216 results on '"White MG"'
Search Results
2. Molecular, Socioeconomic, and Clinical Factors Affecting Racial and Ethnic Disparities in Colorectal Cancer Survival.
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Yousef M, Yousef A, Chowdhury S, Fanaeian MM, Knafl M, Peterson J, Zeineddine M, Alfaro K, Zeineddine F, Goldstein D, Hornstein N, Dasari A, Huey R, Johnson B, Higbie V, Bent A, Kee B, Lee M, Morelli MP, Morris VK, Halperin D, Overman MJ, Parseghian C, Vilar E, Wolff R, Raghav KP, White MG, Uppal A, Sun R, Wang W, Kopetz S, Willis J, and Shen JP
- Abstract
Importance: Disparity in overall survival (OS) and differences in the frequency of driver gene variants by race and ethnicity have been separately observed in patients with colorectal cancer; however, how these differences contribute to survival disparity is unknown., Objective: To quantify the association of molecular, socioeconomic, and clinical covariates with racial and ethnic disparities in overall survival among patients with colorectal cancer., Design, Setting, and Participants: This single-center cohort study was conducted at a tertiary-level cancer center using relevant data on all patients diagnosed with colorectal cancer from January 1, 1973, to March 1, 2023. The relative contribution of variables to the disparity was determined using mediation analysis with sequential multivariate Cox regression models., Main Outcome: OS, from diagnosis date and from start of first-line chemotherapy., Results: The study population of 47 178 patients (median [IQR] age, 57.0 [49-66] years; 20 465 [43.4%] females and 26 713 [56.6%] males; 3.0% Asian, 8.7% Black, 8.8% Hispanic, and 79.4% White individuals) had a median (IQR) follow-up from initial diagnosis of 124 (174) months and OS of 55 (145) months. Compared with White patients, Black patients had worse OS (hazard ratio [HR], 1.16; 95% CI, 1.09-1.24; P <.001), whereas Asian and Hispanic patients had better OS (HR, 0.66; 95% CI, 0.59-0.74; P <.001; and 0.86; 95% CI, 0.81-0.92; P <.001, respectively). When restricted to patients with metastatic disease, the greatest disparity was between Black patients compared with White patients (HR, 1.2; 95% CI, 1.06-1.37; P <.001). Evaluating changes in OS disparity over 20 years showed disparity decreasing among Asian, Hispanic, and White patients, but increasing between Black patients and White patients (HRs, 1.18; 95% CI, 1.07-1.31 for 2008-2012; 1.24, 95% CI, 1.08-1.42 for 2013-2017; and 1.50; 95% CI, 1.20-1.87 for 2018-2023). Survival outcomes for first-line chemotherapy were worse for Black patients compared with White patients (median OS, 18 vs 26 months; HR, 1.30; 95% CI, 1.01-1.70). Among 7628 patients who had clinical molecular testing, APC, KRAS, and PIK3CA showed higher variant frequency in Black patients (false discovery rate [FDR], 0.01; < 0.001; and 0.01, respectively), whereas BRAF and KIT were higher among White patients (FDR, 0.001 and 0.01). Mediation analysis identified neighborhood socioeconomic status as the greatest contributor to OS disparity (29%), followed by molecular characteristics (microsatellite instability status, KRAS variation and BRAF variation, 10%), and tumor sidedness (9%)., Conclusions: This single-center cohort study identified substantial OS disparity and differing frequencies of driver gene variations by race and ethnicity. Socioeconomic status had the largest contribution but accounted for less than one-third of the disparity, with substantial contribution from tumor molecular features. Further study of the associations of genetic ancestry and the molecular pathogenesis of colorectal cancer with chemotherapy response is needed.
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- 2024
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3. Para-aortic Lymph Node Dissection for Colorectal Cancer: Predicting Pathologic Lymph Node Positivity and Optimizing Outcomes.
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Bhutiani N, Ochiai K, Awiwi MO, Rodriguez-Bigas MA, Uppal A, Peacock O, Messick C, White MG, Skibber JM, Bednarski BK, You YN, Chang GJ, Kaur H, and Konishi T
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- Humans, Male, Female, Aged, Middle Aged, Survival Rate, Retrospective Studies, Follow-Up Studies, Prognosis, Neoplasm Recurrence, Local pathology, Neoplasm Recurrence, Local surgery, Colorectal Neoplasms pathology, Colorectal Neoplasms surgery, Colorectal Neoplasms mortality, Lymph Node Excision, Lymph Nodes pathology, Lymph Nodes surgery, Lymphatic Metastasis
- Abstract
Introduction: In colorectal cancer, the presence of para-aortic lymph nodes (PALN) indicates extraregional disease. Appropriately selecting patients for whom PALN dissection will provide oncologic benefit remains challenging. This study identified factors to predict survival among patients undergoing PALN dissection for colorectal cancer., Methods: An institutional database was queried for patients who underwent curative-intent resection of clinically positive PALN for colorectal cancer between 2007 and 2020. Preoperative radiologic images were reviewed, and patients who did and did not have positive PALN on final pathology were compared. Survival analysis was performed to evaluate the impact of pathologically positive PALN on recurrence-free (RFS) and overall survival (OS)., Results: Of 74 patients who underwent PALN dissection, 51 had PALN metastasis at the time of primary tumor diagnosis, whereas 23 had metachronous PALN disease. Preoperative chemotherapy ± radiotherapy was given in 60 cases (81.1%), and 28 (37.8%) had pathologically positive PALN. Independent factors associated with positive PALN pathology included metachronous PALN disease and pretreatment and posttreatment radiographically abnormal PALN. On multivariable analysis, pathologically positive PALN was significantly associated with decreased RFS (hazard ratio 3.90) and OS (HR 4.49). Among patients with pathologically positive PALN, well/moderately differentiated histology was associated with better OS, and metachronous disease trended toward an association with better OS., Conclusions: Pathologically positive PALN are associated with poorer RFS and OS after PALN dissection for colorectal cancer. Clinicopathologic factors may predict pathologic PALN positivity. Curative-intent surgery may provide benefit, especially in patients with well-to-moderately differentiated primary tumors and possibly metachronous PALN disease., (© 2024. Society of Surgical Oncology.)
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- 2024
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4. Evaluation of Self-collected Saliva Samples Without Viral Transport Media for SARS-CoV-2 Testing via RT-PCR and Comparison of Amplicon Sequences Against Commonly Used Primers in Diagnostic Assays.
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Ramos BD, Hudson NR, Gonzales DE, Brown AN, White MG, Browde RJ, McNeary-Garvin AM, Knight CE, Pham KC, Sweatt RJ, Phan LM, Ly E, and Garcia AR
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- Humans, Reverse Transcriptase Polymerase Chain Reaction methods, Nasopharynx virology, COVID-19 Testing methods, Adult, Female, Male, Saliva virology, SARS-CoV-2 genetics, SARS-CoV-2 isolation & purification, COVID-19 diagnosis, COVID-19 virology, Specimen Handling methods, COVID-19 Nucleic Acid Testing methods, COVID-19 Nucleic Acid Testing instrumentation
- Abstract
Introduction: Mass screening for SARS-CoV-2 using nasopharyngeal swabs (NPS) is costly, uncomfortable for patients, and increases the chance of virus exposure to health care workers. Therefore, this study focused on determining if self-collected unpreserved saliva can be an effective alternative to NPS collection in COVID-19 surveillance., Materials and Methods: In this study, patients being tested for SARS-CoV-2 using NPS were asked to provide a saliva sample to compare their results. NPS samples were evaluated for SARS-CoV-2 using BioFire® FilmArray® Torch® or Cepheid® GeneXpert® systems while saliva samples were evaluated using an in-house developed reverse transcriptase polymerase chain reaction (RT-PCR) which targeted the Envelope (E) and Nucleocapsid (N) genes., Results: Detection of SARS-CoV-2 using self-collected saliva was found to be only slightly less accurate (<5%) than testing using NPS. In addition, initial saliva RT-PCR identified 27 positive subjects, 18 of which provided amplicons sufficient for confirmatory sequencing. The sequencing data showed a genetic shift in the virus within our population sometime between 22 June and July 8, 2021 from Alpha to Delta variant., Conclusions: The saliva sample collection method identifies the E gene in SARS COVID-2 samples which provides an alternative specimen source to the NPS. This identifies the S gene and ORF1ab. Saliva collection is more convenient to the patient, yields comparable results to NPS collection, and potentially increases Covid-19 surveillance., (Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2024. This work is written by (a) US Government employee(s) and is in the public domain in the US.)
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- 2024
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5. Momentum-Space Observation of Optically Excited Nonthermal Electrons in Graphene with Persistent Pseudospin Polarization.
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Bakalis J, Chernov S, Li Z, Kunin A, Withers ZH, Cheng S, Adler A, Zhao P, Corder C, White MG, Schönhense G, Du X, Kawakami RK, and Allison TK
- Abstract
The unique optical properties of graphene, with broadband absorption and ultrafast response, make it a critical component of optoelectronic and spintronic devices. Using time-resolved momentum microscopy with high data rate and high dynamic range, we report momentum-space measurements of electrons promoted to the graphene conduction band with visible light and their subsequent relaxation. We observe a pronounced nonthermal distribution of nascent photoexcited electrons with lattice pseudospin polarization in remarkable agreement with results of simple tight-binding theory. By varying the excitation fluence, we vary the relative importance of electron-electron vs electron-phonon scattering in the relaxation of the initial distribution. Increasing the excitation fluence results in increased noncollinear electron-electron scattering and reduced pseudospin polarization, although up-scattered electrons retain a degree of polarization. These detailed momentum-resolved electron dynamics in graphene demonstrate the capabilities of high-performance time-resolved momentum microscopy in the study of 2D materials and can inform the design of graphene devices.
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- 2024
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6. Incomplete Cytoreduction and Need for Major Hepatectomy Predict Shorter Survival in Patients Undergoing Combined Cytoreductive Surgery and Hepatectomy for Metastatic Colorectal Cancer.
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Ayabe RI, Beaty K, Newhook TE, Cao HST, Tzeng CD, Helmink BA, Uppal A, Vauthey JN, Fournier KF, and White MG
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- 2024
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7. Total Neoadjuvant Therapy for Rectal Cancer: Which Regimens to Use?
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Ochiai K, Bhutiani N, Ikeda A, Uppal A, White MG, Peacock O, Messick CA, Bednarski BK, You YN, Skibber JM, Chang GJ, and Konishi T
- Abstract
Total neoadjuvant therapy (TNT) is a novel strategy for rectal cancer that administers both (chemo)radiotherapy and systemic chemotherapy before surgery. TNT is expected to improve treatment compliance, tumor regression, organ preservation, and oncologic outcomes. Multiple TNT regimens are currently available with various combinations of the treatments including induction or consolidation chemotherapy, triplet or doublet chemotherapy, and long-course chemoradiotherapy or short-course radiotherapy. Evidence on TNT is rapidly evolving with new data on clinical trials, and no definitive consensus has been established on which regimens to use for improving outcomes. Clinicians need to understand the advantages and limitations of the available regimens for multidisciplinary decision making. This article reviews currently available evidence on TNT for rectal cancer. A decision making flow chart is provided for tailor-made use of TNT regimens based on tumor location and local and systemic risk.
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- 2024
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8. Understanding the Decomposition of Dimethyl Methyl Phosphonate on Metal-Modified TiO 2 (110) Surfaces Using Ensembles of Product Configurations.
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Bonney MJ, Tesvara C, Sautet P, and White MG
- Abstract
The decomposition of dimethyl methyl phosphonate (DMMP), a simulant for the nerve agent sarin, was investigated on Cu
4 /TiO2 (110) and K/Cu4 /TiO2 (110) surfaces using a combination of near-ambient-pressure X-ray photoelectron spectroscopy (NAP-XPS) and density functional theory calculations (DFT). Mass-selected Cu4 clusters and potassium (K) atoms were deposited onto TiO2 (110) as a metal catalyst and alkali promoter to improve the reactivity and recyclability of the TiO2 surface after exposure to DMMP. Surface reaction products resulting from decomposition of DMMP were probed by NAP-XPS measurements of phosphorus (P) 2p and carbon 1s core-level spectra. The Cu4 /TiO2 (110) surface is found to be very active for DMMP decomposition with highly reduced P-species observed even at room temperature (RT). The codeposition of K atoms and Cu4 clusters further improves the reactivity with no intact DMMP detectable. Temperature-dependent measurements show that the presence of K atoms promotes the removal of residual P-species at temperatures > 600 K. Detailed DFT calculations were performed to determine the surface structures and energetically accessible pathways for DMMP decomposition on Cu4 /TiO2 (110) and K/Cu4 /TiO2 (110) surfaces. The calculations show that DMMP and P-containing reaction products preferentially bind to the TiO2 surface, while the molecular fragments, i.e., methoxy and methyl, bind to both the Cu4 clusters and TiO2 . The Cu4 clusters make the P-O, O-C, and P-C bond cleavages of DMMP markedly more exothermic. The Cu4 clusters are highly fluxional with atomic structures that depend on the configuration of fragments bound to them. Finally, the manifold of P 2p chemical shifts calculated for a large number of energetically favorable configurations of decomposition products is in good agreement with the observed XPS spectra and provides an alternative way of interpreting incompletely resolved core-level spectra using an ensemble of observed structures.- Published
- 2024
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9. Multi-Institutional Study Evaluating the Role of Circulating Tumor DNA in the Management of Appendiceal Cancers.
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Belmont E, Bansal VV, Yousef MMG, Zeineddine MA, Su D, Dhiman A, Liao CY, Polite B, Eng OS, Fournier KF, White MG, Turaga KK, Shen JP, and Shergill A
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- Humans, Male, Female, Middle Aged, Aged, Adult, Neoplasm Recurrence, Local blood, Aged, 80 and over, Circulating Tumor DNA blood, Circulating Tumor DNA genetics, Appendiceal Neoplasms genetics, Appendiceal Neoplasms blood, Appendiceal Neoplasms pathology, Appendiceal Neoplasms therapy, Appendiceal Neoplasms drug therapy
- Abstract
Purpose: Conventional surveillance methods are poorly sensitive for monitoring appendiceal cancers (AC). This study investigated the utility of circulating tumor DNA (ctDNA) in evaluating systemic therapy response and recurrence after surgery for AC., Methods: Patients from two specialized centers who underwent tumor-informed ctDNA testing (Signatera) were evaluated to determine the association between systemic therapy and ctDNA detection. In addition, the accuracy of ctDNA detection during surveillance for the diagnosis of recurrence after complete cytoreductive surgery (CRS) for grade 2-3 ACs with peritoneal metastases (PM) was investigated., Results: In this cohort of 94 patients with AC, most had grade 2-3 tumors (84.0%) and PM (84.0%). Fifty patients completed the assay in the presence of identifiable disease, among which ctDNA was detected in 4 of 7 (57.1%), 10 of 16 (62.5%), and 19 of 27 (70.4%) patients with grade 1, 2, and 3 diseases, respectively. Patients who had recently received systemic chemotherapy had ctDNA detected less frequently (7 of 16 [43.8%] v 26 of 34 [76.5%]; odds ratio, 0.22 [95% CI, 0.06 to 0.82]; P = .02). Among 36 patients with complete CRS for grade 2-3 AC-PM, 16 (44.4%) developed recurrence (median follow-up, 19.6 months). ctDNA detection was associated with shorter recurrence-free survival (median 11.3 months v not reached; hazard ratio, 14.1 [95% CI, 1.7 to 113.8]; P = .01) and showed high accuracy for the detection of recurrence (sensitivity 93.8%, specificity 85.0%). ctDNA was more sensitive than carcinoembryonic antigen (62.5%), CA19-9 (25.0%), and CA125 (18.8%) and was the only elevated biomarker in four (25%) patients with recurrence., Conclusion: This study revealed a reduced ctDNA detection frequency after systemic therapy and accurate recurrence assessment after CRS. These findings underscore the role of ctDNA as a predictive and prognostic biomarker for grade 2-3 AC-PM management.
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- 2024
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10. Metastasis and the Microbiome: The Impact of Bacteria in Disseminated Colorectal Cancer.
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Ayabe RI and White MG
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- Humans, Dysbiosis microbiology, Bacteria classification, Bacteria genetics, Fecal Microbiota Transplantation, Colorectal Neoplasms microbiology, Colorectal Neoplasms pathology, Colorectal Neoplasms therapy, Gastrointestinal Microbiome physiology, Neoplasm Metastasis
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Metastasis remains a leading cause of mortality for patients with solid tumors. An expanding body of literature suggests interplay between the host, gut, and tumoral microbiomes may play a role in cancer initiation and distant dissemination. These associations have been particularly well-studied in colorectal cancer, where gut dysbiosis and an endotoxin-induced inflammatory milieu foster premalignant polyp formation, setting the stage for carcinogenesis. Subsequent violation of the gut vascular barrier enables dissemination of bacterial agents to sites such as the liver, where they contribute to establishment of pre-metastatic niches, which promote tumor cell extravasation and metastatic outgrowth. Intriguingly, breakdown of this vascular barrier has been shown to be aided by the presence of tumoral bacteria. The presence of similar species, including Fusobacterium nucleatum and Escherichia Coli , in both primary and metastatic colorectal tumors, supports this hypothesis and their presence is associated with chemotherapy resistance and an overall poor prognosis. Specific gut microbial populations are also associated with differential response to immunotherapy, which has a growing role in microsatellite unstable colorectal cancers. Recent work suggests that modulation of gut microbiome using dietary modification, targeted antibiotics, or fecal microbiota transplantation may improve response to immunotherapy and oncologic outcomes. Elucidation of the precise mechanistic links between the microbiome and cancer dissemination will open the doors to additional therapeutic possibilities., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). Published by IMR Press.)
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- 2024
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11. Immuno-Oncology: New Insights into Targets and Therapies.
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Schokrpur S, White MG, Roland CL, and Patel SP
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- Humans, Immunotherapy methods, Medical Oncology, T-Lymphocytes, Neoplasms therapy, Vaccines
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The role of immunotherapy in the care of surgical oncology patients promises to expand as investigators and clinicians evaluate new targets and approaches. Currently active clinical trials evaluate new immune checkpoints, including lymphocyte activation gene 3, T cell immunoreceptor with Ig and ITIM domains, and killer Ig-like receptor 2DL1/2L3. Vaccines delivered through mRNA have demonstrated exciting results in early clinical trials and hold promise for expanded application. Investigational approaches include dendritic cell vaccines, peptide vaccines, cytokines therapies, and cellular therapies. These studies have the potential to revolutionize the management of surgical oncology patients and promote durable cures following surgical resection., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)
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- 2024
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12. Androgen drives melanoma invasiveness and metastatic spread by inducing tumorigenic fucosylation.
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Liu Q, Adhikari E, Lester DK, Fang B, Johnson JO, Tian Y, Mockabee-Macias AT, Izumi V, Guzman KM, White MG, Koomen JM, Wargo JA, Messina JL, Qi J, and Lau EK
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- Humans, Male, Female, Androgens, Lewis X Antigen metabolism, Glycosylation, Receptors, Androgen genetics, Receptors, Androgen metabolism, Cell Line, Tumor, Fucosyltransferases genetics, Fucosyltransferases metabolism, Melanoma metabolism, Neural Cell Adhesion Molecule L1 metabolism
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Melanoma incidence and mortality rates are historically higher for men than women. Although emerging studies have highlighted tumorigenic roles for the male sex hormone androgen and its receptor (AR) in melanoma, cellular and molecular mechanisms underlying these sex-associated discrepancies are poorly defined. Here, we delineate a previously undisclosed mechanism by which androgen-activated AR transcriptionally upregulates fucosyltransferase 4 (FUT4) expression, which drives melanoma invasiveness by interfering with adherens junctions (AJs). Global phosphoproteomic and fucoproteomic profiling, coupled with in vitro and in vivo functional validation, further reveal that AR-induced FUT4 fucosylates L1 cell adhesion molecule (L1CAM), which is required for FUT4-increased metastatic capacity. Tumor microarray and gene expression analyses demonstrate that AR-FUT4-L1CAM-AJs signaling correlates with pathological staging in melanoma patients. By delineating key androgen-triggered signaling that enhances metastatic aggressiveness, our findings help explain sex-associated clinical outcome disparities and highlight AR/FUT4 and its effectors as potential prognostic biomarkers and therapeutic targets in melanoma., (© 2024. The Author(s).)
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- 2024
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13. Serum Tumor Markers and Outcomes in Patients With Appendiceal Adenocarcinoma.
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Yousef A, Yousef M, Zeineddine MA, More A, Fanaeian M, Chowdhury S, Knafl M, Edelkamp P, Ito I, Gu Y, Pattalachinti V, Naini ZA, Zeineddine FA, Peterson J, Alfaro K, Foo WC, Jin J, Bhutiani N, Higbie V, Scally CP, Kee B, Kopetz S, Goldstein D, Strach M, Williamson A, Aziz O, Barriuso J, Uppal A, White MG, Helmink B, Fournier KF, Raghav KP, Taggart MW, Overman MJ, and Shen JP
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- Humans, Middle Aged, Aged, Aged, 80 and over, Biomarkers, Tumor, Retrospective Studies, CA-19-9 Antigen, Carcinoembryonic Antigen, CA-125 Antigen, Adenocarcinoma diagnosis, Appendiceal Neoplasms, Neoplasms, Second Primary
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Importance: Serum tumor markers carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), and cancer antigen 125 (CA125) have been useful in the management of gastrointestinal and gynecological cancers; however, there is limited information regarding their utility in patients with appendiceal adenocarcinoma., Objective: To assess the association of serum tumor markers (CEA, CA19-9, and CA125) with clinical outcomes and pathologic and molecular features in patients with appendiceal adenocarcinoma., Design, Setting, and Participants: This is a retrospective cohort study at a single tertiary care comprehensive cancer center. The median (IQR) follow-up time was 52 (21-101) months. Software was used to query the MD Anderson internal patient database to identify patients with a diagnosis of appendiceal adenocarcinoma and at least 1 tumor marker measured at MD Anderson between March 2016 and May 2023. Data were analyzed from January to December 2023., Main Outcomes and Measures: Association of serum tumor markers with survival in patients with appendiceal adenocarcinoma. Cox proportional hazards regression analyses were also performed to assess associations between clinical factors (serum tumor marker levels, demographics, and patient and disease characteristics) and patient outcomes (overall survival)., Results: A total of 1338 patients with appendiceal adenocarcinoma were included, with a median (range) age at diagnosis of 56.5 (22.3-89.6) years. The majority of the patients had metastatic disease (1080 patients [80.7%]). CEA was elevated in 742 of the patients tested (56%), while CA19-9 and CA125 were elevated in 381 patients (34%) and 312 patients (27%), respectively. Individually, elevation of CEA, CA19-9, or CA125 were associated with worse 5-year survival; elevated vs normal was 81% vs 95% for CEA (hazard ratio [HR], 4.0; 95% CI, 2.9-5.6), 84% vs 92% for CA19-9 (HR, 2.2; 95% CI, 1.4-3.4), and 69% vs 93% for CA125 (HR, 4.6; 95% CI, 2.7-7.8) (P < .001 for all). Quantitative evaluation of tumor markers was associated with outcomes. Patients with highly elevated (top 10th percentile) CEA, CA19-9, or CA125 had markedly worse survival, with 5-year survival rates of 59% for CEA (HR, 9.8; 95% CI, 5.3-18.0), 64% for CA19-9 (HR, 6.0; 95% CI, 3.0-11.7), and 57% for CA125 (HR, 7.6; 95% CI, 3.5-16.5) (P < .001 for all). Although metastatic tumors had higher levels of all tumor markers, when restricting survival analysis to 1080 patients with metastatic disease, elevated CEA, CA19-9, or CA125 were all still associated worse survival (HR for CEA, 3.4; 95% CI, 2.5-4.8; P < .001; HR for CA19-9, 1.8; 95% CI, 1.2-2.7; P = .002; and HR for CA125, 3.9; 95% CI, 2.4-6.4; P < .001). Interestingly, tumor grade was not associated with CEA or CA19-9 level, while CA-125 was slightly higher in high-grade tumors relative to low-grade tumors (mean value, 18.3 vs 15.0; difference, 3.3; 95% CI, 0.9-3.7; P < .001). Multivariable analysis identified an incremental increase in the risk of death with an increase in the number of elevated tumor markers, with an 11-fold increased risk of death in patients with all 3 tumor markers elevated relative to those with none elevated. Somatic mutations in KRAS and GNAS were associated with significantly higher levels of CEA and CA19-9., Conclusions and Relevance: In this retrospective study of serum tumor markers in patients with appendiceal adenocarcinoma, CEA, CA19-9, and CA125 were associated with overall survival in appendiceal adenocarcinoma. Given their value, all 3 biomarkers should be included in the initial workup of patients with a diagnosis of appendiceal adenocarcinoma.
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- 2024
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14. The current multidisciplinary management of rectal cancer.
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Bhutiani N, Peacock O, Uppal A, You YN, Bednarski BK, Skibber JM, Messick C, White MG, Chang GJ, and Konishi T
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Multidisciplinary management of rectal cancer has rapidly evolved over the last several years. This review describes recent data surrounding total neoadjuvant therapy, organ preservation, and management of lateral pelvic lymph nodes. It then presents our treatment algorithm for management of rectal cancer at The University of Texas MD Anderson Cancer Center in the context of this and other existing literature. As part of this discussion, the review describes how we tailor management based upon both patient and tumor-related factors in an effort to optimize patient outcomes., Competing Interests: Dr. George J. Chang serves as a member of the editorial board for Annals of Gastroenterological Surgery., (© 2024 The Authors. Annals of Gastroenterological Surgery published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Gastroenterological Surgery.)
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- 2024
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15. Repeat Cytoreduction and Hyperthermic Intraperitoneal Chemotherapy for Recurrent Mucinous Appendiceal Adenocarcinoma: A Viable Treatment Strategy with Demonstrable Benefit.
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Bhutiani N, Grotz TE, Concors SJ, White MG, Helmink BA, Raghav KP, Taggart MW, Beaty KA, Royal RE, Overman MJ, Matamoros A, Scally CP, Rafeeq S, Mansfield PF, and Fournier KF
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- Humans, Hyperthermic Intraperitoneal Chemotherapy, Cytoreduction Surgical Procedures, Combined Modality Therapy, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Neoplasm Recurrence, Local pathology, Retrospective Studies, Survival Rate, Hyperthermia, Induced adverse effects, Peritoneal Neoplasms pathology, Appendiceal Neoplasms pathology, Adenocarcinoma, Mucinous pathology
- Abstract
Introduction: Many patients with mucinous appendiceal adenocarcinoma experience peritoneal recurrence despite complete cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Prior work has demonstrated that repeat CRS/HIPEC can prolong survival in select patients. We sought to validate these findings using outcomes from a high-volume center., Patients and Methods: Patients with mucinous appendiceal adenocarcinoma who underwent CRS/HIPEC at MD Anderson Cancer Center between 2004 and 2021 were stratified by whether they underwent CRS/HIPEC for recurrent disease or as part of initial treatment. Only patients who underwent complete CRS/HIPEC were included. Initial and recurrent groups were compared., Results: Of 437 CRS/HIPECs performed for mucinous appendiceal adenocarcinoma, 50 (11.4%) were for recurrent disease. Patients who underwent CRS/HIPEC for recurrent disease were more often treated with an oxaliplatin or cisplatin perfusion (35%/44% recurrent vs. 4%/1% initial, p < 0.001), had a longer operative time (median 629 min recurrent vs. 511 min initial, p = 0.002), and had a lower median length of stay (10 days repeat vs. 13 days initial, p < 0.001). Thirty-day complication and 90-day mortality rates did not differ between groups. Both cohorts enjoyed comparable recurrence free survival (p = 0.82). Compared with patients with recurrence treated with systemic chemotherapy alone, this select cohort of patients undergoing repeat CRS/HIPEC enjoyed better overall survival (p < 0.001)., Conclusions: In appropriately selected patients with recurrent appendiceal mucinous adenocarcinoma, CRS/HIPEC can provide survival benefit equivalent to primary CRS/HIPEC and that may be superior to that conferred by systemic therapy alone in select patients. These patients should receive care at a high-volume center in the context of a multidisciplinary team., (© 2023. The Author(s).)
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- 2024
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16. Treatment Variation and Long-Term Outcomes of Low-Grade Appendiceal Neoplasms.
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White MG, Bhutiani N, Helmink BA, Taggart M, Foo WC, Mansfield PF, Fournier KF, and Scally CP
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- Humans, Retrospective Studies, Prognosis, Combined Modality Therapy, Cytoreduction Surgical Procedures, Survival Rate, Antineoplastic Combined Chemotherapy Protocols, Appendiceal Neoplasms pathology, Peritoneal Neoplasms therapy, Hyperthermia, Induced adverse effects
- Abstract
Background: Heterogenous nomenclature describing appendiceal neoplasms has added to uncertainty around their appropriate treatment. Although a recent consensus has established the term low-grade appendiceal neoplasm (LAMN), we hypothesize that significant variation remains in the treatment of LAMNs., Methods: We retrospectively reviewed our prospectively maintained appendiceal registry, identifying patients with LAMNs from 2009 to 2019. We assessed variability in treatment, including whether patients underwent colectomy, spread of disease at presentation, and long-term outcomes., Results: Of 136 patients with LAMNs, 88 (35%) presented with localized disease and 48 (35%) with disseminated peritoneal disease. Median follow-up was 2.9 years (IQR 1.9-4.4), and 120 (88%) patients underwent pre-referral surgery. Among 26 pre-referral colectomy patients, 23 (88%) were performed for perceived oncologic need/nodal evaluation; no nodal metastases were identified. In patients with resected LAMNs without radiographic evidence of disseminated disease, 41 (47%) underwent second look diagnostic laparoscopy (DL) to evaluate for occult metastases. No peritoneal metastases were identified. Patients with disseminated disease were treated with cytoreductive surgery/heated intraperitoneal chemotherapy (CRS/HIPEC). For patients undergoing CRS/HIPEC, 5-year recurrence-free survival was 94% (95% CI 81-98%). For patients with localized disease, 5-year RFS was 98% (95% CI 85-99%)., Conclusions: Significant variation exists in treatment patterns for LAMNs, particularly prior to referral to a high-volume center. Patients frequently underwent colectomy without apparent oncologic benefit. In the current era of high-quality cross sectional imaging, routine use of DL has low yield and is not recommended. Recurrence in this population is rare, and low-intensity surveillance can be offered. Overall prognosis is excellent, even with peritoneal disease., (© 2023. Society of Surgical Oncology.)
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- 2023
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17. ASO Author Reflections: Contemporary Management of Low-Grade Appendiceal Mucinous Neoplasms.
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White MG and Scally CP
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- Humans, Appendiceal Neoplasms, Pseudomyxoma Peritonei, Peritoneal Neoplasms
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- 2023
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18. Utility of Circulating Tumor DNA in Appendiceal Tumors.
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Bhutiani N, Helmink BA, Zeineddine M, Uppal A, Shen JP, Spickard E, and White MG
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- Humans, Combined Modality Therapy, Antineoplastic Combined Chemotherapy Protocols, Cytoreduction Surgical Procedures, Retrospective Studies, Survival Rate, Appendiceal Neoplasms genetics, Appendiceal Neoplasms drug therapy, Circulating Tumor DNA genetics, Circulating Tumor DNA therapeutic use, Hyperthermia, Induced
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- 2023
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19. Decreasing Environmental Operating Room Chemotherapy Levels Following Heated Intraperitoneal Chemotherapy (HIPEC) Through Implementation of Standard Protocols.
- Author
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Bhutiani N, White MG, Kim BJ, Scally CP, Helmink BA, Mansfield PF, Fournier KF, and Royal RE
- Subjects
- Humans, Hyperthermic Intraperitoneal Chemotherapy, Combined Modality Therapy, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Cytoreduction Surgical Procedures, Operating Rooms, Hyperthermia, Induced methods
- Published
- 2023
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20. Communication Frameworks for Palliative Surgical Consultations: A Randomized Study of Advanced Cancer Patients.
- Author
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Blumenthaler AN, Robinson KA, Hodge C, Xiao L, Lilley EJ, Griffin JF, White MG, Day R, Tanco K, Bruera E, and Badgwell BD
- Subjects
- Male, Humans, Adult, Middle Aged, Aged, Female, Patients, Physician-Patient Relations, Communication, Surgeons, Neoplasms surgery
- Abstract
Objective: To evaluate whether patients with advanced cancer prefer surgeons to use the best case/worst case (BC/WC) communication framework over the traditional risk/benefit (R/B) framework in the context of palliative surgical scenarios., Background: Identifying the patient's preferred communication frameworks may improve satisfaction and outcome measures during difficult clinical decision-making., Methods: In a video-vignette-based randomized, double-blinded study from November 2020 to May 2021, patients with advanced cancer viewed 2 videos depicting a physician-patient encounter in a palliative surgical scenario, in which the surgeon uses either the BC/WC or the R/B framework to discuss treatment options. The primary outcome was the patients' preferred video surgeon., Results: One hundred fifty-five patients were approached to participate; 66 were randomized and 58 completed the study (mean age 55.8 ± 13.8 years, 60.3% males). 22 patients (37.9%, 95% CI: 25.4%-50.4%) preferred the surgeon using the BC/WC framework, 21 (36.2%, 95% CI: 23.8%-48.6%) preferred the surgeon using the R/B framework, and 15 (25.9%, 95% CI: 14.6%-37.2%) indicated no preference. High trust in the medical profession was inversely associated with a preference for the surgeon using BC/WC framework (odds ratio: 0.83, 95% CI: 0.70-0.98, P = 0.03). The BC/WC framework rated higher for perceived surgeon's listening (4.6 ± 0.7 vs 4.3±0.9, P = 0.03) and confidence in the surgeon's trustworthiness (4.3 ± 0.8 vs 4.0 ± 0.9, P = 0.04)., Conclusions: Surgeon use of the BC/WC communication framework was not universally preferred but was as acceptable to patients as the traditional R/B framework and rated higher in certain aspects of communication. A preference for a surgeon using BC/WC was associated with lower trust in the medical profession. Surgeons should consider the BC/WC framework to individualize their approach to challenging clinical discussions., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)
- Published
- 2023
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21. Intraperitoneal Paclitaxel Is a Safe and Effective Therapeutic Strategy for Treating Mucinous Appendiceal Adenocarcinoma.
- Author
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Ito I, Yousef AMG, Chowdhury S, Dickson PN, Naini ZA, White MG, Fleten KG, Flatmark K, Fournier KF, Fowlkes NW, and Shen JP
- Subjects
- Female, Humans, Animals, Mice, Paclitaxel, Prospective Studies, Adenocarcinoma, Mucinous, Adenocarcinoma pathology, Ovarian Neoplasms drug therapy
- Abstract
Appendiceal adenocarcinomas (AA) are a rare and heterogeneous mix of tumors for which few preclinical models exist. The rarity of AA has made performing prospective clinical trials difficult, which has partly contributed to AA remaining an orphan disease with no chemotherapeutic agents approved by the FDA for its treatment. AA has a unique biology in which it frequently forms diffuse peritoneal metastases but almost never spreads via a hematogenous route and rarely spreads to lymphatics. Given the localization of AA to the peritoneal space, intraperitoneal delivery of chemotherapy could be an effective treatment strategy. Here, we tested the efficacy of paclitaxel given by intraperitoneal administration using three orthotopic patient-derived xenograft (PDX) models of AA established in immunodeficient NSG mice. Weekly intraperitoneal paclitaxel treatment dramatically reduced AA tumor growth in all three PDX models. Comparing the safety and efficacy of intravenous with intraperitoneal administration, intraperitoneal delivery of paclitaxel was more effective, with reduced systemic side effects in mice. Given the established safety record of intraperitoneal paclitaxel in gastric and ovarian cancers, and lack of effective chemotherapeutics for AA, these data showing the activity of intraperitoneal paclitaxel in orthotopic PDX models of mucinous AA support the evaluation of intraperitoneal paclitaxel in a prospective clinical trial., Significance: The activity and safety of intraperitoneal paclitaxel in orthotopic PDX models of mucinous appendiceal adenocarcinoma supports the evaluation of intraperitoneal paclitaxel in a prospective clinical trial of this rare tumor type., (©2023 American Association for Cancer Research.)
- Published
- 2023
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22. Young-onset Rectal Cancer: Unique Tumoral Microbiome and Correlation With Response to Neoadjuvant Therapy.
- Author
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White MG, Damania A, Alshenaifi J, Sahasrabhojane P, Peacock O, Losh J, Wong MC, Lutter-Berkova Z, Chang GJ, Futreal A, Wargo JA, Ajami NJ, Kopetz S, and You YN
- Subjects
- Humans, Middle Aged, Neoadjuvant Therapy, Biopsy, Rectal Neoplasms therapy, Rectal Neoplasms pathology, Microbiota
- Abstract
Objective: External exposures, the host, and the microbiome interact in oncology. We aimed to investigate tumoral microbiomes in young-onset rectal cancers (YORCs) for profiles potentially correlative with disease etiology and biology., Background: YORC is rapidly increasing, with 1 in 4 new rectal cancer cases occurring under the age of 50 years. Its etiology is unknown., Methods: YORC (<50 y old) or later-onset rectal cancer (LORC, ≥50 y old) patients underwent pretreatment biopsied of tumor and tumor-adjacent normal (TAN) tissue. After whole genome sequencing, metagenomic analysis quantified microbial communities comparing tumors versus TANs and YORCs versus LORCs, controlling for multiple testing. Response to neoadjuvant therapy (NT) was categorized as major pathological response (MPR, ≤10% residual viable tumor) versus non-MPR., Results: Our 107 tumors, 75 TANs from 37 (35%) YORCs, and 70 (65%) LORCs recapitulated bacterial species were previously associated with colorectal cancers (all P <0.0001). YORC and LORC tumoral microbiome signatures were distinct. After NT, 13 patients (12.4%) achieved complete pathologic response, whereas MPR occurred in 47 patients (44%). Among YORCs, MPR was associated with Fusobacterium nucleaum , Bacteroides dorei, and Ruminococcus bromii (all P <0.001), but MPR in LORC was associated with R. bromii ( P <0.001). Network analysis of non-MPR tumors demonstrated a preponderance of oral bacteria not observed in MPR tumors., Conclusions: Microbial signatures were distinct between YORC and LORC. Failure to achieve an MPR was associated with oral bacteria in tumors. These findings urge further studies to decipher correlative versus mechanistic associations but suggest a potential for microbial modulation to augment current treatments., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)
- Published
- 2023
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23. Aggregation of Size-Selected Oxide Clusters Deposited onto Au(111).
- Author
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Wang J, Rozycki MT, Tong X, and White MG
- Abstract
Kinetic Monte Carlo (kMC) simulations along with density functional theory (DFT) calculations were used to investigate the aggregation of size-selected Nb
3 Oy ( y = 5, 6, 7) clusters deposited onto the Au(111) surface. Recent STM experiments showed that the cluster binding sites and sizes of the cluster assemblies on the Nb3 Oy /Au(111) surfaces strongly depend on the stoichiometry of the clusters, i.e., the oxygen-to-niobium ratio. To better understand the origins of these differences, kMC simulations of the nucleation and growth of cluster assemblies were performed using energy barriers for diffusion and intercluster interactions estimated from DFT calculations of cluster binding and dimerization energies, respectively. Comparisons of the kMC simulations with STM images of the as-deposited Nb3 Oy /Au(111) surfaces at RT and after high temperature annealing were used to further optimize the energetics and gauge the importance of nearest neighbor interactions. The kMC simulations demonstrate that the assembly of Nb3 Oy clusters on Au(111) are largely controlled by the magnitude of the barriers for diffusion and interparticle-bond formation, while changes at higher temperatures are sensitive to the binding energies between nearest neighbors. Simulations for the Nb3 O5 and Nb3 O6 clusters, which exhibit smaller cluster assembly sizes in STM, required larger diffusion barriers as well as different barriers for interparticle binding, which reflected differences in DFT calculated dimerization energies. The results demonstrate the effectiveness of combined DFT and kMC calculations for understanding how the stoichiometry affects the aggregation of small oxide clusters on a metal surface.- Published
- 2023
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24. The Clinical Significance of CEA, CA19-9, and CA125 in Management of Appendiceal Adenocarcinoma.
- Author
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Yousef A, Yousef M, Zeineddine M, More A, Chowdhury S, Knafl M, Edelkamp P, Ito I, Gu Y, Pattalachinti V, Naini ZA, Zeineddine F, Peterson J, Alfaro K, Foo WC, Jin J, Bhutiani N, Higbie V, Scally C, Kee B, Kopetz S, Goldstein D, Uppal A, White MG, Helmink B, Fournier K, Raghav K, Taggart M, Overman MJ, and Shen JP
- Abstract
Importance: Serum tumor markers CEA, CA19-9, & CA125 have been useful in the management of gastrointestinal and gynecological cancers, however there is limited information regarding their utility in patients with appendiceal adenocarcinoma., Objective: Assessing the association of serum tumor markers (CEA, CA19-9, and CA125) with clinical outcomes, pathologic, and molecular features in patients with appendiceal adenocarcinoma., Design: This is a retrospective study with results reported in 2023. The median follow-up time was 43 months., Setting: Single tertiary care comprehensive cancer center., Participants: Under an approved Institutional Review Board protocol, the Palantir Foundry software system was used to query the MD Anderson internal patient database to identify patients with a diagnosis of appendiceal adenocarcinoma and at least one tumor marker measured at MD Anderson between 2016 and 2023., Results: A total of 1,338 patients with appendiceal adenocarcinoma were included, with a median age of 56.5 years. The majority of the patients had metastatic disease (80.7%). CEA was elevated in more than half of the patients tested (56%), while CA19-9 and CA125 were elevated in 34% and 27%, respectively. Individually, elevation of CEA, CA19-9, or CA125 were associated with worse 5-year survival; 82% vs 95%, 84% vs 92%, and 69% vs 93% elevated vs normal for CEA, CA19-9, and CA125 respectively (all p<0.0001). Quantitative evaluation of tumor markers increased prognostic ability. Patients with highly elevated (top 10
th percentile) CEA, CA19-9 or CA125 had markedly worse survival with 5-year survival rates of 59%, 64%, and 57%, respectively (HR vs. normal : 9.8, 6.0, 7.6, all p<0.0001). Although metastatic tumors had higher levels of all tumor markers, when restricting survival analysis to 1080 patients with metastatic disease elevated CEA, CA19-9 or CA125 were all still associated worse survival (HR vs. normal : 3.4, 1.8, 3.9, p<0.0001 for CEA and CA125, p=0.0019 for CA19-9). Interestingly tumor grade was not associated with CEA or CA19-9 level, while CA-125 was slightly higher in high relative to low-grade tumors (18.3 vs. 15.0, p=0.0009). Multivariable analysis identified an incremental increase in the risk of death with an increase in the number of elevated tumor markers, with a 11-fold increased risk of death in patients with all three tumor markers elevated relative to those with none elevated. Mutation in KRAS and GNAS were associated with significantly higher levels of CEA and CA19-9., Conclusions: These findings demonstrate the utility of measuring CEA, CA19-9, and CA125 in the management of appendiceal adenocarcinoma. Given their prognostic value, all three biomarkers should be included in the initial workup of patients diagnosed with appendiceal adenocarcinoma.- Published
- 2023
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25. Stranger Things: New Roles and Opportunities for Androgen Receptor in Oncology Beyond Prostate Cancer.
- Author
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Leo J, Dondossola E, Basham KJ, Wilson NR, Alhalabi O, Gao J, Kurnit KC, White MG, McQuade JL, Westin SN, Wellberg EA, and Frigo DE
- Subjects
- Humans, Male, Androgen Receptor Antagonists pharmacology, Androgen Receptor Antagonists therapeutic use, Receptors, Androgen genetics, Receptors, Androgen metabolism, Signal Transduction, Antineoplastic Agents pharmacology, Prostatic Neoplasms drug therapy, Prostatic Neoplasms metabolism, Prostatic Neoplasms, Castration-Resistant metabolism
- Abstract
The androgen receptor (AR) is one of the oldest therapeutic targets in oncology and continues to dominate the treatment landscape for advanced prostate cancer, where nearly all treatment regimens include some form of AR modulation. In this regard, AR remains the central driver of prostate cancer cell biology. Emerging preclinical and clinical data implicate key roles for AR in additional cancer types, thereby expanding the importance of this drug target beyond prostate cancer. In this mini-review, new roles for AR in other cancer types are discussed as well as their potential for treatment with AR-targeted agents. Our understanding of these additional functions for AR in oncology expand this receptor's potential as a therapeutic target and will help guide the development of new treatment approaches., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2023
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26. Effects of electron-donating ability of binding sites on coordination number: the interactions of a cyclic Schiff base with copper ions.
- Author
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Ranaweera SA, Donnadieu B, Henry WP, and White MG
- Abstract
The stepwise addition of Cu
2+ ions to the nonplanar cyclic Schiff base 5,9,14,18-tetramethyl-1,4,10,13-tetraazacyclooctadeca-5,8,14,17-tetraene-7,16-dione (H4 daaden, C18 H28 N4 O2 ), yields a one-end-open dinuclear copper chelate. The pyridine adduct of the dinuclear copper chelate, namely, [μ-6,11-dimethyl-7,10-diazahexadeca-5,11-diene-2,4,13,15-tetraolato(4-)](pyridine)dicopper(II), [Cu2 (C16 H20 N2 O4 )(C5 H5 N)], was characterized by single-crystal X-ray crystallography. The two CuII atoms of the copper chelate display different coordination modes, i.e. inner-N2 O2 and outer-O2 O2 . The Cu atom which is bonded in the outer-O2 O2 mode is axially bonded to a pyridine molecule, which suggests that the electron-donating ability of the O2 O2 site to the Cu atom is poor. As a result, the O2 O2 -bonded Cu atom has a coordination number of five, showing square-bipyramidal geometry around the Cu atom. The N2 O2 -coordinated site provides sufficient electron density to the other Cu atom to be stabilized with a coordination number of four, showing square-planar geometry around the Cu atom. The electron-donating ability of the ligand coordination sites plays a key role in determining the coordination number of the Cu atoms of the dicopper chelate.- Published
- 2023
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27. Antitumor activity of intraperitoneal paclitaxel in orthotopic patient-derived xenograft models of mucinous appendiceal adenocarcinoma.
- Author
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Ito I, Yousef AM, Dickson PN, Naini ZA, White MG, Fleten KG, Flatmark K, Fournier KF, Fowlkes NW, and Shen JP
- Abstract
Appendiceal adenocarcinomas (AAs) are a rare and heterogeneous mix of tumors for which few preclinical models exist. The rarity of AA has made performing prospective clinical trials difficult, and in part because of this AA remains an orphan disease with no chemotherapeutic agents approved by the FDA for its treatment. AA has a unique biology in which it frequently forms diffuse peritoneal metastases, but almost never spreads via a hematogenous route and rarely spreads to lymphatics. Given its localization to the peritoneal space we hypothesized that intraperitoneal (IP) delivery of chemotherapy could be an effective treatment strategy. Here we tested the efficacy paclitaxel given by IP administration using three orthotopic PDX models of AA established in NSG mice. Weekly treatment of 25.0 mg/kg of IP paclitaxel dramatically reduced AA tumor growth in TM00351 (81.9% reduction vs. control), PMP-2 (98.3% reduction vs. control), and PMCA-3 (71.4% reduction vs. control) PDX models. Comparing the safety and efficacy of intravenous (IV) to IP administration in PMCA-3, neither 6.25 nor 12.5 mg/kg of IV paclitaxel significantly reduced tumor growth. These results suggest that IP administration of paclitaxel is favorable to IV administration. Given the established safety record of IP paclitaxel in gastric and ovarian cancers, and lack of effective chemotherapeutics for AA, these data showing the activity of IP paclitaxel in orthotopic PDX models of mucinous AA support the evaluation of IP paclitaxel in a prospective clinical trial.
- Published
- 2023
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28. Fucosylation of HLA-DRB1 regulates CD4 + T cell-mediated anti-melanoma immunity and enhances immunotherapy efficacy.
- Author
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Lester DK, Burton C, Gardner A, Innamarato P, Kodumudi K, Liu Q, Adhikari E, Ming Q, Williamson DB, Frederick DT, Sharova T, White MG, Markowitz J, Cao B, Nguyen J, Johnson J, Beatty M, Mockabee-Macias A, Mercurio M, Watson G, Chen PL, McCarthy S, MoranSegura C, Messina J, Thomas KL, Darville L, Izumi V, Koomen JM, Pilon-Thomas SA, Ruffell B, Luca VC, Haltiwanger RS, Wang X, Wargo JA, Boland GM, and Lau EK
- Subjects
- Humans, HLA-DRB1 Chains genetics, HLA-DRB1 Chains metabolism, Immunotherapy, CD4-Positive T-Lymphocytes metabolism, CD4-Positive T-Lymphocytes pathology, Fucose metabolism, Melanoma drug therapy
- Abstract
Immunotherapy efficacy is limited in melanoma, and combinations of immunotherapies with other modalities have yielded limited improvements but also adverse events requiring cessation of treatment. In addition to ineffective patient stratification, efficacy is impaired by paucity of intratumoral immune cells (itICs); thus, effective strategies to safely increase itICs are needed. We report that dietary administration of L-fucose induces fucosylation and cell surface enrichment of the major histocompatibility complex (MHC)-II protein HLA-DRB1 in melanoma cells, triggering CD4
+ T cell-mediated increases in itICs and anti-tumor immunity, enhancing immune checkpoint blockade responses. Melanoma fucosylation and fucosylated HLA-DRB1 associate with intratumoral T cell abundance and anti-programmed cell death protein 1 (PD1) responder status in patient melanoma specimens, suggesting the potential use of melanoma fucosylation as a strategy for stratifying patients for immunotherapies. Our findings demonstrate that fucosylation is a key mediator of anti-tumor immunity and, importantly, suggest that L-fucose is a powerful agent for safely increasing itICs and immunotherapy efficacy in melanoma., (© 2023. The Author(s).)- Published
- 2023
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29. Momentum-Resolved Exciton Coupling and Valley Polarization Dynamics in Monolayer WS_{2}.
- Author
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Kunin A, Chernov S, Bakalis J, Li Z, Cheng S, Withers ZH, White MG, Schönhense G, Du X, Kawakami RK, and Allison TK
- Abstract
Using time- and angle-resolved photoemission, we present momentum- and energy-resolved measurements of exciton coupling in monolayer WS_{2}. We observe strong intravalley coupling between the B_{1s} exciton and A_{n>1} states. Our measurements indicate that the dominant valley depolarization mechanism conserves the exciton binding energy and momentum. While this conservation is consistent with Coulomb exchange-driven valley depolarization, we do not observe a momentum or energy dependence to the depolarization rate as would be expected for the exchange-based mechanism.
- Published
- 2023
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30. The Influence of the Microbiome on Metastatic Colorectal Cancer.
- Author
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Cass S and White MG
- Abstract
The microbiome (bacteria, viruses, and fungi) that exist within a patient's gastrointestinal tract and throughout their body have been increasingly understood to play a critical role in a variety of disease, including a number of cancer histologies. These microbial colonies are reflective of a patient's overall health state, their exposome, and germline genetics. In the case of colorectal adenocarcinoma, significant progress has been made in understanding the mechanism the microbiome plays beyond mere associations in both disease initiation and progression. Importantly, this improved understanding holds the potential to further identify the role these microbes play in colorectal cancer. We hope this improved understanding will be able to be leveraged in the future through either biomarkers or next-generation therapeutics to augment contemporary treatment algorithms through the manipulation of a patient's microbiome-whether through diet, antibiotics, prebiotics, or novel therapeutics. Here we review the role of the microbiome in the setting of patients with stage IV colorectal adenocarcinoma in both the development and progression or disease as well as response to therapeutics., Competing Interests: Conflict of Interest None declared., (Thieme. All rights reserved.)
- Published
- 2023
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31. Author Correction: Androgen receptor blockade promotes response to BRAF/MEK-targeted therapy.
- Author
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Vellano CP, White MG, Andrews MC, Chelvanambi M, Witt RG, Daniele JR, Titus M, McQuade JL, Conforti F, Burton EM, Lastrapes MJ, Ologun G, Cogdill AP, Morad G, Prieto P, Lazar AJ, Chu Y, Han G, Khan MAW, Helmink B, Davies MA, Amaria RN, Kovacs JJ, Woodman SE, Patel S, Hwu P, Peoples M, Lee JE, Cooper ZA, Zhu H, Gao G, Banerjee H, Lau M, Gershenwald JE, Lucci A, Keung EZ, Ross MI, Pala L, Pagan E, Segura RL, Liu Q, Borthwick MS, Lau E, Yates MS, Westin SN, Wani K, Tetzlaff MT, Haydu LE, Mahendra M, Ma X, Logothetis C, Kulstad Z, Johnson S, Hudgens CW, Feng N, Federico L, Long GV, Futreal PA, Arur S, Tawbi HA, Moran AE, Wang L, Heffernan TP, Marszalek JR, and Wargo JA
- Published
- 2023
- Full Text
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32. A role for the claustrum in cognitive control.
- Author
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Madden MB, Stewart BW, White MG, Krimmel SR, Qadir H, Barrett FS, Seminowicz DA, and Mathur BN
- Subjects
- Humans, Basal Ganglia, Neural Pathways, Frontal Lobe, Cognition, Claustrum
- Abstract
Early hypotheses of claustrum function were fueled by neuroanatomical data and yielded suggestions that the claustrum is involved in processes ranging from salience detection to multisensory integration for perceptual binding. While these hypotheses spurred useful investigations, incompatibilities inherent in these views must be reconciled to further conceptualize claustrum function amid a wealth of new data. Here, we review the varied models of claustrum function and synthesize them with developments in the field to produce a novel functional model: network instantiation in cognitive control (NICC). This model proposes that frontal cortices direct the claustrum to flexibly instantiate cortical networks to subserve cognitive control. We present literature support for this model and provide testable predictions arising from this conceptual framework., Competing Interests: Declaration of interests F.S.B. is on the scientific advisory board for Wavepaths, Ltd. and a scientific advisor for Mindstate Design Labs, Inc., (Copyright © 2022 Elsevier Ltd. All rights reserved.)
- Published
- 2022
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33. Stapled Versus Hand-Sewn Anastomosis in Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy.
- Author
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Bhutiani N, Cox DM, Robinson KA, Kim BJ, Mansfield PF, Fournier KF, and White MG
- Subjects
- Humans, Anastomosis, Surgical, Surgical Stapling, Suture Techniques, Hyperthermic Intraperitoneal Chemotherapy, Cytoreduction Surgical Procedures
- Published
- 2022
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34. Oncologic Components of HIPEC: Key Question : In patients with gastric or colorectal adenocarcinoma metastatic to the peritoneum, does cytoreductive surgery (CRS) plus hyperthermic intraperitoneal perfusion with chemotherapy (HIPEC) prolong survival or increase the risk of complications relative to CRS alone?
- Author
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White MG and Badgwell B
- Subjects
- Antineoplastic Combined Chemotherapy Protocols adverse effects, Combined Modality Therapy, Cytoreduction Surgical Procedures adverse effects, Humans, Hyperthermic Intraperitoneal Chemotherapy, Perfusion, Peritoneum pathology, Survival Rate, Adenocarcinoma pathology, Colorectal Neoplasms pathology, Hyperthermia, Induced adverse effects
- Published
- 2022
- Full Text
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35. The Microbiome in Gastrointestinal Cancers.
- Author
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White MG and Wargo JA
- Subjects
- Humans, Immune System, Gastrointestinal Neoplasms, Microbiota
- Abstract
The human microbiome has been recognized as increasingly important to health and disease. This is especially prescient in the development of various cancers, their progression, and the microbiome's modulation of various anticancer therapeutics. Mechanisms behind these interactions have been increasingly well described through modulation of the host immune system as well as induction of genetic changes and local inactivation of cancer therapeutics. Here, we review these associations for a variety of gastrointestinal malignancies as well as contemporary strategies proposed to leverage these associations to improve cancer treatment outcomes., (Copyright © 2022 Elsevier Inc. All rights reserved.)
- Published
- 2022
- Full Text
- View/download PDF
36. Step-stool conformation of a cyclic Schiff base derived from ethylenediamine and heptane-2,4,6-trione: evidence for partial hydrolysis in metal coordination.
- Author
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Ranaweera SA, Bruno D, Henry WP, and White MG
- Abstract
A Schiff base derived from ethylenediamine and heptane-2,4,6-trione, namely, 5,9,14,18-tetramethyl-1,4,10,13-tetraazacyclooctadeca-5,8,14,17-tetraene-7,16-dione (C
18 H28 N4 O2 ), abbreviated H4 daaden, was prepared and characterized for the first time by single-crystal X-ray diffraction. The atoms of the Schiff base occupy two different planes and thus the molecule is essentially nonplanar. An axis running through the C-C atoms of the ethylenediamine groups separate the two planes and these two planes are connected by bridging ethylene groups showing an angle of 117.34 (8)°. As a result, the side view of the molecule shows a `step-stool' conformation. The nonplanar nature of the Schiff base plays an important role in metal coordination, which leads to partial hydrolysis of the ring structure.- Published
- 2022
- Full Text
- View/download PDF
37. Androgen receptor blockade promotes response to BRAF/MEK-targeted therapy.
- Author
-
Vellano CP, White MG, Andrews MC, Chelvanambi M, Witt RG, Daniele JR, Titus M, McQuade JL, Conforti F, Burton EM, Lastrapes MJ, Ologun G, Cogdill AP, Morad G, Prieto P, Lazar AJ, Chu Y, Han G, Khan MAW, Helmink B, Davies MA, Amaria RN, Kovacs JJ, Woodman SE, Patel S, Hwu P, Peoples M, Lee JE, Cooper ZA, Zhu H, Gao G, Banerjee H, Lau M, Gershenwald JE, Lucci A, Keung EZ, Ross MI, Pala L, Pagan E, Segura RL, Liu Q, Borthwick MS, Lau E, Yates MS, Westin SN, Wani K, Tetzlaff MT, Haydu LE, Mahendra M, Ma X, Logothetis C, Kulstad Z, Johnson S, Hudgens CW, Feng N, Federico L, Long GV, Futreal PA, Arur S, Tawbi HA, Moran AE, Wang L, Heffernan TP, Marszalek JR, and Wargo JA
- Subjects
- Animals, Antineoplastic Combined Chemotherapy Protocols adverse effects, Female, Humans, Male, Mice, Protein Kinase Inhibitors therapeutic use, Skin Neoplasms drug therapy, Skin Neoplasms pathology, Survival Analysis, Androgen Receptor Antagonists, Melanoma drug therapy, Melanoma pathology, Mitogen-Activated Protein Kinase Kinases antagonists & inhibitors, Molecular Targeted Therapy, Proto-Oncogene Proteins B-raf antagonists & inhibitors, Receptors, Androgen metabolism
- Abstract
Treatment with therapy targeting BRAF and MEK (BRAF/MEK) has revolutionized care in melanoma and other cancers; however, therapeutic resistance is common and innovative treatment strategies are needed
1,2 . Here we studied a group of patients with melanoma who were treated with neoadjuvant BRAF/MEK-targeted therapy ( NCT02231775 , n = 51) and observed significantly higher rates of major pathological response (MPR; ≤10% viable tumour at resection) and improved recurrence-free survival (RFS) in female versus male patients (MPR, 66% versus 14%, P = 0.001; RFS, 64% versus 32% at 2 years, P = 0.021). The findings were validated in several additional cohorts2-4 of patients with unresectable metastatic melanoma who were treated with BRAF- and/or MEK-targeted therapy (n = 664 patients in total), demonstrating improved progression-free survival and overall survival in female versus male patients in several of these studies. Studies in preclinical models demonstrated significantly impaired anti-tumour activity in male versus female mice after BRAF/MEK-targeted therapy (P = 0.006), with significantly higher expression of the androgen receptor in tumours of male and female BRAF/MEK-treated mice versus the control (P = 0.0006 and P = 0.0025). Pharmacological inhibition of androgen receptor signalling improved responses to BRAF/MEK-targeted therapy in male and female mice (P = 0.018 and P = 0.003), whereas induction of androgen receptor signalling (through testosterone administration) was associated with a significantly impaired response to BRAF/MEK-targeted therapy in male and female patients (P = 0.021 and P < 0.0001). Together, these results have important implications for therapy., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2022
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38. Pathological response following neoadjuvant immunotherapy in mismatch repair-deficient/microsatellite instability-high locally advanced, non-metastatic colorectal cancer.
- Author
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Kothari A, White MG, Peacock O, Kaur H, Palmquist SM, You N, Taggart M, Salem U, Overman M, Kopetz S, and Chang GJ
- Subjects
- DNA Mismatch Repair genetics, Humans, Immunotherapy, Neoadjuvant Therapy, Colorectal Neoplasms genetics, Colorectal Neoplasms pathology, Colorectal Neoplasms therapy, Microsatellite Instability
- Published
- 2022
- Full Text
- View/download PDF
39. Correction to: The Microbiome: the Link to Colorectal Cancer and Research Opportunities.
- Author
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Cass SH, Ajami NJ, and White MG
- Published
- 2022
- Full Text
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40. The Microbiome: the Link to Colorectal Cancer and Research Opportunities.
- Author
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Cass SH, Ajami NJ, and White MG
- Subjects
- Carcinogenesis, Humans, Colorectal Neoplasms etiology, Gastrointestinal Microbiome, Microbiota
- Abstract
Opinion Statement: In recent years, we have seen an increase in the study and interest of the role of the microbiome in the development of malignancies, their progression, and evasion of therapies. This has been particularly fruitful in the case of colorectal cancer; multiple investigators have described correlative observations as well as hypotheses strengthened in preclinical studies that have begun to elucidate the critical role the gut and tumoral microbiome plays in carcinogenesis. Furthermore, these landmark studies lay the groundwork in describing the microbiome's role in carcinogenesis and provide a rich field of future study. Here, we review contemporary understandings of these observations and proposed mechanisms behind them., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
- Published
- 2022
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41. Tumor MHC Class I Expression Associates with Intralesional IL2 Response in Melanoma.
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Pourmaleki M, Jones CJ, Ariyan CE, Zeng Z, Pirun M, Navarrete DA, Li Y, Zhang M, Nandakumar S, Campos C, Nadeem S, Klimstra DS, Temple-Oberle CF, Brenn T, Lipson EJ, Schenk KM, Stein JE, Taube JM, White MG, Traweek R, Wargo JA, Kirkwood JM, Gasmi B, Goff SL, Corwin AD, McDonough E, Ginty F, Callahan MK, Schietinger A, Socci ND, Mellinghoff IK, and Hollmann TJ
- Subjects
- Hepatitis A Virus Cellular Receptor 2, Humans, Immunotherapy methods, Programmed Cell Death 1 Receptor metabolism, Interleukin-2 therapeutic use, Melanoma drug therapy, Melanoma genetics, Melanoma pathology
- Abstract
Cancer immunotherapy can result in lasting tumor regression, but predictive biomarkers of treatment response remain ill-defined. Here, we performed single-cell proteomics, transcriptomics, and genomics on matched untreated and IL2 injected metastases from patients with melanoma. Lesions that completely regressed following intralesional IL2 harbored increased fractions and densities of nonproliferating CD8+ T cells lacking expression of PD-1, LAG-3, and TIM-3 (PD-1-LAG-3-TIM-3-). Untreated lesions from patients who subsequently responded with complete eradication of all tumor cells in all injected lesions (individuals referred to herein as "extreme responders") were characterized by proliferating CD8+ T cells with an exhausted phenotype (PD-1+LAG-3+TIM-3+), stromal B-cell aggregates, and expression of IFNγ and IL2 response genes. Loss of membranous MHC class I expression in tumor cells of untreated lesions was associated with resistance to IL2 therapy. We validated this finding in an independent cohort of metastatic melanoma patients treated with intralesional or systemic IL2. Our study suggests that intact tumor-cell antigen presentation is required for melanoma response to IL2 and describes a multidimensional and spatial approach to develop immuno-oncology biomarker hypotheses using routinely collected clinical biospecimens., (©2022 American Association for Cancer Research.)
- Published
- 2022
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42. Generalized Electrical Substitution Methods and Detectors for Absolute Optical Power Measurements.
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Woods SI, Neira JE, Proctor JE, Rice JP, Tomlin NA, White MG, Stephens MS, and Lehman JH
- Abstract
We have developed generalized methods for electrical substitution optical measurements, as well as cryogenic detectors which can be used to implement them. The new methods detailed here enable measurement of arbitrary periodic waveforms by an electrical substitution radiometer (ESR), which means that spectral and dynamic optical power can be absolutely calibrated directly by a primary standard detector. Cryogenic ESRs are not often used directly by researchers for optical calibrations due to their slow response times and cumbersome operation. We describe two types of ESRs with fast response times, including newly developed cryogenic bolometers with carbon nanotube absorbers, which are manufacturable by standard microfabrication techniques. These detectors have response times near 10 ms, spectral coverage from the ultraviolet to far-infrared, and are ideal for use with generalized electrical substitution. In our first tests of the generalized electrical substitution method with FTS, we have achieved uncertainty in detector response of 0.13 % (k=1) and total measurement uncertainty of 1.1 % (k=1) in the mid-infrared for spectral detector responsivity calibrations. The generalized method and fast detectors greatly expand the range of optical power calibrations which can be made using a wideband primary standard detector, which can shorten calibration chains and improve uncertainties.
- Published
- 2022
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43. Dietary fiber and probiotics influence the gut microbiome and melanoma immunotherapy response.
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Spencer CN, McQuade JL, Gopalakrishnan V, McCulloch JA, Vetizou M, Cogdill AP, Khan MAW, Zhang X, White MG, Peterson CB, Wong MC, Morad G, Rodgers T, Badger JH, Helmink BA, Andrews MC, Rodrigues RR, Morgun A, Kim YS, Roszik J, Hoffman KL, Zheng J, Zhou Y, Medik YB, Kahn LM, Johnson S, Hudgens CW, Wani K, Gaudreau PO, Harris AL, Jamal MA, Baruch EN, Perez-Guijarro E, Day CP, Merlino G, Pazdrak B, Lochmann BS, Szczepaniak-Sloane RA, Arora R, Anderson J, Zobniw CM, Posada E, Sirmans E, Simon J, Haydu LE, Burton EM, Wang L, Dang M, Clise-Dwyer K, Schneider S, Chapman T, Anang NAS, Duncan S, Toker J, Malke JC, Glitza IC, Amaria RN, Tawbi HA, Diab A, Wong MK, Patel SP, Woodman SE, Davies MA, Ross MI, Gershenwald JE, Lee JE, Hwu P, Jensen V, Samuels Y, Straussman R, Ajami NJ, Nelson KC, Nezi L, Petrosino JF, Futreal PA, Lazar AJ, Hu J, Jenq RR, Tetzlaff MT, Yan Y, Garrett WS, Huttenhower C, Sharma P, Watowich SS, Allison JP, Cohen L, Trinchieri G, Daniel CR, and Wargo JA
- Subjects
- Animals, Cohort Studies, Fatty Acids, Volatile analysis, Fecal Microbiota Transplantation, Feces chemistry, Feces microbiology, Female, Humans, Immunotherapy, Male, Melanoma immunology, Melanoma microbiology, Melanoma, Experimental immunology, Melanoma, Experimental microbiology, Melanoma, Experimental therapy, Mice, Mice, Inbred C57BL, Progression-Free Survival, T-Lymphocytes, Dietary Fiber, Gastrointestinal Microbiome, Immune Checkpoint Inhibitors therapeutic use, Melanoma therapy, Probiotics
- Abstract
Gut bacteria modulate the response to immune checkpoint blockade (ICB) treatment in cancer, but the effect of diet and supplements on this interaction is not well studied. We assessed fecal microbiota profiles, dietary habits, and commercially available probiotic supplement use in melanoma patients and performed parallel preclinical studies. Higher dietary fiber was associated with significantly improved progression-free survival in 128 patients on ICB, with the most pronounced benefit observed in patients with sufficient dietary fiber intake and no probiotic use. Findings were recapitulated in preclinical models, which demonstrated impaired treatment response to anti–programmed cell death 1 (anti–PD-1)–based therapy in mice receiving a low-fiber diet or probiotics, with a lower frequency of interferon-γ–positive cytotoxic T cells in the tumor microenvironment. Together, these data have clinical implications for patients receiving ICB for cancer.
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- 2021
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44. Gastrointestinal Surgical Emergencies in the Neutropenic Immunocompromised Patient.
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White MG, Morgan RB, Drazer MW, and Eng OS
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- Emergencies, Humans, Immunocompromised Host, Retrospective Studies, Appendicitis, Neutropenia etiology
- Abstract
Surgeons encounter neutropenic patients through elective or emergency consultation with increasing regularity. As medical management continues to extend the lives of patients with benign hematologic diseases, hematologic malignancies, solid malignancies, or iatrogenic neutropenia, more patients are presenting with infectious complications caused and/or complicated by their neutropenia. This leaves surgeons in the difficult position of managing medically fragile patients with unusual presentations of common disease processes. These patients often fall outside of classical guidelines and treatment pathways. Many studies addressing these issues are retrospective and non-randomized. Here, we review common emergency gastrointestinal surgery scenarios and their management in the setting of a neutropenic patient. While biliary disease, appendicitis, anorectal disease, and perforations will be covered in detail, an extensive appreciation of a patient's medical or oncologic disease course and appropriate utilization of consultants such as interventional radiology, gastroenterology, and hematology is often necessary., (© 2021. The Society for Surgery of the Alimentary Tract.)
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- 2021
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45. Combined mechanical and oral antibiotic bowel preparation is associated with prolonged recurrence-free survival following surgery for colorectal cancer.
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Zhang LM, Schuitevoerder D, White MG, Feldt S, Krishnan P, Hyman N, and Shogan BD
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- Adenocarcinoma surgery, Adolescent, Adult, Aged, Aged, 80 and over, Cohort Studies, Female, Humans, Male, Matched-Pair Analysis, Middle Aged, Preoperative Care, Registries, Retrospective Studies, Young Adult, Antibiotic Prophylaxis, Colorectal Neoplasms mortality, Colorectal Neoplasms surgery, Disease-Free Survival, Laxatives administration & dosage
- Abstract
Background and Objectives: Recent studies suggest that bacteria influence the pathogenesis of primary colorectal cancer (CRC), yet their role in recurrence after resection is largely unknown. We have discovered that collagenase-producing bacteria promote cancer recurrence in mice, and that antibiotic bowel decontamination decreases colonization of these same organisms in humans. We hypothesized that preoperative combined mechanical and oral antibiotic bowel preparation would improve disease-free survival (DFS) in patients undergoing surgery for CRC., Methods: We reviewed a cancer registry of patients treated for CRC at a tertiary center. Patients who received bowel preparation were compared to those that did not via a 1:1-propensity score matched for follow-up, age, sex, BMI, stage, location, chemoradiation, infection, anastomotic leak, and blood transfusion., Results: One thousand two hundred and seventy-nine patients met inclusion criteria. Following propensity score matching, 264 patients receiving bowel prep were matched to 264 patients who did not. Kaplan-Meier estimates showed that patients who received bowel prep had a significantly improved 5-year DFS compared to those that did not (76.3% vs. 64.2%; p < .01). Cox regression demonstrated that bowel prep was associated with improved DFS (HR, 0.57; 95% CI, 0.37-0.89; p < .01)., Conclusion: Combined mechanical and oral antibiotic bowel preparation is independently associated with improved recurrence-free survival in patients undergoing surgery for CRC., (© 2021 Wiley Periodicals LLC.)
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- 2021
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46. Short-term treatment with multi-drug regimens combining BRAF/MEK-targeted therapy and immunotherapy results in durable responses in Braf -mutated melanoma.
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White MG, Szczepaniak Sloane R, Witt RG, Reuben A, Gaudreau PO, Andrews MC, Feng N, Johnson S, Class CA, Bristow C, Wani K, Hudgens C, Nezi L, Manzo T, De Macedo MP, Hu J, Davis R, Jiang H, Prieto P, Burton E, Hwu P, Tawbi H, Gershenwald J, Lazar AJ, Tetzlaff MT, Overwijk W, Woodman SE, Cooper ZA, Marszalek JR, Davies MA, Heffernan TP, and Wargo JA
- Subjects
- Animals, Humans, Immunotherapy, Memory T Cells, Mice, Mitogen-Activated Protein Kinase Kinases, Proto-Oncogene Proteins B-raf genetics, Melanoma drug therapy, Melanoma genetics, Pharmaceutical Preparations
- Abstract
Targeted and immunotherapy regimens have revolutionized the treatment of advanced melanoma patients. Despite this, only a subset of patients respond durably. Recently, combination strategies of BRAF/MEK inhibitors with immune checkpoint inhibitor monotherapy (α-CTLA-4 or α-PD-1) have increased the rate of durable responses. Based on evidence from our group and others, these therapies appear synergistic, but at the cost of significant toxicity. We know from other treatment paradigms (e.g. hematologic malignancies) that combination strategies with multi-drug regimens (>4 drugs) are associated with more durable disease control. To better understand the mechanism of these improved outcomes, and to identify and prioritize new strategies for testing, we studied several multi-drug regimens combining BRAF/MEK targeted therapy and immunotherapy combinations in a Braf -mutant murine melanoma model ( Braf
V600E /Pten-/- ). Short-term treatment with α-PD-1 and α-CTLA-4 monotherapies were relatively ineffective, while treatment with α-OX40 demonstrated some efficacy [17% of mice with no evidence of disease, (NED), at 60-days]. Outcomes were improved in the combined α-OX40/α-PD-1 group (42% NED). Short-term treatment with quadruplet therapy of immunotherapy doublets in combination with targeted therapy [dabrafenib and trametinib (DT)] was associated with excellent tumor control, with 100% of mice having NED after combined DT/α-CTLA-4/α-PD-1 or DT/α-OX40/α-PD-1. Notably, tumors from mice in these groups demonstrated a high proportion of effector memory T cells, and immunologic memory was maintained with tumor re-challenge. Together, these data provide important evidence regarding the potential utility of multi-drug therapy in treating advanced melanoma and suggest these models can be used to guide and prioritize combinatorial treatment strategies., Competing Interests: MCA reports advisory board participation and honoraria from Merck Sharp and Dohme, outside the submitted work. MAD has been a consultant to Roche/Genentech, Array, Novartis, BMS, GlaxoSmithKline (GSK), Sanofi-Aventis, Vaccinex and Apexigen, and he has been the PI of research grants to UT MD Anderson by Roche/Genentech, GSK, Sanofi-Aventis, Merck, Myriad, and Oncothyreon. JEG reports advisory board participation with Merck, Regeneron, BMS, Novartis, and Syndax. AJL reports personal fees from BMS, Novartis, Genentech/Roche, and Merck; personal fees and non-financial support from ArcherDX and Beta-Cat; grants and non-financial support from Medimmune/AstraZeneca and Sanofi; grants, personal fees and non-financial support from Janssen, all outside the submitted work. MTT reports personal fees from Myriad Genetics, Seattle Genetics and Novartis, all outside the submitted work. ZAC is currently an employee of AstraZeneca outside the submitted work. JAW reports speaker fees from Imedex, Dava Oncology, Omniprex, Illumina, Gilead, MedImmune and BMS; consultant/advisor roles or advisory board membership for Roche-Genentech, Novartis, AstraZeneca, GSK, BMS, Merck/MSD, Biothera Pharma, and Microbiome DX; and receives clinical trial support from GSK, Roche-Genentech, BMS, and Novartis, all outside the current work. The remaining authors declare no competing interests., (© 2021 The Author(s). Published with license by Taylor & Francis Group, LLC.)- Published
- 2021
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47. Identification of MicroRNA-mRNA Networks in Melanoma and Their Association with PD-1 Checkpoint Blockade Outcomes.
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Sloane RAS, White MG, Witt RG, Banerjee A, Davies MA, Han G, Burton E, Ajami N, Simon JM, Bernatchez C, Haydu LE, Tawbi HA, Gershenwald JE, Keung E, Ross M, McQuade J, Amaria RN, Wani K, Lazar AJ, Woodman SE, Wang L, Andrews MC, and Wargo JA
- Abstract
Metastatic melanoma is a deadly malignancy with poor outcomes historically. Immuno-oncology (IO) agents, targeting immune checkpoint molecules such as cytotoxic T-lymphocyte associated protein-4 (CTLA-4) and programmed cell death-1 (PD-1), have revolutionized melanoma treatment and outcomes, achieving significant response rates and remarkable long-term survival. Despite these vast improvements, roughly half of melanoma patients do not achieve long-term clinical benefit from IO therapies and there is an urgent need to understand and mitigate mechanisms of resistance. MicroRNAs are key post-transcriptional regulators of gene expression that regulate many aspects of cancer biology, including immune evasion. We used network analysis to define two core microRNA-mRNA networks in melanoma tissues and cell lines corresponding to 'MITF-low' and 'Keratin' transcriptomic subsets of melanoma. We then evaluated expression of these core microRNAs in pre-PD-1-inhibitor-treated melanoma patients and observed that higher expression of miR-100-5p and miR-125b-5p were associated with significantly improved overall survival. These findings suggest that miR-100-5p and 125b-5p are potential markers of response to PD-1 inhibitors, and further evaluation of these microRNA-mRNA interactions may yield further insight into melanoma resistance to PD-1 inhibitors.
- Published
- 2021
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48. Laparoscopic Heated Intraperitoneal Chemotherapy in the Treatment of Carcinomatosis of Gastric Adenocarcinoma Origin.
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White MG and Badgwell BD
- Abstract
The use of heated intraperitoneal chemotherapy (HIPEC) in conjunction with cytoreductive surgery has been gaining increasing traction in treating gastric adenocarcinoma with metastasis to the peritoneum in recent years. The addition of laparoscopic HIPEC (LS-HIPEC) to these treatment algorithms has increased the flexibility and adaptability of HIPEC integrating into treatment sequencing, allowing for iterative protocols of LS-HIPEC prior to cytoreduction as neoadjuvant treatment, as well as in the palliation of patients with unresectable disease and uncontrolled ascites. As the use of HIPEC in gastric adenocarcinoma continues to be refined, LS-HIPEC algorithms should continue to be considered and utilized both in curative treatment algorithms as well as in patients in the palliative setting. Given that LS-HIPEC remains a relatively nascent treatment modality, we advocate for its use in the setting of a clinical trial when feasible.
- Published
- 2021
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49. Robotic Completion Radical Cholecystectomy with Fluorescence Guidance.
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Newton AD, Newhook TE, Ikoma N, White MG, Tzeng CD, Chun YS, Aloia TA, Vauthey JN, and Tran Cao HS
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- Cholangiography, Cholecystectomy, Coloring Agents, Fluorescence, Humans, Indocyanine Green, Cholecystectomy, Laparoscopic, Robotic Surgical Procedures
- Abstract
The application of minimally invasive surgery (MIS) techniques in the treatment of hepatobiliary malignancies offers advantages of shorter length of stay, quicker functional recovery, and decreased need for postoperative opioids. However, MIS completion radical cholecystectomy for incidentally diagnosed gallbladder cancer can be challenging due to a reoperative field and lack of tactile feedback. This video demonstrates the utility of the robotic platform and highlights the ways in which it assists surgeons in overcoming these limitations. These include (1) versatile wristed instruments and excellent visualization that facilitate a thorough regional lymphadenectomy; and (2) built-in fluorescence imaging technology that can be used with intravenous indocyanine green (ICG) to confirm porta hepatis anatomy in a reoperative field. ICG pharmacokinetics enable fluorescence angiography 15-20 s after ICG injection and fluorescence cholangiography 15-20 min after ICG injection as the dye accumulates in the biliary system. Systematic and intentional application of these techniques allows for the safe performance of robotic completion radical cholecystectomy following sound oncologic principles, with excellent perioperative outcomes., (© 2021. Society of Surgical Oncology.)
- Published
- 2021
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50. Phase Angle From Bioelectrical Impedance for the Assessment of Sarcopenia in Cirrhosis With or Without Ascites.
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Ruiz-Margáin A, Xie JJ, Román-Calleja BM, Pauly M, White MG, Chapa-Ibargüengoitia M, Campos-Murguía A, González-Regueiro JA, Macias-Rodríguez RU, and Duarte-Rojo A
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- Ascites diagnosis, Cohort Studies, Electric Impedance, Female, Humans, Liver Cirrhosis complications, Liver Cirrhosis diagnosis, Male, Middle Aged, Sarcopenia diagnosis
- Abstract
Background and Aims: Skeletal muscle index (SMI) from computed tomography (CT) reliably assesses sarcopenia, however, it is expensive and involves serial radiation exposure. Phase angle (PhA) from bioimpedance analysis (BIA) is a noninvasive, low cost, bedside nutritional tool used to monitor changes to nutritional interventions. We aimed to compare the performance of PhA with SMI to assess sarcopenia in cirrhosis., Methods: Ambispective cohort study. Consecutive patients with cirrhosis and available images from abdominal CT scan were included. Monofrequency BIA was performed within 2 weeks CT. Spearman's correlation, ROC curve, and survival analysis with Kaplan-Meier, Cox and competing-risk regression were performed., Results: 136 patients were included with a mean age of 54.5 years (60% female). Most had decompensated disease (66%) with ascites in 47%, and a mean MELD of 14 ± 6. We found positive correlations between SMI and PhA (r = 0.58 , P < .001), irrespective of the presence of ascites. The AUROC of PhA-sarcopenia in all patients was 0.702; (0.748 in males,0.677 in females). The best cutoffs of PhA for diagnosing sarcopenia were ≤5.6° in males and ≤5.4° in females. SMI and PhA were significantly associated with survival in Kaplan-Meier curves. In multivariable analyses, SMI was outperformed by age and MELD, whereas PhA remained independently associated with mortality. Considering transplantation as a competing risk, regression analysis showed both SMI and PhA to be independent predictors of mortality (sHR:0.95 [0.90-0.99] and sHR:0.61 [0.42-0.88])., Conclusion: PhA moderately correlates with SMI for the identification of sarcopenia in patients with cirrhosis. However, its prognostic accuracy is comparable to that of SMI, and it is not influenced by ascites., (Copyright © 2021 AGA Institute. Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
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