Browsing by Author "Schwarz, Roderich E."
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Item Augmentation of Nab-Paclitaxel Chemotherapy Response by Mechanistically Diverse Antiangiogenic Agents in Preclinical Gastric Cancer Models(American Association for Cancer Research, 2018-11) Awasthi, Niranjan; Schwarz, Margaret A.; Zhang, Changhua; Schwarz, Roderich E.; Surgery, School of MedicineGastric adenocarcinoma (GAC) remains the third most common cause of cancer-related deaths worldwide. Systemic chemotherapy is commonly recommended as a fundamental treatment for metastatic GAC; however, standard treatment has not been established yet. Angiogenesis plays a crucial role in the progression and metastasis of GAC. We evaluated therapeutic benefits of mechanistically diverse antiangiogenic agents in combination with nab-paclitaxel, a next-generation taxane, in preclinical models of GAC. Murine survival studies were performed in peritoneal dissemination models, whereas tumor growth studies were performed in subcutaneous GAC cell-derived or patient-derived xenografts. The mechanistic evaluation involved IHC and Immunoblot analysis in tumor samples. Nab-paclitaxel increased animal survival that was further improved by the addition of antiangiogenic agents ramucirumab (or its murine version DC101), cabozantinib and nintedanib. Nab-paclitaxel combination with nintedanib was most effective in improving animal survival, always greater than 300% over control. In cell-derived subcutaneous xenografts, nab-paclitaxel reduced tumor growth while all three antiangiogenic agents enhanced this effect, with nintedanib demonstrating the greatest inhibition. Furthermore, in GAC patient-derived xenografts the combination of nab-paclitaxel and nintedanib reduced tumor growth over single agents alone. Tumor tissue analysis revealed that ramucirumab and cabozantinib only reduced tumor vasculature, whereas nintedanib in addition significantly reduced tumor cell proliferation and increased apoptosis. Effects of nab-paclitaxel, a promising chemotherapeutic agent for GAC, can be enhanced by new-generation antiangiogenic agents, especially nintedanib. The data suggest that nab-paclitaxel combinations with multitargeted antiangiogenic agents carry promising potential for improving clinical GAC therapy.Item Augmentation of response to nab-paclitaxel by inhibition of insulin-like growth factor (IGF) signaling in preclinical pancreatic cancer models(Impact Journals, 2016-07-26) Awasthi, Niranjan; Scire, Emily; Monahan, Sheena; Grojean, Meghan; Zhang, Eric; Schwarz, Margaret A.; Schwarz, Roderich E.; Department of Surgery, IU School of MedicineNab-paclitaxel has recently shown greater efficacy in pancreatic ductal adenocarcinoma (PDAC). Insulin like growth factor (IGF) signaling proteins are frequently overexpressed in PDAC and correlate with aggressive tumor phenotype and poor prognosis. We evaluated the improvement in nab-paclitaxel response by addition of BMS-754807, a small molecule inhibitor of IGF-1R/IR signaling, in preclinical PDAC models. In subcutaneous xenografts using AsPC-1 cells, average net tumor growth in different therapy groups was 248.3 mm3 in controls, 42.4 mm3 after nab-paclitaxel (p = 0.002), 93.3 mm3 after BMS-754807 (p = 0.01) and 1.9 mm3 after nab-paclitaxel plus BMS-754807 (p = 0.0002). In subcutaneous xenografts using Panc-1 cells, average net tumor growth in different therapy groups was: 294.3 mm3 in controls, 23.1 mm3 after nab-paclitaxel (p = 0.002), 118.2 mm3 after BMS-754807 (p = 0.02) and -87.4 mm3 (tumor regression) after nab-paclitaxel plus BMS-754807 (p = 0.0001). In peritoneal dissemination model using AsPC-1 cells, median animal survival was increased compared to controls (21 days) after therapy with nab-paclitaxel (40 days, a 90% increase, p = 0.002), BMS-754807 (27 days, a 29% increase, p = 0.01) and nab-paclitaxel plus BMS-754807 (47 days, a 124% increase, p = 0.005), respectively. Decrease in proliferation and increase in apoptosis by nab-paclitaxel and BMS-754807 therapy correlated with their in vivo antitumor activity. In vitro analysis revealed that the addition of IC25 dose of BMS-754807 decreased the nab-paclitaxel IC50 of PDAC cell lines. BMS-754807 therapy decreased phospho-IGF-1R/IR and phospho-AKT expression, and increased cleavage of caspase-3 and PARP-1. These results support the potential of BMS-754807 in combination with nab-paclitaxel as an effective targeting option for pancreatic cancer therapy.Item Augmenting Experimental Gastric Cancer Activity of Irinotecan through Liposomal Formulation and Antiangiogenic Combination Therapy(American Association for Cancer Research, 2022) Awasthi, Niranjan; Schwarz, Margaret A.; Zhang, Changhua; Klinz, Stephan G.; Meyer-Losic, Florence; Beaufils, Benjamin; Thiagalingam, Arunthathi; Schwarz, Roderich E.; Surgery, School of MedicineGastric adenocarcinoma (GAC) is the third most common cause of cancer-related deaths worldwide. Combination chemotherapy remains the standard treatment for advanced GAC. Liposomal irinotecan (nal-IRI) has improved pharmacokinetics (PK) and drug biodistribution compared with irinotecan (IRI, CPT-11). Angiogenesis plays a crucial role in the progression and metastasis of GAC. We evaluated the antitumor efficacy of nal-IRI in combination with novel antiangiogenic agents in GAC mouse models. Animal survival studies were performed in peritoneal dissemination xenografts. Tumor growth and PK studies were performed in subcutaneous xenografts. Compared with controls, extension in animal survival by nal-IRI and IRI was >156% and >94%, respectively. The addition of nintedanib or DC101 extended nal-IRI response by 13% and 15%, and IRI response by 37% and 31% (MKN-45 xenografts); nal-IRI response by 11% and 3%, and IRI response by 16% and 40% (KATO-III xenografts). Retardation of tumor growth was greater with nal-IRI (92%) than IRI (71%). Nintedanib and DC101 addition tend to augment nal-IRI or IRI response in this model. The addition of antiangiogenic agents enhanced tumor cell proliferation inhibition effects of nal-IRI or IRI. The tumor vasculature was decreased by nintedanib (65%) and DC101 (58%), while nal-IRI and IRI alone showed no effect. PK characterization in GAC xenografts demonstrated that compared with IRI, nal-IRI treatment groups had higher retention, circulation time, and tumor levels of CPT-11 and its active metabolite SN-38. These findings indicate that nal-IRI, alone and in combination with antiangiogenic agents, has the potential for improving clinical GAC therapy.Item Clinical trends and effects on quality metrics for surgical gastroesophageal cancer care(AME Publishing Company, 2018-07-19) Schwarz, Roderich E.; Surgery, School of MedicineBackground: Surgical therapy of mid-stage gastric cancer (GC) and other neoplastic conditions requiring gastric resection remains at the center of curative outcomes, while epidemiologic changes and multimodality treatment options have evolved rapidly. Putative quality metrics for gastrectomy such as R0 rate, total lymph node (LN) count or postoperative morbidity may depend partly on changing disease and treatment patterns, and deserve evaluation under various practice conditions. Methods: Data within a U.S.-based single surgical oncologist's practice over 15 years were prospectively recorded and retrospectively analyzed for clinicopathologic factors, operative treatment aspects and outcomes. Trends and spectrum changes over three time intervals were analyzed with contingency analysis and continuous data comparative statistics. Results: Of 179 patients undergoing gastric resection, 119 were male and 60 female, with a median age of 63 years (range, 24-98 years). Resections included 56 total, 56 subtotal/distal, 30 proximal and 37 segmental gastrectomies. Diagnoses included 96 GCs, 31 gastroesophageal (GE) junction (GEJ) cancers, 21 GI stromal tumors (GISTs), and 31 other conditions. Significant trends from first towards last time interval were observed for resection type (16% to 32% proximal, 9% to 30% segmental, P=0.0003), curative intent (76% to 98%, P=0.002), diagnosis (5% to 42% GEJ cancer, P<0.0001) and preoperative therapy use (0% to 58%, P<0.0001), among others. Intraoperative aspects showed significantly reduced blood loss (median: 500 to 150 mL) and transfusion requirements (39% to 4%), and an increased use of minimally invasive techniques over time (all at P<0.001). Among patients undergoing curative intent GC resection with LN dissection, total LN counts remained steady (mean: 26), while the number of involved LNs decreased (9.0 to 3.7, P=0.0003) and the R0 resection rate increased from 74% to 85% (P=0.05). The number of specimens with >15 LNs examined increased from 69.0% to 92.5% (P=0.022). At the same time, spleen preservation rate (91% overall) and major morbidity (16%) remained unchanged throughout. Postoperative length of stay decreased from a median of 12 to 8 days (P<0.0001). Conclusions: This experience represents some variable practice patterns within a clinicopathologic spectrum of GE diseases. Postoperative or oncologic quality metrics have been sustained or did improve, which would support their utility for various practice settings; they compare favorably to other published U.S. experiences during the same time period.Item Enhancing gastric cancer conventional chemotherapy effects by triple angiokinase inhibitor nintedanib in preclinical models(Frontiers Media, 2023-05-10) Awasthi, Niranjan; Schwarz, Margaret A.; Kaurich, Quinn; Zhang, Changhua; Hilberg, Frank; Schwarz, Roderich E.; Surgery, School of MedicineBackground: Gastric adenocarcinoma (GAC) is the fourth leading cause of cancer death worldwide. Systemic chemotherapy is a preferred treatment option for advanced and recurrent GAC, but response rates and survival prolongation remain limited. Tumor angiogenesis plays a critical role in GAC growth, invasion and metastasis. We investigated the antitumor efficacy of nintedanib, a potent triple angiokinase inhibitor for VEGFR-1/2/3, PDGFR-α/β and FGFR-1/2/3, alone or in combination with chemotherapy, in preclinical models of GAC. Methods: Animal survival studies were performed in peritoneal dissemination xenografts in NOD/SCID mice using human GAC cell lines MKN-45 and KATO-III. Tumor growth inhibition studies were performed in subcutaneous xenografts in NOD/SCID mice using human GAC cell lines MKN-45 and SNU-5. The mechanistic evaluation involved Immunohistochemistry analyses in tumor tissues obtained from subcutaneous xenografts. In vitro cell viability assays were performed using a colorimetric WST-1 reagent. Results: In MKN-45 GAC cell-derived peritoneal dissemination xenografts, animal survival was improved by nintedanib (33%), docetaxel (100%) and irinotecan (181%), while oxaliplatin, 5-FU and epirubicin had no effect. The addition of nintedanib to docetaxel (157%) or irinotecan (214%) led to a further extension in animal survival. In KATO-III GAC cell-derived xenografts carrying FGFR2 gene amplification, nintedanib extended survival by 209%. Again, the addition of nintedanib further enhanced the animal survival benefits of docetaxel (273%) and irinotecan (332%). In MKN-45 subcutaneous xenografts, nintedanib, epirubicin, docetaxel and irinotecan reduced tumor growth (range: 68-87%), while 5-FU and oxaliplatin had a smaller effect (40%). Nintedanib addition to all chemotherapeutics demonstrated a further reduction in tumor growth. Subcutaneous tumor analysis revealed that nintedanib attenuated tumor cell proliferation, reduced tumor vasculature and increased tumor cell death. Conclusion: Nintedanib showed notable antitumor efficacy and significantly improved taxane or irinotecan chemotherapy responses. These findings indicate that nintedanib, alone and in combination with a taxane or irinotecan, has the potential for improving clinical GAC therapy.Item Experience with a simplified feeding jejunostomy technique for enteral nutrition following major visceral operations(AME Publishing Company, 2018-07-19) Minarich, Michael J.; Schwarz, Roderich E.; Surgery, School of MedicineBackground: Background: Perioperative nutrition support has been shown to impact on outcomes for patients with gastrointestinal cancer. Postoperative benefits of feeding tubes must be weighed against morbidity related to placement and use. A simplified jejunostomy tube technique was evaluated for outcomes. Methods: A 16-Fr rubber tube is secured at the jejunal entry site without Witzel tunnel, followed by a continuous, circumferential and alternating suture between jejunal wall and parietal peritoneum. Prospectively collected data were analyzed. Results: The technique was performed in 343 of 803 major hepatopancreatobiliary and upper gastrointestinal (GI) resections (43%). Of these patients (male =57%, median age: 65.8 years, range, 24.0-98.0 years), 89% had a cancer diagnosis. The procedures included pancreatectomy (n=189, 55%), gastrectomy (n=109, 32%), esophagectomy (n=19, 6%) and others (n=26, 7%). The operative intent was curative in 78%, palliative in 10%, or combined in 12% of patients. Postoperative morbidity rate was 40%, with 19 lethal events (5.5%), and a median length of stay of 10 days (range, 4-111 days). Tube feeds were administered in 139 patients (41%), and in 17% continued beyond discharge. Use of the feeding tube was linked to treatment interval, length of stay, major complication grade (all at P<0.0001), metastatic stage (P=0.0007) and noncurative intent (P=0.001). Tube feeds beyond discharge were associated with time interval (P<0.0001), length of stay (P=0.0006) and noncurative intent (P=0.014). Tube-specific events in 38 patients (11%) were all minor, without any intraabdominal leak, infection or obstruction. Conclusions: The technique described is safe and expedient, and the overall tube-related morbidity is low. This procedure can be recommended in cases at risk for major morbidity and nutrition support needs.Item Inhibition of the MEK/ERK pathway augments nab-paclitaxel-based chemotherapy effects in preclinical models of pancreatic cancer(Impact Journals, 2017-12-25) Awasthi, Niranjan; Monahan, Sheena; Stefaniak, Alexis; Schwarz, Margaret A.; Schwarz, Roderich E.; Surgery, School of MedicineNab-paclitaxel (NPT) combination with gemcitabine (Gem) represents the standard chemotherapy for pancreatic ductal adenocarcinoma (PDAC). Genetic alterations of the RAS/RAF/MEK/ERK (MAPK) signaling pathway yielding constitutive activation of the ERK cascade have been implicated as drivers of PDAC. Inhibition of downstream targets in the RAS-MAPK cascade such as MEK remains a promising therapeutic strategy. The efficacy of trametinib (Tra), a small molecule inhibitor of MEK1/2 kinase activity, in combination with nab-paclitaxel-based chemotherapy was evaluated in preclinical models of PDAC. The addition of trametinib to chemotherapy regimens showed a trend for an additive effect on tumor growth inhibition in subcutaneous AsPC-1 and Panc-1 PDAC xenografts. In a peritoneal dissemination model, median animal survival compared to controls (20 days) was increased after therapy with NPT (33 days, a 65% increase), Tra (31 days, a 55% increase), NPT+Tra (37 days, a 85% increase), NPT+Gem (39 days, a 95% increase) and NPT+Gem+Tra (49 days, a 145% increase). Effects of therapy on intratumoral proliferation and apoptosis corresponded with tumor growth inhibition. Trametinib effects were specifically accompanied by a decrease in phospho-ERK and an increase in cleaved caspase-3 and cleaved PARP-1 proteins. These findings suggest that the effects of nab-paclitaxel-based chemotherapy can be enhanced through specific inhibition of MEK1/2 kinase activity, and supports the clinical application of trametinib in combination with standard nab-paclitaxel-based chemotherapy in PDAC patients.Item Institutional Variants For Lymph Node Counts After Pancreatic Resections(Elsevier, 2017) Schwarz, Roderich E.; Department of Surgery, IU School of MedicineBackground Lymph node (LN) counts from pancreatectomy are postulated as quality metric for surgical therapy of pancreatic malignancy. Methods Prospectively collected data from a single surgeon's pancreatectomy experience were analyzed for predictors of LN counts. Results Of 315 consecutive patients (54% female, median age: 65, range 18–88), 239 had a proven cancer diagnosis (76%). Operations included pancreatoduodenectomy (69%), distal pancreatectomy (26%), total pancreatectomy (1%) and others (4%). Patients were treated in 4 different tertiary cancer center settings (Institution A: 11%; B: 46%; C: 27%; D: 16%) with consistent regional dissection standards. Mean total LN counts differed between institutions for malignancies (A: 18, B: 13, C: 26, D: 26, p < 0.0001) and benign diseases (p = 0.003). At least 15 LNs were reported in 63% of cancer patients (institution range: 34–92%, p < 0.0001). Conclusions Pathologic processing should be standardized if LN numbers are to be adopted as quality metric for pancreatic cancer resections.Item Managing the Unmanageable: A Two-Staged Palliative Resection to Control Life-Threatening Duodenal Bleeding Due to Recurrent Paraganglioma(International Scientific Information, 2018-04-02) Smucker, Levi Y.; Hardy, Ashley N.; O’Neil, Peter J.; Schwarz, Roderich E.; Surgery, School of MedicineBACKGROUND This report presents therapeutic decision-making and management of refractory, life-threatening duodenal bleeding in a young man with recurrent metastatic retroperitoneal paraganglioma. CASE REPORT The patient had been symptom free for 8 years after radioactive MIBG (metaiodobenzylguanidine) therapy. Failure of endoscopic or angiographic bleeding control led to urgent need to evaluate possible endocrine functional status, tumor curability, safety of incomplete resection, intra- and postoperative support needs, and anticipated recovery potential and postoperative function. Aside from these considerations, impact of tumor biology, alternative therapeutic options, current management guidelines, and ethical challenges of resource utilization for such complex palliative operative intervention were reviewed. CONCLUSIONS Based on the observed outcomes after an urgent presentation of an unusual tumor-related complication, palliation-intent therapy was justifiable even if significant treatment-related risks were expected and complex resources were required.Item N-terminus of pro-EMAP II regulates its binding with C-terminus, Arginyl-tRNA Synthetase, and Neurofilament light protein(2015-04) Xu, Haiming; Malinin, Nikolay L.; Awasthi, Niranjan; Schwarz, Roderich E.; Schwarz, Margaret A.; Department of Pediatrics, Indiana University School of MedicinePro-EMAP II, one component of the Multi-Aminoacyl tRNA Synthetase (MSC) Complex, plays multiple roles in physiological and pathological processes of protein translation, signal transduction, immunity, lung development and tumor growth. Recent studies determined that pro-EMAP II has an essential role in maintaining axon integrity in central and peripheral neural systems where deletion of pro-EMAP IIs C-terminus was reported in a consanguineous Israeli Bedouin kindred suffering from Pelizaeus-Merzbacher-like disease. We hypothesized that pro-EMAP IIs N-terminus had an important role in the regulation of protein-protein interactions. Using a GFP reporter system, we defined a putative leucine-zipper in the N-terminus of human pro-EMAP II protein (amino acid residues 1-70), which can form specific strip-like punctate structures. Through GFP punctate analysis, we uncovered that pro-EMAP IIs C-terminus (147-312 amino acid residues) can repress the GFP punctate formation. Pull-down assays confirmed the binding between pro-EMAP II N-terminus and its C-terminus is mediated by a putative leucine-zipper. Furthermore, the pro-EMAP II 1-70 aa region was identified as the binding partner of the arginyl-tRNA synthetase (RARS), a polypeptide of MSC complex. We also determined that the punctate GFP pro-EMAP II 1-70aa aggregate co-localizes and binds to the neurofilament light (NFL) subunit protein that is associated with pathologic neurofilament network disorganization and degeneration of motor neurons. These findings indicate the structure and binding interaction of Pro-EMAP II protein and suggest a role of this protein in the pathological neurodegenerative diseases.