Background: Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of US cancer related deaths. This study assessed the oncologic benefit of a neoadjuvant chemotherapy (NAC) treatment strategy for patients with clinical Stage I/II PDAC. Methods: Patients with biopsy confirmed PDAC and clinical Stage I/II disease were treated with a protocol of NAC. The primary study endpoint was median overall survival (OS). Kaplan-Meier survival curves were compared using the log-rank test. Results: 56 patients met inclusion criteria. Of these, 21 patients (38%) had Stage I disease and 35 (62%) had Stage II disease. The median OS for the entire study population was 18.7 months. A total of 22 (39%) patients were managed with NAC+S; 34 (61%) received NAC alone. Median OS and 2-year survival rates were greater in those completing NAC+S compared to NAC alone (median OS 28.8 months vs. 17.3 months: p=0.05; 2-year OS: 55% vs 21%: p=0.01) . Interestingly, patients managed with NAC who were not candidates for surgical resection after restaging demonstrated a survival advantage (17.3 months) compared to what was previously reported in historical controls. Conclusion: NAC+S provided a significant 11.5 month improvement in median OS compared to treatment with NAC alone. Modern NAC may contribute a significant oncologic benefit in the overall treatment strategy for patients with Stage I/II PDAC, even if surgery is not ultimately pursued.

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BACKGROUND. The cytologic differentiation between neoplastic and reactive/reparative processes in the endoscopic ultrasound-guided fine-needle aspirations (EUS-FNA) of the pancreas can be difficult. Malignant transformation of the pancreatic ductal epithelium changes the expression of apomucins. The goal of the current study was to determine an optimal immunohistochemical panel of mucin (MUC) antibodies that would allow the cytomorphologic distinction of pancreatic ductal adenocarcinoma and its differentiation from reactive/reparative processes and inadvertently sampled gastric and duodenal mucosa. METHODS. Pancreatic EUS-FNA specimens performed on 351 patients were reviewed. Expression profiles of MUC1, 2, 5AC, and 6 were examined on 56 cell block sections and 26 follow-up pancreatectomy specimens. RESULTS. MUC1 and 6 expression was found in nonneoplastic pancreatic samples, whereas there was an absence of expression of MUC2 and 5AC. MUC2 was detected in mucosal goblets cells of the duodenum, MUC6 in Brunner glands, and MUC5AC in gastric foveolar cells. MUC5AC expression in differentiating ductal adenocarcinomas from benign conditions demonstrated better operating characteristics than either MUC1 or MUC6. The apomucin expression pattern both in cytology and follow-up surgical pathology specimens was similar. In surgical pathology specimens, the panel of 3 antibodies, MUC1+/MUC2-/MUC5AC+, was noted in 15 of 17 ductal carcinomas (88.2%). In nonneoplastic pancreatic tissue, the expression panel MUC1+/MUC2-/MUC5AC- was observed in 14 of 17 (82.4%) cases. In cytology specimens, the combination of MUC1+/MUC2-/MUC5AC+ was noted in 21 of 30 ductal carcinoma cases (70.0%), 3 of 6 atypical cases (50%), and 1 of 1 suspicious for malignancy cases (100%). The combination MUC1+/MUC2-/MUC5AC+ was not observed in any of the negative for malignancy or reactive cases (0 of 6). CONCLUSIONS. The most optimal panel for the diagnosis of ductal adenocarcinoma in both the EUS-FNA specimens is a panel including MUC1/MUC2/MUC5AC, whereas a panel of all 4 antibodies (MUC1, 2, 5AC, and 6) will in addition aid in differentiating inadvertently sampled normal/reactive duodenal and gastric epithelium from neoplastic pancreatic tissue.

Indiana University-Purdue University Indianapolis (IUPUI) / Pancreatic ductal adenocarcinoma (PDAC) is an extremely deadly disease characterized by aggressive metastasis and therapeutic resistance. Reactive stroma in pancreatic tumors contributes to tumor signaling, fibrosis, inflammation, and hypoxia. Hypoxia signaling creates a more aggressive phenotype with increased potential for metastasis and decreased therapeutic efficacy. Carbonic anhydrase IX (CA9) functions as part of the cellular response to hypoxia by regulating intracellular pH to promote cell survival. Apurinic/Apyrimidinic Endonuclease-1-Reduction/oxidation Effector Factor 1 (APE1/Ref-1) is a multi-functional protein with two major activities: endonuclease activity in DNA base excision repair and a redox signaling activity that reduces oxidized transcription factors, enabling them to bind target sequences in DNA. APE1/Ref-1 is a central node in redox signaling, contributing to the activation of transcription factors involved in tumor survival, growth, and hypoxia signaling. This work evaluates the mechanisms underlying PDAC cell responses to hypoxia and APE1/Ref-1 redox signaling control of hypoxia inducible factor 1 alpha (HIF1a), a critical factor in hypoxia-induced CA9 transcription. We hypothesized that obstructing the HIF-CA9 axis at two points via APE1/Ref-1 inhibition and CA9 inhibition results in enhanced PDAC cell killing under hypoxic conditions. We found that HIF1a-mediated induction of CA9 is significantly attenuated following APE1/Ref-1 knock-down or redox signaling inhibition in patient-derived PDAC cells and pancreatic cancer-associated fibroblast cells. Additionally, dual-targeting of APE1/Ref-1 redox signaling activity and CA9 activity results in enhanced acidification and cytotoxicity of PDAC cells under hypoxic conditions as well as decreased tumor growth in an ex-vivo 3-dimensional tumor co-culture model. Further experiments characterized novel analogs of clinically relevant drugs targeting the key enzymes in this pathway, resulting in improved potency. These results underscore the notion that combination therapy is essential and demonstrate the potential clinical utility of blocking APE1/Ref-1 and CA9 function for novel PDAC therapeutic treatment.

Pancreatic ductal adenocarcinoma (PDAC) is a highly fatal cancer, accounting for 3.2% of new cancer cases yearly but nearly 8% of all yearly cancer mortalities. Over the past twenty years, our understanding of cancer biology has greatly improved which has resulted in vastly improved prognoses for many cancers. However, the prognosis of pancreatic ductal adenocarcinoma has not improved despite the advance in cancer treatments. This is especially apparent with cancer immunotherapies, a newer therapeutic strategy that utilizes the innate defense mechanism of the body to target malignancies. Immune checkpoint inhibitors are a type of cancer immunotherapy that act by inhibiting the PD-1/PD-L1 and CTLA-4 immune checkpoint pathways and allowing T lymphocytes to proliferate and generate an antitumor response. They have greatly improved the prognosis for many types of malignancies, but clinical studies show that immune checkpoint inhibition has had a limited effect on the prognosis of PDAC. Recent studies have demonstrated that the immune microenvironment of PDAC is highly immunosuppressive, which is a probable factor in limiting the therapeutic efficacy of immune checkpoint inhibitors. Myeloid derived suppressor cells (MDSCs) are a main component of the immune microenvironment in PDAC. They are immature cells of myeloid origin that express CD11b+Gr-1+ on their surface, making them phenotypically distinct from mature dendritic cells. Their infiltration of the PDAC microenvironment early on in the course of the disease is promoted in a large part by the cytokine GM-CSF. MDSCs are believed to contribute to the limited efficacy of immune checkpoint inhibitor therapy both directly and indirectly. Indirect mechanisms are mediated by promoting the activity of other immunosuppressive cells in the PDAC microenvironment such as tumor associated macrophages and regulatory T lymphocytes. MDSCs induce the transformation of naïve CD4+ T lymphocytes into protumorigenic regulatory T lymphocytes. They also promote the polarization of macrophages to the tumor associated macrophage phenotype (IL-10high IL-12low) by secreting IL-10, which decreases IL-12 synthesis by macrophages present in the tumor microenvironment. On top of mediating immunosuppression through other cell types, MDSCs directly mediate immunosuppression by decreasing the amounts of amino acids necessary for anti-tumor immunity in the tumor microenvironment and disrupting the activity of antigen presenting cells and the signaling needed to initiate a cytotoxic T lymphocyte response. The decreased amount of arginine limits the ability of T cells to proliferate, resulting in a weaker cytotoxic response. These mechanisms limit the antitumor response against pancreatic ductal adenocarcinoma, resulting in the decreased response to immune checkpoint inhibitor therapy observed in clinical trials. Future attempts to strengthen the anti-tumor immune response must be combinatorial therapies that incorporate therapeutic strategies that seek to alleviate MDSC-mediated immunosuppression of T lymphocytes from the tumor microenvironment in addition to the more widely available immune checkpoint inhibitor therapy. Such therapeutics are currently being studied in murine models and have shown promising preliminary results but have yet to have been examined in clinical trials. These therapies are an ideal avenue to explore in a search for more effective therapy for this highly lethal disease.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18128号 / 医博第3848号 / 新制||医||1001(附属図書館) / 30986 / 京都大学大学院医学研究科医学専攻 / (主査)教授 福山 秀直, 教授 戸井 雅和, 教授 平岡 眞寛 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DGAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19567号 / 医博第4074号 / 新制||医||1013(附属図書館) / 32603 / 京都大学大学院医学研究科医学専攻 / (主査)教授 武田 俊一, 教授 小川 誠司, 教授 野田 亮 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21420号 / 医博第4410号 / 京都大学大学院医学研究科医学専攻 / (主査)教授 羽賀 博典, 教授 武田 俊一, 教授 坂井 義治 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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