Publications by authors named "Jeffrey E Lee"

489 Publications

ASO Author Reflections: Accelerating the Learning Curve of Robotic Pancreatectomy and Gastrectomy Through a Composite Robotic Foregut Surgical Oncology Program.

Ann Surg Oncol 2021 Sep 30. Epub 2021 Sep 30.

Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

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http://dx.doi.org/10.1245/s10434-021-10826-0DOI Listing
September 2021

HIF-1α Hydroxyprolines Modulate Oxygen-Dependent Protein Stability Via Single VHL Interface With Comparable Effect on Ubiquitination Rate.

J Mol Biol 2021 Sep 16;433(22):167244. Epub 2021 Sep 16.

Department of Biochemistry, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Laboratory Medicine and Pathobiology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address:

The basic molecular mechanism underlying mammalian oxygen-dependent regulation of hypoxia-inducible factor (HIF) via the von Hippel-Lindau E3 ubiquitin ligase is well established. The principal step in this critical cellular process is the hydroxylation of either or both of the two conserved proline residues P402 and P564 within the oxygen-dependent degradation domain (ODD) of HIF-1α subunit via prolyl hydroxylases, which is necessary for binding VHL. However, the significance of the two prolines has remained unclear considering that only one hydroxyproline is sufficient for the recruitment of VHL. Here, we show using biophysical analyses that both hydroxyprolines bind to the same interface on VHL with similar affinity; VHL binding affinity to HIF-1α ODD remains relatively unchanged regardless of whether the ODD contains one or two hydroxyprolines; ODD with two hydroxyprolines can accommodate two VHLs; and the rate of in vitro ubiquitination of ODD with one hydroxyproline via VHL E3 ligase is comparable to the rate observed with ODD containing two hydroxyprolines. However, the two hydroxyprolines show distinct contributions to the intracellular stability of HIF-1α ODD. These results demonstrate for the first time that the graduated HIF-1α stability profile observed over a range of oxygen tension is not attributed to the binding of or ubiquitination via VHL per se, but is likely due to the preceding events such as the efficacy of oxygen-dependent prolyl hydroxylase-mediated hydroxylation of HIF-1α.
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http://dx.doi.org/10.1016/j.jmb.2021.167244DOI Listing
September 2021

Early Experience of a Robotic Foregut Surgery Program at a Cancer Center: Video of Shared Steps in Robotic Pancreatoduodenectomy and Gastrectomy.

Ann Surg Oncol 2021 Sep 13. Epub 2021 Sep 13.

Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Over the past few decades, robotic surgery techniques required to resect gastric and pancreatic malignancies have evolved remarkably; however, the safety and generalizability of robotic pancreatoduodenectomy remain unknown. At our cancer center, gastrectomies and pancreatectomies are performed in a combined foregut minimally-invasive surgery program; this effectively increases the composite case volume and shortens the learning curve for any individual surgeon. In this video, we demonstrate the shared steps in pancreatoduodenectomy and gastrectomy and explain how the skills gained through robotic gastrectomy can be used during robotic pancreatoduodenectomy. During the initial 2-year period of our robotic foregut surgery program, we performed 120 pancreatic and gastric operations, including 22 pancreatoduodenectomies and 37 gastrectomies. Our first robotic pancreatoduodenectomy was performed following successful completion of 45 other robotic foregut operations. Of those 22 patients who underwent robotic pancreatoduodenectomy, the median hospital stay was 4 days (range 3-17 days) and the readmission rate was 14% (3/22). The rate of grade B/C pancreatic fistula was 9% (2/22) and there was no 90-day mortality. In conclusion, the presented video showing the shared steps in robotic pancreatoduodenectomy and gastrectomy demonstrates the potential for a combined robotic surgery program to increase composite case volumes and to shorten the learning curve. At our cancer center, implementation of this approach has been helpful in accelerating the development of our new robotic pancreatectomy program, especially in honing the skills necessary to perform robotic pancreatoduodenectomy.
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http://dx.doi.org/10.1245/s10434-021-10721-8DOI Listing
September 2021

The cell biology of fertilization: Gamete attachment and fusion.

J Cell Biol 2021 Oct 30;220(10). Epub 2021 Aug 30.

Department of Laboratory Medicine and Pathobiology, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.

Fertilization is defined as the union of two gametes. During fertilization, sperm and egg fuse to form a diploid zygote to initiate prenatal development. In mammals, fertilization involves multiple ordered steps, including the acrosome reaction, zona pellucida penetration, sperm-egg attachment, and membrane fusion. Given the success of in vitro fertilization, one would think that the mechanisms of fertilization are understood; however, the precise details for many of the steps in fertilization remain a mystery. Recent studies using genetic knockout mouse models and structural biology are providing valuable insight into the molecular basis of sperm-egg attachment and fusion. Here, we review the cell biology of fertilization, specifically summarizing data from recent structural and functional studies that provide insights into the interactions involved in human gamete attachment and fusion.
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http://dx.doi.org/10.1083/jcb.202102146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8406655PMC
October 2021

GRP78 expression and prognostic significance in patients with pancreatic ductal adenocarcinoma treated with neoadjuvant therapy versus surgery first.

Pancreatology 2021 Aug 18. Epub 2021 Aug 18.

Department of Anatomical Pathology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA; Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA. Electronic address:

Background: Glucose-regulated protein 78 (GRP78) plays an essential role in protein folding, transportation, and degradation, thus regulates ER homeostasis and promotes cell survival, proliferation and invasion. GRP78 expression in PDAC patients who received neoadjuvant therapy has not been reported.

Methods: This retrospective study of resected PDAC patients included 125 patients treated with neoadjuvant therapy (NAT) and 140 patients treated with surgery first (SF). The expression of GRP78 was evaluated by immunohistochemistry on tissue microarrays and the results were correlated with clinicopathologic parameters and survival.

Results: GRP78 expression was higher in SF patients compared to NAT patients (P < 0.001). In SF cohort, the median disease-free survival (DFS) and overall survival (OS) for patients with GRP78-positive tumors were 11.2 months and 25.0 months, respectively, compared to DFS of 52.1 months (P = 0.008) and OS of 69.5 months (P = 0.02) for those with GRP78-negative tumors. GRP78 expression correlated with higher frequency of recurrent/metastasis (P = 0.045). In NAT cohort, GRP78 expression correlated with shorter OS (P = 0.03), but not DFS (P = 0.08). GRP78 expression was an independent prognosticator for both DFS (P = 0.02) and OS (P = 0.049) in SF cohort and was an independent prognosticator for OS (P = 0.03), but not for DFS (P = 0.06) in NAT cohort by multivariate analysis.

Conclusions: Our study showed that GRP78 expression in NAT cohort is lower than that in SF cohort. GRP78 expression correlated with shorter survival in both SF and NAT patients. Our findings suggest that targeting GRP78 may help to improve the prognosis in PDAC patients.
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http://dx.doi.org/10.1016/j.pan.2021.08.006DOI Listing
August 2021

Incidence of Lymph Node Metastases and Impact of Radical Surgery for Duodenal Neuroendocrine Tumors.

J Surg Res 2021 Aug 17;268:419-431. Epub 2021 Aug 17.

Departments of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Electronic address:

Background: Despite the high frequency of regional lymph node (LN) metastases associated with duodenal neuroendocrine tumors (D-NETs), the impact of these metastases on survival and the ideal extent of LN dissection are unknown. We used the National Cancer Database (NCDB) to investigate factors associated with survival, including LN metastases and types of surgery, in patients with D-NETs.

Methods: All patients with D-NETs recorded in the NCDB between 2004 and 2016 were included in the study. We applied a multivariate Cox regression model to assess the relationship between the clinicopathological characteristics and overall survival (OS).

Results: We identified 7613 patients, among whom 4886 local excisions and 233 radical surgeries had been performed. Among patients with at least 1 LN pathologically examined, the overall incidence of LN metastasis was 41.2%. For all patients, the median OS was 10.6 years. Univariate analyses showed equivalent OS in N0 and N1 groups (HR,0.83; 95% CI,0.64-1.09) and diminished OS in those who had undergone radical surgery compared with those who had undergone local resection (HR,1.35; 95% CI,1.02-1.8). In multivariable analyses, tumor size >50 mm and having more than 9 positive LNs were associated with diminished OS (HR,1.64 and 5.2; 95% CI,1.25-2.16 and 1.91-14.18), whereas the type of surgery did not remain in the model.

Conclusion: Our study revealed that the presence of regional LN metastases and extent of surgery did not affect OS among patients with D-NETs. Radical resection to clear occult LN metastases for nonfunctioning, sporadic D-NETs was not supported by the current study.
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http://dx.doi.org/10.1016/j.jss.2021.06.085DOI Listing
August 2021

Perioperative blood transfusions and survival in resected pancreatic adenocarcinoma patients given multimodality therapy.

J Surg Oncol 2021 Aug 16. Epub 2021 Aug 16.

Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Background And Objectives: The impact of perioperative blood transfusion (PBT) on outcomes for pancreatic ductal adenocarcinoma (PDAC) patients given multimodality therapy (MMT) remains undefined. We sought to evaluate the association of PBT with survival after PDAC resection.

Methods: Pancreatectomy patients (July 2011-December 2017) who received MMT were abstracted from a prospective database. Overall survival (OS) was compared by PBT within 30 days, 24 h (24HR-BT), or 24 h until 30 days (Postop-BT).

Results: Most (76.6%) of 312 MMT patients underwent neoadjuvant therapy (NT). Eighty-nine patients (28.5%) received PBT; 58 (18.6%) 24HR-BT, and 31 (9.9%) Postop-BT. Compared with surgery-first, NT patients received more 24HR-BTs (22.2% vs. 6.8%, p = 0.003) and PBTs overall (32.6% vs. 15.1%, p = 0.004). Overall median OS was 45 months. The association of PBT with shorter median OS appeared limited to first 24-h transfusions (34 months 24HR-BT vs. 48 months Postop-BT vs. 53 months no-PBT, p = 0.009) and was dose-dependent, with a median OS of 52 months for 0 units 24HR-BT, 35 months for 1 unit, and 25 months for ≥2 units (p = 0.004). Independent predictors of OS included node-positivity (hazard ratio [HR]: 1.93, p < 0.001), perineural invasion (HR: 1.64, p = 0.050), postoperative pancreatic fistula (HR: 1.94, p = 0.018), and 24HR-BT (HR: 1.75, p = 0.001).

Conclusions: Transfusions given within 24 h are associated with dose-dependent decreases in survival after pancreatectomy for PDAC.
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http://dx.doi.org/10.1002/jso.26650DOI Listing
August 2021

Genetic variants of SDCCAG8 and MAGI2 in mitosis-related pathway genes are independent predictors of cutaneous melanoma-specific survival.

Cancer Sci 2021 Oct 27;112(10):4355-4364. Epub 2021 Aug 27.

Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA.

Mitosis is a prognostic factor for cutaneous melanoma (CM), but accurate mitosis detection in CM tissues is difficult. Therefore, the 8th Edition of the American Joint Committee on Cancer staging system has removed the mitotic rate as a category criterion of the tumor T-category, based on the evidence that the mitotic rate was not an independent prognostic factor for melanoma survival. As single-nucleotide polymorphisms (SNPs) have been shown to be potential predictors for cutaneous melanoma-specific survival (CMSS), we investigated the potential prognostic value of SNPs in mitosis-related pathway genes in CMSS by analyzing their associations with outcomes of 850 CM patients from The University of Texas MD Anderson Cancer Center in a discovery dataset and validated the findings in another dataset of 409 CM patients from the Harvard University Nurses' Health Study and Health Professionals Follow-up Study. In both datasets, we identified two SNPs (SDCCAG8 rs10803138 G>A and MAGI2 rs3807694 C>T) as independent prognostic factors for CMSS, with adjusted allelic hazards ratios of 1.49 (95% confidence interval = 1.17-1.90, P = .001) and 1.45 (1.13-1.86, P = .003), respectively. Furthermore, their combined unfavorable alleles also predicted a poor survival in both discovery and validation datasets in a dose-response manner (P  = .0006 and .0001, respectively). Additional functional analysis revealed that both SDCCAG8 rs10803138 A and MAGI2 rs3807694 T alleles were associated with elevated mRNA expression levels in normal tissues. Therefore, these findings suggest that SDCCAG8 rs10803138 G>A and MAGI2 rs3807694 C>T are independent prognostic biomarkers for CMSS, possibly by regulating the mRNA expression of the corresponding genes involved in mitosis.
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http://dx.doi.org/10.1111/cas.15102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8486203PMC
October 2021

Recurrence after successful parathyroidectomy-Who should we worry about?

Surgery 2021 Jul 30. Epub 2021 Jul 30.

University of Texas MD Anderson Cancer Center, Department of Surgical Oncology, Houston, TX. Electronic address:

Background: Preventing cervical reoperations is important-especially after parathyroidectomy. We sought to examine early predictors of recurrence of primary hyperparathyroidism after surgical cure.

Methods: Adult patients with sporadic primary hyperparathyroidism treated with parathyroidectomy between September 1, 1997, and September 1, 2019, with confirmed eucalcemia at 6 months postoperatively were identified. Recurrence was defined as hypercalcemia (>10.2 mg/dL) with an elevated or nonsuppressed parathyroid hormone level on subsequent follow-up.

Results: Parathyroidectomy was performed in 522 patients (median age, 62.1 years, 77% female) with the majority undergoing planned minimally invasive parathyroidectomy (85.4%, n = 446). After a median follow-up of 30.9 months, 13 patients (2.5%) recurred (median time to recurrence 50.2 months, interquartile range 27.9-66.5), all of whom underwent planned minimally invasive parathyroidectomy (n = 13/446, 2.9%). Recurrence was more common in those with higher (but still normal) 6-month calcium (10.1 vs 9.3 mg/dL, P < .001) or parathyroid hormone values (64 vs 46 pg/mL, P < .01). Multivariate analysis revealed that age >66.5 years, calcium ≥9.8mg/dL and parathyroid hormone ≥80 pg/mL at 6 months were associated with increased risk of recurrence. In addition, the presence of at least 1 preoperative imaging study that conflicted with intraoperative findings among minimally invasive parathyroidectomy patients (n = 446) was associated with increased risk of recurrence (hazard ratio 4.93, 95% confidence interval 1.25-16.53, P = .016).

Conclusion: Recurrence of sporadic primary hyperparathyroidism after initial surgical cure in the era of minimally invasive parathyroidectomy is 2.5%. Identification of those at risk for recurrence using 6-month serum calcium ≥9.8 mg/dL, parathyroid hormone ≥80 pg/mL, and/or potentially conflicting localization studies may inform surveillance strategies.
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http://dx.doi.org/10.1016/j.surg.2021.06.035DOI Listing
July 2021

Genetic variants of and in myeloid cell-related pathway genes independently predict cutaneous melanoma-specific survival.

Am J Cancer Res 2021 15;11(6):3252-3262. Epub 2021 Jun 15.

Duke Cancer Institute, Duke University Medical Center Durham, NC 27710, USA.

Both and evidence has supported a key role of myeloid cells in immune suppression in melanoma and in promoting melanocytic metastases. Some single-nucleotide polymorphisms (SNPs) have been shown to predict cutaneous melanoma-specific survival (CMSS), but the association between genetic variation in myeloid cell-related genes and cutaneous melanoma (CM) patient survival remains unknown.

Methods: we investigated associations between SNPs in myeloid cell-related pathway genes and CMSS in a discovery dataset of 850 CM patients and replicated the findings in another dataset of 409 CM patients.

Results: we identified two SNPs ( rs10151787 A>G and rs2069018 T>C) as independent prognostic factors for CMSS, with adjusted allelic hazards ratios of 1.56 (95% confidence interval =1.19-2.05, =0.001) and 1.66 (1.22-2.26, =0.001), respectively; so were their combined unfavorable alleles in a dose-response manner in both discovery and replication datasets ( <0.001 and 0.002, respectively). Additional functional analysis revealed that both rs10151787 G and rs2069018 C alleles were associated with elevated mRNA expression levels in normal tissues.

Conclusions: Our findings suggest that rs10151787 A>G and rs2069018 T>C are independent prognostic biomarkers for CMSS.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263692PMC
June 2021

Surgical Eligibility Does Not Imply Surgical Equity: Recommendations for Curative Treatment in Patients with Stage I/II Pancreatic Head Adenocarcinoma Differ by Age and Race.

Ann Surg 2021 Jun 25. Epub 2021 Jun 25.

Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Objective: We sought to characterize differences in pancreatectomy recommendation rates to surgically eligible patients with pancreatic ductal adenocarcinoma (PDAC) of the pancreatic head across age and racial groups.

Background: Pancreatectomy is not recommended in almost half of otherwise healthy patients with stage I/II pancreatic ductal adenocarcinoma (PDAC) lacking a surgical contraindication. We characterized differences in pancreatectomy recommendation among surgically eligible patients across age and racial groups.

Methods: Non-Hispanic White (NHW) and Non-Hispanic Black (NHB) patients were identified in the National Cancer Database with clinical stage I/II pancreatic head adenocarcinoma, Charlson Comorbidity Index of 0-1, and age 40-89 years. Rates of surgery recommendation and overall survival (OS) by age and race were compared. A Pancreatectomy Recommendation Equivalence Point (PREP) was defined as the age at which the rate of not recommending surgery matched the rate of recommending and completing surgery. Marginal standardization was used to identify association of age and race with recommendation. OS was compared using Kaplan-Meier and Cox regression models.

Results: Among 40,866 patients, 36,133 (88%) were NHW and 4,733 (12%) were NHB. For the entire cohort, PREP was 79 years. PREP was 5 years younger in NHB patients than in NHW patients (75 vs 80 years). Adjusted rates of not recommending surgery were significantly higher for NHB than for NHW patients in each age group. After adjusting for surgery recommendation, we found no difference in OS between NHW and NHB patients (hazard ratio 0.98 [95% CI 0.94-1.02]).

Conclusions: PREP of NHB patients was 5 years younger than NHW patients, and in every age group, the rate of not recommending pancreatectomy was higher in NHB patients. Age and race disparities in treatment recommendations may contribute to shorter longevity of NHB patients.
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http://dx.doi.org/10.1097/SLA.0000000000005033DOI Listing
June 2021

Genomic Sequencing and Insight into Clinical Heterogeneity and Prognostic Pathway Genes in Patients with Metastatic Colorectal Cancer.

J Am Coll Surg 2021 08 7;233(2):272-284.e13. Epub 2021 Jun 7.

Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX. Electronic address:

Background: An understanding of signaling pathways has not been fully incorporated into prognostication and therapeutic options. We evaluated the hypothesis that information about cancer-related signaling pathways can improve prognostic stratification and explain some of the clinical heterogeneity in patients with metastatic colorectal cancer.

Study Design: We analyzed prognostic relevance of signaling pathways in patients undergoing resection of colorectal liver metastases (CLM) from 2004-2017, and clinical actionability of gene alterations in 7 signaling pathways: p53, Wnt, RTK-RAS, PI3K, TGFβ, Notch, and cell cycle. To assess the wide applicability, the results were validated in an external retrospective cohort including patients with unresectable metastatic colorectal cancer.

Results: Of 579 patients, the numbers of patients with pathway alterations were as follows: p53, n = 420 (72.5%); Wnt, 340 (58.7%); RTK-RAS, 333 (57.5%); PI3K, 110 (19.0%); TGFβ, 65 (11.2%); Notch, 41 (7.1%); and cell cycle, 15 (2.6%). More than 80% of alterations in each pathway occurred in a single predominant gene TP53, APC, KRAS, PIK3CA, FBXW7, and RB1 in p53, Wnt, RTK-RAS, PI3K, Notch, and cell cycle pathways, respectively. Alterations of 4 pathways (p53, RTK-RAS, TGFβ, and Notch) and corresponding predominant genes (TP53, RAS/BRAF, SMAD4, and FBXW7) were significantly associated with worse overall survival (OS), and alterations of Wnt pathway (APC) were associated with better OS in the median follow-up duration of 3.8 years. Similarly, in the external cohort, alterations of p53 (TP53) and RTK-RAS (RAS/BRAF) were significantly associated with worse OS, whereas alteration of Wnt (APC) was associated with better OS in the median follow-up duration of 2.6 years.

Conclusions: Genomic sequencing provides insights into clinical heterogeneity and permits finer prognostic stratification in patients with metastatic colorectal cancer.
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http://dx.doi.org/10.1016/j.jamcollsurg.2021.05.027DOI Listing
August 2021

Snapshot of an influenza virus glycoprotein fusion intermediate.

Cell Rep 2021 May;35(7):109152

Department of Laboratory Medicine and Pathobiology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address:

Enveloped virus entry requires the fusion of cellular and viral membranes, a process directed by their viral fusion glycoproteins. Our current knowledge of this process has been shaped by structural studies of the pre- and post-fusion conformations of these viral fusogens. These structural snapshots have revealed the start and end states necessary for fusion, but the dynamics of the intermediate conformations have remained unclear. Using the influenza C virus hemagglutinin-esterase-fusion glycoprotein as a model, we report the structural and biophysical characterization of a trapped intermediate. Crystallographic studies revealed a structural reorganization of the C terminus to create a second chain reversal region, resulting in the N and C termini being positioned in opposing directions. Intrinsic tryptophan fluorescence and bimane-induced quenching measurements suggest intermediate formation is mediated by conserved hydrophobic residues. Our study reveals a late-stage extended intermediate structural event. This work adds to our understanding of virus cell fusion.
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http://dx.doi.org/10.1016/j.celrep.2021.109152DOI Listing
May 2021

Nodal Recurrence is a Primary Driver of Early Relapse for Patients with Sentinel Lymph Node-Positive Melanoma in the Modern Therapeutic Era.

Ann Surg Oncol 2021 Jul 15;28(7):3480-3489. Epub 2021 Apr 15.

Division of Radiation Oncology, Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Background: Management of patients with sentinel lymph node (SLN)-positive melanoma has changed dramatically over the last few years such that completion lymph node dissection (CLND) has become uncommon, and many patients receive adjuvant immunotherapy or targeted therapy. This study seeks to characterize patterns and predictors of early recurrence in this setting.

Patients And Methods: All patients with primary cutaneous melanoma undergoing sentinel lymph node biopsy (SLNB) between 3/2016 and 12/2019 were identified. The subset with a positive SLN who did not undergo CLND were examined for further analysis of outcomes and predictors of recurrence.

Results: Overall, 215 patients with SLN-positive melanoma who did not have CLND were identified. Adjuvant systemic therapy was administered to 102 (47%), with 93% of this subset receiving immunotherapy (n = 95). Median follow-up from SLNB was 20 months (IQR 12-28.5 months), and 57 patients (27%) recurred during this time. The SLN basin was the most common site of recurrence (n = 38, 67% of recurrence), with isolated nodal recurrence being the most common first site of recurrent disease (n = 22, 39% of recurrence). On multivariable analysis, lymphovascular invasion (LVI) of the primary tumor, two or more involved nodes, and > 1 mm nodal deposit were independently associated with higher rates of nodal relapse.

Conclusions: Nodal recurrence is a primary driver of early disease relapse for patients with SLN-positive melanoma who do not undergo CLND in the era of effective adjuvant systemic therapy. LVI, ≥ 2 nodes, or > 1 mm nodal disease identifies patients at particularly high risk of nodal relapse.
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http://dx.doi.org/10.1245/s10434-021-09804-3DOI Listing
July 2021

Association of genetic variants of and in the peroxisome pathway with cutaneous melanoma-specific survival.

Ann Transl Med 2021 Mar;9(5):396

Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA.

Background: Peroxisomes are ubiquitous and dynamic organelles that are involved in the metabolism of reactive oxygen species (ROS) and lipids. However, whether genetic variants in the peroxisome pathway genes are associated with survival in patients with melanoma has not been established. Therefore, our aim was to identify additional genetic variants in the peroxisome pathway that may provide new prognostic biomarkers for cutaneous melanoma (CM).

Methods: We assessed the associations between 8,397 common single-nucleotide polymorphisms (SNPs) in 88 peroxisome pathway genes and CM disease-specific survival (CMSS) in a two-stage analysis. For the discovery, we extracted the data from a published genome-wide association study from The University of Texas MD Anderson Cancer Center (MDACC). We then replicated the results in another dataset from the Nurse Health Study (NHS)/Health Professionals Follow-up Study (HPFS).

Results: Overall, 95 (11.1%) patients in the MDACC dataset and 48 (11.7%) patients in the NHS/HPFS dataset died of CM. We found 27 significant SNPs in the peroxisome pathway genes to be associated with CMSS in both datasets after multiple comparison correction using the Bayesian false-discovery probability method. In stepwise Cox proportional hazards regression analysis, with adjustment for other covariates and previously published SNPs in the MDACC dataset, we identified 2 independent SNPs ( rs567403 C>G and rs7969508 A>G) that predicted CMSS (P=0.003 and 0.031, respectively, in an additive genetic model). The expression quantitative trait loci analysis further revealed that the rs567403 GG and rs7969508 GG genotypes were associated with increased and decreased levels of mRNA expression of their genes, respectively.

Conclusions: Once our findings are replicated by other investigators, these genetic variants may serve as novel biomarkers for the prediction of survival in patients with CM.
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http://dx.doi.org/10.21037/atm-20-2117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8033299PMC
March 2021

Overexpression of CD73 in pancreatic ductal adenocarcinoma is associated with immunosuppressive tumor microenvironment and poor survival.

Pancreatology 2021 Aug 1;21(5):942-949. Epub 2021 Apr 1.

Department of Anatomical Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address:

Background: CD73, a newly recognized immune checkpoint mediator, is expressed in several types of malignancies. However, CD73 expression and its impact on tumor microenvironment and clinical outcomes in pancreatic ductal adenocarcinoma (PDAC) remain unclear.

Methods: This study included two cohorts: 138 patients from our institution (MDA) and 176 patients from TCGA dataset. CD73 expression, CD4, CD8, CD21 and CD45RO + tumor infiltrating lymphocytes (TILs) were evaluated by immunohistochemistry using tissue microarrays. The results of CD73 expression were correlated with clinicopathologic parameters, survival and TILs.

Results: CD73 overexpression correlated with poor differentiation (P = 0.002) and tumor size (P = 0.049). For CD73-low group, median overall survival (OS) and recurrence-free survival (RFS) were 26.9 ± 3.8 months and 12.6 ± 2.6 months, respectively, compared to 16.9 ± 4.4 months (P = 0.01) and 7.9 ± 1.2 months (P = 0.01), respectively, in CD73-high group. CD73 was an independent predictor for both RFS (P = 0.02) and OS (P = 0.01) by multivariate variate analysis. Similarly, CD73-high tumors had significantly shorter OS than CD73-low tumors in TCGA dataset (P < 0.0001). CD73-high correlated with decreased CD4 TILs in MDA cohort and decreased CD8A and CR2 (CD21) expression in TCGA cohort.

Conclusions: CD73 overexpression is associated with poor differentiation, tumor size, and shorter survival, and is an independent prognostic factor in PDAC patients. CD73 overexpression is associated with decreased CD4, CD8 and CD21 TILs. Our data support that CD73 plays an important role in immunosuppressive tumor microenvironment and promote tumor progression in PDAC.
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http://dx.doi.org/10.1016/j.pan.2021.03.018DOI Listing
August 2021

History of preoperative therapy for pancreatic cancer and the MD Anderson experience.

J Surg Oncol 2021 May;123(6):1414-1422

Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Systemic chemotherapy improves the survival of patients who undergo pancreatectomy, but whether chemotherapy should be delivered before or after surgery remains debated. At The University of Texas MD Anderson Cancer Center, localized pancreatic ductal adenocarcinoma (PDAC) has been preferentially treated with preoperative therapy-a practice supported by a robust history of institutional and national trials. In the following review, we discuss the historical use of perioperative therapy, our experience with it at MD Anderson Cancer Center and internationally, and the future of treatment and trials for PDAC.
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http://dx.doi.org/10.1002/jso.26394DOI Listing
May 2021

Sustained reduction in discharge opioid volumes through provider education: Results of 1168 cancer surgery patients over 2 years.

J Surg Oncol 2021 Jul 22;124(1):143-151. Epub 2021 Mar 22.

Department of Surgical Oncology, MD Anderson Cancer Center, The University of Texas, Houston, Texas, USA.

Background: An opioid reduction education program to decrease discharge opioid prescriptions was initiated in our Department of Surgical Oncology. The study's aim was to measure the results and sustainability of these interventions 1 year later.

Methods: This prospective quality improvement project identified patients undergoing resection in five index tumor sites (peritoneal surface, sarcoma, stomach, pancreas, liver) at a high-volume cancer center. Patients were grouped into pre-education (PRE: July 2017-July 2018) and posteducation (POST: September 2018-July 2019) periods, before and after departmental education talks and videos in August 2018. Opioids were converted to oral morphine equivalents (OME) to compare the groups.

Results: Of 1168 evaluable patients (PRE 646, 55%; POST 522, 45%), the median last-24-h inpatient OME was 15 mg in PRE patients and 10 mg in POST patients (p < .001). Median discharge OME decreased from 200 mg in PRE to 100 mg in POST patients (p < .001). The frequency of patients with zero discharge opioids increased from 11% to 19% (p < .001). This discharge OME reduction amounted to 52,200 mg OME saved, or the equivalent of 6960 5-mg oxycodone pills not disseminated.

Conclusions: A perioperative opioid reduction education program targeted to providers halved discharge OME, with sustained reductions 1 year later.
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http://dx.doi.org/10.1002/jso.26476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260254PMC
July 2021

Identification of RSV Fusion Protein Interaction Domains on the Virus Receptor, Nucleolin.

Viruses 2021 02 8;13(2). Epub 2021 Feb 8.

Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada.

Nucleolin is an essential cellular receptor to human respiratory syncytial virus (RSV). Pharmacological targeting of the nucleolin RNA binding domain RBD1,2 can inhibit RSV infections in vitro and in vivo; however, the site(s) on RBD1,2 which interact with RSV are not known. We undertook a series of experiments designed to: document RSV-nucleolin co-localization on the surface of polarized MDCK cells using immunogold electron microscopy, to identify domains on nucleolin that physically interact with RSV using biochemical methods and determine their biological effects on RSV infection in vitro, and to carry out structural analysis toward informing future RSV drug development. Results of immunogold transmission and scanning electron microscopy showed RSV-nucleolin co-localization on the cell surface, as would be expected for a viral receptor. RSV, through its fusion protein (RSV-F), physically interacts with RBD1,2 and these interactions can be competitively inhibited by treatment with Palivizumab or recombinant RBD1,2. Treatment with synthetic peptides derived from two 12-mer domains of RBD1,2 inhibited RSV infection in vitro, with structural analysis suggesting these domains are potentially feasible for targeting in drug development. In conclusion, the identification and characterization of domains of nucleolin that interact with RSV provide the essential groundwork toward informing design of novel nucleolin-targeting compounds in RSV drug development.
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http://dx.doi.org/10.3390/v13020261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915953PMC
February 2021

Developing a Value Framework: Utilizing Administrative Data to Assess an Enhanced Care Initiative.

J Surg Res 2021 06 6;262:115-120. Epub 2021 Feb 6.

Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Electronic address:

Background: There remains no tool to quantify the total value of comparative processes in health care. Hospital administrative data sets are emerging as valuable sources to evaluate performance. Thus, we use a framework to simultaneously assess multiple domains of value associated with an enhanced recovery initiative using national administrative data.

Materials And Methods: Risk-stratified clinical pathways for patients undergoing pancreatic surgery were implemented in 2016 at our institution. We used a national administrative database to characterize changes in value associated with this initiative. Value metrics assessed included in-hospital mortality, complication rates, length of stay (LOS), 30-day readmission rates, and institutional costs. We compared our performance with other hospitals both before and after implementation of the pathways. Metrics were graphed on radar charts to assess overall value.

Results: 22,660 cases were assessed. Comparing 75 cases at our institution and 5520 cases at all other hospitals before pathway implementation, mean in-hospital LOS was 9.6 versus 10.8 d, in-hospital mortality was 0.0% versus 1.9%, mean costs were $23,585 versus $21,387, 30-day readmission rates were 1.3% versus 7.4%, and complication rates were 8.0% versus 11.2%, respectively. Comparing 334 cases at our institution and 16,731 cases at all other hospitals after pathway implementation, mean in-hospital LOS was 7.7 versus 10.3 d, in-hospital mortality was 0.3% versus 1.6%, mean costs were $19,428 versus $22,032, 30-day readmission rates were 6.6% versus 7.5%, and complication rates were 6.3% versus 10.3%, respectively. Notably, LOS and institutional costs were reduced at our institution after implementation of the enhanced clinical care pathways. Our costs were higher than comparators before implementation, but lower than comparators after implementation.

Conclusions: Herein, we used an analytic framework and used national administrative data to assess the value of an enhanced care initiative as benchmarked with data from other hospitals. We thus illustrate how to identify and measure opportunities for targeted improvements in health care delivery. We also recognize the limitations of the use of administrative data in a comprehensive assessment of value in health care.
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http://dx.doi.org/10.1016/j.jss.2020.12.061DOI Listing
June 2021

Measurement of Portal Vein Blood Circulating Tumor Cells is Safe and May Correlate With Outcomes in Resected Pancreatic Ductal Adenocarcinoma.

Ann Surg Oncol 2021 Aug 7;28(8):4615-4622. Epub 2021 Jan 7.

Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Background: This study investigated the safety and feasibility of intraoperative portal vein blood (PVB) collection at the time of pancreatic ductal adenocarcinoma (PDAC) resection. Relationships of circulating tumor cells (CTCs) in PVB and peripheral blood (PB) with overall survival (OS) and recurrence-free survival were studied.

Methods: Patients undergoing PDAC resection were offered enrollment in a prospective liquid biopsy protocol. The patients had PB drawn before incision and PVB drawn before tumor mobilization, then again immediately after resection. Using standard CellSearch protocols, CTCs were identified and compared with OS.

Results: Of the 34 patients enrolled in this study, 23 (68%) underwent pancreaticoduodenectomy, 8 (23%) underwent distal pancreatectomy, and 3 (9%) underwent total pancreatectomy. Peripheral blood was available for 22 (65%) and PVB for 31 (91%) of the patients. No bleeding or thrombotic complications occurred with the PVB draws. The CTC counts per 7.5 mL of PVB collected before and after resection were highly correlated (R = 0.89). The study found CTCs in 11 (50%) of 22 PB samples and 22 (71%) of 31 PVB samples. The OS rate at 18 months was 92% for the patients with < 3 CTCs, 71% for the patients with ≥ 3 CTCs per 7.5 mL of PB (p = 0.30), 100% for the patients without PVB CTCs, and 70% for the patients with PVB CTCs (p < 0.01).

Conclusions: Collection of PVB during PDAC resection is safe. In this pilot study, PVB CTC counts but not PB CTC counts were significantly correlated with OS. This opens the door for future studies on selective omission of adjuvant chemotherapy for patients treated preoperatively and tailored surveillance intensity for patients without PVB CTCs at PDAC resection.
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http://dx.doi.org/10.1245/s10434-020-09518-yDOI Listing
August 2021

FRETing over SARS-CoV-2: Conformational Dynamics of the Spike Glycoprotein.

Cell Host Microbe 2020 12;28(6):778-779

Department of Laboratory Medicine and Pathobiology, Temerty Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada. Electronic address:

In this issue of Cell Host & Microbe, Lu et al. utilize single-molecule FRET to reveal the conformation dynamics of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein, showing transitions from a closed ground state to the open receptor-accessible conformation via an on-path intermediate. These insights into spike conformations will facilitate rational immunogen design.
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http://dx.doi.org/10.1016/j.chom.2020.11.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7725053PMC
December 2020

Characterization of novel neutralizing mouse monoclonal antibody JM1-24-3 developed against MUC18 in metastatic melanoma.

J Exp Clin Cancer Res 2020 Dec 5;39(1):273. Epub 2020 Dec 5.

Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.

Background: MUC18 is a glycoprotein highly expressed on the surface of melanoma and other cancers which promotes tumor progression and metastasis. However, its mechanism of action and suitability as a therapeutic target are unknown.

Methods: A monoclonal antibody (mAb) (JM1-24-3) was generated from metastatic melanoma tumor live cell immunization, and high-throughput screening identified MUC18 as the target.

Results: Analysis of molecular interactions between MUC18 and JM1-24-3 revealed that the downstream signaling events depended on binding of the mAb to a conformational epitope on the extracellular domain of MUC18. JM1-24-3 inhibited melanoma cell proliferation, migration and invasion in vitro and reduced tumor growth and metastasis in vivo.

Conclusion: These results confirm that MUC18 is mechanistically important in melanoma growth and metastasis, suggest that the MUC18 epitope identified is a promising therapeutic target, and that the JM1-24-3 mAb may serve as the basis for a potential therapeutic agent.
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http://dx.doi.org/10.1186/s13046-020-01722-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718695PMC
December 2020

Electronic Health Record Use among Ophthalmology Residents while on Call.

J Acad Ophthalmol 2020 Jul;12(2):e143-e150

Viterbi Family Department of Ophthalmology, Shiley Eye Institute, University of California San Diego, La Jolla, California.

Background: As electronic health record (EHR) use becomes more widespread, detailed records of how users interact with the EHR, known as EHR audit logs, are being used to characterize the clinical workflows of physicians including residents. After-hours EHR use is of particular interest given its known association with physician burnout. Several studies have analyzed EHR audit logs for residents in other fields, such as internal medicine, but none thus far in ophthalmology. Here, we focused specifically on EHR use during on-call shifts outside of normal clinic hours.

Methods: In this retrospective study, we analyzed raw EHR audit log data from on-call shifts for 12 ophthalmology residents at a single institution over the course of a calendar year. Data were analyzed to characterize total time spent using the EHR, clinical volume, diagnoses of patients seen on call, and EHR tasks.

Results: Across all call shifts, the median and interquartile range (IQR) of the time spent logged into the EHR per shift were 88 and 131 minutes, respectively. The median (IQR) unique patient charts accessed per shift was 7 (9) patients. When standardized to per-hour measures, weekday evening shifts were the busiest call shifts with regard to both EHR use time and clinical volume. Total EHR use time and clinical volume were greatest in the summer months (July to September). Chart review comprised a majority (63.4%) of ophthalmology residents' on-call EHR activities.

Conclusion: In summary, EHR audit logs demonstrate substantial call burden for ophthalmology residents outside of regular clinic hours. These data and future studies can be used to further characterize the clinical exposure and call burden of ophthalmology residents and could potentially have broader implications in the fields of physician burnout and education policy.
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http://dx.doi.org/10.1055/s-0040-1716411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710324PMC
July 2020

Risk-Stratified Pancreatectomy Clinical Pathway Implementation and Delayed Gastric Emptying.

J Gastrointest Surg 2021 Sep 24;25(9):2221-2230. Epub 2020 Nov 24.

Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, 1400 Pressler St., Unit 1484, Houston, TX, 77030, USA.

Background: Delayed gastric emptying (DGE) is a frequent complication after pancreaticoduodenectomy (PD) that impairs recovery and quality of life. The purpose of this study was to assess the impact risk-stratified pancreatectomy clinical pathways (RSPCPs) had on delayed gastric emptying (DGE) and identify factors associated with DGE in a contemporary period.

Methods: A single-institution, prospective database was queried for consecutive PDs during July 2011-November 2019. Using international definitions, DGE rates were compared between periods before and after RSPCPs were implemented in 2016, classifying patients according to their postoperative pancreatic fistula (POPF) risk. Risk factors were analyzed to identify modifiable targets.

Results: Among 724 elective PDs, 552 (76%) were for adenocarcinoma and 172 (24%) for other diagnoses. Of the 197 (27%) patients with DGE, 119 (16%) had type A, 41 (6%) type B, and 38 (5%) type C. In the overall cohort, DGE rates were higher with pylorus-preserving vs. classic hand-sewn reconstruction (odds ratio [OR] - 1.84; p < 0.001), postoperative abscess (OR - 2.54; p = 0.003), and non-white patients (p = 0.007), but lower after implementation of RSPCPs (OR - 0.34, p < 0.001). In the 374 patients treated with RSPCPs, only 17% (n = 65/374) developed DGE. Patients with protocol-compliant NGT removal ≤ 48 h were less likely to experience DGE (OR - 1.46, p = 0.042).

Conclusion: Our data suggest that implementation of preoperatively assigned RSPCPs as a care bundle was the most important factor in decreasing DGE. These gains were accentuated in patients who underwent early nasogastric tube removal and had a classic hand-sewn gastro-jejunostomy reconstruction. Application of these modifiable factors is generalizable with low implementation barriers.
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http://dx.doi.org/10.1007/s11605-020-04877-zDOI Listing
September 2021

Clinicopathological correlation of radiologic measurement of post-therapy tumor size and tumor volume for pancreatic ductal adenocarcinoma.

Pancreatology 2021 Jan 14;21(1):200-207. Epub 2020 Nov 14.

Department of Anatomical Pathology, University of Texas, MD Anderson Cancer Center, 515 Holcombe Blvd, Houston, TX, 77030, USA; Department of Translational Molecular Pathology, University of Texas MD, Anderson Cancer Center, 515 Holcombe Blvd, Houston, TX, 77030, USA. Electronic address:

Objectives: Tumor size measurement is critical for accurate tumor staging in patients with pancreatic ductal adenocarcinoma (PDAC). However, accurate tumor size measurement is challenging in patients who received neoadjuvant therapy before resection, due to treatment-induced fibrosis and tumor invasion beyond the grossly identified tumor area. In this study, we evaluated the correlation between the tumor size and tumor volume measured on post-therapy computed tomography (CT) scans and the pathological measurement. Also, we investigated the correlation between these measurements and clinicopathological parameters and survival.

Materials And Methods: Retrospectively, we evaluated 343 patients with PDAC who received neoadjuvant therapy, followed by pancreaticoduodenectomy and had pre-operative pancreatic protocol CT imaging. We measured the longest tumor diameter (RadL) and the radiological tumor volume (RadV) on the post-therapy CT scan, then we categorized RadL into four radiologic tumor stages (RTS) based on the current AJCC staging (8th edition) protocol and RadV based on the median. Pearson correlation or Spearman's coefficient (δ), T-test and ANOVA was used to test the correlation between the radiological and pathological measurement. Chi-square analysis was used to test the correlation with the tumor pathological response, lymph-node metastasis and margin status and Kaplan-Meier and Cox-proportional hazard for survival analysis. P-value < 0.05 was considered significant.

Results: As a continuous variable, RadL showed a positive linear correlation with the post-therapy pathologic tumor size in the overall patient population (Pearson correlation coefficient: 0.72, P < 0.001) and RadV (δ: 0.63, p < 0.0001). However, there was no correlation between RadL and pathologic tumor size in patients with ypT0 and those with pathologic tumor size of ≤1.0 cm. Post-therapy RTS and RadV group correlated with ypT stage, tumor response grades using either CAP or MDA grading system, distance of superior mesenteric artery margin and tumor recurrence/metastasis.

Conclusion: Although RadL tends to understage ypT in PDAC patients who had no radiologically detectable tumor or small tumors (RTS0 or RTS1), radiologic measurement of post-therapy tumor size may be used as a marker for the pathologic tumor staging and tumor response to neoadjuvant therapy.
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http://dx.doi.org/10.1016/j.pan.2020.11.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855532PMC
January 2021

Natural history and prognostic factors for localised small bowel adenocarcinoma.

ESMO Open 2020 11;5(6):e000960

Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. Electronic address:

Objective: Small bowel adenocarcinoma (SBA) is a rare malignancy with limited evidence regarding outcomes after curative resection of localised disease. We aimed to evaluate presentation and prognostic factors affecting overall survival (OS), relapse-free survival (RFS) and recurrence of SBA.

Methods: Consecutive patients with completely resected localised SBA (1979-2019) were retrospectively reviewed for presentation, patient and tumour characteristics, perioperative treatment, recurrence, outcomes, and prognostic factors.

Results: Among 257 total patients, median age was 58 years. Primary location was in the duodenum, jejunum and ileum in 52%, 29%, and 19% of patients, respectively. Median OS was 57.5 months and median follow-up was 40 months. In multivariate analysis, lymph node involvement, lymphovascular invasion, histologic grade and race were independent predictors of RFS, while race, stage and histologic grade were independent predictors of OS. No significant difference in OS or RFS was seen when evaluating the role of perioperative treatment. Median time to diagnosis from first medical evaluation was 31 days and did not change over time. Overall recurrence rate was 56%. Recurrence rate was higher in ileal (77%), than duodenal (54%) and jejunal (65%) SBA (p=0.01). Recurrence presented most commonly as distant metastasis (71%). Proficient mismatch repair was associated with decreased risk of locoregional recurrence (LR) but increased risk of distant recurrence (DR) when compared with deficient mismatch repair (dMMR) in univariate analysis.

Conclusions: Despite advances in diagnostic modalities, this study did not show any improvement in earlier diagnosis of SBA over the course of the past three decades. The predominant pattern of disease recurrence was distant across all SBA locations, but dMMR status demonstrated a robust predilection for LR as opposed to DR. Perioperative treatment did not improve outcomes; however, a lower stage disease was seen in patients that received neoadjuvant therapy, suggesting further exploration of this approach.
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http://dx.doi.org/10.1136/esmoopen-2020-000960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7668374PMC
November 2020

Novel genetic variants of and of the endosome-related pathway predict cutaneous melanoma-specific survival.

Am J Cancer Res 2020 1;10(10):3382-3394. Epub 2020 Oct 1.

Duke Cancer Institute, Duke University Medical Center Durham, NC 27710, USA.

Endosomes regulate cell polarity, adhesion, signaling, immunity, and tumor progression, which may influence cancer outcomes. Here we evaluated associations between 36,068 genetic variants of 228 endosome-related pathway genes and cutaneous melanoma disease-specific survival (CMSS) using genotyping data from two previously published genome-wide association studies. The discovery dataset included 858 CM patients with 95 deaths from The University of Texas MD Anderson Cancer Center, and the replication dataset included 409 CM patients with 48 deaths from the Nurses' Health Study (NHS) and the Health Professionals Follow-up Study (HPFS). In multivariate Cox proportional hazards regression analysis, we found that two novel SNPs ( rs11666894 A>C and rs12376285 C>T) predicted CMSS, with adjusted hazards ratios of 1.47 (95% confidence interval = 1.15-1.89 and = 0.002) and 1.73 (1.30-2.31 and 0.0002), respectively. Combined analysis of risk genotypes of these two SNPs revealed a dose-dependent decrease in CMSS associated with an increased number of risk genotypes ( = 0.0002). Subsequent expression quantitative trait loci (eQTL) analysis revealed that rs11666894 was associated with mRNA expression levels in lymphoblastoid cell lines from 373 European descendants (<0.0001) and that rs12376285 was associated with mRNA expression levels in cultured fibroblasts from 605 European-Americans (<0.0001). Our findings suggest that novel genetic variants of and in the endosome-related pathway genes may be promising prognostic biomarkers for CMSS, but these results need to be validated in future larger studies.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642651PMC
October 2020

Computed Tomography-Based Biomarker Outcomes in a Prospective Trial of Preoperative FOLFIRINOX and Chemoradiation for Borderline Resectable Pancreatic Cancer.

JCO Precis Oncol 2019 23;3. Epub 2019 Aug 23.

University of Texas MD Anderson Cancer Center, Houston, TX.

Purpose: Effective preoperative regimens and biomarkers for pancreatic ductal adenocarcinoma (PDAC) are lacking. We prospectively evaluated fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX)-based treatment and imaging-based biomarkers for borderline resectable PDAC.

Methods: Eligible patients had treatment-naïve, histology-confirmed PDAC and one or more high-risk features: mesenteric vessel involvement, CA 19-9 level of 500 mg/dL or greater, and indeterminate metastatic lesions. Patients received modified FOLFIRINOX and chemoradiation before anticipated pancreatectomy. Tumors were classified on baseline computed tomography as high delta (well-defined interface with parenchyma) or low delta (ill-defined interface). We designated computed tomography interface response after therapy as type I (remained or became well defined) or type II (became ill defined). The study had 80% power to differentiate a 60% from 40% resection rate (α = .10). Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method, and subgroups were compared using log-rank tests.

Results: Thirty-three patients initiated therapy; 45% underwent pancreatectomy. The median OS was 24 months (95% CI, 16.2 to 29.6 months). For patients who did and did not undergo pancreatectomy, the median OS was 42 months (95% CI, 17.7 months to not estimable) and 14 months (95% CI, 9.0 to 24.8 months), respectively. Patients with high-delta tumors had lower 3-year PFS (4% 40%) and 3-year OS rates (20% 60%) than those with low-delta tumors (both < .05). Patients with type II interface responses had lower 3-year PFS (0% 29%) and 3-year OS rates (16% 47%) than those with type I responses (both < .001).

Conclusion: Preoperative FOLFIRINOX followed by chemoradiation for high-risk borderline resectable PDAC was associated with a resection rate of 45% and median OS of approximately 2 years. Our imaging-based biomarker validation indicates that personalized treatment may be achieved using these biomarkers at baseline and post-treatment.
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http://dx.doi.org/10.1200/PO.19.00001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446521PMC
August 2019

Surgical decision-making and prioritization for cancer patients at the onset of the COVID-19 pandemic: A multidisciplinary approach.

Surg Oncol 2020 Sep 28;34:182-185. Epub 2020 Apr 28.

Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.

In the midst of the coronavirus disease 2019 (COVID-19) pandemic, governmental agencies, state medical boards, and healthcare organizations have called for restricting "elective" operations to mitigate the risk of transmission of the virus amongst patients and healthcare providers and to preserve essential resources for potential regional surges of COVID patients. While the fear of delaying surgical care for many of our patients is deeply challenging for us as cancer care providers, we must balance our personal commitment to providing timely and appropriate oncologic care to our cancer patients with our societal responsibility to protect our patients (including those on whom we are operating), co-workers, trainees, families, and community, from undue risks of contracting and propagating COVID-19. Herein, we present guidelines for surgical decision-making and case prioritization developed among all adult disease specialties in the MD Anderson Cancer Center Departments of Surgical Oncology and Breast Surgical Oncology in Houston, Texas.
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http://dx.doi.org/10.1016/j.suronc.2020.04.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7187856PMC
September 2020
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