models and human disease and may represent new druggable targets.

Disruption of CCR5-dependent homing of regulatory T cells inhibits tumor growth in a murine model of pancreatic cancer.

Tumors evade immune destruction by actively inducing immune tolerance through the recruitment of CD4(+)CD25(+)Foxp3(+) regulatory T cells (Treg). We have previously described increased prevalence of these cells in pancreatic adenocarcinoma, but it remains unclear what mechanisms are involved in recruiting Tregs into the tumor microenvironment. Here, we postulated that chemokines might direct Treg homing to tumor. We show, in both human pancreatic adenocarcinoma and a murine pancreatic tumor model (Pan02), that tumor cells produce increased levels of ligands for the CCR5 chemokine receptor and, reciprocally, that CD4(+) Foxp3(+) Tregs, compared with CD4(+) Foxp3(-) effector T cells, preferentially express CCR5. When CCR5/CCL5 signaling is disrupted, either by reducing CCL5 production by tumor cells or by systemic administration of a CCR5 inhibitor (N,N-dimethyl-N-{{4-{[2-(4-methylphenyl)-6,7-dihydro-5H-benzocyclohepten-8-yl]carbonyl}amino}}benzyl]-N,N-dimethyl-N- {{{4-{{{[2-(4-methylphenyl)-6,7-dihydro-5H-benzocycloheptan-8-yl]carbonyl}amino}}benzyl}}}tetrahydro-2H-pyran-4-aminiumchloride; TAK-779), Treg migration to tumors is reduced and tumors are smaller than in control mice. Thus, this study demonstrates the importance of Tregs in immune evasion by tumors, how blockade of Treg migration might inhibit tumor growth, and, specifically in pancreatic adenocarcinoma, the role of CCR5 in the homing of tumor-associated Tregs. Selective targeting of CCR5/CCL5 signaling may represent a novel immunomodulatory strategy for the treatment of cancer.