Publications by authors named "Terence M Williams"

100 Publications

Regulation of DNA duplication by the mTOR signaling pathway.

Cell Cycle 2021 Mar 10:1-10. Epub 2021 Mar 10.

Department of Radiation Oncology, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA.

Accurate and complete DNA replication and separation are essential for genetic information inheritance and organism maintenance. Errors in DNA duplication are the main source of genetic instability. Understanding DNA duplication regulation is the key to elucidate the mechanisms and find treatment strategies for human genetic disorders, especially cancer. The mechanistic target of rapamycin (mTOR) is a central regulator of cell growth and proliferation by integrating and processing extracellular and intracellular signals to monitor the well-being of cell physiology. mTOR signaling dysregulation is associated with many human diseases including cancer and diabetes. Emerging evidence has demonstrated that mTOR signaling plays a key role in DNA duplication. We herein review the current knowledge of mTOR signaling in the regulation of DNA replication origin licensing, replication fork progression, and stabilization.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/15384101.2021.1897271DOI Listing
March 2021

Increasing neutrophil-to-lymphocyte ratio following radiation is a poor prognostic factor and directly correlates with splenic radiation dose in pancreatic cancer.

Radiother Oncol 2021 Mar 3;158:207-214. Epub 2021 Mar 3.

Department of Radiation Oncology, City of Hope National Medical Center, Duarte, CA, United States. Electronic address:

Purpose: Neutrophil-to-lymphocyte ratio has been correlated with clinical outcomes in many cancers. We investigated whether the delta-NLR (ΔNLR) following radiation therapy (RT) could predict achieving surgical resection and the overall survival (OS) of patients with borderline resectable (BRPC) and locally advanced pancreatic cancer (LAPC), and whether the splenic radiation dose impacted ΔNLR.

Methods/materials: 101 patients with biopsy-proven BRPC or LAPC who received induction chemotherapy followed by RT were retrospectively enrolled. Following contouring of spleens, dose-volume histograms (DVHs) for splenic dosimetric parameters were calculated. Pre- and post-RT complete blood counts (CBC) within two weeks were recorded. Delta (Δ) values were calculated by subtracting the post-RT value from the pre-RT value. Cox regression survival analysis for pre and postradiation CBC values and OS was performed. Receiver operating curves (ROC) were generated and optimal cutoff points for highest sensitivity and specificity were identified. Kaplan-Meier curves for OS were generated.

Results: On univariate Cox regression analysis, the only significant CBC value associated with OS was ΔNLR (HR 1.06, CI 1.03-1.09, p < 0.001). On multivariate analysis, ΔNLR, age, and completed resection all significantly predicted for worse OS (p < 0.05). ΔNLR significantly predicted achieving surgical resection (p = 0.04) and the optimal cutoff point for ΔNLR was 2.5. Patients with ΔNLR < 2.5 had significantly longer OS (log rank p = 0.046). Spleen radiation dose parameters were all significantly higher in patients with a ΔNLR ≥ 2.5. Optimal radiation cutoff points to predict a ΔNLR ≥ 2.5 were splenic Dmean of 308 cGy and V5 of 10.3%.

Conclusions: Among patients with BRPC or LAPC who have received induction chemotherapy, elevated ΔNLR after RT significantly predicts worse OS and decreased odds of achieving resection. Furthermore, ΔNLR is correlated with higher splenic doses, suggesting the spleen may be an important organ at risk.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.radonc.2021.02.035DOI Listing
March 2021

Neoadjuvant therapy versus surgery first for ampullary carcinoma: A propensity score-matched analysis of the NCDB.

J Surg Oncol 2021 Feb 17. Epub 2021 Feb 17.

Division of Surgical Oncology, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.

Background: The role of neoadjuvant therapy (NT) for ampullary carcinoma (AC) has not been clearly established.

Methods: Patients who underwent pancreatoduodenectomy for AC between 2004 and 2016 were identified in the National Cancer Database. Overall survival (OS) was compared between those who received NT before resection and those who underwent surgery first (SF). Propensity score matching (PSM) was performed using age, pathologic T and N stage, and tumor differentiation.

Results: Among 8688 patients with AC, 175 (2.0%) received NT before surgery. While patients who received NT were younger (p = .022) and more likely to have nodal metastasis (43.3% vs. 35.1%, p < .001), there was no difference in OS on univariate (43 vs. 33 months; hazard ratio [HR]: 1.10, 95% confidence interval [CI]: 0.88-1.37, p = .401) or multivariate (HR: 1.09, 95% CI: 0.88-1.36, p = .416) analysis between groups. After PSM, there remained no difference in OS between NT or SF groups on univariate (37 vs. 32 months; HR: 1.20, 95% CI: 0.87-1.64, p = .350) or multivariate (HR: 0.99, 95% CI: 0.71-1.38, p = .943) analysis.

Conclusion: NT followed by surgery was not associated with improved survival outcomes compared with SF among patients with localized AC. While NT is an acceptable alternative for patients with advanced disease, SF should remain the standard of care.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jso.26435DOI Listing
February 2021

MYBL2-Driven Transcriptional Programs Link Replication Stress and Error-prone DNA Repair With Genomic Instability in Lung Adenocarcinoma.

Front Oncol 2020 8;10:585551. Epub 2021 Jan 8.

Department of Biochemistry & Molecular Genetics, University of Virginia, Charlottesville, VA, United States.

It has long been recognized that defects in cell cycle checkpoint and DNA repair pathways give rise to genomic instability, tumor heterogeneity, and metastasis. Despite this knowledge, the transcription factor-mediated gene expression programs that enable survival and proliferation in the face of enormous replication stress and DNA damage have remained elusive. Using robust omics data from two independent studies, we provide evidence that a large cohort of lung adenocarcinomas exhibit significant genome instability and overexpress the DNA damage responsive transcription factor MYB proto-oncogene like 2 (MYBL2). Across two studies, elevated expression was a robust marker of poor overall survival and disease-free survival outcomes, regardless of disease stage. Clinically, elevated expression identified patients with aggressive early onset disease, increased lymph node involvement, and increased incidence of distant metastases. Analysis of genomic sequencing data demonstrated that High lung adenocarcinomas had elevated somatic mutation burden, widespread chromosomal alterations, and alterations in single-strand DNA break repair pathways. In this study, we provide evidence that impaired single-strand break repair, combined with a loss of cell cycle regulators TP53 and RB1, give rise to MYBL2-mediated transcriptional programs. Omics data supports a model wherein tumors with significant genomic instability upregulate MYBL2 to drive genes that control replication stress responses, promote error-prone DNA repair, and antagonize faithful homologous recombination repair. Our study supports the use of checkpoint kinase 1 (CHK1) pharmacological inhibitors, in targeted High patient cohorts, as a future therapy to improve lung adenocarcinoma patient outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fonc.2020.585551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821388PMC
January 2021

Potential Molecular Targets in the Setting of Chemoradiation for Esophageal Malignancies.

J Natl Cancer Inst 2020 Dec 22. Epub 2020 Dec 22.

Radiation Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Rockville, MD.

While the development of effective combined chemoradiation regimens for esophageal cancers has resulted in statistically significant survival benefits, the majority of patients treated with curative intent develop locoregional and/or distant relapse. Further improvements in disease control and survival will require the development of individualized therapy based on the knowledge of host and tumor genomics, and potentially harnessing the host immune system. Although there are a number of gene targets that are amplified and proteins that are overexpressed in esophageal cancers, attempts to target several of these have not proven successful in unselected patients. Herein, we review our current state of knowledge regarding the molecular pathways implicated in esophageal carcinoma, and the available agents for targeting these pathways that may rationally be combined with standard chemoradiation, with the hope that this commentary will guide future efforts of novel combinations of therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jnci/djaa195DOI Listing
December 2020

EMT-Induced Gemcitabine Resistance in Pancreatic Cancer Involves the Functional Loss of Equilibrative Nucleoside Transporter 1.

Mol Cancer Ther 2021 02 9;20(2):410-422. Epub 2020 Dec 9.

Division of Pharmaceutics and Pharmacology, The Ohio State University College of Pharmacy, Columbus, Ohio.

Epithelial-mesenchymal transition (EMT) in cancer cells drives cancer chemoresistance, yet the molecular events of EMT that underpin the acquisition of chemoresistance are poorly understood. Here, we demonstrate a loss of gemcitabine chemosensitivity facilitated by human equilibrative nucleoside transporter 1 (ENT1) during EMT in pancreatic cancer and identify that cadherin switching from the epithelial (E) to neuronal (N) type, a hallmark of EMT, contributes to this loss. Our findings demonstrate that N-cadherin decreases ENT1 expression, membrane localization, and gemcitabine transport, while E-cadherin augments each of these. Besides E- and N-cadherin, another epithelial cell adhesion molecule, EpCAM, played a more prominent role in determining ENT1 membrane localization. Forced expression of EpCAM opposed cadherin switching with restored ENT1 expression, membrane localization, and gemcitabine transport in EMT-committed pancreatic cancer cells. In gemcitabine-treated mice, EpCAM-positive tumors had high ENT1 expression and reduced metastasis, whereas tumors with N-cadherin expression resisted gemcitabine treatment and formed extensive secondary metastatic nodules. Tissue microarray profiling and multiplexed IHC analysis of pancreatic cancer patient-derived primary tumors revealed EpCAM and ENT1 cell surface coexpression is favored, and ENT1 plasma membrane expression positively predicted median overall survival times in patients treated with adjuvant gemcitabine. Together, our findings identify ENT1 as an inadvertent target of EMT signaling mediated by cadherin switching and provide a mechanism by which mesenchymal pancreatic cancer cells evade gemcitabine therapy during EMT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1535-7163.MCT-20-0316DOI Listing
February 2021

Predictive Modeling for Voxel-Based Quantification of Imaging-Based Subtypes of Pancreatic Ductal Adenocarcinoma (PDAC): A Multi-Institutional Study.

Cancers (Basel) 2020 Dec 5;12(12). Epub 2020 Dec 5.

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

Previously, we characterized qualitative imaging-based subtypes of pancreatic ductal adenocarcinoma (PDAC) on computed tomography (CT) scans. Conspicuous (high delta) PDAC tumors are more likely to have aggressive biology and poorer clinical outcomes compared to inconspicuous (low delta) tumors. Here, we developed a quantitative classification of this imaging-based subtype (quantitative delta; q-delta). Retrospectively, baseline pancreatic protocol CT scans of three cohorts (cohort#1 = 101, cohort#2 = 90 and cohort#3 = 16 [external validation]) of patients with PDAC were qualitatively classified into high and low delta. We used a voxel-based method to volumetrically quantify tumor enhancement while referencing normal-pancreatic-parenchyma and used machine learning-based analysis to build a predictive model. In addition, we quantified the stromal content using hematoxylin- and eosin-stained treatment-naïve PDAC sections. Analyses revealed that PDAC quantitative enhancement values are predictive of the qualitative delta scoring and were used to build a classification model (q-delta). Compared to high q-delta, low q-delta tumors were associated with improved outcomes, and the q-delta class was an independent prognostic factor for survival. In addition, low q-delta tumors had higher stromal content and lower cellularity compared to high q-delta tumors. Our results suggest that q-delta classification provides a clinically and biologically relevant tool that may be integrated into ongoing and future clinical trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers12123656DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762105PMC
December 2020

Association of Pre- and Posttreatment Neutrophil-Lymphocyte Ratio With Recurrence and Mortality in Locally Advanced Non-Small Cell Lung Cancer.

Front Oncol 2020 5;10:598873. Epub 2020 Nov 5.

Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH, United States.

Objectives: Neutrophil-lymphocyte ratio (NLR) has been associated with mortality in non-small cell lung cancer (NSCLC), but its association with recurrence in locally advanced NSCLC (LA-NSCLC), specifically, is less established. We hypothesized pre- and posttreatment NLR would be associated with recurrence and mortality.

Methods: We studied the association of pretreatment NLR (pre-NLR) and posttreatment NLR at 1 (post-NLR) and 3 months (post-NLR) with outcomes in patients with LA-NSCLC treated with chemoradiation. Pre-NLR was dichotomized by 5, an cutoff previously shown to be prognostic in LA-NSCLC. Post-NLR and post-NLR were dichotomized by their medians.

Results: We identified 135 patients treated with chemoradiation for LA-NSCLC between 2007 and 2016. Median follow-up for living patients was 61.1 months. On multivariable analysis, pre-NLR ≥ 5 was associated with worse overall survival (HR = 1.82; 95% CI 1.15 - 2.88; p = 0.011), but not with any recurrence, locoregional recurrence, or distant recurrence. Post-NLR ≥ 6.3 was not associated with recurrence or survival. Post-NLR ≥ 6.6 was associated with worse overall survival (HR = 3.27; 95% CI 2.01- 5.31; p < 0.001), any recurrence (HR = 2.50; 95% CI 1.53 - 4.08; p < 0.001), locoregional recurrence (HR = 2.50; 95% CI 1.40 - 4.46; p = 0.002), and distant recurrence (HR = 2.53; 95% CI 1.49 - 4.30; p < 0.001).

Conclusion: Pretreatment NLR is associated with worse overall survival and posttreatment NLR is associated with worse survival and recurrence. These findings should be validated independently and prospectively studied.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fonc.2020.598873DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7676908PMC
November 2020

Morphologic changes associated with neoadjuvant-treated pancreatic ductal adenocarcinoma and comparison of two tumor regression grading systems.

Hum Pathol 2021 Mar 24;109:1-11. Epub 2020 Nov 24.

Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, 43210, USA. Electronic address:

Pancreatic ductal adenocarcinoma (PDAC) is aggressive, with an overall five-year survival rate of 9%, and few patients are candidates for pancreatectomy at presentation. The role of neoadjuvant therapy (NAT) is evolving, especially for high-risk potentially resectable tumors. Owing to the increasing number of NAT resection specimens, we aim to characterize the histologic changes associated with NAT and to compare two tumor regression grading schemes. One hundred eighteen resections for PDAC were selected from the cases between 2011 and 2018, 59 not treated and 59 treated with NAT. All H&E stained tumor slides were reviewed for histologic changes and graded using the four-tier modified Ryan score (recommended by College of American Pathologists) and the three-tier MD Anderson (MDA) score. The histologic changes evaluated included blue/grey fibrosis, islet cell hyperplasia, dystrophic calcification, amyloid deposition, cholesterol clefts, nerve hypertrophy, elastotic stromal/vascular change, abscess formation, and eosinophilic tumor cell changes. There were statistically significant differences for dystrophic calcification, eosinophilic tumor cell changes, elastotic stromal/vascular change, islet cell hyperplasia, and nerve hypertrophy between the two groups, with these features seen more frequently in NAT cases. Blue/grey stromal fibrosis was present in all cases regardless of NAT, except few complete regression cases and one treated case with intraneural invasion only. Blue/grey fibrosis is a useful histologic visual clue to suggest the possibility of adjacent tumor in the majority of PDAC cases regardless of NAT. By Kaplan-Meier analysis, neither grading scheme correlated with overall survival in our cohort. However, the MDA score was significantly correlated with both time to primary tumor recurrence (p = 0.002) and time to distant recurrence (p = 0.04), whereas the modified Ryan score was not.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.humpath.2020.11.010DOI Listing
March 2021

A narrative review of toxicity of chemoradiation and immunotherapy for unresectable, locally advanced non-small cell lung cancer.

Transl Lung Cancer Res 2020 Oct;9(5):2040-2050

Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, Ohio, USA.

Despite declining smoking rates, lung cancer remains the second most common malignancy in the United States and the leading cause of cancer-related mortality. Non-small cell lung cancer (NSCLC) comprises roughly 85% of cases, and patients tend to present with advanced disease. Historically, concurrent chemoradiotherapy (CRT) has been the standard of care for stage III unresectable NSCLC but outcomes even with multimodal therapy have remained relatively poor. Efforts to improve outcomes through radiation dose escalation with conventional dose fractionation were unsuccessful with RTOG 0617, demonstrating significantly decreased overall survival (OS) with high dose radiation with respect to standard therapy. The recent PACIFIC trial established a new role for consolidative immune checkpoint blockade therapy after CRT using the programmed death ligand 1 (PD-L1) inhibitor durvalumab, by demonstrating significantly improved progression free survival and OS. Although promising, the addition of immunotherapy to multimodal therapy has generated debate regarding the most effective immune pathways to target, appropriate sequencing of therapy, most effective radiation techniques, and toxicity-related concerns. This review will highlight recent and ongoing trials in unresectable, locally advanced NSCLC that incorporate chemotherapy, radiation, and immunotherapy with an emphasis on analysis of treatment-related toxicities and implications for future study design.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21037/tlcr-20-638DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653152PMC
October 2020

Altered Gemcitabine and Nab-paclitaxel Scheduling Improves Therapeutic Efficacy Compared with Standard Concurrent Treatment in Preclinical Models of Pancreatic Cancer.

Clin Cancer Res 2021 Jan 21;27(2):554-565. Epub 2020 Oct 21.

Department of Radiation Oncology, The Ohio State University Wexner Medical Center, Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, Columbus, Ohio.

Purpose: Concurrent gemcitabine and nab-paclitaxel treatment is one of the preferred chemotherapy regimens for metastatic and locally advanced pancreatic ductal adenocarcinoma (PDAC). Previous studies demonstrate that caveolin-1 (Cav-1) expression is critical for nab-paclitaxel uptake into tumors and correlates with response. Gemcitabine increases nab-paclitaxel uptake by increasing Cav-1 expression. Thus, we hypothesized that pretreatment with gemcitabine would further enhance the sensitivity of PDAC to nab-paclitaxel by increasing Cav-1 expression and nab-paclitaxel uptake.

Experimental Design: We investigated the sensitivity of different gemcitabine and nab-paclitaxel treatment regimens in a panel of PDAC cell lines and orthotopic xenograft models. The sensitivity of different treatment regimens was compared with the standard concurrent treatment.

Results: Pretreatment with gemcitabine before nab-paclitaxel increased Cav-1 and albumin uptake and significantly decreased proliferation and clonogenicity compared with concurrent treatment, which correlated with increased levels of apoptosis. Cav-1 silencing reduced the uptake of albumin, and therapeutic advantage was observed when cells were pretreated with gemcitabine prior to nab-paclitaxel. In addition, we observed that pretreatment with gemcitabine resulted in partial synchronization of cells in the G-M-phase at the time of nab-paclitaxel treatment, providing another mechanism for the benefit of altered scheduling. In heterotopic and orthotopic xenograft models, the altered schedule of gemcitabine prior to nab-paclitaxel significantly delayed tumor growth compared with concurrent delivery without added toxicity.

Conclusions: Pretreatment with gemcitabine significantly increased nab-paclitaxel uptake and correlated with an increased treatment efficacy and survival benefit in preclinical models, compared with standard concurrent treatment. These results justify preclinical and clinical testing of this altered scheduling combination.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-20-1422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855515PMC
January 2021

Neoadjuvant Therapy Versus Immediate Surgery for Resectable Pancreas Cancer: Still Open for Debate.

Am J Clin Oncol 2020 10;43(10):752-754

Radiation Oncology, The Ohio State Wexner Medical Center, Columbus, OH.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/COC.0000000000000728DOI Listing
October 2020

Contemporary Understandings of Cardiovascular Disease After Cancer Radiotherapy: a Focus on Ischemic Heart Disease.

Curr Cardiol Rep 2020 Sep 23;22(11):151. Epub 2020 Sep 23.

Cardio-Oncology Program, Division of Cardiology, The Ohio State University Medical Center, Columbus, OH, USA.

Purpose Of Review: Radiation-induced cardiovascular disease, including coronary artery disease, is a well-known sequela of radiation therapy and represents a significant source of morbidity and mortality for cancer survivors. This review examines current literature and guidelines to care for this growing population of cancer survivors.

Recent Findings: The development of radiation-induced ischemic heart disease following radiation can lead even to early cardiotoxicities, inclusive of coronary artery disease, which limit cancer treatment outcomes. These coronary lesions tend to be diffuse, complex, and proximal. Early detection with multimodality imaging and targeted intervention is required to minimize these risks. Early awareness, detection, and management of radiation-induced cardiovascular disease are paramount as cancer survivorship continues to grow.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11886-020-01380-4DOI Listing
September 2020

The oncogenic potential of a mutant TP53 gene explored in two spontaneous lung cancer mice models.

BMC Cancer 2020 Aug 8;20(1):738. Epub 2020 Aug 8.

Department of Human & Molecular Genetics, Herbert Wertheim College of Medicine, The Florida International University, Miami, Florida, 33199, USA.

Background: Lung cancer is the number one cancer killer worldwide. A major drawback in the lung cancer treatment field is the lack of realistic mouse models that replicate the complexity of human malignancy and immune contexture within the tumor microenvironment. Such models are urgently needed. Mutations of the tumor protein p53 are among the most common alterations in human lung cancers.

Methods: Previously, we developed a line of lung cancer mouse model where mutant human TP53-273H is expressed in a lung specific manner in FVB/N background. To investigate whether the human TP53 mutant has a similar oncogenic potential when it is expressed in another strain of mouse, we crossed the FVB/N-SPC-TP53-273H mice to A/J strain and created A/J-SPC-TP53-273H transgenic mice. We then compared lung tumor formation between A/J-SPC-TP53-273H and FVB/N-SPC-TP53-273H.

Results: We found the TP53-273H mutant gene has a similar oncogenic potential in lung tumor formation in both mice strains, although A/J strain mice have been found to be a highly susceptible strain in terms of carcinogen-induced lung cancer. Both transgenic lines survived more than 18 months and developed age related lung adenocarcinomas. With micro CT imaging, we found the FVB-SPC-TP53-273H mice survived more than 8 weeks after initial detection of lung cancer, providing a sufficient window for evaluating new anti-cancer agents.

Conclusions: Oncogenic potential of the most common genetic mutation, TP53-273H, in human lung cancer is unique when it is expressed in different strains of mice. Our mouse models are useful tools for testing novel immune checkpoint inhibitors or other therapeutic strategies in the treatment of lung cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12885-020-07212-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414707PMC
August 2020

Surgery vs Stereotactic Body Radiation Therapy for Early-Stage Non-Small Cell Lung Cancer: Time to Settle the Debate: Reply.

Ann Thorac Surg 2021 03 25;111(3):1093. Epub 2020 Jul 25.

Department of Radiation Oncology, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Comprehensive Cancer Center, 460 W 10th Ave, Columbus, OH 43210. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.athoracsur.2020.05.151DOI Listing
March 2021

A Pilot Trial Evaluating Stereotactic Body Radiation Therapy to Induce Hyperemia in Combination With Transarterial Chemoembolization for Hepatocellular Carcinoma.

Int J Radiat Oncol Biol Phys 2020 12 23;108(5):1276-1283. Epub 2020 Jul 23.

Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, Ohio. Electronic address:

Purpose: Despite the survival benefit of transarterial chemoembolization (TACE) for unresectable hepatocellular carcinoma (HCC), a majority of tumors recur, attributed to hypovascularity and treatment resistance. Preclinical studies show that moderate radiation doses induce changes in tumor permeability and perfusion, suggesting an opportunity for TACE sensitization by radiation. In this prospective phase 1 trial, we evaluated the feasibility, safety, tolerability, response, and functional magnetic resonance imaging (MRI) changes associated with single-fraction stereotactic body radiation therapy (SBRT) followed by TACE within 24 hours.

Methods And Materials: Patients with HCC, 1 to 3 lesions, Childs-Pugh A/B liver function, and no major vascular invasion were enrolled. The primary objective was to establish the feasibility of single-dose SBRT (7.5 or 10 Gy) followed by TACE within 24 hours. Secondary endpoints included safety, tolerability, perfusional changes via functional MRI, overall response rate (ORR), clinical benefit rate (CBR), freedom from local progression, progression-free survival, and overall survival.

Results: Sixteen patients were enrolled, and 13 received SBRT and TACE. Median follow-up was 15.3 months. Best overall ORR and CBR were 76.9% and 92.3%, respectively. The 1- and 3-month ORR was 76.9% and 69.2%, respectively, and 1- and 3-month CBR was 92.3% and 69.2%, respectively. Median overall survival, progression-free survival, and freedom from local progression were 14.0, 5.2, and 5.9 months, respectively. Crude rates of grade 1+ and grade 2+ toxicity were 85% and 38%, respectively. No grade 3 to 4 toxicities were recorded. One grade 5 toxicity occurred due to hemorrhage 4 days after TACE. On dynamic contrast-enhanced MRI, the transfer rate constant from blood plasma to extracellular extravascular space (k) increased within 6 hours post-SBRT but decreased by 24 hours.

Conclusions: We hypothesized a strategy of SBRT preceding TACE for the purpose of enhancing TACE delivery and efficacy and tested this strategy in a small pilot study. We found that single-dose SBRT followed by TACE within 24 hours is feasible and tolerable. Dynamic contrast-enhanced MRI revealed acute changes in tumor permeability/perfusion after SBRT. Additional studies are needed to establish the safety and efficacy of this combination and the effects of SBRT on the HCC microenvironment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijrobp.2020.07.033DOI Listing
December 2020

CD200 promotes immunosuppression in the pancreatic tumor microenvironment.

J Immunother Cancer 2020 06 23;8(1). Epub 2020 Jun 23.

The James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, United States

Background: A significant challenge to overcome in pancreatic ductal adenocarcinoma (PDAC) is the profound systemic immunosuppression that renders this disease non-responsive to immunotherapy. Our supporting data provide evidence that CD200, a regulator of myeloid cell activity, is expressed in the PDAC microenvironment. Additionally, myeloid-derived suppressor cells (MDSC) isolated from patients with PDAC express elevated levels of the CD200 receptor (CD200R). Thus, we hypothesize that CD200 expression in the PDAC microenvironment limits responses to immunotherapy by promoting expansion and activity of MDSC.

Methods: Immunofluorescent staining was used to determine expression of CD200 in murine and human PDAC tissue. Flow cytometry was utilized to test for CD200R expression by immune populations in patient blood samples. In vivo antibody blocking of CD200 was conducted in subcutaneous MT-5 tumor-bearing mice and in a genetically engineered PDAC model (KPC-Brca2 mice). Peripheral blood mononuclear cells (PBMC) from patients with PDAC were analyzed by single-cell RNA sequencing. MDSC expansion assays were completed using healthy donor PBMC stimulated with IL-6/GM-CSF in the presence of recombinant CD200 protein.

Results: We found expression of CD200 by human pancreatic cell lines (BxPC3, MiaPaca2, and PANC-1) as well as on primary epithelial pancreatic tumor cells and smooth muscle actin+ stromal cells. CD200R expression was found to be elevated on CD11b+CD33+HLA-DR MDSC immune populations from patients with PDAC (p=0.0106). Higher expression levels of CD200R were observed in CD15+ MDSC compared with CD14+ MDSC (p<0.001). In vivo studies demonstrated that CD200 antibody blockade limited tumor progression in MT-5 subcutaneous tumor-bearing and in KPC-Brca2 mice (p<0.05). The percentage of intratumoral MDSC was significantly reduced in anti-CD200 treated mice compared with controls. Additionally, in vivo blockade of CD200 can also significantly enhance the efficacy of PD-1 checkpoint antibodies compared with single antibody therapies (p<0.05). Single-cell RNA sequencing of PBMC from patients revealed that CD200R+ MDSC expressed genes involved in cytokine signaling and MDSC expansion. Further, in vitro cytokine-driven expansion and the suppressive activity of human MDSC was enhanced when cocultured with recombinant CD200 protein.

Conclusions: These results indicate that CD200 expression in the PDAC microenvironment may regulate MDSC expansion and that targeting CD200 may enhance activity of checkpoint immunotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jitc-2019-000189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7312341PMC
June 2020

A Genome-Wide Pooled shRNA Screen Identifies PPP2R2A as a Predictive Biomarker for the Response to ATR and CHK1 Inhibitors.

Cancer Res 2020 08 10;80(16):3305-3318. Epub 2020 Jun 10.

Department of Radiation Oncology, The Ohio State University James Comprehensive Cancer Center and College of Medicine, Ohio.

There is currently a lack of precise predictive biomarkers for patient selection in clinical trials of inhibitors targeting replication stress (RS) response proteins ATR and CHK1. The objective of this study was to identify novel predictive biomarkers for the response to these agents in treating non-small cell lung cancer (NSCLC). A genome-wide loss-of-function screen revealed that tumor suppressor PPP2R2A, a B regulatory subunit of protein phosphatase 2 (PP2A), determines sensitivity to CHK1 inhibition. A synthetic lethal interaction between PPP2R2A deficiency and ATR or CHK1 inhibition was observed in NSCLC and and was independent of p53 status. ATR and CHK1 inhibition resulted in significantly increased levels of RS and altered replication dynamics, particularly in PPP2R2A-deficient NSCLC cells. Mechanistically, PPP2R2A negatively regulated translation of oncogene c-Myc protein. c-Myc activity was required for PPP2R2A deficiency-induced alterations of replication initiation/RS and sensitivity to ATR/CHK1 inhibitors. We conclude that PPP2R2A deficiency elevates RS by upregulating c-Myc activity, rendering cells reliant on the ATR/CHK1 axis for survival. Our studies show a novel synthetic lethal interaction and identify PPP2R2A as a potential new predictive biomarker for patient stratification in the clinical use of ATR and CHK1 inhibitors. SIGNIFICANCE: This study reveals new approaches to specifically target PPP2R2A-deficient lung cancer cells and provides a novel biomarker that will significantly improve treatment outcome with ATR and CHK1 inhibitors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/0008-5472.CAN-20-0057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7518641PMC
August 2020

Neoadjuvant-modified FOLFIRINOX vs nab-paclitaxel plus gemcitabine for borderline resectable or locally advanced pancreatic cancer patients who achieved surgical resection.

Cancer Med 2020 07 16;9(13):4711-4723. Epub 2020 May 16.

Department of Radiation Oncology, Ohio State University James Comprehensive Cancer Center, Columbus, OH, USA.

We conducted an institutional study to compare the clinical and pathological efficacy between the neoadjuvant therapy (NAT)-modified FOLFIRINOX (mFOLF) vs nanoparticle albumin-bound paclitaxel plus gemcitabine (nab-P/G) for borderline resectable pancreatic cancer (BRPC) and locally advanced pancreatic cancer (LAPC) patients who completed resection. The study retrospectively enrolled patients with pathologically confirmed BRPC or LAPC from 2010 to 2018 at our institution. The survival rates were determined by the Kaplan-Meier method and log-rank test was used to test differences. Cox's proportional hazard model was used to assess survival with respect to covariates. Seventy-two patients who completed at least two cycles of neoadjuvant chemotherapy and surgical resection were included, with 52 (72.2%) patients receiving mFOLF and 20 (27.8%) receiving nab-P/G. Patients treated with mFOLF had statistically higher rates of RECIST 1.1 partial or complete response (16/52 vs 1/20, P = .028). Additionally, mFOLF patients had greater pathological tumor size reduction, fewer positive lymph nodes, and higher treatment response grade compared to the nab-P/G patients (all P < .05). The median overall survival was 33.3 months vs 27.1 months (P = .105), and distant metastasis-free survival (DMFS) was 21.3 months vs 14.6 months (P = .042) in the mFOLF vs nab-P/G groups, respectively. On multivariate analysis, mFOLF (hazard ratio, 0.428; 95% confidence interval [CI], 0.186-0.987) and abnormal postoperative CA 19-9 (hazard ratio, 2.47; 95% CI, 1.06-5.76) were associated with DMFS. Among patients with BRPC and LAPC who complete surgical resection, neoadjuvant mFOLF was associated with improved pathological and clinical outcomes compared with nab-P/G.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cam4.3075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7333854PMC
July 2020

TTF-1 Positive Primary Small Cell Carcinoma of the Breast: A Case Report and Review of the Literature.

Front Endocrinol (Lausanne) 2020 29;11:228. Epub 2020 Apr 29.

Stefanie Spielman Comprehensive Breast Cancer, The Ohio State University, Columbus, OH, United States.

Primary small cell carcinoma of the breast (SCCB) is a rare tumor subtype comprising <0.1% of all breast carcinomas. Here we present a case of thyroid transcription factor-1 (TTF-1) positive SCCB that recurred within 3 years of diagnosis in the lung and lymph nodes. Given the small number of cases, no clear guidelines exist on the appropriate management of patients with these aggressive tumors. We present a case study and review the current literature to highlight the knowledge gaps and needs of patients with these rare tumors. A 50-year-old premenopausal woman with no family history, presented with a palpable right breast mass. Biopsy was consistent with primary SCCB that was poorly differentiated, positive for synaptophysin and chromogranin and TTF-1 and presence of ductal carcinoma component showing neuroendocrine differentiation. Imaging with PET, CT, and MRI brain excluded any other sites of primary disease. She underwent a right lumpectomy with axillary lymph node dissection and was treated with adjuvant cisplatin-based chemotherapy and concurrent radiation therapy. Thirty-four months later, routine scans showed a new right lower-lobe lung nodule and an enlarged sub-carinal node that was proven to be poorly differentiated neuroendocrine cancer. This case report sheds light on a rarely described disease and provides a comprehensive approach to diagnosis and management. Primary SCCB is an extremely rare, aggressive form of breast cancer that is molecularly and histologically similar to SCLC. However, a review of the literature highlights recent mutational analyses that show important differences between these two cancer types, including an increase in PIK3CA mutations in primary SCCB. Further studies, including genomic analyses are needed to better define this malignancy and to develop a standard treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fendo.2020.00228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7201766PMC
April 2020

Recurrence After Stereotactic Body Radiation Therapy Versus Lobectomy for Non-Small Cell Lung Cancer.

Ann Thorac Surg 2020 09 27;110(3):998-1005. Epub 2020 Apr 27.

Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, Ohio. Electronic address:

Background: Although lobectomy remains the standard of care for early-stage non-small cell lung cancer, several studies suggest equipoise between lobectomy and stereotactic body radiation therapy (SBRT). However randomized evidence is lacking. We compared outcomes of early-stage non-small cell lung cancer patients treated with lobectomy or SBRT.

Methods: We included clinical T1-2N0 non-small cell lung cancer treated with lobectomy or SBRT to a biologically effective dose of ≥100 Gy. We used Cox proportional hazards and nearest-neighbor propensity score (2:1) matching to adjust for confounders. Kaplan-Meier curves were used to assess survival and recurrence.

Results: We identified 554 patients treated with lobectomy (n = 389) or SBRT (n = 165) at our institution between 2008 and 2018. After propensity score matching, there were 132 SBRT patients and 85 lobectomy patients. SBRT was associated with increased local recurrence (hazard ratio [HR], 6.80; 95% confidence interval [CI], 1.92-24.10; P = .003) and regional nodal recurrence (HR, 2.58; 95% CI, 1.17-5.68; P = .018), and with worse overall survival (HR, 2.00; 95% CI, 1.21-3.32; P = .007) and progression-free survival (HR, 2.34; 95% CI, 1.50-3.67; P < .001). There was no difference in distant recurrence (HR, 1.19; 95% CI, 0.57-2.52; P = .64).

Conclusions: We found superior outcomes in patients with early-stage non-small cell lung cancer treated with lobectomy compared with SBRT, including locoregional control. These findings should be interpreted with caution because of selection bias but underscore the importance of robust randomized prospective data to clarify the relative efficacy of these modalities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.athoracsur.2020.03.073DOI Listing
September 2020

Immune Checkpoint Inhibitors in Hepatocellular Cancer: Current Understanding on Mechanisms of Resistance and Biomarkers of Response to Treatment.

Gene Expr 2020 06 27;20(1):53-65. Epub 2020 Apr 27.

Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical CenterColumbus, OHUSA.

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy worldwide and a leading cause of death worldwide. Its incidence continues to increase in the US due to hepatitis C infection and nonalcoholic steatohepatitis. Liver transplantation and resection remain the best therapeutic options for cure, but these are limited by the shortage of available organs for transplantation, diagnosis at advanced stage, and underlying chronic liver disease found in most patients with HCC. Immune checkpoint inhibitors (ICIs) have been shown to be an evolving novel treatment option in certain advanced solid tumors and have been recently approved for inoperable, advanced, and metastatic HCC. Unfortunately, a large cohort of patients with HCC fail to respond to immunotherapy. In this review, we discuss the ICIs currently approved for HCC treatment and their various mechanisms of action. We will highlight current understanding of mechanism of resistance and limitations to ICIs. Finally, we will describe emerging biomarkers of response to ICIs and address future direction on overcoming resistance to immune checkpoint therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3727/105221620X15880179864121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7284108PMC
June 2020

Perineural invasion predicts for locoregional failure in patients with oesophageal adenocarcinoma treated with neoadjuvant chemoradiotherapy.

J Clin Pathol 2021 Apr 21;74(4):228-233. Epub 2020 Apr 21.

Department of Radiation Oncology, Ohio State University James Cancer Hospital, Columbus, Ohio, USA

Aim: The prognostic significance of perineural invasion (PNI) in oesophageal adenocarcinoma (EAC) is unclear. We examined the association of PNI with clinical outcomes in patients treated with neoadjuvant chemoradiotherapy (nCRT) and surgery.

Methods: We performed a single institutional retrospective study. We evaluated the association of PNI with locoregional recurrence-free survival (LRFS), distant metastasis-free survival, disease-free survival (DFS) and overall survival using log-rank and Cox proportional hazard modelling.

Results: 29 out of 73 patients (40%) had PNI at the time of surgery. The median follow-up was 20.1 months. The median DFS was 18.4 months for patients with PNI vs 41.3 months for patients without PNI (p<0.05). The median LRFS was 23.3 months for patients with PNI and median not reached for patients without PNI (p<0.01). In a multivariate model including age and pathological variables, PNI remained a significant independent predictor of LRFS (HR 0.20, 95% CI 0.07 to 0.60; p=0.004).

Conclusions: For patients with EAC treated with nCRT, PNI found at the time of surgery is significantly associated with worse LRFS. Our data support attempts to validate this finding and perhaps testing the role of adjuvant therapy in patients with PNI.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jclinpath-2020-206424DOI Listing
April 2021

Phase I Trial of Trametinib with Neoadjuvant Chemoradiation in Patients with Locally Advanced Rectal Cancer.

Clin Cancer Res 2020 07 6;26(13):3117-3125. Epub 2020 Apr 6.

Moffitt Cancer Center, Tampa, Florida.

Purpose: The RAS/RAF/MEK/ERK signaling pathway is critical to the development of colorectal cancers, and , , and mutations foster resistance to radiation. We performed a phase I trial to determine the safety of trametinib, a potent MEK1/2 inhibitor, with 5-fluorouracil (5-FU) chemoradiation therapy (CRT) in patients with locally advanced rectal cancer (LARC).

Patients And Methods: Patients with stage II/III rectal cancer were enrolled on a phase I study with 3+3 study design, with an expansion cohort of 9 patients at the MTD. Following a 5-day trametinib lead-in, with pre- and posttreatment tumor biopsies, patients received trametinib and CRT, surgery, and adjuvant chemotherapy. Trametinib was given orally daily at 3 dose levels: 0.5 mg, 1 mg, and 2 mg. CRT consisted of infusional 5-FU 225 mg/m/day and radiation dose of 28 daily fractions of 1.8 Gy (total 50.4 Gy). The primary endpoint was to identify the MTD and recommended phase II dose. IHC staining for phosphorylated ERK (pERK) and genomic profiling was performed on the tumor samples.

Results: Patients were enrolled to all dose levels, and 18 patients were evaluable for toxicities and responses. Treatment was well tolerated, and there was one dose-limiting toxicity of diarrhea, which was attributed to CRT rather than trametinib. At the 2 mg dose level, 25% had pathologic complete response. IHC staining confirmed dose-dependent decrease in pERK with increasing trametinib doses.

Conclusions: The combination of trametinib with 5-FU CRT is safe and well tolerated, and may warrant additional study in a phase II trial, perhaps in a -mutant selected population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-19-4193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334091PMC
July 2020

Wee1 Kinase Inhibitor AZD1775 Effectively Sensitizes Esophageal Cancer to Radiotherapy.

Clin Cancer Res 2020 07 27;26(14):3740-3750. Epub 2020 Mar 27.

The Ohio State University Medical Center, Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, Columbus, Ohio.

Purpose: Esophageal cancer is a deadly malignancy with a 5-year survival rate of only 5% to 20%, which has remained unchanged for decades. Esophageal cancer possesses a high frequency of mutations leading to dysfunctional G cell-cycle checkpoint, which likely makes esophageal cancer cells highly reliant upon G-M checkpoint for adaptation to DNA replication stress and DNA damage after radiation. We aim to explore whether targeting Wee1 kinase to abolish G-M checkpoint sensitizes esophageal cancer cells to radiotherapy.

Experimental Design: Cell viability was assessed by cytotoxicity and colony-forming assays, cell-cycle distribution was analyzed by flow cytometry, and mitotic catastrophe was assessed by immunofluorescence staining. Human esophageal cancer xenografts were generated to explore the radiosensitizing effect of AZD1775 .

Results: The IC concentrations of AZD1775 on esophageal cancer cell lines were between 300 and 600 nmol/L. AZD1775 (100 nmol/L) as monotherapy did not alter the viability of esophageal cancer cells, but significantly radiosensitized esophageal cancer cells. AZD1775 significantly abrogated radiation-induced G-M phase arrest and attenuation of p-CDK1-Y15. Moreover, AZD1775 increased radiation-induced mitotic catastrophe, which was accompanied by increased γH2AX levels, and subsequently reduced survival after radiation. Importantly, AZD1775 in combination with radiotherapy resulted in marked tumor regression of esophageal cancer tumor xenografts.

Conclusions: Abrogation of G-M checkpoint by targeting Wee1 kinase with AZD1775 sensitizes esophageal cancer cells to radiotherapy and in mouse xenografts. Our findings suggest that inhibition of Wee1 by AZD1775 is an effective strategy for radiosensitization in esophageal cancer and warrants clinical testing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-19-3373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7367716PMC
July 2020

A microRNA-based signature predicts local-regional failure and overall survival after pancreatic cancer resection.

Oncotarget 2020 Mar 10;11(10):913-923. Epub 2020 Mar 10.

The Ohio State University Medical Center, Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, Columbus, OH, USA.

Resectable pancreatic adenocarcinoma (PC) is generally managed with surgery followed by chemotherapy, but the role of postoperative chemoradiation (pCRT) is controversial. We sought to identify a microRNA (miRNA) expression profile associated with higher risk for local-regional recurrence (LRR), which might help identify patients that may benefit from pCRT. Total RNA was isolated from viable tumor from 88 patients who underwent PC resection with or without chemotherapy, but did not receive radiation. Digital miRNA expression profiling was performed and risk scores were calculated based on the expression levels of the four most significantly correlated miRNAs, and dichotomized about the median to detect correlations between risk group, LRR and overall survival (OS). Two cohorts from The Cancer Genome Atlas (TCGA) and Seoul National University (SNU) were used for validation. Patients with high-risk scores had significantly worse LRR ( 0.001) and worse OS ( 0.034). Two-year OS rates for the high- and low-risk groups were 27.7% and 52.2%, respectively. On multivariable analysis, the risk score remained significantly associated with LRR ( 0.018). When validated on TCGA data, a high-risk score was associated with worse OS on univariate ( 0.03) and multivariable analysis ( 0.017). When validated on the SNU cohort, a high-risk score was likewise associated with worse OS ( 0.042). We have developed a 4-miRNA molecular signature that is associated with risk of LRR and OS after PC resection and validated on two separate cohorts. This signature has the potential to select patients most likely to benefit from pCRT, and should be tested further.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.27496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7075466PMC
March 2020

Pathologic complete response following neoadjuvant therapy for pancreatic ductal adenocarcinoma: defining the incidence, predictors, and outcomes.

HPB (Oxford) 2020 Nov 13;22(11):1569-1576. Epub 2020 Feb 13.

Department of Surgery The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.

Background: Neoadjuvant therapy (NT) is increasingly utilized for patients with pancreatic ductal adenocarcinoma (PDAC) but the nationwide incidence and long-term prognosis of a pathologic complete response (pCR) remains poorly understood.

Methods: Patients with localized PDAC and known cT and pT stage who received NT prior to pancreatectomy from 2004 to 2016 were identified using the National Cancer Database. The clinicopathologic characteristics and long-term outcomes of patients who did and did not experience a pCR were compared.

Results: Among 7,902 patients who underwent NT prior to pancreatectomy, 244 (3.1%) experienced a pCR while 7,658 (96.9%) did not. On multivariable regression, longer duration of NT (OR 1.20, 95% CI 1.14-1.27 per month) and use of preoperative radiation (OR 9.98, 95% CI 3.05-32.71) were independently associated with a pCR. Median overall survival (OS) was longer among patients who experienced a pCR (77 vs 26 months, p < 0.001). On multivariate analysis, pCR was the strongest predictor of improved OS (HR 0.43, 95%CI 0.32-0.58, p < 0.001).

Conclusion: A pCR following NT for PDAC occurs infrequently but is associated with significantly improved OS. Better predictors of response and more effective preoperative regimens should be aggressively sought.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.hpb.2020.01.013DOI Listing
November 2020

Recurrence After Resection of Pancreatic Ductal Adenocarcinoma.

JAMA Surg 2020 04;155(4):361-362

Department of Radiation Oncology, University of Colorado Cancer Center, Aurora.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamasurg.2019.5464DOI Listing
April 2020

BRAF Inhibitor Radiosensitizes Thyroid Cancer-Response.

Clin Cancer Res 2019 11;25(21):6557

The Ohio State University Medical Center, Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, Columbus, Ohio.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-19-2705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6903400PMC
November 2019