Osteosarcoma occurs mostly in children and young adults, who are treated with multiple agents in combination with limb-salvage surgery. However, the overall 5-year survival rate for patients with recurrent or metastatic osteosarcoma is 20-30% which has not improved significantly over 30 years. Refractory patients would benefit from precise individualized therapy. We report here that a patient-derived osteosarcoma growing in a subcutaneous nude-mouse model was regressed by tumor-targeting Salmonella typhimurium A1-R (S. typhimurium A1-R, p<0.001 compared to untreated control). The osteosarcoma was only partially sensitive to the molecular-targeting drug sorafenib, which did not arrest its growth. S. typhimurium A1-R was significantly more effective than sorafenib (P <0.001). S. typhimurium grew in the treated tumors and caused extensive necrosis of the tumor tissue. These data show that S. typhimurium A1-R is powerful therapy for an osteosarcoma patient-derived xenograft model.

In the present study, we evaluated the efficacy of trabectedin (TRAB) and temozolomide (TEM) compared to cisplatinum (CDDP) on a patient-derived orthotopic xenogrraft (PDOX) of a lung-metastasis from an osteosarcoma of a patient who failed CDDP therapy. Osteosarcoma resected from the patient was implanted orthotopically in the distal femur of mice to establish PDOX models which were randomized into the following groups when tumor volume reached approximately 100 mm3: G1, control without treatment; G2, CDDP (6 mg/kg, intraperitoneal injection, weekly, for 2 weeks); G3, TRAB (0.15 mg/kg, intravenous injection, weekly, for 2 weeks); G4, TEM (25 mg/kg, oral, daily, for 14 days). Tumor size and body weight were measured with calipers and a digital balance, respectively, twice a week. On day 14 after initiation of treatment, TEM and TRAB, but not CDDP, significantly inhibited tumor volume compared to untreated control: control (G1): 814.5±258.8 mm3; CDDP (G2): 608.6±126.9 mm3; TRAB (G3): 286.6±133.0 mm3; TEM (G4): 182.9±69.1 mm3. CDDP vs. control, p=0.07; TRAB vs. control, p=0.0004; TEM vs. control p =0.0002; TRAB vs. CDDP, p =0.0002; TEM vs. CDDP, p =0.00003. The results of the present study show that a PDOX model of an osteosarcoma lung-metastasis that recurred after adjuvant CDDP-treatment has identified potentially, highly-effective drugs for this recalcitrant disease, while accurately maintaining the CDDP resistance of the tumor in the patient, thereby demonstrating the potential of the osteosarcoma PDOX model for precision oncology.

In the present study, a patient-derived orthotopic xenograft (PDOX) model of recurrent cisplatinum (CDDP)-resistant metastatic osteosarcoma was treated with Salmonella typhimurium A1-R (S. typhimurium A1-R), which decoys chemoresistant quiescent cancer cells to cycle, and recombinant methioninase (rMETase), which selectively traps cancer cells in late S/G, and chemotherapy. The PDOX models were randomized into the following groups 14 days after implantation: G1, control without treatment; G2, CDDP (6 mg/kg, intraperitoneal (i.p.) injection, weekly, for 2 weeks); G3, rMETase (100 unit/mouse, i.p., daily, for 2 weeks). G4, S. typhimurium A1-R (5 × 10 CFU/100 μl, i.v., weekly, for 2 weeks); G5, S. typhimurium A1-R (5 × 10 CFU/100 μl, i.v., weekly, for 2 weeks) combined with rMETase (100 unit/mouse, i.p., daily, for 2 weeks); G6, S. typhimurium A1-R (5 × 10 CFU/100 μl, i.v., weekly, for 2 weeks) combined with rMETase (100 unit/mouse, i.p., daily, for 2 weeks) and CDDP (6 mg/kg, i.p. injection, weekly, for 2 weeks). On day 14 after initiation, all treatments except CDDP alone, significantly inhibited tumor growth compared to untreated control: (CDDP: p = 0.586; rMETase: p = 0.002; S. typhimurium A1-R: p = 0.002; S. typhimurium A1-R combined with rMETase: p = 0.0004; rMETase combined with both S. typhimurium A1-R and CDDP: p = 0.0001). The decoy, trap and kill combination of S. typhimurium A1-R, rMETase and CDDP was the most effective of all therapies and was able to eradicate the metastatic osteosarcoma PDOX.

Preoperative biliary stenting and coriticosteroid use increase superficial SSI, even in patients receiving perioperative piperacillin-tazobactam. Additional measures, including extended broad-spectrum perioperative antibiotic treatment, should be considered in these patients. Organ/space SSIs appear to be related to pancreatic fistulae, which are not modifiable. Reporting these different subtypes as a single, overall rate may be misleading.

Histopathologic phenotype is a better prognosticator of survival in patients with periampullary adenocarcinomas than tumor anatomic location. Those with PB-type duodenal, ampullary, or distal CBD adenocarcinomas have survival similar to those with PDAC.

Functional lysosomes mediate autophagy and macropinocytosis for nutrient acquisition. Pancreatic ductal adenocarcinoma (PDAC) tumors exhibit high basal lysosomal activity, and inhibition of lysosome function suppresses PDAC cell proliferation and tumor growth. However, the codependencies induced by lysosomal inhibition in PDAC have not been systematically explored. We performed a comprehensive pharmacological inhibition screen of the protein kinome and found that replication stress response (RSR) inhibitors were synthetically lethal with chloroquine (CQ) in PDAC cells. CQ treatment reduced de novo nucleotide biosynthesis and induced replication stress. We found that CQ treatment caused mitochondrial dysfunction and depletion of aspartate, an essential precursor for de novo nucleotide synthesis, as an underlying mechanism. Supplementation with aspartate partially rescued the phenotypes induced by CQ. The synergy of CQ and the RSR inhibitor VE-822 was comprehensively validated in both 2D and 3D cultures of PDAC cell lines, a heterotypic spheroid culture with cancerassociated fibroblasts, and in vivo xenograft and syngeneic PDAC mouse models. These results indicate a codependency on functional lysosomes and RSR in PDAC and support the translational potential of the combination of CQ and RSR inhibitors. lysosome | autophagy | replication stress | pancreatic cancer | nucleotide metabolism P ancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death in the United States, and its incidence is increasing (1). PDAC carries a 5-y survival of less than 10%, as it is often diagnosed at a late stage and is widely refractory to available therapies. This lack of effective treatment options suggests an incomplete understanding of the biologic complexity of PDAC and mechanisms of therapeutic resistance.PDAC tumors are hypoperfused, resulting in poor nutrient delivery (2). To exist in this hostile microenvironment, PDAC cells rely on intracellular and extracellular scavenging pathways to acquire metabolic substrates for growth. Autophagy, a selfdegradative mechanism employed to recycle damaged cytosolic proteins and organelles, and macropinocytosis, the process of uptaking bulk extracellular material, are up-regulated in PDAC (3-6). As the final step of both autophagy and macropinocytosis, autophagic and endocytic cargo fuse with the lysosome, where macromolecules are degraded and substrates for metabolism are released (3, 4, 7). Inhibition of these pathways suppresses PDAC tumor growth and prolongs survival in animal models (4, 6, 8). Additionally, engaging autophagic programs confers resistance to chemoradiation in PDAC cells (9-11), and high levels of autophagy markers are correlated with worse survival in resected PDAC patients (12).The study of lysosomal function often focuses on proteolysis, which degrades misfolded proteins and damaged organelles (13,14). However, lysosomal degradation pathways also play a critical role in lipid (15-17) and nucleic acid metabolism. The recycling of nucleic ac...

Although the LN scoring in the seventh PDAC AJCC Staging System was sufficient to predict OS of our patients, more LNs than previously considered (20 vs. 15) were optimal to detect pathologic involvement. Preoperative LN detection was an accurate predictor of pN1 disease for treatment naïve patients without biliary obstruction.

In this single-center, retrospective analysis, an MPD diameter of 7.2 mm was identified as an optimal cutoff for a prognostic factor for malignant disease in MD or mixed IPMN. These data support lowering the accepted criteria for MPD diameter when selecting patients for resection vs surveillance so as not to overlook cancer in IPMN.