Publications by authors named "Andrew C Chang"

167 Publications

Transhiatal robot-assisted minimally invasive esophagectomy: unclear benefits compared to traditional transhiatal esophagectomy.

J Robot Surg 2021 Sep 28. Epub 2021 Sep 28.

Section of Thoracic Surgery, Department of Surgery, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI, 48109, USA.

Esophagectomy is a high-risk operation, regardless of technique. Minimally invasive transthoracic esophagectomy could reduce length of stay and pulmonary complications compared to traditional open approaches, but the benefits of minimally invasive transhiatal esophagectomy are unclear. We performed a retrospective review of prospectively gathered data for open transhiatal esophagectomies (THEs) and transhiatal robot-assisted minimally invasive esophagectomies (TH-RAMIEs) performed at a high-volume academic center between 2013 and 2017. Multivariate logistic regression was used to calculate adjusted odds ratios (aORs) for outcomes. 465 patients met inclusion criteria (378 THE and 87 TH-RAMIE). THE patients more likely had an ASA score of 3 + (89.1% vs 77.0%, p = 0.012), whereas TH-RAMIE patients more likely had a pathologic staging of 3+ (43.7% vs. 31.2%, p = 0.026). TH-RAMIE patients were less likely to receive epidurals (aOR 0.06, 95% confidence interval [CI] 0.03-0.14, p < 0.001), but epidural use itself was not associated with differences in outcomes. TH-RAMIE patients experienced higher rates of pulmonary complications (adjusted odds ratio [OR] 1.82, 95% CI 1.03-3.22, p = 0.040), particularly pulmonary embolus (aOR 5.20, 95% CI 1.30-20.82, p = 0.020). There were no statistically significant differences in lymph node harvest, unexpected ICU admission, length of stay, in-hospital mortality, or 30-day readmission or mortality rates. The TH-RAMIE approach had higher rates of pulmonary complications. There were no statistically significant advantages to the TH-RAMIE approach. Further investigation is needed to understand the benefits of a minimally invasive approach to the open transhiatal esophagectomy.
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http://dx.doi.org/10.1007/s11701-021-01311-7DOI Listing
September 2021

Commentary: Anatomic resection after neoadjuvant TKI therapy-To be forewarned.

Authors:
Andrew C Chang

JTCVS Tech 2021 Jun 2;7:298. Epub 2021 Mar 2.

Michigan Medicine, University of Michigan, Ann Arbor, Mich.

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http://dx.doi.org/10.1016/j.xjtc.2021.02.047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8311863PMC
June 2021

Commentary: Up, down, right, left: Addressing the shortage of donor lungs for transplantation.

JTCVS Tech 2020 Dec 15;4:398. Epub 2020 Sep 15.

Section of Thoracic Surgery, University of Michigan, Ann Arbor, Mich.

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http://dx.doi.org/10.1016/j.xjtc.2020.08.066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8306607PMC
December 2020

Analytic Morphomics Are Related to Outcomes After Lung Volume Reduction Surgery.

Semin Thorac Cardiovasc Surg 2021 Jun 22. Epub 2021 Jun 22.

Division of Acute Care Surgery, University of Michigan Medical School, Ann Arbor, Michigan.

:Lung volume reduction surgery continues to have a high morbidity despite National Emphysema Treatment Trial selection criteria. This study evaluated the association between analytic morphomics on chest computed tomography scans and outcomes after lung volume reduction surgery. In a retrospective review of 85 lung volume reduction surgery patients from 1998-2013, dorsal muscle group area, subcutaneous and visceral fat area, and bone mineral density were assessed using analytic morphomics. Lung density was divided into five levels of increasing density (Lung density 1, emphysema; 2, normal lung; 4-5, scarring). Outcomes including survival, hospital length of stay, readmission at 30 days, and pulmonary complications were analyzed using univariate and multivariable techniques. Pulmonary complications developed in 27.1% (23/85). Mortality at 90 days was 9.4% (8/85). On multivariable analysis, lower bone mineral density (Odds ratio 0.61; 95% confidence interval 0.39-0.95) was associated with decreased survival, longer length of stay (0.83; 0.77-0.89), and readmissions (0.39; 0.15-1.00). Higher lung density 5:lung density 2 volume (1.84; 1.05-3.23), possibly due to scarring, was associated with pulmonary complications and longer length of stay (1.32; 1.23-1.41) while lower subcutaneous fat area:height was associated with readmissions which may reflect decreased metabolic reserve (0.35; 0.13-0.93). Patients with signs of frailty including lower bone mineral density may be at increased risk of adverse outcomes including decreased survival after lung volume reduction surgery. The results of this hypothesis-generating study will need to be confirmed in larger, multicenter trials to determine whether analytic morphomics can improve risk stratification and patient selection.
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http://dx.doi.org/10.1053/j.semtcvs.2021.06.015DOI Listing
June 2021

Increased tissue stiffness triggers contractile dysfunction and telomere shortening in dystrophic cardiomyocytes.

Stem Cell Reports 2021 Sep 20;16(9):2169-2181. Epub 2021 May 20.

Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CCSR Room 4215, 269 Campus Drive, Stanford, CA 94305-5175, USA; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA. Electronic address:

Duchenne muscular dystrophy (DMD) is a rare X-linked recessive disease that is associated with severe progressive muscle degeneration culminating in death due to cardiorespiratory failure. We previously observed an unexpected proliferation-independent telomere shortening in cardiomyocytes of a DMD mouse model. Here, we provide mechanistic insights using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Using traction force microscopy, we show that DMD hiPSC-CMs exhibit deficits in force generation on fibrotic-like bioengineered hydrogels, aberrant calcium handling, and increased reactive oxygen species levels. Furthermore, we observed a progressive post-mitotic telomere shortening in DMD hiPSC-CMs coincident with downregulation of shelterin complex, telomere capping proteins, and activation of the p53 DNA damage response. This telomere shortening is blocked by blebbistatin, which inhibits contraction in DMD cardiomyocytes. Our studies underscore the role of fibrotic stiffening in the etiology of DMD cardiomyopathy. In addition, our data indicate that telomere shortening is progressive, contraction dependent, and mechanosensitive, and suggest points of therapeutic intervention.
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http://dx.doi.org/10.1016/j.stemcr.2021.04.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8452491PMC
September 2021

Similar Quality of Life After Conventional and Robotic Transhiatal Esophagectomy.

Ann Thorac Surg 2021 Mar 18. Epub 2021 Mar 18.

Department of Surgery, University of Michigan, Ann Arbor, Michigan; University of Michigan Medical School, Ann Arbor, Michigan; Section of Thoracic Surgery, Department of Surgery, University of Michigan, Ann Arbor, Michigan. Electronic address:

Background: Patient-reported outcomes (PROs) for minimally invasive esophagectomy (MIE) have demonstrated benefits compared with open transthoracic or 3-hole esophagectomy. PROs, including quality of life (QoL) and fear of recurrence (FoR), comparing open transhiatal esophagectomy (THE) and transhiatal robotic-assisted MIE (Th-RAMIE) have been limited.

Methods: At a single, high-volume academic center, patients undergoing THE and Th-RAMIE with gastric conduit for clinical stage I to III esophageal cancer from 2013 to 2018 were evaluated. The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30), the EORTC Quality of Life Questionnaire in Esophageal Cancer (QLQ-OES18), and the FoR survey were administered preoperatively and at 1, 6, and 12 months postoperatively. Linear mixed-effects models were used for QoL and FoR score comparisons. Perioperative outcomes were also compared.

Results: A total of 309 patients (212 in the group and 97 in the Th-RAMIE group) were included. The Th-RAMIE cohort had a significantly higher number of lymph nodes harvested (14 ± 0.8 vs 11.2 ± 0.4; P = .01), a shorter length of stay (days, 10.0 ± 6.7 vs 12.1 ± 7.0; P = .03), lower rates of postoperative ileus (5% vs 15%; P = .02), and fewer opioids prescribed at discharge (71% vs 85%; P = .03). After adjustment, there were no significant differences in QLQ-C30, QLQ-OES18, and FoR scores between the groups out to 1 year postoperatively.

Conclusions: There were no clear patient-reported benefits of Th-RAMIE over THE for esophageal cancer. However, Th-RAMIE conferred several perioperative benefits.
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http://dx.doi.org/10.1016/j.athoracsur.2021.03.018DOI Listing
March 2021

A Lower Tidal Volume Regimen during One-lung Ventilation for Lung Resection Surgery Is Not Associated with Reduced Postoperative Pulmonary Complications.

Anesthesiology 2021 04;134(4):562-576

Background: Protective ventilation may improve outcomes after major surgery. However, in the context of one-lung ventilation, such a strategy is incompletely defined. The authors hypothesized that a putative one-lung protective ventilation regimen would be independently associated with decreased odds of pulmonary complications after thoracic surgery.

Methods: The authors merged Society of Thoracic Surgeons Database and Multicenter Perioperative Outcomes Group intraoperative data for lung resection procedures using one-lung ventilation across five institutions from 2012 to 2016. They defined one-lung protective ventilation as the combination of both median tidal volume 5 ml/kg or lower predicted body weight and positive end-expiratory pressure 5 cm H2O or greater. The primary outcome was a composite of 30-day major postoperative pulmonary complications.

Results: A total of 3,232 cases were available for analysis. Tidal volumes decreased modestly during the study period (6.7 to 6.0 ml/kg; P < 0.001), and positive end-expiratory pressure increased from 4 to 5 cm H2O (P < 0.001). Despite increasing adoption of a "protective ventilation" strategy (5.7% in 2012 vs. 17.9% in 2016), the prevalence of pulmonary complications did not change significantly (11.4 to 15.7%; P = 0.147). In a propensity score matched cohort (381 matched pairs), protective ventilation (mean tidal volume 6.4 vs. 4.4 ml/kg) was not associated with a reduction in pulmonary complications (adjusted odds ratio, 0.86; 95% CI, 0.56 to 1.32). In an unmatched cohort, the authors were unable to define a specific alternative combination of positive end-expiratory pressure and tidal volume that was associated with decreased risk of pulmonary complications.

Conclusions: In this multicenter retrospective observational analysis of patients undergoing one-lung ventilation during thoracic surgery, the authors did not detect an independent association between a low tidal volume lung-protective ventilation regimen and a composite of postoperative pulmonary complications.

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http://dx.doi.org/10.1097/ALN.0000000000003729DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8274370PMC
April 2021

The Landmark Series: Multimodal Therapy for Esophageal Cancer.

Ann Surg Oncol 2021 Jun 24;28(6):3375-3382. Epub 2021 Feb 24.

Section of Thoracic Surgery, Department of Surgery, Michigan Medicine, Ann Arbor, MI, USA.

Introduction: Esophagectomy is the mainstay of treatment for patients with resectable esophageal cancer, and chemotherapy and chemoradiation have become essential adjuncts to improve survival. Controversy remains regarding the optimal perioperative therapy.

Methods: This review focuses on three landmark, randomized, controlled trials that have greatly influenced esophageal cancer management and established chemotherapy and chemoradiotherapy as standard of care: Medical Research Council Adjuvant Gastric Infusional Chemotherapy Trial (MAGIC); The United Kingdom Medical Research Council Esophageal Cancer Trial (OEO2); and Chemoradiotherapy for Oesophageal Cancer Followed by Surgery Study (CROSS).

Results: The findings from these landmark studies are reviewed and summarized.

Conclusion: Chemotherapy regimens are heterogeneous but centered around platinum-based therapy and should be included in the management for all appropriate patients. Ongoing and future studies will further delineate the roles of various chemo- and chemoradiotherapy regimens and also will investigate the promising area of immunotherapy in the treatment of esophageal cancer.
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http://dx.doi.org/10.1245/s10434-020-09565-5DOI Listing
June 2021

The influence of tobacco load versus smoking status on outcomes following lobectomy for lung cancer in a statewide quality collaborative.

J Thorac Cardiovasc Surg 2021 Nov 10;162(5):1375-1385.e1. Epub 2020 Dec 10.

Department of Thoracic Surgery, St Joseph Mercy Hospital, Ann Arbor, Mich. Electronic address:

Background: Collaborative quality consortia can facilitate implementation of quality measures arising from clinical databases. Our statewide general thoracic surgery (GTS) collaborative investigated the influences of cigarette smoking status on mortality and major morbidity following lobectomy for lung cancer.

Methods: Society of Thoracic Surgeons General Thoracic Surgery Database records were identified from 14 institutions participating in a statewide thoracic surgical quality collaborative between 2012 and 2017. We excluded patients with nonelective procedures, stage 0 tumors, American Society of Anesthesiologists class VI disease, and missing clinical characteristics. Outcomes analysis included the combined mortality and major postoperative morbidity rates and the influence of patient characteristics, including smoking status, on composite rate and on postoperative complications.

Results: The study cohort included 2267 patient records for analysis. Overall combined mortality and major morbidity rate was 10.2% (n = 231). Postoperative 30-day mortality was 1.5%, and major morbidity 9.6%. Significant predictors of the combined outcome included male sex (P = .004), body mass index (P < .001), Zubrod score (P = .02), smoking pack-years (P = .03), and thoracotomy (P < .001). Higher American Society of Anesthesiologists disease class and advanced tumor stage were marginally associated with worse combined outcome (P = .06). Smoking status; that is, current, past (no smoking within 30 days), or never smoked, was not associated with worse combined outcome (P = .56) and had no significant influence on major complications.

Conclusions: Smoking status was not associated with worse outcomes; however, smoking dose (pack-years) was associated with worse combined mortality and major morbidity. A statewide quality collaborative provides constructive feedback for participating institutions and surgeons, promoting quality improvement in perioperative patient care strategies and improved outcomes.
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http://dx.doi.org/10.1016/j.jtcvs.2020.10.162DOI Listing
November 2021

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

J Natl Cancer Inst 2021 Jun;113(6):665-679

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

Although 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.
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http://dx.doi.org/10.1093/jnci/djaa195DOI Listing
June 2021

Commentary: Quantifying "fit for esophagectomy"-Grasping for more metrics.

J Thorac Cardiovasc Surg 2021 03 24;161(3):833-834. Epub 2020 Nov 24.

Section of Thoracic Surgery, Department of Surgery, Michigan Medicine, Ann Arbor, Mich. Electronic address:

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http://dx.doi.org/10.1016/j.jtcvs.2020.11.059DOI Listing
March 2021

Commentary: Factors associated with short- versus long-term survival following lung transplant: Not yet the LASt word in organ allocation.

J Thorac Cardiovasc Surg 2020 Oct 23. Epub 2020 Oct 23.

Section of Thoracic Surgery, Michigan Medicine, Ann Arbor, Mich. Electronic address:

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http://dx.doi.org/10.1016/j.jtcvs.2020.10.055DOI Listing
October 2020

Immune determinants of Barrett's progression to esophageal adenocarcinoma.

JCI Insight 2021 01 11;6(1). Epub 2021 Jan 11.

Department of Surgery, Section of Thoracic Surgery, University of Michigan, Ann Arbor, Michigan, USA.

Esophageal adenocarcinoma (EAC) develops from Barrett's esophagus (BE), a chronic inflammatory state that can progress through a series of transformative dysplastic states before tumor development. While molecular and genetic changes of EAC tumors have been studied, immune microenvironment changes during Barrett's progression to EAC remain poorly understood. In this study, we identify potential immunologic changes that can occur during BE-to-EAC progression. RNA sequencing (RNA-Seq) analysis on tissue samples from EAC patients undergoing surgical resection demonstrated that a subset of chemokines and cytokines, most notably IL6 and CXCL8, increased during BE progression to EAC. xCell deconvolution analysis investigating immune cell population changes demonstrated that the largest changes in expression during BE progression occurred in M2 macrophages, pro-B cells, and eosinophils. Multiplex immunohistochemical staining of tissue microarrays showed increased immune cell populations during Barrett's progression to high-grade dysplasia. In contrast, EAC tumor sections were relatively immune poor, with a rise in PD-L1 expression and loss of CD8+ T cells. These data demonstrate that the EAC microenvironment is characterized by poor cytotoxic effector cell infiltration and increased immune inhibitory signaling. These findings suggest an immunosuppressive microenvironment, highlighting the need for further studies to explore immune modulatory therapy in EAC.
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http://dx.doi.org/10.1172/jci.insight.143888DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821593PMC
January 2021

Consensus for Thoracoscopic Left Upper Lobectomy-Essential Components and Targets for Simulation.

Ann Thorac Surg 2021 08 27;112(2):436-442. Epub 2020 Oct 27.

Division of Thoracic Surgery, New York-Presbyterian Hospital, Weill Cornell Medical College, New York, New York.

Background: Simulation-based training is a valuable component of cardiothoracic surgical education. Effective curriculum development requires consensus on procedural components and focused attention on specific learning objectives. Through use of a Delphi process, we established consensus on the steps of video-assisted thoracoscopic surgery (VATS) left upper lobectomy and identified targets for simulation.

Methods: Experienced thoracic surgeons were randomly selected for participation. Surgeons voted and commented on the necessity of individual steps comprising VATS left upper lobectomy. Steps with greater than 80% of participants in agreement of their necessity were determined to have established "consensus." Participants voted on the physical or cognitive complexity of each, or both, and chose steps most amenable to focused simulation.

Results: Thirty thoracic surgeons responded and joined in the voting process. Twenty operative steps were identified, with surgeons reaching consensus on the necessity of 19. Components deemed most difficult and amenable to simulation included those related to dissection and division of the bronchus, artery, and vein.

Conclusions: Through a Delphi process, surgeons with a variety of practice patterns can achieve consensus on the operative steps of left upper lobectomy and agreement on those most appropriate for simulation. This information can be implemented in the development of targeted simulation for VATS lobectomy.
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http://dx.doi.org/10.1016/j.athoracsur.2020.06.152DOI Listing
August 2021

Enhancing thoracic surgical trainee competence in the coronavirus disease 2019 (COVID-19) era: Challenges and opportunities for mentorship.

J Thorac Cardiovasc Surg 2020 10 26;160(4):1126-1129. Epub 2020 Jun 26.

Division of Cardiac Surgery, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass. Electronic address:

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http://dx.doi.org/10.1016/j.jtcvs.2020.06.062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7319623PMC
October 2020

Per-oral Endoscopic Myotomy Biopsies of Achalasia Patients Reveal Schwann Cell Depletion in the Muscularis Propria.

Clin Gastroenterol Hepatol 2021 06 12;19(6):1294-1295. Epub 2020 Jul 12.

Esophageal Motility Program, Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan.

Achalasia is a neurodegenerative condition resulting in abnormal lower esophageal sphincter relaxation and impaired upstream esophageal body peristalsis. The pathophysiology and natural history of achalasia remain unclear, and evaluation of the histopathogenesis of achalasia has traditionally been challenging because the esophageal wall muscularis propria is not typically accessible via routine endoscopic biopsies.
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http://dx.doi.org/10.1016/j.cgh.2020.07.007DOI Listing
June 2021

Higher Long-term Quality of Life Metrics After Video-Assisted Thoracoscopic Surgery Lobectomy Compared With Robotic-Assisted Lobectomy.

Ann Thorac Surg 2020 Jun 26. Epub 2020 Jun 26.

Department of Surgery, University of Michigan, Ann Arbor, Michigan; Section of Thoracic Surgery, University of Michigan, Ann Arbor, Michigan. Electronic address:

Background: Robotic-assisted thoracic surgery (RATS) lung lobectomy has emerged as an alternative approach to video-assisted thoracoscopic surgery (VATS). Patient-reported outcomes comparing these approaches have been limited.

Methods: At a single, high-volume academic center, patients undergoing VATS and RATS lobectomies for stage I and II non-small cell lung cancer from 2014 to 2018 were evaluated. The European Organisation for Research and Treatment of Cancer Quality of Life of Cancer Patients Questionnaire (QLQ-C30) and Quality of Life Questionnaire in Lung Cancer (QLQ-LC13), along with the Fear of Recurrence (FoR) survey, were administered preoperatively and at 1, 6, and 12 months postoperatively. Raw scores underwent linear transformation (0-100 scale). Linear mixed-effects models were used for quality of life and FoR score comparisons.

Results: The study included 219 patients (139 VATS and 80 RATS). RATS patients had longer (P < .05) operative times and a higher incidence (P < .05) of postoperative myocardial infarction compared to VATS patients. VATS patients reported higher (P < .05) QLQ-C30 summary scores postoperatively and at 12 months, including higher (P < .05) Social Functioning and Cognitive scores, and less (P < .05) appetite loss. VATS patients reported decreased (P < .05) QLQ-LC13 symptom summary scores at 6 months postoperatively, including decreased (P < .05) dyspnea, neuropathy, and pain compared with RATS patients. VATS patients also reported lower (P < .05) FoR summary scores at 6 months postoperatively.

Conclusions: VATS patients report improvement in select quality of life and FoR measures after lobectomy. Further study comparing these 2 approaches is required.
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http://dx.doi.org/10.1016/j.athoracsur.2020.05.033DOI Listing
June 2020

Long-Term Quality of Life Following Endoscopic Therapy Compared to Esophagectomy for Neoplastic Barrett's Esophagus.

Dig Dis Sci 2021 05 9;66(5):1580-1587. Epub 2020 Jun 9.

Barrett's Esophagus Program, Division of Gastroenterology, University of Michigan, 1500 E Medical Center Dr., Ann Arbor, MI, 48109, USA.

Introduction: Endoscopic therapy (ET) and esophagectomy result in similar survival for Barrett's esophagus (BE) with high-grade dysplasia (HGD) or T1a esophageal adenocarcinoma (EAC), but the long-term quality of life (QOL) has not been compared.

Aims: We aimed to compare long-term QOL between patients who had undergone ET versus esophagectomy.

Methods: Patients were included if they underwent ET or esophagectomy at the University of Michigan since 2000 for the treatment of HGD or T1a EAC. Two validated survey QOL questionnaires were mailed to the patients. We compared QOL between and within groups (ET = 91, esophagectomy = 62), adjusting for covariates.

Results: The median time since initial intervention was 6.8 years. Compared to esophagectomy, ET patients tended to be older, had a lower prevalence of EAC, and had a shorter duration since therapy. ET patients had worse adjusted physical and role functioning than esophagectomy patients. However, the adjusted odds ratio (OR) of having symptoms was significantly less with ET for diarrhea (0.287; 95% confidence interval [CI] = 0.114, 0.724), trouble eating (0.207; 0.0766, 0.562), choking (0.325; 0.119, 0.888), coughing (0.291; 0.114, 0.746), and speech difficulty (0.306; 0.0959, 0.978). Amongst the ET patients, we found that the number of therapy sessions and need for dilation were associated with worse outcomes.

Discussion: Multiple measures of symptom status were better with ET compared to esophagectomy following treatment of BE with HGD or T1a EAC. We observed worse long-term physical and role functioning in ET patients which could reflect unmeasured baseline functional status rather than a causal effect of ET.
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http://dx.doi.org/10.1007/s10620-020-06377-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8327124PMC
May 2021

Clinical impact of routine esophagram after peroral endoscopic myotomy.

Gastrointest Endosc 2021 01 3;93(1):102-106. Epub 2020 Jun 3.

Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan, USA.

Background And Aims: It is unclear whether the common practice of postoperative day (POD) 1 esophagram impacts clinical care or reliably identifies significant adverse events (AEs) related to peroral endoscopic myotomy (POEM). Therefore, we aimed to correlate the most clinically relevant esophagram findings with postoperative outcomes after POEM.

Methods: Patients were retrospectively reviewed and included if they underwent POEM at 1 of the 3 study institutions between 2014 and 2018. Patient outcomes were assessed in relation to relevant POD 1 esophagram findings such as esophageal dissection or leak.

Results: One hundred seventy post-POEM contrast esophagrams (139 fluoroscopy-based vs 31 CT-based) performed on POD 1 were included. Most esophagrams (n = 98) contained abnormal findings but only 5 showed esophageal leak or dissection. Confirmed postoperative AEs of leak or dissection occurred in 4 patients. In 2 patients, POD 1 esophagram appropriately identified the leak or dissection, but in the other 2 patients the initial esophagram was negative, and the AEs were not recognized before clinical deterioration. One patient had a false-positive leak and dissection noted on esophagram leading to an unremarkable endoscopy.

Conclusions: Despite the low AE rate after POEM, follow-up esophagram on POD 1 frequently shows expected, unremarkable postprocedural findings and occasionally fails to diagnose serious AEs. This results in pitfalls in accuracy regarding agreement between esophagram versus clinical and endoscopic findings. Relying exclusively on esophagram for post-POEM clinical decision-making can lead to unnecessary additional testing or missed AEs.
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http://dx.doi.org/10.1016/j.gie.2020.05.046DOI Listing
January 2021

Inconsistent effects of limestone on rice cadmium uptake: Results from multi-scale field trials and large-scale investigation.

Sci Total Environ 2020 Mar 20;709:136226. Epub 2019 Dec 20.

State Key Laboratory of Urban and Regional Ecology, Research Center for Eco-environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China; University of Chinese Academy of Sciences, Beijing 100049, China.

Adding limestone into acidic paddy soils might reduce cadmium (Cd) accumulation in rice plants and the harvested grains but with inconsistent results in the field practice. We conducted three experiments of different field scales, including small-plots, multi-location trial, and large-scale field samplings of rice grown in a major production region of southern China, to investigate whether liming could sustainably limit the Cd phytoavailability to rice. Forty-eight physical, chemical, and biological attributes associated with paired soils and plants were collectively analyzed. Rice Cd uptake was significantly reduced when moderate dosage (2.25-3 t ha) of liming was present in the soils. The limes decreased rice Cd uptake by reducing the Cd concentrations of soil solution phase and regulating Ca and Cd competitions for absorption sites at root surfaces. Soil Zn hardly any effect on rice Cd uptake. Rice Cd uptake was suppressed at the higher rates of liming (4.5-9 t ha) due to the heavy loss of soil labile Mn. The tendencies of over compensating were soil-, plant-, and climate-dependent and were estimated by a transfer function and the risks were characterized using probabilistic analysis. The sustainable doses of limestone that reduced grain Cd accumulation, but did not compromise yield, or disrupt the rice rhizosphere was 3 t ha annually incorporated two weeks before the seedlings were transplanted.
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http://dx.doi.org/10.1016/j.scitotenv.2019.136226DOI Listing
March 2020

Validation of a serum 4-microRNA signature for the detection of lung cancer.

Transl Lung Cancer Res 2019 Oct;8(5):636-648

School of Medicine, Southern University of Science and Technology, Shenzhen 518055, China.

Background: Our previous studies have identified a serum-based 4-microRNA (4-miRNA) signature that may help distinguish patients with lung cancer (LC) from non-cancer controls (NCs). Here, we used an extended independent cohort of 398 subjects to further validate the diagnostic ability of this 4-miRNA signature.

Methods: Using quantitative reverse transcription polymerase chain reaction (qRT-PCR), expression of the 4-miRNAs was assessed in a total of 398 sera that included 213 LC patients and 185 NCs. A logistic regression model using training-test sets, receiver operating characteristic (ROC) curve analysis and t-test were used to test the impact of varying expression of these miRNAs on its diagnostic accuracy for LC. The cell proliferation and colony formation affected by these miRNAs, as well as gene ontology (GO) analysis of miRNA target genes were performed.

Results: The levels of the 4-miRNAs were significantly higher in the serum of patients with LCs as compared to NCs. Using a logistic regression prediction model based on training and test sets analysis, we obtained the area under the curve (AUC) of 0.921 [95% confidence interval (CI), 0.876-0.966] on the test set with specificity 90.6%, sensitivity 77.9%, accuracy 84.1%, positive predictive value (PPV) 89.8% and negative predictive value (NPV) 79.5%.

Conclusions: We have verified that this serum 4-miRNA signature could provide a promising noninvasive biomarker for the prediction of LC, particularly in patients with indeterminate lung nodules on screening CT scans.
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http://dx.doi.org/10.21037/tlcr.2019.09.11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6835096PMC
October 2019

Isoforms of RNF128 Regulate the Stability of Mutant P53 in Barrett's Esophageal Cells.

Gastroenterology 2020 02 9;158(3):583-597.e1. Epub 2019 Nov 9.

Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan; Department of Surgery, Thoracic Surgery, University of Michigan, Ann Arbor, Michigan. Electronic address:

Background & Aims: Barrett's esophagus (BE) can progress to dysplasia and esophageal adenocarcinoma (EAC), accompanied by mutations in TP53 that increase the stability of its product, p53. We analyzed BE tissues for messenger RNAs (mRNAs) that associate with BE progression and identified one that affects the stabilization of p53.

Methods: We obtained 54 BE samples collected from patients with high-grade dysplasia (HGD) or esophageal adenocarcinoma (EAC), from 1992 through 2015, and performed RNA sequence analyses, including isoform-specific analyses. We performed reverse-transcription polymerase chain reaction analyses of 166 samples and immunohistochemical analyses of tissue microarrays that contained BE tissues from 100 patients with HGD or EAC and normal esophageal squamous mucosa (controls). Proteins were expressed from transfected plasmids or knocked down with small interfering RNAs in BE cells and analyzed by immunoblots and in immunoprecipitation and ubiquitin ligase assays. Athymic nude mice bearing EAC xenograft tumors (grown from OE-33 cells) were given intraperitoneal injections of simvastatin; tumor growth was monitored and tumors were collected and analyzed by immunoblotting for levels of RNF128, p53, and acetylated p53.

Results: Progression of BE to HGD or EAC associated with changes in expression of mRNAs that encoded mucins and promoted inflammation and activation of ATM and the DNA damage response. As tissues progressed from BE to HGD to EAC, they increased expression of mRNAs encoding isoform 1 of RNF128 (Iso1) and decreased expression of Iso2 of RNF128. RNF128 is an E3 ubiquitin ligase that targets p53 for degradation. Incubation of BE cells with interferon gamma caused them to increase expression of Iso1 and reduce expression of Iso2. Iso1 was heavily glycosylated with limited ubiquitin ligase activity for p53, resulting in p53 stabilization. Knockdown of Iso1 in BE and EAC cells led to degradation of the mutant form of p53 and reduced clonogenic survival. In contrast, Iso2 was a potent ligase that reduced levels of the mutant form of p53 in BE cells. In BE cells, Iso2 was hypoglycosylated and degraded, via ATM and GSK3β-mediated phosphorylation and activation of the beta-TrCP1-containing SCF ubiquitin ligase complex. Simvastatin, which degrades the mutant form of p53, also degraded RNF128 Iso1 protein in BE cells and slowed growth of EAC xenograft tumors in mice.

Conclusions: We found that isoform 2 of RNF128 is decreased in BE cells, resulting in increased levels of mutant p53, whereas isoform 1 of RNF128 is increased in BE cells, further promoting the stabilization of mutant p53.
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http://dx.doi.org/10.1053/j.gastro.2019.10.040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429981PMC
February 2020

The Society of Thoracic Surgeons Composite Score Rating for Pulmonary Resection for Lung Cancer.

Ann Thorac Surg 2020 03 2;109(3):848-855. Epub 2019 Nov 2.

Department of Surgery, Washington University School of Medicine, St Louis, Missouri.

Background: The Society of Thoracic Surgeons (STS) General Thoracic Surgery Database (GTSD) has developed composite quality measures for lobectomy and esophagectomy. This study sought to develop a composite measure including all resections for lung cancer.

Methods: The STS lung cancer composite score is based on 2 outcomes: risk-adjusted mortality and morbidity. GTSD data were included from January 2015 to December 2017. "Star ratings" were created for centers with 30 or more cases by using 95% Bayesian credible intervals. The Bayesian model was performed with and without inclusion of the minimally invasive approach to assess the impact of approach on the composite measure.

Results: The study population included 38,461 patients from 256 centers. Overall operative mortality was 1.3% (495 of 38,461). The major complication rate was 7.9% (3045 of 38,461). The median number of nodes examined was 10 (interquartile range, 5 to 16); the median number of nodal stations sampled was 4 (interquartile range, 3 to 5). Positive resection margins were identified in 3.7% (1420 of 38,461). A total of 214 centers with 30 or more cases were assigned star ratings. There were 7 1-star, 194 2-star, and 13 3-star programs; 70.6% of resections were performed through a minimally invasive approach. Inclusion of minimally invasive approach, which was adjusted for in previous models, altered the star ratings for 3% (6 of 214) of the programs.

Conclusions: Participants in the STS GTSD perform lung cancer resection with low morbidity and mortality. Lymph node data suggest that participants are meeting contemporary staging standards. There is wide variability among participants in application of minimally invasive approaches. The study found that risk adjustment for approach altered ratings in 3% of participants.
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http://dx.doi.org/10.1016/j.athoracsur.2019.08.114DOI Listing
March 2020

Morphomic Factors Associated With Complete Response to Neoadjuvant Therapy in Esophageal Carcinoma.

Ann Thorac Surg 2020 01 21;109(1):241-248. Epub 2019 Sep 21.

Section of Thoracic Surgery, University of Michigan Medical Center, Ann Arbor, Michigan. Electronic address:

Background: In patients undergoing neoadjuvant chemoradiotherapy (nCRT) followed by surgery for locally advanced esophageal squamous cell carcinoma (ESCC), patients with a pathologic complete response (pCR) have the greatest benefit. The purpose of this study was to identify morphomic factors obtained from pretreatment computed tomography scans associated with a pCR in ESCC.

Methods: We retrospectively analyzed patients with ESCC treated with nCRT who underwent esophagectomy between 2006 and 2016. Clinical and morphomic characteristics pre-nCRT were analyzed to identify factors associated with pCR using univariate and multivariable analyses.

Results: There were 183 patients with ESCC included in this study, and 45 (24.6%) patients achieved pCR. The overall survival in patients with pCR was better than that in patients without pCR (5.8 years vs 1.2 years; P < .001). On univariate analysis, increased age, radiation dose greater than or equal to 4000 cGy, and larger subcutaneous adipose tissue area were correlated with pCR. On multivariable logistic regression, increased age (odds ratio, 1.53; P = .03), radiation dose greater than or equal to 4000 cGy (odds ratio, 2.19; P = .04), and larger dorsal muscle group normal-density area (odds ratio, 1.59; P = .03) were independently associated with pCR.

Conclusions: Increased age, radiation dose greater than or equal to 4000 cGy, and larger dorsal muscle group normal-density area were significantly associated with pCR. These factors may be useful in determining which patients are most likely to benefit from nCRT followed by esophagectomy.
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http://dx.doi.org/10.1016/j.athoracsur.2019.08.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7150584PMC
January 2020

Gender Disparity in Referral for Definitive Care of Malignant Pleural Effusions.

J Surg Res 2019 12 17;244:409-416. Epub 2019 Jul 17.

Department of Thoracic Surgery, University of Michigan, Ann Arbor, Michigan. Electronic address:

Background: Gender disparities exist in cancer care. Malignant pleural effusions (MPEs) carry a poor prognosis and are managed by different physicians. This study sought to evaluate referral patterns and gender differences for definitive treatment and outcomes of MPE patients.

Materials And Methods: Patients diagnosed with MPE from 1999 to 2015 at a quaternary care hospital were retrospectively reviewed to obtain patient history, referral to thoracic surgery for definitive management, and outcomes. Analysis was performed using chi-squared/Fisher's exact test, logistic regression models, and multivariate analysis.

Results: 224/686 patients (32.7%) were referred to thoracic surgery. No survival difference existed between referral and nonreferral groups or referred patients who received or did not receive pleurodesis. 405 patients (59.0%) were women. Women were statistically significantly less likely to be referred than men (27.9% versus 39.5%, P = 0.0014). This disparity persisted when comorbidities were controlled for (P = 0.0004) and when gynecologic cancers (e.g., uterine, ovarian, but not including breast; 55 female patients) were excluded from analysis (28.9% versus 39.5%, P = 0.0049). Women had statistically significantly more thoracenteses (3.34 versus 2.19, P < 0.0001) and improved survival compared with males (median survival = 136 d versus 54; P = 0.0004).

Conclusions: Gender disparity exists in referral patterns for definitive management of MPE; women are less likely to be referred than men. Women have longer survival and a greater number of thoracenteses performed, despite a lower referral rate for definitive care. Further research is needed to understand the differences in referral rates and outcomes between men and women.
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http://dx.doi.org/10.1016/j.jss.2019.06.068DOI Listing
December 2019

Circular RNA modulates autophagy via -STAT3-PRKAA/AMPKα signaling in STK11 mutant lung cancer.

Autophagy 2020 04 28;16(4):659-671. Epub 2019 Jun 28.

School of Medicine, Southern University of Science and Technology, Shenzhen, China.

The role of circular RNA in cancer is emerging. A newly reported circular RNA ( is critical in cell proliferation of various cancer types, although its role in non-small cell lung cancer (NSCLC), has yet to be elucidated. Our results provided evidence that silencing of significantly impaired cell proliferation, migration, invasion and induced macroautophagy/autophagy. Mechanistically, we uncovered that autophagy was induced upon loss of via the -STAT3-PRKAA/AMPKa axis in STK11 mutant lung cancer cell lines (A549 and H838). STAT3 abrogation as well as transfection with a mimic, recapitulated the induction of autophagy. We also demonstrated antagonistic regulation on autophagy between and linear (). We therefore propose that the ratio between and (C:L ratio) may reflect autophagy levels in cancer cells. We observed that a high C:L ratio (>0.49) was an indicator of poor survival, especially in advanced-stage NSCLC patients. These results support that is a key autophagy regulator in a subset of lung cancer and has potential clinical use as a prognostic factor. The circular RNA ( functions as an oncogene and autophagy regulator may potential use as a prognostic marker and therapeutic target in lung cancer. 3-MA: 3-methyladenine; AMPK: AMP-activated protein kinase; ATG7: autophagy related 7; Baf-A: bafilomycin A; BECN1: beclin 1; : circular HIPK3; CQ: chloroquine; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; HIPK3: homeodomain interacting protein kinase 3; IL6R: interleukin 6 receptor; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; NSCLC: non-small cell lung cancer; RFP: red fluorescent protein; RPS6KB1/S6K: ribosomal protein S6 kinase B1; SQSTM1/p62: sequestosome 1; STAT3: signal transducer and activator of transcription 3; STK11: serine/threonine kinase 11.
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http://dx.doi.org/10.1080/15548627.2019.1634945DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7138221PMC
April 2020

Adjuvant Therapy for Node-Positive Esophageal Cancer After Induction and Surgery: A Multisite Study.

Ann Thorac Surg 2019 09 20;108(3):828-836. Epub 2019 Jun 20.

Department of Surgery, Washington University in St Louis, St Louis, Missouri. Electronic address:

Background: The benefit of adjuvant treatment for esophageal cancer patients with positive lymph nodes after induction therapy and esophagectomy is uncertain. This in-depth multicenter study assessed the benefit of adjuvant therapy in this population.

Methods: A retrospective cohort study from 9 institutions included patients who received neoadjuvant treatment, underwent esophagectomy from 2000 to 2014, and had positive lymph nodes on pathology. Factors associated with administration of adjuvant therapy were assessed using multilevel random-intercept modeling to account for institutional variation in practice. Kaplan-Meier analyses were performed based on adjuvant treatment status. Variables associated with survival were identified using Cox proportional hazards modeling.

Results: The study analyzed 1082 patients with node-positive cancer after induction therapy and esophagectomy: 209 (19.3%) received adjuvant therapy and 873 (80.7%) did not. Administration of adjuvant treatment varied significantly from 3.2% to 50.0% between sites (P < .001). Accounting for institution effect, factors associated with administration of adjuvant therapy included clinically positive and negative prognostic characteristics: younger age, higher pathologic stage, pathologic grade, no neoadjuvant radiotherapy nonsmoking status, and absence of postoperative infection. Kaplan-Meier analysis showed patients receiving adjuvant therapy had a longer median survival of 2.6 years vs 2.3 years (P = .02). Cox modeling identified adjuvant treatment as independently associated with improved survival, with a 24% reduction in mortality (hazard ratio, 0.76; P = .005).

Conclusions: Adjuvant therapy was associated with improved overall survival. Therefore, consideration should be given to administration of adjuvant therapy to esophageal cancer patients who have persistent node-positive disease after induction therapy and esophagectomy and are able to tolerate additional treatment.
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http://dx.doi.org/10.1016/j.athoracsur.2019.04.099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904117PMC
September 2019

Targeting lonidamine to mitochondria mitigates lung tumorigenesis and brain metastasis.

Nat Commun 2019 05 17;10(1):2205. Epub 2019 May 17.

Center for Disease Prevention Research, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA.

Lung cancer often has a poor prognosis, with brain metastases a major reason for mortality. We modified lonidamine (LND), an antiglycolytic drug with limited efficacy, to mitochondria-targeted mito-lonidamine (Mito-LND) which is 100-fold more potent. Mito-LND, a tumor-selective inhibitor of oxidative phosphorylation, inhibits mitochondrial bioenergetics in lung cancer cells and mitigates lung cancer cell viability, growth, progression, and metastasis of lung cancer xenografts in mice. Mito-LND blocks lung tumor development and brain metastasis by inhibiting mitochondrial bioenergetics, stimulating the formation of reactive oxygen species, oxidizing mitochondrial peroxiredoxin, inactivating AKT/mTOR/p70S6K signaling, and inducing autophagic cell death in lung cancer cells. Mito-LND causes no toxicity in mice even when administered for eight weeks at 50 times the effective cancer inhibitory dose. Collectively, these findings show that mitochondrial targeting of LND is a promising therapeutic approach for investigating the role of autophagy in mitigating lung cancer development and brain metastasis.
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http://dx.doi.org/10.1038/s41467-019-10042-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6525201PMC
May 2019
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