High-Altitude Medicinal Plants as Promising Source of Phytochemical Antioxidants to Combat Lifestyle-Associated Oxidative Stress-Induced Disorders.

Oxidative stress, driven by reactive oxygen, nitrogen, and sulphur species (ROS, RNS, RSS), poses a significant threat to cellular integrity and human health. Generated during mitochondrial respiration, inflammation, UV exposure and pollution, these species damage cells and contribute to pathologies like cardiovascular issues, neurodegeneration, cancer, and metabolic syndromes. Lifestyle factors exert a substantial influence on oxidative stress levels, with mitochondria emerging as pivotal players in ROS generation and cellular equilibrium. Phytochemicals, abundant in plants, such as carotenoids, ascorbic acid, tocopherols and polyphenols, offer diverse antioxidant mechanisms. They scavenge free radicals, chelate metal ions, and modulate cellular signalling pathways to mitigate oxidative damage. Furthermore, plants thriving in high-altitude regions are adapted to extreme conditions, and synthesize secondary metabolites, like flavonoids and phenolic compounds in bulk quantities, which act to form a robust antioxidant defence against oxidative stress, including UV radiation and temperature fluctuations. These plants are promising sources for drug development, offering innovative strategies by which to manage oxidative stress-related ailments and enhance human health. Understanding and harnessing the antioxidant potential of phytochemicals from high-altitude plants represent crucial steps in combating oxidative stress-induced disorders and promoting overall wellbeing. This study offers a comprehensive summary of the production and physio-pathological aspects of lifestyle-induced oxidative stress disorders and explores the potential of phytochemicals as promising antioxidants. Additionally, it presents an appraisal of high-altitude medicinal plants as significant sources of antioxidants, highlighting their potential for drug development and the creation of innovative antioxidant therapeutic approaches.

Human AKR1C3 binds agonists of GPR84 and participates in an expanded polyamine pathway.

Altered human aldo-keto reductase family 1 member C3 (AKR1C3) expression has been associated with poor prognosis in diverse cancers, ferroptosis resistance, and metabolic diseases. Despite its clinical significance, the endogenous biochemical roles of AKR1C3 remain incompletely defined. Using untargeted metabolomics, we identified a major transformation mediated by AKR1C3, in which a spermine oxidation product "sperminal" is reduced to "sperminol." Sperminal causes DNA damage and activates the DNA double-strand break response, whereas sperminol induces autophagy in vitro. AKR1C3 also pulls down acyl-pyrones and pyrone-211 inhibits AKR1C3 activity. Through G protein-coupled receptor ligand screening, we determined that pyrone-211 is also a potent agonist of the semi-orphan receptor GPR84. Strikingly, mammalian fatty acid synthase produces acyl-pyrones in vitro, and this production is modulated by NADPH. Taken together, our studies support a regulatory role of AKR1C3 in an expanded polyamine pathway and a model linking fatty acid synthesis and NADPH levels to GPR84 signaling.

A machine learning and drug repurposing approach to target ferroptosis in colorectal cancer stratified by sex and KRAS.

The landscape of sex differences in Colorectal Cancer (CRC) has not been well characterized with respect to the mechanisms of action for oncogenes such as KRAS. However, our recent study showed that tumors from male patients with KRAS mutations have decreased iron-dependent cell death called ferroptosis. Building on these findings, we further examined ferroptosis in CRC, considering both sex of the patient and KRAS mutations, using public databases and our in-house CRC tumor cohort. Through subsampling inference and variable importance analysis (VIMP), we identified significant differences in gene expression between KRAS mutant and wild type tumors from male patients. These genes suppress (e.g., SLC7A11 ) or drive (e.g., SLC1A5 ) ferroptosis, and these findings were further validated with Gaussian mixed models. Furthermore, we explored the prognostic value of ferroptosis regulating genes and discovered sex- and KRAS-specific differences at both the transcriptional and metabolic levels by random survival forest with backward elimination algorithm (RSF-BE). Of note, genes and metabolites involved in arginine synthesis and glutathione metabolism were uniquely associated with prognosis in tumors from males with KRAS mutations. Additionally, drug repurposing is becoming popular due to the high costs, attrition rates, and slow pace of new drug development, offering a way to treat common and rare diseases more efficiently. Furthermore, increasing evidence has shown that ferroptosis inhibition or induction can improve drug sensitivity or overcome chemotherapy drug resistance. Therefore, we investigated the correlation between gene expression, metabolite levels, and drug sensitivity across all CRC primary tumor cell lines using data from the Genomics of Drug Sensitivity in Cancer (GDSC) resource. We observed that ferroptosis suppressor genes such as DHODH , GCH1 , and AIFM2 in KRAS mutant CRC cell lines were resistant to cisplatin and paclitaxel, underscoring why these drugs are not effective for these patients. The comprehensive map generated here provides valuable biological insights for future investigations, and the findings are supported by rigorous analysis of large-scale publicly available data and our in-house cohort. The study also emphasizes the potential application of VIMP, Gaussian mixed models, and RSF-BE models in the multi-omics research community. In conclusion, this comprehensive approach opens doors for leveraging precision molecular feature analysis and drug repurposing possibilities in KRAS mutant CRC.

Asparagine synthetase and G-protein coupled estrogen receptor are critical responders to nutrient supply in KRAS mutant colorectal cancer.

Survival differences exist in colorectal cancer (CRC) patients by sex and disease stage. However, the potential molecular mechanism(s) are not well understood. Here we show that asparagine synthetase (ASNS) and G protein-coupled estrogen receptor-1 (GPER1) are critical sensors of nutrient depletion and linked to poorer outcomes for females with CRC. Using a 3D spheroid model of isogenic SW48 KRAS wild-type (WT) and G12A mutant (MT) cells grown under a restricted nutrient supply, we found that glutamine depletion inhibited cell growth in both cell lines, whereas ASNS and GPER1 expression were upregulated in KRAS MT versus WT. Estradiol decreased growth in KRAS WT but had no effect on MT cells. Selective GPER1 and ASNS inhibitors suppressed cell proliferation with increased caspase-3 activity of MT cells under glutamine depletion condition particularly in the presence of estradiol. In a clinical colon cancer cohort from The Cancer Genome Atlas, both high GPER1 and ASNS expression were associated with poorer overall survival for females only in advanced stage tumors. These results suggest KRAS MT cells have mechanisms in place that respond to decreased nutrient supply, typically observed in advanced tumors, by increasing the expression of ASNS and GPER1 to drive cell growth. Furthermore, KRAS MT cells are resistant to the protective effects of estradiol under nutrient deplete conditions. The findings indicate that GPER1 and ASNS expression, along with the interaction between nutrient supply and KRAS mutations shed additional light on the mechanisms underlying sex differences in metabolism and growth in CRC, and have clinical implications in the precision management of KRAS mutant CRC.

Perioperative Modified FOLFIRINOX for Resectable Pancreatic Cancer: A Nonrandomized Controlled Trial.

Importance: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignant tumor, and durable disease control is rare with the current standard of care, even for patients who undergo surgical resection. Objective: To assess whether neoadjuvant modified 5-fluorouracil, leucovorin, oxaliplatin, and irinotecan (mFOLFIRINOX) leads to early control of micrometastasis and improves survival. Design, Setting, and Participants: This open-label, single-arm, phase 2 nonrandomized controlled trial for resectable PDAC was conducted at the Yale Smilow Cancer Hospital from April 3, 2014, to August 16, 2021. Pancreatic protocol computed tomography was performed at diagnosis to assess surgical candidacy. Data were analyzed from January to July 2023. Interventions: Patients received 6 cycles of neoadjuvant mFOLFIRINOX before surgery and 6 cycles of adjuvant mFOLFIRINOX. Whole blood was collected and processed to stored plasma for analysis of circulating tumor DNA (ctDNA) levels. Tumors were evaluated for treatment response and keratin 17 (K17) expression. Main Outcomes and Measures: The primary end point was 12-month progression-free survival (PFS) rate. Additional end points included overall survival (OS), ctDNA level, tumor molecular features, and K17 tumor levels. Survival curves were summarized using Kaplan-Meier estimator. Results: Of 46 patients who received mFOLFIRINOX, 31 (67%) were male, and the median (range) age was 65 (46-80) years. A total of 37 (80%) completed 6 preoperative cycles and 33 (72%) underwent surgery. A total of 27 patients (59%) underwent resection per protocol (25 with R0 disease and 2 with R1 disease); metastatic or unresectable disease was identified in 6 patients during exploration. Ten patients underwent surgery off protocol. The 12-month PFS was 67% (90% CI, 56.9-100); the median PFS and OS were 16.6 months (95% CI, 13.3-40.6) and 37.2 months (95% CI, 17.5-not reached), respectively. Baseline ctDNA levels were detected in 16 of 22 patients (73%) and in 3 of 17 (18%) after 6 cycles of mFOLFIRINOX. Those with detectable ctDNA levels 4 weeks postresection had worse PFS (hazard ratio [HR], 34.0; 95% CI, 2.6-4758.6; P = .006) and OS (HR, 11.7; 95% CI, 1.5-129.9; P = .02) compared with those with undetectable levels. Patients with high K17 expression had nonsignificantly worse PFS (HR, 2.7; 95% CI, 0.7-10.9; P = .09) and OS (HR, 3.2; 95% CI, 0.8-13.6; P = .07). Conclusions and Relevance: This nonrandomized controlled trial met its primary end point, and perioperative mFOLFIRINOX warrants further evaluation in randomized clinical trials. Postoperative ctDNA positivity was strongly associated with recurrence. K17 and ctDNA are promising biomarkers that require additional validation in future prospective studies. Trial Registration: ClinicalTrials.gov Identifier: NCT02047474.

Growth characteristics of HCT116 xenografts lacking asparagine synthetase vary according to sex.

BACKGROUND: Sex-related differences in colorectal (CRC) incidence and mortality are well-documented. However, the impact of sex on metabolic pathways that drive cancer growth is not well understood. High expression of asparagine synthetase (ASNS) is associated with inferior survival for female CRC patients only. Here, we used a CRISPR/Cas9 technology to generate HCT116 ASNS-/- and HCT 116 ASNS+/+ cancer cell lines. We examine the effects of ASNS deletion on tumor growth and the subsequent rewiring of metabolic pathways in male and female Rag2/IL2RG mice. RESULTS: ASNS loss reduces cancer burden in male and female tumor-bearing mice (40% reduction, q < 0.05), triggers metabolic reprogramming including gluconeogenesis, but confers a survival improvement (30 days median survival, q < 0.05) in female tumor-bearing mice alone. Transcriptomic analyses revealed upregulation of G-protein coupled estrogen receptor (GPER1) in tumors from male and female mice with HCT116 ASNS-/- xenograft. Estradiol activates GPER1 in vitro in the presence of ASNS and suppresses tumor growth. CONCLUSIONS: Our study indicates that inferior survival for female CRC patients with high ASNS may be due to metabolic reprogramming that sustains tumor growth. These findings have translational relevance as ASNS/GPER1 signaling could be a future therapeutic target to improve the survival of female CRC patients.

Digital spatial proteomic profiling reveals immune checkpoints as biomarkers in lymphoid aggregates and tumor microenvironment of desmoplastic melanoma.

BACKGROUND: Desmoplastic melanoma (DM) is a rare melanoma subtype characterized by dense fibrous stroma, a propensity for local recurrence, and a high response rate to programmed cell death protein 1 (PD-1) blockade. Occult sentinel lymph node positivity is significantly lower in both pure and mixed DM than in conventional melanoma, underscoring the need for better prognostic biomarkers to inform therapeutic strategies. METHODS: We assembled a tissue microarray comprising various cores of tumor, stroma, and lymphoid aggregates from 45 patients with histologically confirmed DM diagnosed between 1989 and 2018. Using a panel of 62 validated immune-oncology markers, we performed digital spatial profiling using the NanoString GeoMx platform and quantified expression in three tissue compartments defined by fluorescence colocalization (tumor (S100+/PMEL+/SYTO+), leukocytes (CD45+/SYTO+), and non-immune stroma (S100-/PMEL-/CD45-/SYTO+)). RESULTS: We observed higher expression of immune checkpoints (lymphocyte-activation gene 3 [LAG-3] and cytotoxic T-lymphocyte associated protein-4 [CTLA-4]) and cancer-associated fibroblast (CAF) markers (smooth muscle actin (SMA)) in the tumor compartments of pure DMs than mixed DMs. When comparing lymphoid aggregates (LA) to non-LA tumor cores, LAs were more enriched with CD20+B cells, but non-LA intratumoral leukocytes were more enriched with macrophage/monocytic markers (CD163, CD68, CD14) and had higher LAG-3 and CTLA-4 expression levels. Higher intratumoral PD-1 and LA-based LAG-3 expression appear to be associated with worse survival. CONCLUSIONS: Our proteomic analysis reveals an intra-tumoral population of SMA+CAFs enriched in pure DM. Additionally, increased expressions of immune checkpoints (LAG-3 and PD-1) in LA and within tumor were associated with poorer prognosis. These findings might have therapeutic implications and help guide treatment selection in addition to informing potential prognostic significance.

SASAN: ground truth for the effective segmentation and classification of skin cancer using biopsy images.

OBJECTIVES: Early skin cancer diagnosis can save lives; however, traditional methods rely on expert knowledge and can be time-consuming. This calls for automated systems using machine learning and deep learning. However, existing datasets often focus on flat skin surfaces, neglecting more complex cases on organs or with nearby lesions. METHODS: This work addresses this gap by proposing a skin cancer diagnosis methodology using a dataset named ASAN that covers diverse skin cancer cases but suffers from noisy features. To overcome the noisy feature problem, a segmentation dataset named SASAN is introduced, focusing on Region of Interest (ROI) extraction-based classification. This allows models to concentrate on critical areas within the images while ignoring learning the noisy features. RESULTS: Various deep learning segmentation models such as UNet, LinkNet, PSPNet, and FPN were trained on the SASAN dataset to perform segmentation-based ROI extraction. Classification was then performed using the dataset with and without ROI extraction. The results demonstrate that ROI extraction significantly improves the performance of these models in classification. This implies that SASAN is effective in evaluating performance metrics for complex skin cancer cases. CONCLUSIONS: This study highlights the importance of expanding datasets to include challenging scenarios and developing better segmentation methods to enhance automated skin cancer diagnosis. The SASAN dataset serves as a valuable tool for researchers aiming to improve such systems and ultimately contribute to better diagnostic outcomes.

Anaplastic Large Cell Lymphoma of the Spine: Report of a Rare Case.

This abstract discusses a rare case of anaplastic large cell lymphoma (ALCL) involving the cervical and dorsal spine in a 17-year-old female. ALCL is a distinct subtype of lymphoma characterized by abnormal proliferation of lymphocytes and is divided into ALK-positive and ALK-negative subtypes. Spinal involvement in ALCL is uncommon, particularly in the cervical and dorsal regions. The patient presented with persistent fever, weakness, and delayed onset of severe neck pain. Diagnosis involved imaging, bone marrow biopsy, and lymph node biopsy. Treatment strategies for ALCL typically involve a multimodal approach, including chemotherapy, radiotherapy, and targeted therapy. However, due to the rarity of spinal involvement, treatment decisions are based on extrapolation from other ALCL cases. Prognosis is influenced by disease stage and ALK status, but specific outcomes for spinal involvement remain poorly established. This case emphasizes the need for considering lymphoma in patients with unexplained symptoms and abnormal imaging findings. It highlights the importance of further research to improve the understanding and management of ALCL with spinal involvement.

PROTAC-mediated dual degradation of BCL-xL and BCL-2 is a highly effective therapeutic strategy in small-cell lung cancer.

BCL-xL and BCL-2 are validated therapeutic targets in small-cell lung cancer (SCLC). Targeting these proteins with navitoclax (formerly ABT263, a dual BCL-xL/2 inhibitor) induces dose-limiting thrombocytopenia through on-target BCL-xL inhibition in platelets. Therefore, platelet toxicity poses a barrier in advancing the clinical translation of navitoclax. We have developed a strategy to selectively target BCL-xL in tumors, while sparing platelets, by utilizing proteolysis-targeting chimeras (PROTACs) that hijack the cellular ubiquitin proteasome system for target ubiquitination and subsequent degradation. In our previous study, the first-in-class BCL-xL PROTAC, called DT2216, was shown to have synergistic antitumor activities when combined with venetoclax (formerly ABT199, BCL-2-selective inhibitor) in a BCL-xL/2 co-dependent SCLC cell line, NCI-H146 (hereafter referred to as H146), in vitro and in a xenograft model. Guided by these findings, we evaluated our newly developed BCL-xL/2 dual degrader, called 753b, in three BCL-xL/2 co-dependent SCLC cell lines and the H146 xenograft models. 753b was found to degrade both BCL-xL and BCL-2 in these cell lines. Importantly, it was considerably more potent than DT2216, navitoclax, or DT2216+venetoclax to reduce the viability of BCL-xL/2 co-dependent SCLC cell lines in cell culture. In vivo, 5 mg/kg weekly dosing of 753b leads to significant tumor growth delay similar to the DT2216+venetoclax combination in H146 xenografts by degrading both BCL-xL and BCL-2. Additionally, 753b administration at 5 mg/kg every four days induced tumor regressions. 753b at this dosage was well tolerated in mice without induction of severe thrombocytopenia as seen with navitoclax nor induced significant changes in mouse body weights. These results suggest that the BCL-xL/2 dual degrader could be an effective and safe therapeutic for a subset of SCLC patients warranting clinical trials in future.

PROTAC-Mediated Dual Degradation of BCL-xL and BCL-2 Is a Highly Effective Therapeutic Strategy in Small-Cell Lung Cancer.

BCL-xL and BCL-2 are validated therapeutic targets in small-cell lung cancer (SCLC). Targeting these proteins with navitoclax (formerly ABT263, a dual BCL-xL/2 inhibitor) induces dose-limiting thrombocytopenia through on-target BCL-xL inhibition in platelets. Therefore, platelet toxicity poses a barrier in advancing the clinical translation of navitoclax. We have developed a strategy to selectively target BCL-xL in tumors, while sparing platelets, by utilizing proteolysis-targeting chimeras (PROTACs) that hijack the cellular ubiquitin proteasome system for target ubiquitination and subsequent degradation. In our previous study, the first-in-class BCL-xL PROTAC, called DT2216, was shown to have synergistic antitumor activities when combined with venetoclax (formerly ABT199, BCL-2-selective inhibitor) in a BCL-xL/2 co-dependent SCLC cell line, NCI-H146 (hereafter referred to as H146), in vitro and in a xenograft model. Guided by these findings, we evaluated our newly developed BCL-xL/2 dual degrader, called 753b, in three BCL-xL/2 co-dependent SCLC cell lines and the H146 xenograft models. 753b was found to degrade both BCL-xL and BCL-2 in these cell lines. Importantly, it was considerably more potent than DT2216, navitoclax, or DT2216 + venetoclax in reducing the viability of BCL-xL/2 co-dependent SCLC cell lines in cell culture. In vivo, 5 mg/kg weekly dosing of 753b was found to lead to significant tumor growth delay, similar to the DT2216 + venetoclax combination in H146 xenografts, by degrading both BCL-xL and BCL-2. Additionally, 753b administration at 5 mg/kg every four days induced tumor regressions. At this dosage, 753b was well tolerated in mice, without observable induction of severe thrombocytopenia as seen with navitoclax, and no evidence of significant changes in mouse body weights. These results suggest that the BCL-xL/2 dual degrader could be an effective and safe therapeutic for a subset of SCLC patients, warranting clinical trials in future.

Precision Oncology in Gastrointestinal and Colorectal Cancer Surgery.

Precision medicine is used to treat gastrointestinal malignancies including esophageal, gastric, small bowel, colorectal, and pancreatic cancers. Cutting-edge assays to detect and treat these cancers are active areas of research and will soon become standard of care. Colorectal cancer is a prime example of precision oncology as disease site is no longer the final determinate of treatment. Here, the authors describe how leveraging an understanding of tumor biology translates to individualized patient care using evidence-based practices.

Immunotherapy utilization in stage IIIA melanoma: less may be more.

Background: Immunotherapy agents are approved for adjuvant treatment of stage III melanoma; however, evidence for survival benefit in early stage III disease is lacking. Current guidelines for adjuvant immunotherapy utilization in stage IIIA rely on clinician judgment, creating an opportunity for significant variation in prescribing patterns. This study aimed to characterize current immunotherapy practice variations and to compare patient outcomes for different prescribing practices in stage IIIA melanoma. Study design: Patients with melanoma diagnosed from 2015-2019 that met American Joint Committee on Cancer 8th edition criteria for stage IIIA and underwent resection were identified in the National Cancer Database. Multiple imputation by chained equations replaced missing values. Factors associated with receipt of adjuvant immunotherapy were identified. Multivariable Cox proportional hazards regression compared overall survival across groups. Results: Of 4,432 patients included in the study, 34% received adjuvant immunotherapy. Patients had lower risk-adjusted odds of receiving immunotherapy if they were treated at an academic center (OR=0.48, 95%CI=0.33-0.72, p<0.001 vs. community facility) or at a high-volume center (OR=0.69, 0.56-0.84, p<0.001 vs. low-volume). Immunotherapy receipt was not associated with risk-adjusted survival (p=0.095). Moreover, patients treated at high-volume centers experienced longer overall risk-adjusted survival than those treated at low-volume centers (HR=0.52, 0.29-0.93, p=0.030). Risk-adjusted survival trended toward being longer at academic centers than at community centers, but the difference was not statistically significant. Conclusion: Academic and high-volume centers utilize significantly less adjuvant immunotherapy in stage IIIA melanoma than community and low-volume centers without compromise in overall survival. These findings suggest that this population may benefit from more judicious immunotherapy utilization.

Immunotherapy Initiation at the End of Life in Patients With Metastatic Cancer in the US.

Importance: While immunotherapy is being used in an expanding range of clinical scenarios, the incidence of immunotherapy initiation at the end of life (EOL) is unknown. Objective: To describe patient characteristics, practice patterns, and risk factors concerning EOL-initiated (EOL-I) immunotherapy over time. Design, Setting, and Participants: Retrospective cohort study using a US national clinical database of patients with metastatic melanoma, non-small cell lung cancer (NSCLC), or kidney cell carcinoma (KCC) diagnosed after US Food and Drug Administration approval of immune checkpoint inhibitors for the treatment of each disease through December 2019. Mean follow-up was 13.7 months. Data analysis was performed from December 2022 to May 2023. Exposures: Age, sex, race and ethnicity, insurance, location, facility type, hospital volume, Charlson-Deyo Comorbidity Index, and location of metastases. Main Outcomes and Measures: Main outcomes were EOL-I immunotherapy, defined as immunotherapy initiated within 1 month of death, and characteristics of the cohort receiving EOL-I immunotherapy and factors associated with its use. Results: Overall, data for 242 371 patients were analyzed. The study included 20 415 patients with stage IV melanoma, 197 331 patients with stage IV NSCLC, and 24 625 patients with stage IV KCC. Mean (SD) age was 67.9 (11.4) years, 42.5% were older than 70 years, 56.0% were male, and 29.3% received immunotherapy. The percentage of patients who received EOL-I immunotherapy increased over time for all cancers. More than 1 in 14 immunotherapy treatments in 2019 were initiated within 1 month of death. Risk-adjusted patients with 3 or more organs involved in metastatic disease were 3.8-fold more likely (95% CI, 3.1-4.7; P < .001) to die within 1 month of immunotherapy initiation than those with lymph node involvement only. Treatment at an academic or high-volume center rather than a nonacademic or very low-volume center was associated with a 31% (odds ratio, 0.69; 95% CI, 0.65-0.74; P < .001) and 30% (odds ratio, 0.70; 95% CI, 0.65-0.76; P < .001) decrease in odds of death within a month of initiating immunotherapy, respectively. Conclusions and Relevance: Findings of this cohort study show that the initiation of immunotherapy at the EOL is increasing over time. Patients with higher metastatic burden and who were treated at nonacademic or low-volume facilities had higher odds of receiving EOL-I immunotherapy. Tracking EOL-I immunotherapy can offer insights into national prescribing patterns and serve as a harbinger for shifts in the clinical approach to patients with advanced cancer.

Perfluorooctanesulfonic Acid and Perfluorooctanoic Acid Promote Migration of Three-Dimensional Colorectal Cancer Spheroids.

Perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) are persistent environmental contaminants that are of increasing public concern worldwide. However, their relationship with colorectal cancer (CRC) is poorly understood. This study aims to comprehensively investigate the effect of PFOS and PFOA on the development and progression of CRC in vitro using a series of biological techniques and metabolic profiling. Herein, the migration of three-dimensional (3D) spheroids of two CRC cell lines, SW48 KRAS wide-type (WT) and SW48 KRAS G12A, were observed after exposure to PFOS and PFOA at 2 µM and 10 µM for 7 days. The time and dose-dependent migration phenotype induced by 10 µM PFOS and PFOA was further confirmed by wound healing and trans-well migration assays. To investigate the mechanism of action, derivatization-mass spectrometry-based metabolic profiles were examined from 3D spheroids of SW48 cell lines exposed to PFOS and PFOA (2 µM and 10 µM). Our findings revealed this exposure altered epithelial-mesenchymal transition related metabolic pathways, including fatty acid ß-oxidation and synthesis of proteins, nucleotides, and lipids. Furthermore, this phenotype was confirmed by the downregulation of E-cadherin and upregulation of N-cadherin and vimentin. These findings show novel insight into the relationship between PFOS, PFOA, and CRC.

Role of colectomy in the management of appendiceal tumors: a retrospective cohort study.

BACKGROUND: Appendiceal tumors represent a range of histologies that vary in behavior. Recommendations for treatment with appendectomy versus right hemicolectomy (RHC) for different tumor types are evolving and sometimes conflicting. This study sought to characterize variation in the United States around surgical treatment of major appendiceal tumor types over time and describe differences in outcomes based on procedure. METHODS: Patients diagnosed with appendiceal goblet cell adenocarcinoma (GCA), mucinous adenocarcinoma, neuroendocrine neoplasm (NEN), or non-mucinous adenocarcinoma from 2004-2017 were identified in the National Cancer Database. Trends in RHC over time and predictors of RHC were identified. Surgical outcomes for each histologic type and stage were compared. RESULTS: Of 18,216 patients, 11% had GCAs, 34% mucinous adenocarcinoma, 31% NENs, and 24% non-mucinous adenocarcinoma. Rate of RHC for NEN decreased from 68% in 2004 to 40% in 2017 (p = 0.008) but remained constant around 60-75% for other tumor types. Higher stage was associated with increased odds of RHC for all tumor types. RHC was associated with higher rate of unplanned readmission (5% vs. 3%, p < 0.001) and longer postoperative hospital stay (median 5 days vs. 3 days, p < 0.001). On risk-adjusted analysis, RHC was significantly associated with increased survival versus appendectomy for stage 2 disease of all tumor types (HRs 0.43 to 0.63) and for stage 1 non-mucinous adenocarcinoma (HR = 0.56). CONCLUSIONS: Most patients with appendiceal tumors undergo RHC, which is associated with increased readmission, longer length of stay, and improved survival for stage 2 disease of all types. RHC should be offered selectively for appendiceal tumors.

Multi-omic analysis reveals metabolic pathways that characterize right-sided colon cancer liver metastasis.

There are well demonstrated differences in tumor cell metabolism between right sided (RCC) and left sided (LCC) colon cancer, which could underlie the robust differences observed in their clinical behavior, particularly in metastatic disease. As such, we utilized liquid chromatography-mass spectrometry to perform an untargeted metabolomics analysis comparing frozen liver metastasis (LM) biobank samples derived from patients with RCC (N = 32) and LCC (N = 58) to further elucidate the unique biology of each. We also performed an untargeted RNA-seq and subsequent network analysis on samples derived from an overlapping subset of patients (RCC: N = 10; LCC: N = 18). Our biobank redemonstrates the inferior survival of patients with RCC-derived LM (P = 0.04), a well-established finding. Our metabolomic results demonstrate increased reactive oxygen species associated metabolites and bile acids in RCC. Conversely, carnitines, indicators of fatty acid oxidation, are relatively increased in LCC. The transcriptomic analysis implicates increased MEK-ERK, PI3K-AKT and Transcription Growth Factor Beta signaling in RCC LM. Our multi-omic analysis reveals several key differences in cellular physiology which taken together may be relevant to clinical differences in tumor behavior between RCC and LCC liver metastasis.

The Representation of Surgery in Oncology Clinical Trials: 2001 to 2022.

BACKGROUND: Surgery is a mainstay of cancer care. Since the advancement of cancer treatment occurs through clinical trials, it is critical to investigate the degree and nature of representation of surgery in oncological clinical trials. METHODS: This observational analysis used publicly available data from clinicaltrials.gov to investigate non-industry-funded oncological clinical trials in the United States between 2012 and 2022. RESULTS: From 2012 to 2022, 1,861 (15.7%) of the 11,843 registered oncologic clinical trials were surgical. There was a 43.2% increase in proportional surgical trials and an 18.9% increase in oncology trials over the last two decades. Surgery+diagnostic-technique trials increased from 5.14 to 12.6% (P < 0.001, 95%CI [- 0.097, - 0.052]), surgery+radiation trials increased from 5.24 to 8.1% (P = 0.004, 95%CI [- 0.047, - 0.0088]), surgery+systemic-therapy trials decreased from 34.5 to 29.2% (P = 0.003, 95%CI [0.018, 0.088]), surgery+supportive-therapy trials increased from 8.0 to 11.3% (P = 0.004, 95%CI [- 0.056, - 0.01]) and 'surgery-as-the-variable' trials decreased from 12.0 to 3.5% (P < 0.001, 95%CI[0.065, 0.1]). Systemic therapy with biologics increased from 38.1 to 53.9% (P < 0.001, 95%CI [- 0.22, - 0.091]). Surgery-vs.-no-surgery trials increased from 16.8 to 37.3% (P = 0.001, 95%CI [- 0.32, - 0.078]). CONCLUSION: Surgical oncology trials increased by 43.2% over the last 10 years. The focus of clinical trials is changing to the encouragement of innovation in more diagnostic and less invasive techniques, and targeted therapies.