Pancreatoduodenectomy with or without Pyloric Preservation: A Clinical Outcomes Comparison

Pyloric preservation (PP) can frequently be performed at the time of pancreatoduodenectomy (PD), although some reports have linked it to inferior outcomes such as delayed gastric emptying (DGE). We reviewed records in a single-surgeon practice to assess outcomes after PD with or without PP. There were 133 PDs with 67 PPPDs and 66 PDs. Differences between PPPD and PD groups included cancer frequency, tumor size, OR time, blood loss, and transfusion rate. However, postoperative morbidity rate and grade, NG tube duration, NGT reinsertion rate, DGE, and length of stay were similar. There was no difference among patients with pancreatic cancer. No detrimental outcomes are associated with pyloric preservation during PD. Greater intraoperative ease and superior survival in the PPPD group are due to confounding, tumor-related variables in this nonrandomized comparison. Nevertheless, we intend to continue the use of PP with our technique in patients who meet the stated criteria

The Adnectin CT-322 is a novel VEGF receptor 2 inhibitor that decreases tumor burden in an orthotopic mouse model of pancreatic cancer

<p>Abstract</p> <p>Background</p> <p>Pancreatic cancer continues to have a 5-year survival of less than 5%. Therefore, more effective therapies are necessary to improve prognosis in this disease. Angiogenesis is required for tumor growth, and subsequently, mediators of angiogenesis are attractive targets for therapy. Vascular endothelial growth factor (VEGF) is a well-characterized mediator of tumor angiogenesis that functions primarily by binding and activating VEGF receptor 2 (VEGFR2). In this study, we evaluate the use of CT-322, a novel biologic (Adnectin). This small protein is based on a human fibronectin domain and has beneficial properties in that it is fully human, stable, and is produced in bacteria. CT-322 binds to and inhibits activation of VEGFR2.</p> <p>Methods</p> <p>The efficacy of CT-322 was evaluated <it>in vivo </it>using two orthotopic pancreatic tumor models. The first model was a human tumor xenograft where MiaPaCa-2 cells were injected into the tail of the pancreas of nude mice. The second model was a syngeneic tumor using Pan02 cells injected into pancreas of C57BL/6J mice. In both models, therapy was initiated once primary tumors were established. Mice bearing MiaPaCa-2 tumors were treated with vehicle or CT-322 alone. Gemcitabine alone or in combination with CT-322 was added to the treatment regimen of mice bearing Pan02 tumors. Therapy was given twice a week for six weeks, after which the animals were sacrificed and evaluated (grossly and histologically) for primary and metastatic tumor burden. Primary tumors were also evaluated by immunohistochemistry for the level of apoptosis (TUNEL), microvessel density (MECA-32), and VEGF-activated blood vessels (Gv39M).</p> <p>Results</p> <p>Treatment with CT-322 was effective at preventing pancreatic tumor growth and metastasis in orthotopic xenograft and syngeneic models of pancreatic cancer. Additionally, CT-322 treatment increased apoptosis, reduced microvessel density and reduced the number of VEGF-activated blood vessels in tumors. Finally, CT-322, in combination with gemcitabine was safe and effective at controlling the growth of syngeneic pancreatic tumors in immunocompetent mice.</p> <p>Conclusion</p> <p>We conclude that CT-322 is an effective anti-VEGFR2 agent and that further investigation of CT-322 for the treatment of pancreatic cancer is warranted.</p

Cytokine Levels Correlate with Immune Cell Infiltration after Anti-VEGF Therapy in Preclinical Mouse Models of Breast Cancer

The effect of blocking VEGF activity in solid tumors extends beyond inhibition of angiogenesis. However, no studies have compared the effectiveness of mechanistically different anti-VEGF inhibitors with respect to changes in tumor growth and alterations in the tumor microenvironment. In this study we use three distinct breast cancer models, a MDA-MB-231 xenograft model, a 4T1 syngenic model, and a transgenic model using MMTV-PyMT mice, to explore the effects of various anti-VEGF therapies on tumor vasculature, immune cell infiltration, and cytokine levels. Tumor vasculature and immune cell infiltration were evaluated using immunohistochemistry. Cytokine levels were evaluated using ELISA and electrochemiluminescence. We found that blocking the activation of VEGF receptor resulted in changes in intra-tumoral cytokine levels, specifically IL-1β, IL-6 and CXCL1. Modulation of the level these cytokines is important for controlling immune cell infiltration and ultimately tumor growth. Furthermore, we demonstrate that selective inhibition of VEGF binding to VEGFR2 with r84 is more effective at controlling tumor growth and inhibiting the infiltration of suppressive immune cells (MDSC, Treg, macrophages) while increasing the mature dendritic cell fraction than other anti-VEGF strategies. In addition, we found that changes in serum IL-1β and IL-6 levels correlated with response to therapy, identifying two possible biomarkers for assessing the effectiveness of anti-VEGF therapy in breast cancer patients

Effect of complications on oncologic outcomes after pancreaticoduodenectomy for pancreatic cancer

Although adjuvant therapy (AT) is a necessary component of multimodality therapy for pancreatic ductal adenocarcinoma (PDAC), its application can be hindered by post-pancreaticoduodenectomy (PD) complications. The primary aim of this study was to evaluate the impact of post-PD complications on AT utilization and overall survival (OS). Patients undergoing PD without neoadjuvant therapy for stages I-III PDAC at a single institution (2007-2015) were evaluated. Ninety-day postoperative major complications (PMCs) were defined as grade ≥3. Records were linked to the Kentucky Cancer Registry for AT/OS data. Early AT was given 16 wk was not considered to be AT. Complication effects on AT timing/utilization and OS were evaluated. Of 93 consecutive patients treated with surgery upfront with AT data, 64 (69%) received AT (41 [44%] early; 23 [25%] late). There were 32 patients (34%) with low-grade complications and 24 (26%) with PMC. With PMC, only six of 24 patients (25%) received early AT and 13 of 24 (54%) received any (early/late) AT versus 35 of 69 (51%) early AT and 51 of 69 (74%) any AT without PMC. PMCs were associated with worse median OS (7.1 versus 24.6 mo, without PMC, P 2 cm (HR: 3.39), node-positivity (HR: 2.16), and PMC (HR: 3.69, all P < 0.02). Independent of AT utilization and biologic factors, PMC negatively impacted OS in patients treated with surgery first. These data suggest that strategies to decrease PMC and treatment sequencing alternatives to increase multimodality therapy rates may improve oncologic outcomes for PDAC

Lack of host SPARC enhances vascular function and tumor spread in an orthotopic murine model of pancreatic carcinoma

Utilizing subcutaneous tumor models, we previously validated SPARC (secreted protein acidic and rich in cysteine) as a key component of the stromal response, where it regulated tumor size, angiogenesis and extracellular matrix deposition. In the present study, we demonstrate that pancreatic tumors grown orthotopically in Sparc-null (Sparc−/−) mice are more metastatic than tumors grown in wild-type (Sparc+/+) littermates. Tumors grown in Sparc−/− mice display reduced deposition of fibrillar collagens I and III, basement membrane collagen IV and the collagen-associated proteoglycan decorin. In addition, microvessel density and pericyte recruitment are reduced in tumors grown in the absence of host SPARC. However, tumors from Sparc−/− mice display increased permeability and perfusion, and a subsequent decrease in hypoxia. Finally, we found that tumors grown in the absence of host SPARC exhibit an increase in alternatively activated macrophages. These results suggest that increased tumor burden in the absence of host SPARC is a consequence of reduced collagen deposition, a disrupted vascular basement membrane, enhanced vascular function and an immune-tolerant, pro-metastatic microenvironment