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1.
World J Surg ; 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31686157

RESUMO

BACKGROUND: Hypoparathyroidism occurs relatively frequently after thyroid surgery in children. However, few studies have reported risk factors. We aimed to identify risk factors for hypoparathyroidism that occurred after total thyroidectomy for proven or suspected malignancy in children. METHODS: Children (aged ≤ 18 years) who underwent total thyroidectomy for neoplasm or RET germline mutation at our institution between 1997 and 2018 were included. We retrospectively reviewed demographics, surgical indications, perioperative and follow-up laboratory results, pathologic results, and duration of calcium/calcitriol supplementation. Risk factors for hypoparathyroidism were identified by multivariate analysis. RESULTS: Of 184 consecutive patients, 111 had undergone surgery for neoplasm; these diseases were primarily malignancies (106, 95.5%), predominantly papillary carcinoma (103, 92.8%). The remaining 73 patients had undergone early thyroidectomy for RET germline mutation. Among all patients, 67 (36.4%) had hypoparathyroidism: 61 transient and 6 permanent. In a multivariate analysis, central neck dissection (odds ratio 4.3, 95% confidence interval 2.0-9.1) and gross extrathyroidal extension (odds ratio 4.9, 95% confidence interval 2.0-12.1) predicted overall hypoparathyroidism; however, no significant factors were associated with permanent hypoparathyroidism. Most patients with permanent hypoparathyroidism (5 of 6) had undergone therapeutic central neck dissection. When central neck dissection was performed, younger children had a higher risk of overall hypoparathyroidism. CONCLUSIONS: In pediatric total thyroidectomies, central neck dissection and gross extrathyroidal extension were major predictors for overall hypoparathyroidism. Surgeons performing thyroidectomy in such patients should be aware of the relatively high risk, preserve parathyroid tissue to the extent possible, and be conscientious regarding postoperative calcium monitoring and replacement.

2.
Pancreas ; 48(10): 1367-1372, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31688603

RESUMO

OBJECTIVES: Epithelial-mesenchymal transition (EMT) plays an important role in the progression, metastasis, and chemoresistance of pancreatic duct adenocarcinoma (PDAC); however, the expression of EMT markers and their clinical significance in PDAC patients who received neoadjuvant therapy (NAT) are unclear. METHODS: We examined the expression of EMT markers, including Zeb-1 (zinc finger E-box-binding homeobox 1), E-cadherin, and vimentin by immunohistochemistry in 120 PDAC patients who received NAT and pancreatectomy from 1999 to 2007. The results were correlated with clinicopathologic parameters and survival. RESULTS: Among 120 cases, 45 (37.5%) and 14 (11.7%) were positive for Zeb-1 and vimentin, respectively, and 25 (20.8%) were E-cadherin-low. The median overall survival and disease-free survival were 35.3 (standard deviation [SD], 2.8) and 15.9 (SD, 3.6) months, respectively, in vimentin-negative group compared with 16.1 (SD, 1.1) (P = 0.03) and 7.0 (SD, 1.1) months (P = 0.02) in the vimentin-positive group. In multivariate analysis, vimentin expression was an independent predictor of shorter disease-free survival (hazard ratio, 2.50; 95% confidence interval, 1.31-4.78; P = 0.016) and overall survival (hazard ratio, 2.55; 95% confidence interval, 1.33-4.89; P = 0.01). CONCLUSIONS: Epithelial-mesenchymal transition markers are frequently expressed in treated PDAC. Vimentin expression is a prognostic biomarker for survival in PDAC patients who received NAT.

3.
J Phys Act Health ; : 1-10, 2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31592772

RESUMO

BACKGROUND: Physical activity and exercise appear to benefit patients receiving preoperative treatment for cancer. Supports and barriers must be considered to increase compliance with home-based exercise prescriptions in this setting. Such influences have not been previously examined. METHODS: The authors used quantitative and qualitative methods to examine potential physical activity influences among patients who were prescribed home-based aerobic and strengthening exercises concurrent with preoperative chemotherapy or chemoradiation for pancreatic cancer. Physical activity was measured using exercise logs and accelerometers. Social support for exercise and perceived neighborhood walkability were measured using validated surveys. Relationships between influences and physical activity were evaluated using linear regression analyses and qualitative interviews. RESULTS: Fifty patients received treatment for a mean of 16 (9) weeks prior to planned surgical resection. Social support from friends and neighborhood esthetics were positively associated with physical activity (P < .05). In interviews, patients confirmed the importance of these influences and cited encouragement from health care providers and desire to complete and recover from treatment as additional motivators. CONCLUSIONS: Interpersonal and environmental motivators of exercise and physical activity must be considered in the design of future home-based exercise interventions designed for patients receiving preoperative therapy for cancer.

4.
Carcinogenesis ; 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31630191

RESUMO

Genome-wide association study (GWAS)-identified single-nucleotide polymorphisms (SNPs) are tag SNPs located in both transcribed and noncoding regulatory DNA regions, rather than representing causal or functional variants for disease. To identify functional variants or genes for melanoma susceptibility, we used FUMA to perform functional annotation of the summary statistics of 2541 significant melanoma risk SNPs (P < 5×10-8) identified by GWAS. The original GWAS melanoma study included 15,990 cases and 26,409 controls, representing the largest international meta-analysis of melanoma susceptibility. We prioritized 330 unique genes, including those in immune cytokine signaling pathways, from 19 loci through positional, expression quantitative trait locus, and chromatin interaction mapping. In comparison, only 38 melanoma-related genes were identified in the original meta-analysis. In addition to the well-known melanoma susceptibility genes confirmed in the meta-analysis (MC1R, CDKN2A, TERT, OCA2, and ARNT/SETDB1), we also identified additional novel genes using FUMA to map SNPs to genes. Through chromatin interaction mapping, we prioritized IFNA7, IFNA10, IFNA16, IFNA17, IFNA14, IFNA6, IFNA21, IFNA4, IFNE, and IFNA5; these 10 most significant genes are all involved in immune system and cytokine signaling pathways. In the gene analysis, we identified 72 genes with a P < 2.5×10-6. The genes associated with melanoma risk were DEF8 (P = 1.09×10-57), DBNDD1 (P = 2.19×10-42), SPATA33 (P = 3.54×10-38), and MC1R (P = 1.04×10-36). In summary, this study identifies novel putative melanoma susceptibility genes and provides a guide for further experimental validation of functional variants and disease-related genes.

5.
J Immunother Cancer ; 7(1): 253, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31533818

RESUMO

BACKGROUND: Adrenocortical carcinoma (ACC) is a rare malignancy without good treatment options. There are limited data about the use of immunotherapy in ACC. We investigated the efficacy and safety of pembrolizumab in patients with metastatic ACC. METHODS: This is a pre-specified cohort of a single-center, investigator-initiated, phase II clinical trial using pembrolizumab monotherapy in patients with rare malignancies. Patients must have had prior treatment fail in the past 6 months before study enrollment. Patients were enrolled from August 2016 to October 2018. Follow-up data were updated as of March 26, 2019. Patients received 200 mg pembrolizumab intravenously every 3 weeks without concomitant oncologic therapy. The primary endpoint was non-progression rate (NPR) at 27 weeks. Other endpoints included adverse events, tumor responses measured independently by objective radiologic criteria, and select immunological markers. RESULTS: Sixteen patients with ACC (including eight women [50%]) were included in this cohort. Ten patients (63%) had evidence of hormonal overproduction (seven had cortisol-producing ACC). Non-progression rate at 27 weeks was evaluable in 14 patients, one patient was lost to follow-up, and one patient left the study because of an adverse event. Five of 14 patients were alive and progression-free at 27 weeks (non-progression rate at 27 weeks was 36, 95% confidence interval 13-65%). Of the 14 patients evaluable for imaging response by immune-related Response Evaluation Criteria in Solid Tumors, two had a partial response (including one with cortisol-producing ACC), seven had stable disease (including three with cortisol-producing ACC), and five had progressive disease, representing an objective response rate of 14% (95% confidence interval 2-43%). Of those who had stable disease, six had disease stabilization that lasted ≥4 months. Severe treatment-related adverse events (≥grade 3) were seen in 2 of 16 patients (13%) and resulted in one patient discontinuing study participation. All studied tumor specimens (14/14) were negative for programmed cell death ligand-1 expression. Thirteen of 14 tumor specimens (93%) were microsatellite-stable. Eight of 14 patients (57%) had a high tumor-infiltrating lymphocyte score on immunohistochemistry staining. CONCLUSIONS: Single-agent pembrolizumab has modest efficacy as a salvage therapy in ACC regardless of the tumor's hormonal function, microsatellite instability status, or programmed cell death ligand-1 status. Treatment was well tolerated in most study participants, with a low rate of severe adverse events. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02721732 , Registered March 29, 2016.

6.
Protein Sci ; 2019 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-31518043

RESUMO

Human immunodeficiency virus (HIV) is a retroviral pathogen that targets human immune cells such as CD4+ T cells, macrophages, and dendritic cells. The human apolipoprotein B mRNA-editing catalytic polypeptide 3 (APOBEC3 or A3) cytidine deaminases are a key class of intrinsic restriction factors that inhibit replication of HIV. When HIV-1 enters the cell, the immune system responds by inducing the activation of the A3 family proteins, which convert cytosines to uracils in single-stranded DNA replication intermediates, neutralizing the virus. HIV counteracts this intrinsic immune response by encoding a protein termed viral infectivity factor (Vif). Vif targets A3 to an E3 ubiquitin ligase complex for poly-ubiquitination and proteasomal degradation. Vif is unique in that it can recognize and counteract multiple A3 restriction factor substrates. Structural biology studies have provided significant insights into the overall architectures and functions of Vif and A3 proteins; however, a structure of the Vif-A3 complex has remained elusive. In this review, we summarize and re-analyze experimental data from recent structural, biochemical, and functional studies to provide key perspectives on the residues involved in Vif-A3 protein-protein interactions. This article is protected by copyright. All rights reserved.

7.
World J Surg ; 2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31493191

RESUMO

BACKGROUND: The American Joint Committee on Cancer 8th edition staging manual for adrenocortical carcinoma (ACC) redefines T stage to include large vessel invasion (T4, previously undescribed) and restricts stage IV to those with distant metastases. We evaluated the prognostic power of the 8th edition. METHODS: Patients with ACC treated between January 1, 2000, and December 31, 2015, were identified. Overall survival (OS) was compared using Kaplan-Meier and Cox proportional hazard models. RESULTS: Of 290 patients evaluated, the change in T stage nomenclature impacted 13 (4.5%) who were previously categorized as T3; 61 had large vessel involvement but were already T4 based on invasion of adjacent organs. The restriction of stage IV to patients with distant metastases downstaged 41 (14.1%; T4N0M0 or T3-4N1M0) to stage III. In the 7th edition, the hazard ratio (HR) for death was similar between patients with stage II and III disease, with 5-year OS 66.7%, 54.4%, 57.2%, and 14.0% (stages I, II, III, and IV, respectively). In the 8th edition, stages I and II remain unchanged, with 5-year OS for stage III and IV 44.1% and 9.2%, respectively. The c-index for the 7th and 8th editions was similar (83.4 and 82.7, respectively). CONCLUSIONS: While 8th edition changes impact a relatively small proportion of ACC patients, they represent progress toward a common staging system that accurately reflects prognosis. In the 8th edition, the inclusion of patients with T4 tumors or nodal disease as stage III rather than IV results in improved stratification between stages II and III.

9.
Mol Carcinog ; 58(11): 2091-2103, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31435991

RESUMO

Glutamine dependence is a unique metabolic defect seen in cutaneous melanoma (CM), directly influencing the treatment and prognosis. Here, we investigated the associations between 6025 common single-nucleotide polymorphisms (SNPs) in 77 glutamine metabolic pathway genes with CM-specific survival (CMSS) using genotyping datasets from two published genome-wide association studies (GWASs). In the single-locus analysis, 76 SNPs were found to be significantly associated with CMSS (P < .050, false-positive report probability < 0.2 and Bayesian false discovery probability < 0.8) in the discovery dataset, of which seven SNPs were replicated in the validation dataset and three SNPs (HAL rs17676826T > C, LGSN rs12663017T > A, and NOXRED1 rs8012548A > G) independently predicted CMSS, with an effect-allele attributed adjusted hazards ratio of 1.52 (95% confidence interval = 1.19-1.93) and P < .001, 0.68 (0.54-0.87) and P = .002 and 0.62 (0.46-0.83) and P = .002, respectively. The model including the number of unfavorable genotypes (NUGs) of these three SNPs and covariates improved the five-year CMSS prediction (P = .012) than the one with other covariates only. Further expression quantitative trait loci (eQTL) analysis found that the LGSN rs12663017 A allele was significantly associated with increased messenger RNA (mRNA) expression levels (P = 8.89 × 10 -11 ) in lymphoblastoid cell lines of the 1000 Genomes Project database. In the analysis of the genotype tissue expression (GTEx) project datasets, HAL rs17676826 C and NOXRED1 rs8012548 G alleles were significantly associated with their mRNA expression levels in sun-exposed skin of the lower leg (P = 6.62 × 10-6 and 1.37 × 10-7 , respectively) and in sun-not-exposed suprapubic skin (P < .001 and 1.43 × 10-8 , respectively). Taken together, these genetic variants of glutamine-metabolic pathway genes may be promising predictors of survival in patients with CM.

10.
Nat Commun ; 10(1): 3293, 2019 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-31337753

RESUMO

Duplication of ancestral hypoxia-inducible factor (HIF)α coincided with the evolution of vertebrate species. Paralogs HIF1α and HIF2α are the most well-known factors for modulating the cellular transcriptional profile following hypoxia. However, how the processes of natural selection acted upon the coding region of these two genes to optimize the cellular response to hypoxia during evolution remains unclear. A key negative regulator of HIFα is von Hippel-Lindau (VHL) tumour suppressor protein. Here we show that evolutionarily-relevant substitutions can modulate a secondary contact between HIF1α Met561 and VHL Phe91. Notably, HIF1α binds more tightly than HIF2α to VHL due to a conserved Met to Thr substitution observed in the vertebrate lineage. Similarly, substitution of VHL Phe91 with Tyr, as seen in invertebrate species, decreases VHL affinity for both HIF1α and HIF2α. We propose that vertebrate evolution involved a more complex hypoxia response with fine-tuned divergence of VHL affinity for HIF1α and HIF2α.

11.
Science ; 365(6448)2019 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-31273097

RESUMO

Multiple cytosolic innate sensors form large signalosomes after activation, but this assembly needs to be tightly regulated to avoid accumulation of misfolded aggregates. We found that the eIF2α kinase heme-regulated inhibitor (HRI) controls NOD1 signalosome folding and activation through a process requiring eukaryotic initiation factor 2α (eIF2α), the transcription factor ATF4, and the heat shock protein HSPB8. The HRI/eIF2α signaling axis was also essential for signaling downstream of the innate immune mediators NOD2, MAVS, and TRIF but dispensable for pathways dependent on MyD88 or STING. Moreover, filament-forming α-synuclein activated HRI-dependent responses, which suggests that the HRI pathway may restrict toxic oligomer formation. We propose that HRI, eIF2α, and HSPB8 define a novel cytosolic unfolded protein response (cUPR) essential for optimal innate immune signaling by large molecular platforms, functionally homologous to the PERK/eIF2α/HSPA5 axis of the endoplasmic reticulum UPR.

12.
Ann Surg ; 2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31274655

RESUMO

OBJECTIVE: We sought to identify potential radiologic and serologic markers of pancreatic tumor response to therapy, using pathologic major response (pMR) as the objective endpoint. BACKGROUND: We previously demonstrated that a pMR to preoperative therapy, defined as detection of <5% viable cancer cells in the surgical specimen on histopathological analysis, is an important prognostic factor for patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: Pretreatment and posttreatment computed tomography scans of consecutive patients who received preoperative chemotherapy and/or (chemo)radiation before pancreatectomy for PDAC between January 2010 and December 2018 were rereviewed. Response per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, other radiographic changes in tumor size and anatomic extent, and posttreatment CA 19-9 levels were compared between patients who did and did not have a pMR on final histopathologic analysis of their surgical specimens. RESULTS: A total of 290 patients with localized PDAC underwent pancreatectomy between 2010 and 2018 after receiving preoperative chemotherapy (n = 36; 12%), (chemo)radiation (n = 87; 30%), or both (n = 167; 58%). Among them, 28 (10%) experienced pMR, including 9 (3.1%) who experienced pathologic complete response. On multivariable logistic regression, low posttreatment CA 19-9 level, RECIST partial response, and reduction in tumor volume were confirmed to be independently associated with pMR (P < 0.01). CONCLUSIONS: We identified serologic and radiographic indicators of pMR that could help inform the delivery of preoperative therapy to patients with PDAC.

13.
Protein Sci ; 28(8): 1501-1512, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31228294

RESUMO

The HIV fusion inhibitor T20 has been approved to treat those living with HIV/AIDS, but treatment gives rise to resistant viruses. Using combinatorial phage-displayed libraries, we applied a saturation scan approach to dissect the entire T20 sequence for binding to a prefusogenic five-helix bundle (5HB) mimetic of HIV-1 gp41. Our data set compares all possible amino acid substitutions at all positions, and affords a complete view of the complex molecular interactions governing the binding of T20 to 5HB. The scan of T20 revealed that 12 of its 36 positions were conserved for 5HB binding, which cluster into three epitopes: hydrophobic epitopes at the ends and a central dyad of hydrophilic residues. The scan also revealed that the T20 sequence was highly adaptable to mutations at most positions, demonstrating a striking structural plasticity that allows multiple amino acid substitutions at contact points to adapt to conformational changes, and also at noncontact points to fine-tune the interface. Based on the scan result and structural knowledge of the gp41 fusion intermediate, a library was designed with tailored diversity at particular positions of T20 and was used to derive a variant (T20v1) that was found to be a highly effective inhibitor of infection by multiple HIV-1 variants, including a common T20-escape mutant. These findings show that the plasticity of the T20 functional sequence space can be exploited to develop variants that overcome resistance of HIV-1 variants to T20 itself, and demonstrate the utility of saturation scanning for rapid epitope mapping and protein engineering.

14.
Ann Surg Oncol ; 26(9): 2667-2674, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31168736

RESUMO

BACKGROUND: Complex general surgical oncology (CGSO) fellowships recently obtained Accreditation Council for Graduate Medical Education (ACGME) accreditation and board certification eligibility. We aimed to characterize the applicant pool and identify factors predictive of matching into our program. METHODS: We conducted a retrospective review of CGSO fellowship applications to a major cancer center from 2008 to 2018. Data were analyzed for trends over time, including a comparison of pre- versus post-American Board of Surgery (ABS) certification eligibility. RESULTS: A total of 846 applications were reviewed. Most applicants (86.2%) trained in a US residency program; 58.4% performed ≥ 1 research year during residency; 29.6% had a dual degree. Fewer applicants (34.5%) were female, a trend which did not change over time. Post-ABS, applicants were more likely to complete ≥ 1 year between residency and fellowship (20.9% versus 13.2%, p = 0.003), to be in practice at the time of application (12.2% versus 6.6%, p = 0.005), and to reapply (5.5% versus 1.0%, p < 0.001). Post-ABS applicants listed more peer-reviewed publications (8 [interquartile range (IQR) 4, 15] versus 5 [IQR 2, 10]; p < 0.001). On multivariable analysis, factors associated with matching into our program included: US allopathic medical school graduation [odds ratio (OR) 4.6, 95% confidence interval (CI) 1.8-11.7], Alpha Omega Alpha (AOA) Honor Medical Society distinction (OR 2.7, 95% CI 1.6-4.7), dual degree (OR 2.0, 95% CI 1.1-3.4), and performance of a clinical/research rotation at our institution (OR 4.9, 95% CI 2.2-10.7). CONCLUSIONS: After establishment of CGSO board certification eligibility, applicants were more likely to apply while in practice and to reapply. A number of factors, including having a dual degree and rotating at our institution, were associated with matriculation.

15.
Ann Surg Oncol ; 26(11): 3428-3435, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31243665

RESUMO

BACKGROUND: Despite advances in enhanced surgical recovery programs, strategies limiting postoperative inpatient opioid exposure have not been optimized for pancreatic surgery. The primary aims of this study were to analyze the magnitude and variations in post-pancreatectomy opioid administration and to characterize predictors of low and high inpatient use. METHODS: Clinical characteristics and inpatient oral morphine equivalents (OMEs) were downloaded from electronic records for consecutive pancreatectomy patients at a high-volume institution between March 2016 and August 2017. Regression analyses identified predictors of total OMEs as well as highest and lowest quartiles. RESULTS: Pancreatectomy was performed for 158 patients (73% pancreaticoduodenectomy). Transversus abdominus plane (TAP) block was performed for 80% (n = 127) of these patients, almost always paired with intravenous patient-controlled analgesia (IV-PCA), whereas 15% received epidural alone. All the patients received scheduled non-opioid analgesics (median, 2). The median total OME administered was 423 mg (range 0-4362 mg). Higher total OME was associated with preoperative opioid prescriptions (p < 0.001), longer hospital length of stay (LOS; p < 0.001), and no epidural (p = 0.006). The lowest and best quartile cutoff was 180 mg of OME or less, whereas the highest and worst quartile cutoff began at 892.5 mg. After adjustment for inpatient team, only epidural use [odds ratio (OR) 0.3; p = 0.04] predicted lowest-quartile OME. Preoperative opioid prescriptions (OR 8.1; p < 0.001), longer operative time (OR 3.4; p = 0.05), and longer LOS (OR 1.1; p = 0.007) predicted highest-quartile OME. CONCLUSIONS: Preoperative opioid prescriptions and longer LOS were associated with increased inpatient OME, whereas epidural use reduced inpatient OME. Understanding the predictors of inpatient opioid use and the variables predicting the lowest and highest quartiles can inform decision-making regarding preoperative counseling, regional anesthetic block choice, and novel inpatient opioid weaning strategies to reduce initial postoperative opioid exposure.

16.
J Surg Res ; 243: 90-99, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31170555

RESUMO

BACKGROUND: Portal vein (PV) circulating tumor cells (CTCs) and elevated peripheral blood (PB) levels of biomarkers have been associated with poor outcomes in pancreatic ductal adenocarcinoma (PDAC). Although transforming growth factor-beta (TGFß) is associated with CTCs in breast cancer, there are limited data evaluating a comprehensive biomarker panel and CTCs in PDAC patients. The authors hypothesized that tumor progression biomarkers would be associated with PV CTCs. METHODS: PDAC patients at one institution were enrolled January to August 2018 and underwent preincision PB draws (T0) and on postoperative day 1 (T3), plus intraoperative PV draws before tumor manipulation (T1) and after resection (T2). CTCs were detected using CellSearch. Plasma biomarker levels (pg/mL) were measured with a multiplex bead assay. Patients were divided into two groups: high (≥3 CTCs/7.5 mL blood) versus low (<3). Clinicopathologic variables and biomarkers were compared in the two groups. RESULTS: Fourteen had complete blood draws with PDAC resection, with five demonstrating high CTCs. Fewer patients in the high-CTC group received preoperative radiation (78 versus 20%), whereas more of the high-CTC had pT3 tumors (80 versus 11%) (all P < 0.037). High-CTC patients demonstrated higher TGFß-2 levels (T0 [906 versus 586], T1 [1337 versus 627], T2 [1149 versus 445]), as well as higher TGFß-3 (T0 [320 versus 173], T2 [605 versus 120]) (all P < 0.021). CONCLUSIONS: PDAC patients with high CTCs demonstrated a distinct biomarker profile with elevated PB and PV levels of immunosuppressive cytokines (TGFß-2 and TGFß-3). These exploratory results prompt further study into interrupting TGFß signaling.

17.
J Invest Dermatol ; 139(11): 2352-2358.e3, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31176707

RESUMO

To investigate the role of tumor cytokines/chemokines in melanoma immune response, we estimated the proportions of immune cell subsets in melanoma tumors from The Cancer Genome Atlas, followed by evaluation of the association between cytokine/chemokine expression and these subsets. We then investigated the association of immune cell subsets, chemokines, and cytokines with patient survival. Finally, we evaluated the immune cell tumor-infiltrating lymphocyte (TIL) score for correlation with melanoma patient outcome in a separate cohort. There was good agreement between RNA sequencing estimation of T-cell subset and pathologist-determined TIL score. Expression levels of cytokines IL-12A, IFNG, and IL-10, and chemokines CXCL9 and CXCL10 were positively correlated with PDCD1, CTLA-4, and CD8+ T-cell subset, but negatively correlated with tumor purity (Bonferroni-corrected P < 0.05). In multivariable analysis, higher expression levels of cytokines IFN-γ and TGFB1, but not chemokines, were associated with improved overall survival. A higher expression level of CD8+ T-cell subset was also associated with improved overall survival (hazard ratio [HR] = 0.06, 95% confidence interval [CI] = 0.01-0.35, P = 0.002). Finally, multivariable analysis showed that patients with a brisk TIL score had improved melanoma-specific survival than those with a nonbrisk score (HR = 0.51, 95% CI = 0.27-0.98, P = 0.0423). These results suggest that the expression of specific tumor cytokines represents important biomarkers of melanoma immune response.

18.
Pancreas ; 48(6): 837-843, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31210666

RESUMO

OBJECTIVES: Neoadjuvant therapy (NT) is used for advanced pancreatic ductal adenocarcinoma (PDAC). No clear guidelines exist for switching therapies when patients do not respond to initial NT. We sought to characterize patients who underwent early switch from FOLFIRINOX to gemcitabine/nab-paclitaxel (GA) as NT for PDAC. METHODS: We identified patients at a single institution switched from FOLFIRINOX to GA within the first 4 months of NT for PDAC during 2012-2017. We compared clinicopathologic data and oncologic outcomes. RESULTS: Of 25 patients who met the criteria, 21 showed a serologic or radiographic response to GA; 11 (52%) reached resection. Responders had decreased carbohydrate antigen (CA) 19-9 levels from pretreatment to post-GA (P = 0.036). Resected responders had significantly decreased CA 19-9 comparing preswitch to post-GA (P = 0.048). The only predictor of GA response was prechemotherapy CA 19-9 of less than1000 U/mL (P = 0.021). Predictors of reaching resection were head/uncinate tumor (P = 0.010) and presenting stage lower than locally advanced (P = 0.041). CONCLUSIONS: When patients do not respond to neoadjuvant FOLFIRINOX, early switch to GA should be considered. Future efforts should be directed toward identifying markers that will allow correct choice of initial therapy rather than attempting to rescue patients who respond poorly to first-line therapy.

19.
Ann Surg Oncol ; 26(11): 3593-3599, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31111352

RESUMO

BACKGROUND: Development of distant metastases (DM) is associated with markedly decreased survival in parathyroid carcinoma (PC). We sought to identify factors associated with development of DM and to quantify the effect that development of DM had on overall survival (OS). METHODS: Patients with surgically resected local/regional PC treated or surveilled at a tertiary-referral cancer hospital from 1980 to 2017 were included. We assessed the association between biochemical and clinicopathologic factors (preoperative parathyroid hormone (PTH) levels, sex, race, age, preoperative serum calcium levels, serum calcium levels at 6 months postop, tumor size, and extent of resection) with the development of DM. We also assessed the effect of development of DM on OS. RESULTS: Seventy-five patients with PC were assessed; 17 (22.7%) developed DM at a median follow-up of 77 months. The cumulative incidence of DM in the cohort was 20, 30, and 38% at 5, 10, and 20 years respectively. Tumor size > 3.2 cm based on recursive partitioning analysis was the only significant predictor for development of DM (hazard ratio (HR) = 3.51; 95% confidence interval [CI] 1.04-11.91; p = 0.04). Median OS for the entire cohort was 17 years compared with 40 months for the cohort who developed DM. The HR for death after distant metastasis was 9.6 (95% CI 4.2-22.3; p < 0.0001). CONCLUSIONS: Development of distant metastasis during surveillance is associated with decreased OS, including late recurrences. Primary tumor size should be considered in future interval surveillance and development of treatment algorithms.

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