Medicine and Health Sciences Commons^™

Repurposing The Fda-Approved Anthelmintic Pyrvinium Pamoate For Pancreatic Cancer Treatment: Study Protocol For A Phase I Clinical Trial In Early-Stage Pancreatic Ductal Adenocarcinoma, Francesca M. Ponzini, Christopher W. Schultz, Benjamin E. Leiby, Shawnna Cannaday, T. Yeo, James Posey, Wilbur B. Bowne, Charles Yeo, Jonathan R. Brody, Harish Lavu, Avinoam Nevler

Department of Surgery Faculty Papers

BACKGROUND: Recent reports of the utilisation of pyrvinium pamoate (PP), an FDA-approved anti-helminth, have shown that it inhibits pancreatic ductal adenocarcinoma (PDAC) cell growth and proliferation in-vitro and in-vivo in preclinical models. Here, we report about an ongoing phase I open-label, single-arm, dose escalation clinical trial to determine the safety and tolerability of PP in PDAC surgical candidates.

METHODS AND ANALYSIS: In a 3+3 dose design, PP is initiated 3 days prior to surgery. The first three patients will be treated with the initial dose of PP at 5 mg/kg orally for 3 days prior to surgery. Dose doubling will …

Adjuvant Nab-Paclitaxel + Gemcitabine In Resected Pancreatic Ductal Adenocarcinoma: Results From A Randomized, Open-Label, Phase Iii Trial, Margaret A. Tempero, Uwe Pelzer, Eileen M. O'Reilly, Jordan Winter, Do-Youn Oh, Chung-Pin Li, Giampaolo Tortora, Heung-Moon Chang, Charles D. Lopez, Tanios Bekaii-Saab, Andrew H. Ko, Armando Santoro, Joon Oh Park, Marcus S. Noel, Giovanni Luca Frassineti, Yan-Shen Shan, Andrew Dean, Hanno Riess, Eric Van Cutsem, Jordan Berlin, Philip Philip, Malcolm Moore, David Goldstein, Josep Tabernero, Mingyu Li, Stefano Ferrara, Yvan Le Bruchec, George Zhang, Brian Lu, Andrew V. Biankin, Michele Reni

Department of Surgery Faculty Papers

PURPOSE

This randomized, open-label trial compared the efficacy and safety of adjuvant nab-paclitaxel + gemcitabine with those of gemcitabine for resected pancreatic ductal adenocarcinoma (ClinicalTrials.gov identifier: NCT01964430). METHODS

We assigned 866 treatment-naive patients with pancreatic ductal adenocarcinoma to nab-paclitaxel (125 mg/m2) + gemcitabine (1,000 mg/m2) or gemcitabine alone to one 30-40 infusion on days 1, 8, and 15 of six 28-day cycles. The primary end point was independently assessed disease-free survival (DFS). Additional end points included investigator-assessed DFS, overall survival (OS), and safety. RESULTS

Two hundred eighty-seven of 432 patients and 310 of 434 patients completed nab …

Interleukin-8 Produced From Cancer-Associated Fibroblasts Suppresses Proliferation Of The Ocuch-Lm1 Cancer Cell Line, Ryota Tanaka, Kenjiro Kimura, Shimpei Eguchi, Go Ohira, Shogo Tanaka, Ryosuke Amano, Hiroaki Tanaka, Masakazu Yashiro, Masaichi Ohira, Shoji Kubo

Department of Medical Oncology Faculty Papers

Background: Cancer-associated fibroblasts (CAFs) play an important role in cancer growth by interacting with cancer cells, but their effects differ depending on the type of cancer. This study investigated the role of CAFs in biliary tract cancers (BTCs), compared with pancreatic ductal adenocarcinoma (PDAC) as a comparison cohort.

Methods: We retrospectively evaluated alpha-smooth muscle actin (αSMA) expression in CAFs from 114 cases of PDAC and 154 cases of BTCs who underwent surgical treatment at our institution from 1996 to 2017. CAFs were isolated from resected specimens of BTC and PDAC, and tested for the effects of their supernatants and cytokines …

Reduced Rates Of Post-Transplant Recurrent Hepatocellular Carcinoma In Non-Alcoholic Steatohepatitis: A Propensity Score Matched Analysis, Ryan Lamm, Peter J Altshuler, Keyur Patel, Osama Shaheen, Angel Paulo Amante, Jesse Civan, Warren Maley, Adam Frank, Carlo Ramirez, Jaime Glorioso, Ashesh Shah, Hien Dang, Adam S Bodzin

Department of Surgery Faculty Papers

Non-alcoholic steatohepatitis (NASH)-related hepatocellular carcinoma (HCC) has become the second leading cause of HCC-related liver transplantation in the United States. This study investigated post-transplant recurrence and survival for patients transplanted for NASH-related HCC compared to non-NASH HCC etiologies. Retrospective review of the United Network for Organ Sharing (UNOS) Organ Procurement and Transplantation Network (OPTN) database identified 7,461 patients with HCC—1,405 with underlying NASH and 6,086 with non-NASH underlying diseases. After propensity score matching (PSM) to account for patient- and tumor-related confounders 1,175 remained in each group. Primary outcomes assessed were recurrence rate and recurrence-free survival. Recurrent malignancy at 5 years …

18 Fdg Pet/Ct Imaging In Carcinoma Cesophagus, Maseeh Uz Zaman, Nosheen Fatima

Department of Radiology

No abstract provided.

Hepatocellular Carcinoma With Extrahepatic Blood Supply From Right Renal Artery, Amir Humza Sohail, Ahmad Musa, Muhammad Salman Khan, Hassan Raza Hashmi, Basit Salam, Collin E M. Brathwaite

Department of Radiology

Extrahepatic blood supply is seen in around 17-27% of hepatocellular carcinoma lesions. Evidence suggests that this extrahepatic supply most commonly originates from a right intercostal artery (70-83%) followed by left intercostal, omental and right renal arteries. Thus a comprehensive knowledge of variations in standard vascular anatomy and cognisance of factors influencing or predicting extrahepatic blood supply in HCC is instrumental in ensuring the success of surgical and interventional procedures. We present the unusual case of a 66-year-old male with HCC in Segment I of the liver with aberrant blood supply from the right renal artery in the absence of any …

A Standardized Comparison Of Peri-Operative Complications After Minimally Invasive Esophagectomy: Ivor Lewis Versus Mckeown., Andrew M. Brown, Michael J. Pucci, Adam C. Berger, Talar Tatarian, Nathaniel R. Evans Iii, Ernest L. Rosato, Francesco Palazzo

Department of Surgery Faculty Papers

BACKGROUND: While our institutional approach to esophageal resection for cancer has traditionally favored a minimally invasive (MI) 3-hole, McKeown esophagectomy (MIE 3-hole) during the last five years several factors has determined a shift in our practice with an increasing number of minimally invasive Ivor Lewis (MIE IL) resections being performed. We compared peri-operative outcomes of the two procedures, hypothesizing that MIE IL would be less morbid in the peri-operative setting compared to MIE 3-hole.

METHODS: Our institution's IRB-approved esophageal database was queried to identify all patients who underwent totally MI esophagectomy (MIE IL vs. MIE 3-hole) from June 2011 to …

Posttranscriptional Regulation Of Parg Mrna By Hur Facilitates Dna Repair And Resistance To Parp Inhibitors, Saswati N. Chand, Mahsa Zarei, M. J. Schiewer, Akshay R. Sanan, Carmella Romeo, Shruti Lal, Joseph A. Cozzitorto, Avinoam Nevler, Laura Scolaro, Eric R. Londin, Wei Jiang, Nicole Meisner-Kober, Michael J. Pishvaian, Karen E. Knudsen, Charles Yeo, John M Pascal, Jordan M. Winter, Jonathan R. Brody

Department of Surgery Faculty Papers

The majority of pancreatic ductal adenocarcinomas (PDAC) rely on the mRNA stability factor HuR (ELAV-L1) to drive cancer growth and progression. Here, we show that CRISPR-Cas9–mediated silencing of the HuR locus increases the relative sensitivity of PDAC cells to PARP inhibitors (PARPi). PDAC cells treated with PARPi stimulated translocation of HuR from the nucleus to the cytoplasm, specifically promoting stabilization of a new target, poly (ADP-ribose) glycohydrolase (PARG) mRNA, by binding a unique sequence embedded in its 3⁰ untranslated region. HuR-dependent upregulation of PARG expression facilitated DNA repair via hydrolysis of polyADP-ribose on related repair proteins. Accordingly, strategies to …

Crispr Knockout Of The Hur Gene Causes A Xenograft Lethal Phenotype., Shruti Lal, Edwin C, Cheung, Mahsa Zarei, Ranjan Preet, Saswati N. Chand, Nicole C. Mambelli-Lisboa, Carmella Romeo, Matthew C. Stout, Eric Londin, Austin Goetz, Cinthya Y. Lowder, Avinoam Nevler, Charles Yeo, Paul M. Campbell, Jordan M. Winter, Dan A. Dixon, Jonathan Brody

Department of Surgery Faculty Papers

Pancreatic ductal adenocarcinoma (PDA) is the third leading cause of cancer-related deaths in the United States, whereas colorectal cancer is the third most common cancer. The RNA-binding protein HuR (ELAVL1) supports a pro-oncogenic network in gastrointestinal (GI) cancer cells through enhanced HuR expression. Using a publically available database, HuR expression levels were determined to be increased in primary PDA and colorectal cancer tumor cohorts as compared with normal pancreas and colon tissues, respectively. CRISPR/Cas9 technology was successfully used to delete the HuR gene in both PDA (MIA PaCa-2 and Hs 766T) and colorectal cancer (HCT116) cell lines. HuR deficiency has …

Management And Prognosis In Synchronous Solitary Resected Brain Metastasis From Non–Small-Cell Lung Cancer, Alexander Louie, George Rodrigues, Brian Yaremko, Edward Yu, A. Dar, Brian Dingle, Mark Vincent, Michael Sanatani, Richard Malthaner, Richard Inculet

Richard A. Malthaner

Background: Reports in the medical literature have described cases of extended survival of patients with non-small-cell lung cancer (NSCLC) with solitary metastatic disease who have received aggressive treatment both to the brain metastasis and to the local/regional disease. The objective of this research is to analyze prognostic factors that predict for outcome in this unique patient population.

Patients and methods: A single-institution, retrospective chart review was performed on 35 patients with NSCLC and a synchronous solitary brain metastasis (SSBM) treated with craniotomy and whole-brain radiation therapy. Eight patients (22.9%) had chest surgery, 24 (68.6%) had chemotherapy, and 14 (40%) had …

Neoadjuvant Or Adjuvant Therapy For Resectable Esophageal Cancer: A Clinical Practice Guideline, Richard Malthaner, Rebecca Wong, R. Rumble, Lisa Zuraw

Richard A. Malthaner

Background: Carcinoma of the esophagus is an aggressive malignancy with an increasing incidence. Its virulence, in terms of symptoms and mortality, justifies a continued search for optimal therapy. A clinical practice guideline was developed based on a systematic review investigating neoadjuvant or adjuvant therapy on resectable thoracic esophageal cancer. Methods: A systematic review with meta-analysis was developed and clinical recommendations were drafted. External review of the practice guideline report by practitioners in Ontario, Canada was obtained through a mailed survey, and incorporated. Final approval of the practice guideline was obtained from the Practice Guidelines Coordinating Committee. Results: The systematic review …

Subsets More Likely To Benefit From Surgery Or Prophylactic Cranial Irradiation After Chemoradiation For Localized Non-Small-Cell Lung Cancer, Bruce Keith, Mark Vincent, Larry Stitt, Anna Tomiak, Richard Malthaner, Edward Yu, Pauline Truong, Richard Inculet, Michael Lefcoe, A. Dar, Walter Kocha, Ian Craig

Richard A. Malthaner

After chemoradiation for localized non-small-cell lung cancer, surgery and prophylactic cranial irradiation (PCI) have been used as additional therapies. Less than a third of patients develop brain recurrences, or have local recurrence as their sole initial site of recurrence; these are groups that would benefit from PCI or surgery, respectively. Pretreatment identification of patients more likely to benefit from surgery or PCI would be useful. A retrospective analysis of 80 patients was performed to determine prognostic factors for such patterns of failure. Twenty-nine patients were subsequently selected for surgery in a nonrandomized manner. Seventeen patients had isolated local initial recurrence …

Management And Prognosis In Synchronous Solitary Resected Brain Metastasis From Non–Small-Cell Lung Cancer, Alexander Louie, George Rodrigues, Brian Yaremko, Edward Yu, A. Dar, Brian Dingle, Mark Vincent, Michael Sanatani, Richard Malthaner, Richard Inculet

Richard A. Malthaner

Background: Reports in the medical literature have described cases of extended survival of patients with non-small-cell lung cancer (NSCLC) with solitary metastatic disease who have received aggressive treatment both to the brain metastasis and to the local/regional disease. The objective of this research is to analyze prognostic factors that predict for outcome in this unique patient population.

Patients and methods: A single-institution, retrospective chart review was performed on 35 patients with NSCLC and a synchronous solitary brain metastasis (SSBM) treated with craniotomy and whole-brain radiation therapy. Eight patients (22.9%) had chest surgery, 24 (68.6%) had chemotherapy, and 14 (40%) had …

Neoadjuvant Or Adjuvant Therapy For Resectable Esophageal Cancer: A Clinical Practice Guideline, Richard Malthaner, Rebecca Wong, R. Rumble, Lisa Zuraw

Richard A. Malthaner

Background: Carcinoma of the esophagus is an aggressive malignancy with an increasing incidence. Its virulence, in terms of symptoms and mortality, justifies a continued search for optimal therapy. A clinical practice guideline was developed based on a systematic review investigating neoadjuvant or adjuvant therapy on resectable thoracic esophageal cancer.

Methods: A systematic review with meta-analysis was developed and clinical recommendations were drafted. External review of the practice guideline report by practitioners in Ontario, Canada was obtained through a mailed survey, and incorporated. Final approval of the practice guideline was obtained from the Practice Guidelines Coordinating Committee.

Results: The systematic review …

Subsets More Likely To Benefit From Surgery Or Prophylactic Cranial Irradiation After Chemoradiation For Localized Non-Small-Cell Lung Cancer, Bruce Keith, Mark Vincent, Larry Stitt, Anna Tomiak, Richard Malthaner, Edward Yu, Pauline Truong, Richard Inculet, Michael Lefcoe, A. Dar, Walter Kocha, Ian Craig

Richard A. Malthaner

After chemoradiation for localized non-small-cell lung cancer, surgery and prophylactic cranial irradiation (PCI) have been used as additional therapies. Less than a third of patients develop brain recurrences, or have local recurrence as their sole initial site of recurrence; these are groups that would benefit from PCI or surgery, respectively. Pretreatment identification of patients more likely to benefit from surgery or PCI would be useful. A retrospective analysis of 80 patients was performed to determine prognostic factors for such patterns of failure. Twenty-nine patients were subsequently selected for surgery in a nonrandomized manner. Seventeen patients had isolated local initial recurrence …

Failure Patterns In Resected Pancreas Adenocarcinoma: Lack Of Predicted Benefit To Smad4 Expression., Jordan M. Winter, Laura H. Tang, David S. Klimstra, Weiguo Liu, Irena Linkov, Murray F. Brennan, Michael I. DʼAngelica, Ronald P. Dematteo, Yuman Fong, William R. Jarnagin, Eileen M. OʼReilly, Peter J. Allen

Department of Surgery Faculty Papers

OBJECTIVE: To determine whether SMAD4 expression is associated with recurrence pattern after resection for pancreatic ductal adenocarcinoma (PDA).

BACKGROUND: SMAD4 expression status has been reported to be associated with patterns of failure in PDA, but studies have not examined recurrence patterns after resection.

METHODS: A tissue microarray was constructed including 127 patients with resected PDA and either short-term (<12 >months) or long-term (>30 months) survival. SMAD4 expression was evaluated by immunohistochemistry and categorized as present or lost in tumor cells. Conventional pathologic features (lymph node metastases, positive resection margin, poor grade, and tumor size) were recorded, and disease-specific outcomes …

Major Perioperative Morbidity Does Not Affect Long-Term Survival In Patients Undergoing Esophagectomy For Cancer Of The Esophagus Or Gastroesophageal Junction., Brent T Xia, Ernest L Rosato, Karen A Chojnacki, Albert G. Crawford, Benny Weksler, Adam C. Berger

Department of Surgery Faculty Papers

INTRODUCTION: The incidence of cancer of the esophagus/GE junction is dramatically increasing but continues to have a dismal prognosis. Esophagectomy provides the best opportunity for long-term cure but is hampered by increased rates of perioperative morbidity. We reviewed our large institutional experience to evaluate the impact of postoperative complications on the long-term survival of patients undergoing resection for curative intent.

METHODS: We identified 237 patients who underwent esophagogastrectomy, with curative intent, for cancer between 1994 and 2008. Complications were graded using the previously published Clavien scale. Survival was calculated using Kaplan-Meier methodology and survival curves were compared using log-rank tests. …

Hepatocellular Carcinoma Survival In Uninsured And Underinsured Patients, John A Harvin, George Van Buren, Kuojen Tsao, Putao Cen, Tien C Ko, Curtis J Wray

Journal Articles

BACKGROUND: The incidence of hepatitis C virus (HCV) and hepatocellular carcinoma (HCC) is increasing. The purpose of this study is to establish baseline survival in a medically-underserved population and to evaluate the effect of HCV seropositivity on our patient population.

MATERIALS AND METHODS: We reviewed clinicopathologic parameters from a prospective tumor registry and medical records from the Harris County Hospital District (HCHD). Outcomes were compared using Kaplan-Meier survival analysis and log-rank tests.

RESULTS: A total of 298 HCC patients were identified. The median survival for the entire cohort was 3.4 mo. There was no difference in survival between the HCV …

One Year Survival With Poorly Differentiated Metastatic Pancreatic Carcinoma Following Chemoembolization With Gemcitabine And Cisplatin., Daniel B Brown, Carin F Gonsalves, Charles J Yeo, Agnes K Witkiewicz, Brian I Carr

Department of Radiology Faculty Papers

While hepatic arterial chemoembolization is efficacious for a number of malignancies, there is scant data regarding treatment of pancreatic adenocarcinoma. We report a complete radiographic response at one year from diagnosis of metastatic pancreatic carcinoma. Gemcitabine/cisplatin based chemoembolization may be of potential benefit for patients with liver-dominant metastases from pancreatic carcinoma. Given the typical survival of 6 months or less in this patient group with standard therapies, further research is warranted.

Analysis Of Epstein-Barr Virus Reservoirs In Paired Blood And Breast Cancer Primary Biopsy Specimens By Real Time Pcr., R Serene Perkins, Katherine Sahm, Cindy Marando, Diana Dickson-Witmer, Gregory R Pahnke, Mark Mitchell, Nicholas J Petrelli, Irving M Berkowitz, Patricia Soteropoulos, Virginie M Aris, Stephen P Dunn, Leslie J Krueger

Department of Surgery Faculty Papers

INTRODUCTION: Epstein-Barr virus (EBV) is present in over 90% of the world's population. This infection is considered benign, even though in limited cases EBV is associated with infectious and neoplastic conditions. Over the past decade, the EBV association with breast cancer has been constantly debated. Adding to this clinical and biological uncertainty, different techniques gave contradictory results for the presence of EBV in breast carcinoma specimens. In this study, minor groove binding (MGB)-TaqMan real time PCR was used to detect the presence of EBV DNA in both peripheral blood and tumor samples of selected patients. METHODS: Peripheral blood and breast …

Patterns Of Breast Recurrence In A Pilot Study Of Brachytherapy Confined To The Lumpectomy Site For Early Breast Cancer With Six Years' Minimum Follow-Up, Francisco Perera, Edward Yu, Jay Engel, Ronald Holliday, Leslie Scott, Frank Chisela, Varagur Venkatesan

Edward Yu

PURPOSE: In this pilot study of high-dose-rate brachytherapy to the lumpectomy site as the sole radiation, ipsilateral and contralateral breast recurrences are documented with specific attention to the location of recurrence relative to the lumpectomy site. METHODS: Between March 1992 and January 1996, 39 patients with T1 (32 patients) and T2 breast cancers received 37.2 Gy in 10 fractions (b.i.d.) over 1 week prescribed to a volume encompassing the surgical clips. Thirteen received adjuvant tamoxifen, and 4 received chemotherapy. Follow-up included annual bilateral mammograms and clinical breast examination every 3 to 6 months. Whereas 13 patients had intraoperative implantation of …

Subsets More Likely To Benefit From Surgery Or Prophylactic Cranial Irradiation After Chemoradiation For Localized Non-Small-Cell Lung Cancer, Bruce Keith, Mark Vincent, Larry Stitt, Anna Tomiak, Richard Malthaner, Edward Yu, Pauline Truong, Richard Inculet, Michael Lefcoe, A. Dar, Walter Kocha, Ian Craig

Edward Yu

After chemoradiation for localized non-small-cell lung cancer, surgery and prophylactic cranial irradiation (PCI) have been used as additional therapies. Less than a third of patients develop brain recurrences, or have local recurrence as their sole initial site of recurrence; these are groups that would benefit from PCI or surgery, respectively. Pretreatment identification of patients more likely to benefit from surgery or PCI would be useful. A retrospective analysis of 80 patients was performed to determine prognostic factors for such patterns of failure. Twenty-nine patients were subsequently selected for surgery in a nonrandomized manner. Seventeen patients had isolated local initial recurrence …

Nipple Aspirate Cytology And Pathologic Parameters Predict Residual Cancer And Nodal Involvement After Excisional Breast Biopsy., E R Sauter, H Ehya, A Mammen, G Klein

Department of Surgery Faculty Papers

We previously demonstrated that abnormal nipple aspirate fluid (NAF) cytology predicted residual breast cancer (RC) and tumour size after excisional biopsy (EB), although normal NAF cytology did not exclude RC. Tumour size correlates with the risk of lymph node (LN) metastases. LN metastases provide prognostic information allowing medical and radiation oncologists to determine the need for adjuvant therapy. We hypothesized that pathologic factors known after EB, combined with NAF cytology, would predict with a high degree of accuracy the presence of RC and LN spread. NAF cytology and pathologic parameters: tumour distance from biopsy margins, multifocal and multicentric disease, sub-type …