Inhibition of focal adhesion kinase enhances antitumor response of radiation therapy in pancreatic cancer through CD8+ T cells

Objective:Pancreatic ductal adenocarcinoma(PDAC)is a deadly malignancy,due in large part to its resistance to conventional therapies,including radiotherapy(RT).Despite RT exerting a modest antitumor response,it has also been shown to promote an immunosuppressive tumor microenvironment.Previous studies demonstrated that focal adhesion kinase inhibitors(FAKi)in clinical development inhibit the infiltration of suppressive myeloid cells and T regulatory(T regs)cells,and subsequently enhance effector T cell infiltration.FAK inhibitors in clinical development have not been investigated in combination with RT in preclinical murine models or clinical studies.Thus,we investigated the impact of FAK inhibition on RT,its potential as an RT sensitizer and immunomodulator in a murine model of PDAC.Methods:We used a syngeneic orthotopic murine model to study the effect of FAKi on hypofractionated RT.Results:In this study we showed that IN10018,a small molecular FAKi,enhanced antitumor response to RT.Antitumor activity of the combination of FAKi and RT is T cell dependent.FAKi in combination with RT enhanced CD8+T cell infiltration significantly in comparison to the radiation or FAKi treatment alone(P<0.05).FAKi in combination with radiation inhibited the infiltration of granulocytes but enhanced the infiltration of macrophages and T regs in comparison with the radiation or FAKi treatment alone(P<0.01).Conclusions:These results support the clinical development of FAKi as a radiosensitizer for PDAC and combining FAKi with RT to prime the tumor microenvironment of PDAC for immunotherapy.

Pancreatic cancer surgery: past, present, and future

The history of pancreatic cancer surgery, though fraught with failure and setbacks, is punctuated by periods of incremental progress dependent upon the state of the art and the mettle of the surgeons daring enough to attempt it. Surgical anesthesia and the aseptic techniques developed during the latter half of the 19 th century were instrumental in establishing a viable setting for pancreatic surgery to develop. Together, they allowed for bolder interventions and improved survival through the postoperative period. Surgical management began with palliative procedures to address biliary obstruction in advanced disease. By the turn of the century, surgical pioneers such as Alessandro Codivilla and Walther Kausch were demonstrating the technical feasibility of pancreatic head resections and applying principles learned from palliation to perform complicated anatomical reconstructions. Allen O. Whipple, the namesake of the pancreaticoduodenectomy（PD）, was the first to take a systematic approach to refining the procedure. Perhaps his greatest contribution was sparking a renewed interest in the surgical management of periampullary cancers and engendering a community of surgeons who advanced the field through their collective efforts. Though the work of Whipple and his contemporaries legitimized PD as an accepted surgical option, it was the establishment of high-volume centers of excellence and a multidisciplinary approach in the later decades of the 20^th century that made it a viable surgical option. Today, pancreatic surgeons are experimenting with minimally invasive surgical techniques, expanding indications for resection, and investigating new methods for screening and early detection. In the future, the effective management of pancreatic cancer will depend upon our ability to reliably detect the earliest cancers and precursor lesions to allow for truly curative resections.

International expert consensus on laparoscopic pancreaticoduodenectomy

Importance:While laparoscopic pancreaticoduodenectomy(LPD)is being adopted with increasing enthusiasm worldwide,it is still challenging for both technical and anatomical reasons.Currently,there is no consensus on the technical standards for LPD.Objective:The aim of this consensus statement is to guide the continued safe progression and adoption of LPD.Evidence Review:An international panel of experts was selected based on their clinical and scientific expertise in laparoscopic and open pancreaticoduodenectomy.Statements were produced upon reviewing the literature and assessed by the members of the expert panel.The literature search and its critical appraisal were limited to articles published in English during the period from 1994 to 2019.The Web of Science,Medline,and Cochrane Library and Clinical Trials databases were searched,The search strategy included,but was not limited to,the terms'laparoscopic','pancreaticoduodenectomy,'pancreatoduodenectomy','Whipple's operation',and'minimally invasive surgery'.Reference lists from the included articles were manually checked for any additional studies,which were included when appropriate.Delphi method was used to establish expert consensus and the AGREE II-GRS Instrument was applied to assess the methodological quality and externally validate the final statements.The statements were further discussed during a one-day face-to-face meeting at the 1st Summit on Minimally Invasive Pancreatico-Biliary Surgery in Wuhan,China.Findings:Twenty-eight international experts from 8 countries constructed the expert panel.Sixteen statements were produced by the members of the expert panel.At least 80%of responders agreed with the majority(80%)of statements.Other than three randomized controlled trials published to date,most evidences were based on level 3 or 4 studies according to the AGREE II-GRS Instrument.Conclusions and Relevance:The Wuhan international expert consensus meeting on LPD has produced a set of clinical practice statements for the safe development and progression of LPD.LPD is currently in its development and exploration stages,as defined by the international IDEAL framework for surgical innovation.More robust randomized controlled trial and registry study are essential to proceed with the assessment of LPD.

Impact and clinical usefulness of genetic data in the surgical management of colorectal cancer liver metastasis: a narrative review

Importance:In patients who undergo surgery for colorectal cancer liver metastases(CRLM),a number of somatic mutations have been associated with worse overall(OS)and recurrence-free survival(RFS).Although useful,an association with prognosis does not necessarily equate to an impact on surgical management.Objective:The aim of this review was to investigate whether the best-studied somatic mutations impact surgical management of CRLM by informing:(I)post-hepatectomy surveillance;(II)selection of surgical technique;(III)selection of optimal margin width;and(IV)selection of patients for surgery.Lastly,we discuss the refinement of genetic data from overall mutation status to specific variants,as well as lesser studied somatic mutations.Evidence Review:We conducted a computerized search using PubMed and Google Scholar for reports published so far,using mesh headings and keywords related to genetic data and CRLM.Findings:Genetic data may impact surgical management of CRLM in three ways.Firstly,KRAS mutations can predict lung recurrences.Secondly,KRAS mutations may help tailor margin width.Thirdly,KRAS mutations may help tailor surgical technique.Conclusions:Although genetic data may impact post-hepatectomy surveillance,selection of surgical technique and optimal margin width,their use to guide surgical selection remains elusive,as the data cannot support denying surgery to patients according to their somatic mutation profile.

Lessons learned from hepatocellular carcinoma may cause a paradigm shift in intraductal papillary mucinous neoplasms:a narrative review and discussion of conceptual similarities in tumor progression and recurrence

Although the natural history of recurrence/progression in patients with intraductal papillary mucinous neoplasms (IPMN) of the pancreas has not been studied thoroughly, the three principal mechanisms have been identified: (a) presence of residual disease at the transection margin, (b) presence of intraductal/intraparenchymal metastases and (c) development of new primary lesions. Mechanisms (a) and (b) result in metastatic lesions that are genetically related to the primary, while new primary lesions (mechanism c) are genetically distinct. Interestingly, recurrence/progression in IPMN displays conceptual parallels with the well-established paradigm of disease recurrence in patients with hepatocellular carcinoma (HCC). Specifically, patients with HCC may also develop recurrent tumors due to microscopic residual disease/intrahepatic metastasis which are genetically similar to the primary while the development of genetically unrelated, de novo HCC after curative-intent resection is also common. The latter has been attributed to the presence of a widespread genetic abnormality ( "field defect" ) in the liver (ie, cirrhosis). Given the conceptual similarities between IPMN and HCC, a pancreatic "field defect" may also be hypothesized to exist. This review does not suggest that HCC and IPMN have identical pathogeneses, but rather that they have conceptual similarities in tumor recurrence/progression;thus, lessons learned from HCC could be applied to IPMN research and subsequent management. Conceptual similarities in tumor progression and recurrence may also be observed between IPMN and other malignancies. However, HCC was selected because it is well studied and can serve as a paradigm.

Clinicopathological features and surgical outcomes of resected functional pancreatic neuroendocrine tumors: a single institution experience

Background:Functional pancreatic neuroendocrine tumors(f-PanNETs)are rare tumors of the pancreas that are associated with excess hormone production.A majority of literature available on these tumors is limited to case reports and small series and discusses a particular subtype.Here,we report the clinicopathological features and outcomes of all f-PanNETs from a high-volume pancreatectomy center.Methods:A prospectively maintained database was used to identify patients who underwent resection for f-PanNETs between January 1995 and December 2015.Patients were stratified by the type of f-PanNET,and their clinicopathological features and outcomes were analyzed and reported.Results:We identified 69 patients with a mean age of 52±16 years,and the majority were female(62%).The most common type of f-PanNET were insulinomas(70%)followed by gastrinomas(15%),and vasoactive intestinal peptidomas(VIPomas)(10%).There was considerable heterogeneity in the presenting symptoms.Patients with insulinomas presented with smaller tumors compared to the other subtypes.Nodal disease was most frequent in patients with VIPomas(71%),and gastrinomas(50%).The median overall survival(OS)was 7.4 years.Elevated Ki-67 and age>65 years were associated with poorer OS.Recurrence was observed in 8 patients(12%)and was most frequent in patients with VIPomas.Recurrence was associated with a poorer OS(P=.012).Conclusion:f-PanNETs are exceedingly rare and present with a wide variety of symptoms,histopathological findings,and outcomes.Surgical resection can help achieve good long-term survival.