Publications by authors named "Richard A Burkhart"

69 Publications

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

Cancer Biol Med 2021 Feb;18(1):206-214

The Sydney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore 21287, MD, USA.

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 ( < 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 ( < 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.
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http://dx.doi.org/10.20892/j.issn.2095-3941.2020.0273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877172PMC
February 2021

Guidelines on management of pancreatic cysts detected in high-risk individuals: An evaluation of the 2017 Fukuoka guidelines and the 2020 International Cancer of the Pancreas Screening (CAPS) consortium statements.

Pancreatology 2021 Feb 2. Epub 2021 Feb 2.

Department of Medicine, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD, USA. Electronic address:

Background: Objectives: Pancreatic cysts are frequently detected in high-risk individuals (HRI) undergoing surveillance for pancreatic cancer. The International Cancer of the Pancreas Screening (CAPS) Consortium developed consensus recommendations for surgical resection of pancreatic cysts in HRI that are similar to the Fukuoka guidelines used for the management of sporadic cysts. We compared the performance characteristics of CAPS criteria for pancreatic cyst management in HRI with the Fukuoka guidelines originally designed for the management of cysts in non-HRI.

Methods: Using prospectively collected data from CAPS studies, we determined for each patient with resected screen-detected cyst(s) whether Fukuoka guidelines or CAPS consensus statements would have recommended surgery. We compared sensitivity, specificity, PPV, NPV, and Receiver Operator Characteristics (ROC) curves of these guidelines at predicting the presence of high-grade dysplasia or invasive cancer in pancreatic cysts.

Results: 356/732 HRI had ≥ one pancreatic cyst detected; 24 had surgery for concerning cystic lesions. The sensitivity, specificity, PPV, and NPV for the Fukuoka criteria were 40%, 85%, 40%, and 85%, while those of the CAPS criteria were 60%, 85%, 50%, 89%, respectively. ROC curve analyses showed no significant difference between the Fukuoka and CAPS criteria.

Conclusions: In HRI, the CAPS and Fukuoka criteria are moderately specific, but not sufficiently sensitive for detecting advanced neoplasia in cystic lesions. New approaches are needed to guide the surgical management of cystic lesions in HRI.
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http://dx.doi.org/10.1016/j.pan.2021.01.017DOI Listing
February 2021

Impact of Margin Status on Survival in Patients with Pancreatic Ductal Adenocarcinoma Receiving Neoadjuvant Chemotherapy.

J Am Coll Surg 2020 Dec 16. Epub 2020 Dec 16.

Division of Hepatobiliary and Pancreatic Surgery, Johns Hopkins University School of Medicine, Baltimore, MD. Electronic address:

Background: Historically, a positive margin after pancreatectomy for pancreatic ductal adenocarcinoma (PDAC) was associated with decreased survival. In an era when neoadjuvant chemotherapy (NAC) is being used frequently, the prognostic significance of margin status is unclear.

Study Design: Patients with localized PDAC who received NAC and underwent pancreatectomy from 2011 to 2018 were identified from a single-institution database. Patients with fewer than 2 months of NAC, R2 resection, or fewer than 90 days of follow-up were excluded. A positive margin included tumors within 1 mm of the surgical margin.

Results: Four hundred and sixty-eight patients met inclusion criteria. Median age was 65 years and 53% were female. Preoperative clinical staging demonstrated that most had locally advanced (n = 222 [47%]) or borderline resectable (n = 172 [37%]) disease. Median follow-up was 18.5 months (interquartile range 10.6 to 30.0 months). Median duration of NAC was 119 days (interquartile range 87 to 168 days). FOLFIRINOX was first-line therapy for 67%, and 73% received neoadjuvant radiotherapy. Most underwent pancreaticoduodenectomy (69%). Forty percent were node-positive and 80% had an R0 resection. Fifty-six percent received at least 1 cycle of adjuvant therapy. Median overall survival and recurrence-free survival were 22.0 months (95% CI, 19.4 to 25.1 months) and 11.0 months (95% CI, 10.0 to 12.1 months). On multivariate analysis, margin status was not a significant predictor of overall survival or recurrence-free survival. Factors associated with overall survival included clinical stage, duration of NAC, nodal status, histopathologic treatment response score, and receipt of adjuvant chemotherapy.

Conclusions: Microscopic margin positivity is not associated with recurrence and survival in localized PDAC patients resected after treatment with NAC. Aggressive surgical extirpation in high-volume centers should be considered in selected patients after extensive NAC.
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http://dx.doi.org/10.1016/j.jamcollsurg.2020.11.018DOI Listing
December 2020

The Impact of Clinical and Pathological Features on Intraductal Papillary Mucinous Neoplasm Recurrence After Surgical Resection: Long-Term Follow-Up Analysis.

Ann Surg 2020 Nov 17. Epub 2020 Nov 17.

Department of Surgery, Hepatobiliary and Pancreatic Surgery Section of the Division of Surgical Oncology, Johns Hopkins Hospital, Baltimore, MD.

Objective: This study aimed to identify risk factors for recurrence after pancreatic resection for intraductal papillary mucinous neoplasm (IPMN).

Summary Background Data: Long-term follow-up data on recurrence after surgical resection for IPMN are currently lacking. Previous studies have presented mixed results on the role of margin status in risk of recurrence after surgical resection.

Methods: A total of 126 patients that underwent resection for noninvasive IPMN were followed for a median of 9.5 years. Dedicated pathological and radiological reviews were performed to correlate clinical and pathological features (including detailed pathological features of the parenchymal margin) with recurrence after surgical resection. In addition, in a subset of 32 patients with positive margins, we determined the relationship between the margin and original IPMN using driver gene mutations identified by next-generation sequencing.

Results: Family history of pancreatic cancer and high-grade IPMN was identified as risk factors for recurrence in both uni- and multivariate analysis (adjusted hazard ratio 3.05 and 1.88, respectively). Although positive margin was not significantly associated with recurrence in our cohort, the size and grade of the dysplastic focus at the margin were significantly correlated with recurrence in margin-positive patients. Genetic analyses showed that the neoplastic epithelium at the margin was independent from the original IPMN in at least 9 of 32 cases (28%). The majority of recurrences (74%) occurred after 3 years, and a significant minority (32%) occurred after 5 years.

Conclusion: Sustained postoperative surveillance for all patients is indicated, particularly those with risk factors such has family history and high-grade dysplasia.
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http://dx.doi.org/10.1097/SLA.0000000000004427DOI Listing
November 2020

Perioperative Outcomes of Robotic Pancreaticoduodenectomy: a Propensity-Matched Analysis to Open and Laparoscopic Pancreaticoduodenectomy.

J Gastrointest Surg 2020 Nov 17. Epub 2020 Nov 17.

Department of Surgery, The Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Halsted 614, Baltimore, MD, 21287, USA.

Introduction: Robotic pancreaticoduodenectomy is slowly gaining acceptance within pancreatic surgery. Advantages have been demonstrated for robotic surgery in other fields, but robust data for pancreaticoduodenectomy is limited. The aim of this study was to compare the short-term outcomes of robotic pancreaticoduodenectomy (RPD) to open pancreaticoduodenectomy (OPD) and laparoscopic pancreaticoduodenectomy (LPD).

Methods: Patients who underwent a pancreaticoduodenectomy between January 2011 and July 2019 at the Johns Hopkins Hospital were included in this retrospective propensity-matched analysis. The RPD cohort was matched to patients who underwent OPD in a 1:2 fashion and LPD in a 1:1 fashion. Short-term outcomes were analyzed for all three cohorts.

Results: In total, 1644 patients were included, of which 96 (5.8%) underwent RPD, 131 (8.0%) LPD, and 1417 (86.2%) OPD. RPD was associated with a decreased incidence of delayed gastric emptying (9.4%) compared to OPD (23.5%; P = 0.006). The median estimated blood loss was significantly less in the RPD cohort (RPD vs OPD, 150 vs 487 mL; P < 0.001, RPD vs LPD, 125 vs 300 mL; P < 0.001). Compared to OPD, the robotic approach was associated with a shorter median length of stay (median 8 vs 9 days; P = 0.014) and a decrease in wound complications (4.2% vs 16.7%; P = 0.002). The incidence of other postoperative complications was comparable between RPD and OPD, and RPD and LPD.

Conclusion: In the hands of experienced surgeons, RPD may have a modest yet statistically significant reduction in estimated blood loss, postoperative length of stay, wound complications, and delayed gastric emptying comparing to OPD in similar patients.
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http://dx.doi.org/10.1007/s11605-020-04869-zDOI Listing
November 2020

Challenges of the current precision medicine approach for pancreatic cancer: A single institution experience between 2013 and 2017.

Cancer Lett 2021 Jan 28;497:221-228. Epub 2020 Oct 28.

The Pancreatic Cancer "Precision Medicine" Program, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA. Electronic address:

Recent research on genomic profiling of pancreatic ductal adenocarcinoma (PDAC) has identified many potentially actionable alterations. However, the feasibility of using genomic profiling to guide routine clinical decision making for PDAC patients remains unclear. We retrospectively reviewed PDAC patients between October 2013 and December 2017, who underwent treatment at the Johns Hopkins Hospital and had clinical tumor next-generation sequencing (NGS) through commercial resources. Ninety-two patients with 93 tumors tested were included. Forty-eight (52%) patients had potentially curative surgeries. The median time from the tissue available to the NGS testing ordered was 229 days (interquartile range 62-415). A total of three (3%) patients had matched targeted therapies based on genomic profiling results. Genomic profiling guided personalized treatment for PDAC patients is feasible, but the percentage of patients who receive targeted therapy is low. The main challenges are ordering NGS testing early in the clinical course of the disease and the limited evidence of using a targeted approach in these patients. A real-time department level genomic testing ordering system in combination with an evidence-based flagging system for potentially actionable alterations could help address these shortcomings.
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http://dx.doi.org/10.1016/j.canlet.2020.10.039DOI Listing
January 2021

Duodenal, ampullary, and pancreatic neuroendocrine tumors: Oncologic outcomes are driven by tumor biology and tissue of origin.

J Surg Oncol 2021 Feb 30;123(2):416-424. Epub 2020 Oct 30.

The Division of Hepatobiliary and Pancreatic Surgery, Johns Hopkins Hospital, Baltimore, Maryland, USA.

Background: Periampullary neuroendocrine tumors (NETs) arise from the duodenum, ampulla, and periampullary pancreas. Duodenal and ampullary NETs are rare and may have distinct biologic behavior from pancreatic NETs (P-NETs). We examined the outcomes of these entities.

Methods: An institutional database was queried for patients undergoing resection for pancreatic head, duodenal, or ampullary NETs from 2000 to 2018. Patients with MEN1 syndrome or follow up less than 12 months were excluded.

Results: Three hundred and ten patients were identified. Tumor locations were ampulla (n = 15), duodenum (n = 35) and pancreas (n = 260). Median follow-up and recurrence-free survival (RFS) were 60.9 (interquartile range [IQR]: 34.8-99.3) and 171.7 (IQR: 84.0-NR) months. Clinicopathologic data and survival outcomes were similar for duodenal and ampullary NETs (RFS: p = .347 and overall survival [OS]: p = .246) and were combined into an intestinal subtype (IS) group. There were no differences in OS or RFS when comparing IS-NET and P-NET. On multivariate analysis, tissue of origin was not associated with risk of recurrence. The current American Joint Committee on Cancer staging guidelines, which account for origin tissue, were predictive of outcomes for all subtypes.

Conclusion: Tissue of origin does not appear to impact long-term outcomes when comparing IS-NETs and P-NETs. The AJCC staging system offers good discriminatory capacity in the context of the tissue type.
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http://dx.doi.org/10.1002/jso.26285DOI Listing
February 2021

An Aggressive Approach to Locally Confined Pancreatic Cancer: Defining Surgical and Oncologic Outcomes Unique to Pancreatectomy with Celiac Axis Resection (DP-CAR).

Ann Surg Oncol 2020 Oct 13. Epub 2020 Oct 13.

The Division of Hepatobiliary and Pancreatic Surgery, Johns Hopkins Hospital, Baltimore, MD, USA.

Background: Modern chemotherapeutics have led to improved systemic disease control for patients with locally advanced pancreatic cancer (LAPC). Surgical strategies such as distal pancreatectomy with celiac axis resection (DP-CAR) are increasingly entertained. Herein we review procedure-specific outcomes and assess biologic rationale for DP-CAR.

Methods: A prospectively maintained single-institution database of all pancreatectomies was queried for patients undergoing DP-CAR. We excluded all patients for whom complete data were not available and those who were not treated with contemporary multi-agent therapy. Data were supplemented with dedicated chart review and outreach for long-term oncologic outcomes.

Results: Fifty-four patients underwent DP-CAR between 2008 and 2018. The median age was 62.7 years. Ninety-eight percent received induction chemotherapy. Arterial reconstruction was performed in 17% and concomitant visceral resection in 30%. The R0 resection rate was 87%. Postoperative complications were common (43%) with chyle leak being the most frequent (17%). Length of stay was 8 days, readmission occurred in one-third, and 90-day mortality was 2%. Disease recurrence occurred in 74% during a median follow up of 17.4 months. Median recurrence-free (RFS) and overall survival (OS) were 9 and 25 months, respectively.

Conclusions: Following modern induction paradigms, DP-CAR can be performed with low mortality, manageable morbidity, and excellent rates of margin-negative resection in high-volume settings. The profile of complications of DP-CAR is distinct from pancreaticoduodenectomy and simple distal pancreatectomy. OS and RFS are similar to those undergoing resection of borderline resectable and resectable disease. Improved systemic disease control will likely lead to increasing utilization of aggressive surgical approaches to LAPC.
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http://dx.doi.org/10.1245/s10434-020-09201-2DOI Listing
October 2020

Periadventitial dissection of the superior mesenteric artery for locally advanced pancreatic cancer: Surgical planning with the "halo sign" and "string sign".

Surgery 2020 Oct 6. Epub 2020 Oct 6.

Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD. Electronic address:

Most patients diagnosed with pancreatic cancer are classified as nonoperative candidates based on the contemporary guidelines of resectability. The advent of more potent control of systemic disease using neoadjuvant chemotherapy has enabled more aggressive operative interventions. In our multidisciplinary practice, patients with Stage III, locally advanced pancreatic cancer and superior mesenteric artery (SMA) encasement are now carefully triaged with high quality, preoperative imaging to determine if they can be considered candidates for operative resection with periadventitial dissection of the SMA. Patients displaying a "halo sign," where the encased SMA remains fully patent and free from arterial invasion, are now candidates for SMA periadventitial dissection. This procedure involves the surgical stripping of the infiltrated neurolymphatic tissue off the SMA leaving behind a bare "skeletonized artery." Alternatively, the "string sign" involving the SMA confers a more likely case of arterial invasion, where a complete oncologic resection cannot be achieved successfully. This method of patient selection in case of SMA involvement abandons the traditional metrics of circumferential degrees of the arterial encasement to guide surgical decisions. Our institutional approach has allowed us to meaningfully expand our operative methods of resection with the potential for improved longitudinal outcomes to pancreatic cancer patients who were deprived historically from the more effective and possibly curative treatment.
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http://dx.doi.org/10.1016/j.surg.2020.08.031DOI Listing
October 2020

Mesoportal bypass, interposition graft, and mesocaval shunt: Surgical strategies to overcome superior mesenteric vein involvement in pancreatic cancer.

Surgery 2020 12 17;168(6):1048-1055. Epub 2020 Sep 17.

Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD. Electronic address:

Background: In pancreatic cancer, extensive tumor involvement of the mesenteric venous system poses formidable challenges to operative resection. Such involvement can result from cavernous collateral veins leading to increased intraoperative blood loss or long-segment vascular defects of not only just the superior mesenteric vein but also even jejunal/ileal branches. Strategies to facilitate margin-free resection and safe vascular reconstruction in pancreatic surgery are important, particularly because systemic control of the tumor is improving with multi-agent chemotherapy regimens.

Methods: We describe a systematic, multidisciplinary assessment for patients with pancreatic cancer that involves the superior mesenteric vein, as well as the preoperative planning of those undergoing operative resection. In addition, detailed descriptions of operative approaches and technical strategies, which evolved with increasing experience at a high-volume center, are presented.

Results: For the preoperative evaluation of tumor-free, vascular locations for potential reconstruction and collateralization, computed tomographic imaging with high-resolution of vascular structures (used with 3-dimensional or cinematic rendering) allows a precise calibration of radiographic data with intraoperative findings. From an operative perspective, we identified 5 potential strategies to consider for resection: collateral preservation, mesoportal bypass (preresection), mesoportal interposition graft (postresection), mesocaval shunt, and various combinations of these strategies. Many of these techniques use interposition grafts, making it essential to assess autologous veins (preferred conduit for reconstruction) or to prepare cryopreserved vascular allografts (an alternative conduit, which must be thawed and should be matched for size and blood type).

Conclusion: Herein we share operative strategies to overcome involvement of the superior mesenteric vein in pancreatic cancer. Improvements in preoperative planning and operative technique can address common barriers to resection with curative intent.
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http://dx.doi.org/10.1016/j.surg.2020.07.054DOI Listing
December 2020

Minimal main pancreatic duct dilatation in small branch duct intraductal papillary mucinous neoplasms associated with high-grade dysplasia or invasive carcinoma.

HPB (Oxford) 2020 Sep 7. Epub 2020 Sep 7.

Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address:

Background: The aim of this study was to determine the incidence of high-grade dysplasia (HGD) or invasive carcinoma in patients with small branch duct intraductal papillary mucinous neoplasms (BD-IPMNs).

Methods: 923 patients who underwent surgical resection for an IPMN were identified. Sendai-negative patients were identified as those without history of pancreatitis or jaundice, main pancreatic duct size (MPD) <5 mm, cyst size <3 cm, no mural nodules, negative cyst fluid cytology for adenocarcinoma, or serum carbohydrate antigen 19-9 (CA 19-9) <37 U/L.

Results: BD-IPMN was identified in 388 (46.4%) patients and 89 (22.9%) were categorized as Sendai-negative. Overall, 68 (17.5%) of BD-IPMN had HGD and 62 (16.0%) had an associated invasive-carcinoma. Among the 89 Sendai-negative patients, 12 (13.5%) had IPMNs with HGD and only one patient (1.1%) had invasive-carcinoma. Of note, older age (OR 1.13, 95% CI 1.03-1.23; P = 0.008) and minimal dilation of MPD (OR 11.3, 95% CI 2.40-53.65; P = 0.002) were associated with high-risk disease in Sendai-negative patients after multivariable risk adjustment.

Conclusion: The risk of harboring a high-risk disease remains low in small BD-IPMNs. However, Sendai-negative patients who are older than 65 years old and those with minimal dilation of MPD (3-5 mm) are at greater risk of high-risk lesions and should be given consideration to be included as a "worrisome feature" in a future guidelines update.
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http://dx.doi.org/10.1016/j.hpb.2020.08.004DOI Listing
September 2020

Defining a minimum number of examined lymph nodes improves the prognostic value of lymphadenectomy in pancreas ductal adenocarcinoma.

HPB (Oxford) 2020 Sep 5. Epub 2020 Sep 5.

Division of Hepatobiliary and Pancreatic Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address:

Background: Lymph node (LN) metastasis is associated with decreased survival following resection for pancreatic ductal adenocarcinoma (PDAC). In N0 disease, increasing total evaluated LN (ELN) correlates with improved outcomes suggesting patients may be understaged when LNs are undersampled. We aim to assess the optimal number of examined lymph nodes (ELN) following pancreatectomy.

Methods: Data from 1837 patients undergoing surgery were prospectively collected. The binomial probability law was utilized to analyze the minimum number of examined LNs (minELN) and accurately characterize each histopathologic stage. LN ratio (LNR) was compared to American Joint Committee on Cancer (AJCC) guidelines.

Results: As ELN total increased, the likelihood of finding node positive disease increased. An evaluation based upon the binomial probability law suggested an optimal minELN of 12 for accurate AJCC N staging. As the number of ELNs increased, the discriminatory capacity of alternative strategies to characterize LN disease exceeded that offered by AJCC N stage.

Conclusion: This is the first study dedicated to optimizing histopathologic staging in PDAC using models of minELN informed by the binomial probability law. This study highlights two separate cutoffs for ELNs depending upon prognostic goal and validates that 12 LNs are adequate to determine AJCC N stage for the majority of patients.
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http://dx.doi.org/10.1016/j.hpb.2020.08.016DOI Listing
September 2020

Blood utilization and clinical outcomes in pancreatic surgery before and after implementation of patient blood management.

Transfusion 2020 Nov 8;60(11):2581-2590. Epub 2020 Sep 8.

Department of Pathology (Transfusion Medicine), The Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.

Background: Over the past decade, patient blood management (PBM) programs have been developed to reduce allogeneic blood utilization. This is particularly important in pancreatic surgery, which has historically been associated with high transfusion requirements and morbid event rates. This study investigated blood utilization and clinical outcomes in pancreatic surgery before, during, and after the implementation of PBM.

Study Design And Methods: A total of 3482 pancreatic surgery patients were assessed in a 10-year retrospective cohort study (2009-2019) at a single academic center. Baseline patient characteristics, transfusion practices, postoperative morbidity (infectious, thrombotic, ischemic, respiratory, and renal complications), mortality, and length of stay were compared between patients in the pre-PBM (2009-2013), early-PBM (2014-2016), and mature-PBM (2017-2019) time periods. Multivariable analysis assessed the odds for composite morbidity/mortality.

Results: Comparing the mature-PBM to pre-PBM cohorts, transfused units per 100 discharged patients decreased by 53% for erythrocytes (155 to 73; P < .0001), 81% for plasma (79 to 15; P < .038), and 75% for platelets (10 to 2.5; P < .005). Clinical outcomes improved as well, with composite morbid event rates decreasing by more than 50%, from 236 in 1438 patients (16.4%) to 85 in 1145 patients (7.4%) (P < .0001). Mortality and length of stay remained unchanged. Compared to the pre-PBM time period, early-PBM was associated with a risk-adjusted decrease in composite morbidity/mortality (OR 0.73; 95% CI 0.57-0.93; P = .010), while mature-PBM demonstrated a further incremental decrease (OR 0.44; 95% CI 0.33-0.57; P < .0001).

Conclusions: The implementation of PBM was associated with substantially decreased blood utilization in pancreatic surgery, without negatively impacting clinical outcomes.
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http://dx.doi.org/10.1111/trf.16063DOI Listing
November 2020

Pancreatic circulating tumor cell detection by targeted single-cell next-generation sequencing.

Cancer Lett 2020 Nov 5;493:245-253. Epub 2020 Sep 5.

Departments of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; Departments of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; Departments of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address:

Background And Aims: Single-cell next-generation sequencing (scNGS) technology has been widely used in genomic profiling, which relies on whole-genome amplification (WGA). However, WGA introduces errors and is especially less accurate when applied to single nucleotide variant (SNV) analysis. Targeted scNGS for SNV without WGA has not been described. We aimed to develop a method to detect circulating tumor cells (CTCs) with DNA SNVs.

Methods: We tested this targeted scNGS method with three driver mutant genes (KRAS/TP53/SMAD4) on one pancreatic cancer cell line AsPC-1 and then applied it to patients with metastatic PDAC for the validation.

Results: All single-cell of AsPC-1 and spiked-in AsPC-1 cells in healthy donor blood, which were isolated by the filtration with size or by flow cytometry, were detected by targeted scNGS method. All blood samples from six patients with metastatic PDAC, for the validation of target scNGS method, showed CTCs with SNVs of KRAS/TP53/SMAD4 and the positive confirmation of immunofluorescent stainings with Pan-CK/Vimentin/CD45. Four patients with early stage disease, one patient with benign pancreatic cyst and a healthy control sample all showed concordant results between targeted scNGS and CTC enumeration.

Conclusions: The novel technique of targeted scNGS for SNV analysis, without pre-amplification, is a promising method for identifying and characterizing circulating tumor cells.
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http://dx.doi.org/10.1016/j.canlet.2020.08.043DOI Listing
November 2020

Intraductal Transplantation Models of Human Pancreatic Ductal Adenocarcinoma Reveal Progressive Transition of Molecular Subtypes.

Cancer Discov 2020 Oct 23;10(10):1566-1589. Epub 2020 Jul 23.

Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.

Pancreatic ductal adenocarcinoma (PDAC) is the most lethal common malignancy, with little improvement in patient outcomes over the past decades. Recently, subtypes of pancreatic cancer with different prognoses have been elaborated; however, the inability to model these subtypes has precluded mechanistic investigation of their origins. Here, we present a xenotransplantation model of PDAC in which neoplasms originate from patient-derived organoids injected directly into murine pancreatic ducts. Our model enables distinction of the two main PDAC subtypes: intraepithelial neoplasms from this model progress in an indolent or invasive manner representing the classical or basal-like subtypes of PDAC, respectively. Parameters that influence PDAC subtype specification in this intraductal model include cell plasticity and hyperactivation of the RAS pathway. Finally, through intratumoral dissection and the direct manipulation of gene dosage, we identify a suite of -regulated secreted and membrane-bound proteins that may represent potential candidates for therapeutic intervention in patients with PDAC. SIGNIFICANCE: Accurate modeling of the molecular subtypes of pancreatic cancer is crucial to facilitate the generation of effective therapies. We report the development of an intraductal organoid transplantation model of pancreatic cancer that models the progressive switching of subtypes, and identify stochastic and RAS-driven mechanisms that determine subtype specification...
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http://dx.doi.org/10.1158/2159-8290.CD-20-0133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7664990PMC
October 2020

Association of Germline Variants in Human DNA Damage Repair Genes and Response to Adjuvant Chemotherapy in Resected Pancreatic Ductal Adenocarcinoma.

J Am Coll Surg 2020 Nov 11;231(5):527-535.e14. Epub 2020 Jul 11.

Department of Surgery, Baltimore, MD; The Johns Hopkins University School of Medicine The Pancreatic Cancer Precision Medicine Center of Excellence, Baltimore, MD; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD. Electronic address:

Background: The frequency and significance of the germline variants in DNA damage repair genes still need to be elucidated in patients with sporadic pancreatic ductal adenocarcinoma (PDAC). Our purpose was to determine whether germline variants in DNA damage repair genes were associated with survival of patients with sporadic PDAC.

Study Design: We retrospectively identified 854 patients with sporadic PDAC with germline DNA sequenced in targeted 22 DNA damage repair genes by next-generation sequencing. Outcomes were compared in terms of clinicopathologic features, disease-free survival (DFS), and overall survival (OS).

Results: Nineteen patients had deleterious mutations; 103 had variant(s) of unknown significance (VUS). Germline DNA damage repair deleterious variant carriers had superior DFS (median, 19.1 months vs 11.9 months, p = 0.012) and OS (median, 29.7 months vs 20.2 months, p = 0.034), as compared with wild-type patients. Germline DNA damage repair VUS variant carriers also had superior DFS when compared with wild-type patients. In subgroup analysis, this improved survival was limited to patients receiving adjuvant chemotherapy, deleterious variant carriers vs wild-type patients DFS (median 36.3 months vs 13.1 months, p = 0.006) and OS (median 43.7 months vs 24.3 months, p = 0.045), VUS variant carriers vs wild-type patients DFS (16.5 months vs 13.1 months, p = 0.007).

Conclusions: Having a deleterious variant in a DNA damage repair gene is associated with improved survival after resection and adjuvant chemotherapy for pancreatic ductal adenocarcinoma.
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http://dx.doi.org/10.1016/j.jamcollsurg.2020.06.019DOI Listing
November 2020

Patient-derived Organoid Pharmacotyping is a Clinically Tractable Strategy for Precision Medicine in Pancreatic Cancer.

Ann Surg 2020 09;272(3):427-435

Division of Hepatobiliary and Pancreatic Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Objective: PDAC patients who undergo surgical resection and receive effective chemotherapy have the best chance of long-term survival. Unfortunately, we lack predictive biomarkers to guide optimal systemic treatment. Ex-vivo generation of PDO for pharmacotyping may serve as predictive biomarkers in PDAC. The goal of the current study was to demonstrate the clinical feasibility of a PDO-guided precision medicine framework of care.

Methods: PDO cultures were established from surgical specimens and endoscopic biopsies, expanded in Matrigel, and used for high-throughput drug testing (pharmacotyping). Efficacy of standard-of-care chemotherapeutics was assessed by measuring cell viability after drug exposure.

Results: A framework for rapid pharmacotyping of PDOs was established across a multi-institutional consortium of academic medical centers. Specimens obtained remotely and shipped to a central biorepository maintain viability and allowed generation of PDOs with 77% success. Early cultures maintain the clonal heterogeneity seen in PDAC with similar phenotypes (cystic-solid). Late cultures exhibit a dominant clone with a pharmacotyping profile similar to early passages. The biomass required for accurate pharmacotyping can be minimized by leveraging a high-throughput technology. Twenty-nine cultures were pharmacotyped to derive a population distribution of chemotherapeutic sensitivity at our center. Pharmacotyping rapidly-expanded PDOs was completed in a median of 48 (range 18-102) days.

Conclusions: Rapid development of PDOs from patients undergoing surgery for PDAC is eminently feasible within the perioperative recovery period, enabling the potential for pharmacotyping to guide postoperative adjuvant chemotherapeutic selection. Studies validating PDOs as a promising predictive biomarker are ongoing.
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http://dx.doi.org/10.1097/SLA.0000000000004200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901605PMC
September 2020

Radical antegrade modular pancreatosplenectomy versus standard distal pancreatosplenectomy for pancreatic cancer, a dual-institutional analysis.

Chin Clin Oncol 2020 Aug 16;9(4):54. Epub 2020 Jun 16.

Department of Surgery, Johns Hopkins Hospital, Baltimore, Maryland, USA.

Background: Radical antegrade modular pancreatosplenectomy (RAMPS) has been adopted by some surgeons in the treatment of left-sided pancreatic cancer (PDAC). Low disease incidence and heterogenous disease biology make robust prospective comparison of RAMPS and standard distal pancreatosplenectomy (DPS) difficult.

Methods: Consecutive cases of chemo-naïve patients undergoing open RAMPS and DPS for PDAC between 2010-2017 at two international high-volume pancreatectomy centers were compared. Cox proportional hazard modeling was utilized for multivariate analysis.

Results: We identified 193 DPS and 253 RAMPS during the study period. DPS was associated with higher rates of median estimated blood loss (500 vs. 300 cc, P<0.001), median total harvested lymph nodes (18 vs. 12, P<0.001) and R0 resection (94.3% vs. 88.9%, P=0.013). There were no differences in rates of postoperative pancreatic fistula (16.5% vs. 17.8%, P=1) or postoperative hemorrhage (5.9% vs. 3.6%, P=0.385) (DPS vs. RAMPS). After controlling for significant clinical pathological parameters, RAMPS was associated with non-superior recurrence-free survival (RFS) (HR 0.29; 95% CI, 0.07-1.27, P=0.101) and overall-survival (HR 1.03; 95% CI, 0.71-1.49, P=0.895) compared with DPS. Similar results were observed in node-positive patients.

Conclusions: RAMPS is safe and effective in the treatment of PDAC, but is not associated with an improvement in either RFS or overall-survival over DPS.
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http://dx.doi.org/10.21037/cco-20-6DOI Listing
August 2020

Pattern of Invasion in Human Pancreatic Cancer Organoids Is Associated with Loss of SMAD4 and Clinical Outcome.

Cancer Res 2020 07 6;80(13):2804-2817. Epub 2020 May 6.

Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy characterized by extensive local invasion and systemic spread. In this study, we employed a three-dimensional organoid model of human pancreatic cancer to characterize the molecular alterations critical for invasion. Time-lapse microscopy was used to observe invasion in organoids from 25 surgically resected human PDAC samples in collagen I. Subsequent lentiviral modification and small-molecule inhibitors were used to investigate the molecular programs underlying invasion in PDAC organoids. When cultured in collagen I, PDAC organoids exhibited two distinct, morphologically defined invasive phenotypes, mesenchymal and collective. Each individual PDAC gave rise to organoids with a predominant phenotype, and PDAC that generated organoids with predominantly mesenchymal invasion showed a worse prognosis. Collective invasion predominated in organoids from cancers with somatic mutations in the driver gene (or its signaling partner ). Reexpression of SMAD4 abrogated the collective invasion phenotype in -mutant PDAC organoids, indicating that SMAD4 loss is required for collective invasion in PDAC organoids. Surprisingly, invasion in passaged -mutant PDAC organoids required exogenous TGFβ, suggesting that invasion in -mutant organoids is mediated through noncanonical TGFβ signaling. The Rho-like GTPases RAC1 and CDC42 acted as potential mediators of TGFβ-stimulated invasion in -mutant PDAC organoids, as inhibition of these GTPases suppressed collective invasion in our model. These data suggest that PDAC utilizes different invasion programs depending on status, with collective invasion uniquely present in PDAC with SMAD4 loss. SIGNIFICANCE: Organoid models of PDAC highlight the importance of SMAD4 loss in invasion, demonstrating that invasion programs in -mutant and wild-type tumors are different in both morphology and molecular mechanism.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-1523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7335355PMC
July 2020

Recurrence in Patients Achieving Pathological Complete Response After Neoadjuvant Treatment for Advanced Pancreatic Cancer.

Ann Surg 2019 Nov 25. Epub 2019 Nov 25.

Division of Surgical Oncology, Section of Hepatobiliary and Pancreatic Surgery, Johns Hopkins Hospital, Baltimore, MD.

Objective: The aim of this study was to characterize the patterns and treatment of disease recurrence in patients achieving a pathological complete response (pCR) following neoadjuvant chemoradiation for advanced pancreatic ductal adenocarcinoma (PDAC).

Summary Of Background Data: A pCR is an independent predictor for improved survival in PDAC. However, disease recurrence is still observed in these patients.

Methods: Patients with advanced PDAC who were treated with neoadjuvant therapy and had a pCR were identified between 2009 and 2017. Overall survival (OS) was determined from the initiation of neoadjuvant, disease-free survival (DFS) from the date of surgery, and post-recurrence survival (PRS) from the date of recurrence. Factors associated with recurrence were analyzed using a Cox-regression model.

Results: Of 331 patients with borderline resectable or locally advanced PDAC, 30 achieved a pCR following neoadjuvant treatment and pancreatectomy. The median DFS for pCR patients was 29 months and OS 76 months. Recurrence was observed in 14 patients. No clinicopathologic or treatment characteristics were associated with survival. The median PRS following recurrence was 25 months. Treatment following recurrence included chemotherapy, radiation or ablation, and surgical resection. Hepatectomy or completion pancreatectomy was accomplished in 2 patients that remain alive 13 and 62 months, respectively, following metastasectomy.

Conclusions: A pCR following neoadjuvant therapy in patients with advanced PDAC is associated with remarkable survival, although recurrence occurs in about half of patients. Nevertheless, patients with pCR and recurrence respond well to treatment and survival remains encouraging. Advanced molecular characterization and longitudinal liquid biopsy may offer additional assistance with understanding tumor biologic behavior after achieving a pCR.
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http://dx.doi.org/10.1097/SLA.0000000000003570DOI Listing
November 2019

Role of Lymph Node Resection and Histopathological Evaluation in Accurate Staging of Nonfunctional Pancreatic Neuroendocrine Tumors: How Many Are Enough?

J Gastrointest Surg 2021 Feb 5;25(2):428-435. Epub 2020 Feb 5.

Department of Surgery, The Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Halsted 614, Baltimore, MD, 21287, USA.

Background: Nodal involvement has been identified as one of the strongest prognostic factors in patients with nonfunctional pancreatic neuroendocrine tumors (NF-PanNETs). Sufficient lymphadenectomy and evaluation is vital for accurate staging. The purpose of this study was to identify the optimal number of examined lymph nodes (ELN) required for accurate staging.

Methods: The SEER database was used to identify patients with resected NF-PanNETs between 2004 and 2014. The distributions of positive lymph nodes (PLN) ratio and total lymph nodes were used to develop a mathematical model. The sensitivity of detecting nodal disease at each cutoff of ELN was estimated and used to identify the optimal cutoff for ELN.

Results: A total of 1098 patients were included in the study of which 391 patients (35.6%) had nodal disease. The median ELN was 12 (interquartile range [IQR]: 7-19.5), and the median PLN was 2 (IQR: 1-4) for patients with nodal disease. With an increase in ELN, the sensitivity of detecting nodal disease increased from 12.0% (ELN: 1) to 92.2% (ELN: 20), plateauing at 20 ELN (< 1% increase in sensitivity with an additional ELN). This sensitivity increase pattern was similar in subgroup analyses with different T stages.

Conclusions: The sensitivity of detecting nodal disease in patients with NF-PanNETs increases with an increase in the number of ELN. Cutoffs for adequate nodal assessment were defined for all T stages. Utilization of these cutoffs in clinical settings will help with patient prognostication and management.
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http://dx.doi.org/10.1007/s11605-020-04521-wDOI Listing
February 2021

The impact of high body mass index on patients undergoing robotic pancreatectomy: A propensity matched analysis.

Surgery 2020 03 11;167(3):556-559. Epub 2019 Dec 11.

Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD; The Pancreatic Cancer Precision Medicine Center of Excellence Program, The Johns Hopkins University School of Medicine, Baltimore, MD. Electronic address:

Background: Patients with high body mass index are associated with a higher risk of complications after open pancreatectomy. We aimed to investigate the perioperative outcome for patients with high body mass index after robotic pancreatectomy.

Methods: This is a retrospective, propensity-score matched cohort analysis. From our prospectively maintained database, we identified consecutive patients with body mass index >25 who underwent robotic pancreatectomy between January 2016 and December 2018. Propensity score matching with open pancreatectomy was applied in 1:2 fashion based on age, gender, American Society of Anesthesiologists classification, surgery type, histology, neoadjuvant therapy, and body mass index during the same study period.

Results: A total of 127 patients were included. The mean age for all patients was 61.7 ± 12.8 years and 65 (51.2%) were male. Median body mass index was 29.9 (interquartile range, 27.0-31.8) for both groups. Propensity score matching provided equally distributed general demographic and clinicopathological factors. Robotic pancreatectomy was associated with decreased blood loss (100 mL vs 300 mL, P < .001) and shorter hospital stay (7 vs 9 days, P = .019).

Conclusion: Robotic pancreatectomy is associated with decreased blood loss and shorter length of hospital stay in overweight patients. Robotic approach may help alleviate morbidity in overweight patients undergoing pancreatectomy.
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http://dx.doi.org/10.1016/j.surg.2019.11.002DOI Listing
March 2020

A Qualitative Review of Neoadjuvant Chemotherapy in Resectable Pancreatic Adenocarcinoma.

Pancreas 2019 09;48(8):973-984

From the Section of Hepatobiliary and Pancreatic Surgery, Division of Surgical Oncology, Johns Hopkins Hospital.

The aim of this study was to evaluate outcomes of patients with resectable pancreatic adenocarcinoma (PDAC) who underwent neoadjuvant chemotherapy. The MEDLINE and PubMed databases were searched to identify relevant original articles investigating neoadjuvant therapy in resectable PDAC. Qualitative analyses were performed to investigate patient selection, disease stage, impact on perioperative outcomes, and cost-effectiveness. Forty-three studies met inclusion criteria for this review. Neoadjuvant chemotherapy for upfront resectable PDAC is cost-effective, safe, may result in lower stage disease and has potential survival advantages. With proper patient selection, neoadjuvant chemotherapy is an appropriate approach for upfront resectable PDAC. Nevertheless, the risk for disease progression and losing a curative surgical window highlights the need for appropriate patient identification, further discovery of superior biomarkers or molecular profiles representative of positive treatment response, and additional prospective comparative study.
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http://dx.doi.org/10.1097/MPA.0000000000001376DOI Listing
September 2019

Disparities in the Use of Chemotherapy in Patients with Resected Pancreatic Ductal Adenocarcinoma.

J Gastrointest Surg 2020 07 3;24(7):1590-1596. Epub 2019 Jul 3.

The John L. Cameron Division of Hepatobiliary and Pancreatic Surgery, The Johns Hopkins Hospital, 600 N. Wolfe St. / Blalock 1222A, Baltimore, MD, 2I287, USA.

Background: Introduction of effective systemic therapies for pancreatic ductal adenocarcinoma (PDAC) has demonstrated survival benefit. However, chemotherapy remains underutilized in these patients. We sought to investigate the implications of disparities on the trends in utilization of chemotherapy.

Methods: A retrospective study using the Surveillance, Epidemiology, and End Results (SEER) database identified patients who underwent surgical resection for PDAC from 1998 to 2014. Clinicopathologic, demographic, racial, and geographical factors were analyzed to assess associations with receipt of chemotherapy and disease-specific survival.

Results: A total of 15,585 patients were included in the study. A majority (N = 9953, 63.9%) received chemotherapy. Factors associated with poorer odds of receiving chemotherapy included older age (p < 0.001), African-American race (p = 0.003), and living in the Southwest region of the USA (p < 0.001). Married patients were at higher odds of receiving chemotherapy (all p < 0.001). Receipt of chemotherapy was independently associated with improved disease-specific survival (p < 0.001).

Conclusions: Receipt of chemotherapy results in an improved survival in patients with resected PDAC. Demographic, racial, and geographic factors influence the rate of receipt of chemotherapy. Despite prior reports, these trends have not changed over the recent decades.
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http://dx.doi.org/10.1007/s11605-019-04311-zDOI Listing
July 2020

Cross-Species Single-Cell Analysis of Pancreatic Ductal Adenocarcinoma Reveals Antigen-Presenting Cancer-Associated Fibroblasts.

Cancer Discov 2019 08 13;9(8):1102-1123. Epub 2019 Jun 13.

Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.

Cancer-associated fibroblasts (CAF) are major players in the progression and drug resistance of pancreatic ductal adenocarcinoma (PDAC). CAFs constitute a diverse cell population consisting of several recently described subtypes, although the extent of CAF heterogeneity has remained undefined. Here we use single-cell RNA sequencing to thoroughly characterize the neoplastic and tumor microenvironment content of human and mouse PDAC tumors. We corroborate the presence of myofibroblastic CAFs and inflammatory CAFs and define their unique gene signatures . Moreover, we describe a new population of CAFs that express MHC class II and CD74, but do not express classic costimulatory molecules. We term this cell population "antigen-presenting CAFs" and find that they activate CD4 T cells in an antigen-specific fashion in a model system, confirming their putative immune-modulatory capacity. Our cross-species analysis paves the way for investigating distinct functions of CAF subtypes in PDAC immunity and progression. SIGNIFICANCE: Appreciating the full spectrum of fibroblast heterogeneity in pancreatic ductal adenocarcinoma is crucial to developing therapies that specifically target tumor-promoting CAFs. This work identifies MHC class II-expressing CAFs with a capacity to present antigens to CD4 T cells, and potentially to modulate the immune response in pancreatic tumors...
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http://dx.doi.org/10.1158/2159-8290.CD-19-0094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6727976PMC
August 2019

Dissecting the Stromal Signaling and Regulation of Myeloid Cells and Memory Effector T Cells in Pancreatic Cancer.

Clin Cancer Res 2019 09 11;25(17):5351-5363. Epub 2019 Jun 11.

The Sydney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Purpose: Myeloid cells are a prominent immunosuppressive component within the stroma of pancreatic ductal adenocarcinoma (PDAC). Previously, targeting myeloid cells has had limited success. Here, we sought to target the myeloid cells through modifying a specific stromal component.

Experimental Design: A murine model of metastatic PDAC treated with an irradiated whole-cell PDAC vaccine and PDAC specimens from patients treated with the same type of vaccine were used to assess the immune-modulating effect of stromal hyaluronan (HA) degradation by PEGPH20.

Results: Targeting stroma by degrading HA with PEGPH20 in combination with vaccine decreases CXCL12/CXCR4/CCR7 immunosuppressive signaling axis expression in cancer-associated fibroblasts, myeloid, and CD8 T cells, respectively. This corresponds with increased CCR7 effector memory T-cell infiltration, an increase in tumor-specific IFNγ, and improved survival. In the stroma of human PDACs treated with the same vaccine, decreased stromal CXCR4 expression significantly correlated with decreased HA and increased cytotoxic activities, suggesting CXCR4 is an important therapeutic target.

Conclusions: This study represents the first to dissect signaling cascades following PDAC stroma remodeling via HA depletion, suggesting this not only overcomes a physical barrier for immune cell trafficking, but alters myeloid function leading to downstream selective increases in effector memory T-cell infiltration and antitumor activity.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-4192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6726532PMC
September 2019

Missed psychosocial risk factors during routine preoperative evaluations are associated with increased complications after elective cancer surgery.

Surgery 2019 08 31;166(2):177-183. Epub 2019 May 31.

Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD. Electronic address:

Background: Certain behavioral traits and inadequate social support are known risk factors for complications after cancer surgery. Despite their importance, it is unclear whether conventional patient preoperative evaluation captures them. This study was conducted to assess concordance between documentation and patient survey of selected risk factors and to determine whether failure to document affected postoperative outcomes.

Methods: Adult patients at a tertiary academic medical center were surveyed before abdominal cancer surgery to assess 6 psychosocial risk factors. Risk factors were also assessed by retrospective chart review and compared with survey results through concordance measures. Thirty-day postoperative complications were abstracted by chart review. Rates of major complications for those with and without clinically missed risk factors were compared.

Results: Comparisons between chart review and screening survey revealed poor-to-moderate positive agreement (0%-47%) for 5 risk factors and strong negative agreement (82%-99%) among all risk factors. Kappa analysis demonstrated poor-to-fair agreement among 5 risk factors (κ = 0.112-0.423). The overall complication rate was 36%. The complication rate for patients with at least 1 clinically missed risk factor was 49% vs 24% in those without (P = .021), with a similar effect replicated for each individual risk factor.

Conclusion: This study shows a high level of discordance between formal screening and routine clinician documentation in a preoperative setting for psychosocial risk factors. There is a significant association between missing these risk factors and worse postoperative outcomes. Future work should examine whether structured screening of psychosocial risk factors may improve preoperative risk stratification through proactive interventions.
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http://dx.doi.org/10.1016/j.surg.2019.04.015DOI Listing
August 2019

Circulating Tumor DNA as a Clinical Test in Resected Pancreatic Cancer.

Clin Cancer Res 2019 08 29;25(16):4973-4984. Epub 2019 May 29.

Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland.

Purpose: In research settings, circulating tumor DNA (ctDNA) shows promise as a tumor-specific biomarker for pancreatic ductal adenocarcinoma (PDAC). This study aims to perform analytical and clinical validation of a ctDNA assay in a Clinical Laboratory Improvement Amendments (CLIA) and College of American Pathology-certified clinical laboratory.

Experimental Design: Digital-droplet PCR was used to detect the major PDAC-associated somatic mutations (G12D, G12V, G12R, and Q61H) in liquid biopsies. For clinical validation, 290 preoperative and longitudinal postoperative plasma samples were collected from 59 patients with PDAC. The utility of ctDNA status to predict PDAC recurrence during follow-up was assessed.

Results: ctDNA was detected preoperatively in 29 (49%) patients and was an independent predictor of decreased recurrence-free survival (RFS) and overall survival (OS). Patients who had neoadjuvant chemotherapy were less likely to have preoperative ctDNA than were chemo-naïve patients (21% vs. 69%; < 0.001). ctDNA levels dropped significantly after tumor resection. Persistence of ctDNA in the immediate postoperative period was associated with a high rate of recurrence and poor median RFS (5 months). ctDNA detected during follow-up predicted clinical recurrence [sensitivity 90% (95% confidence interval (CI), 74%-98%), specificity 88% (95% CI, 62%-98%)] with a median lead time of 84 days (interquartile range, 25-146). Detection of ctDNA during postpancreatectomy follow-up was associated with a median OS of 17 months, while median OS was not yet reached at 30 months for patients without ctDNA ( = 0.011).

Conclusions: Measurement of ctDNA in a CLIA laboratory setting can be used to predict recurrence and survival in patients with PDAC.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-0197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403524PMC
August 2019

Defining and Predicting Early Recurrence in 957 Patients With Resected Pancreatic Ductal Adenocarcinoma.

Ann Surg 2019 06;269(6):1154-1162

Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Objectives: To establish an evidence-based cut-off to differentiate between early and late recurrence and to compare clinicopathologic risk factors between the two groups.

Summary Background Data: A clear definition of "early recurrence" after pancreatic ductal adenocarcinoma resection is currently lacking.

Methods: Patients undergoing pancreatectomy for pancreatic ductal adenocarcinoma between 2000 and 2013 were included. Exclusion criteria were neoadjuvant therapy and incomplete follow-up. A minimum P-value approach was used to evaluate the optimal cut-off value of recurrence-free survival to divide the patients into early and late recurrence cohorts based on subsequent prognosis. Potential risk factors for early recurrence were assessed with logistic regression models.

Results: Of 957 included patients, 204 (21.3%) were recurrence-free at last follow-up. The optimal length of recurrence-free survival to distinguish between early (n = 388, 51.5%) and late recurrence (n = 365, 48.5%) was 12 months (P < 0.001). Patients with early recurrence had 1-, and 2-year post-recurrence survival rates of 20 and 6% compared with 45 and 22% for the late recurrence group (both P < 0.001). Preoperative risk factors for early recurrence included a Charlson age-comorbidity index ≥4 (OR 1.65), tumor size > 3.0 cm on computed tomography (OR 1.53) and CA 19-9 > 210 U/mL (OR 2.30). Postoperative risk factors consisted of poor tumor differentiation grade (OR 1.66), microscopic lymphovascular invasion (OR 1.70), a lymph node ratio > 0.2 (OR 2.49), and CA 19-9 > 37 U/mL (OR 3.38). Adjuvant chemotherapy (OR 0.28) and chemoradiotherapy (OR 0.29) were associated with a reduced likelihood of early recurrence.

Conclusion: A recurrence-free interval of 12 months is the optimal threshold for differentiating between early and late recurrence, based on subsequent prognosis.
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http://dx.doi.org/10.1097/SLA.0000000000002734DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6191366PMC
June 2019

Negative Pressure Wound Therapy for Surgical-site Infections: A Randomized Trial.

Ann Surg 2019 06;269(6):1034-1040

The John L. Cameron Division of Hepatobiliary and Pancreatic Surgery, The Johns Hopkins Hospital, Baltimore, MD.

Objective: This study seeks to evaluate the efficacy of negative pressure wound therapy for surgical-site infection (SSI) after open pancreaticoduodenectomy.

Background: Despite improvement in infection control, SSIs remain a common cause of morbidity after abdominal surgery. SSI has been associated with an increased risk of reoperation, prolonged hospitalization, readmission, and higher costs. Recent retrospective studies have suggested that the use of negative pressure wound therapy can potentially prevent this complication.

Methods: We conducted a single-center randomized, controlled trial evaluating surgical incision closure during pancreaticoduodenectomy using negative pressure wound therapy in patients at high risk for SSI. We randomly assigned patients to receive negative pressure wound therapy or a standard wound closure. The primary end point of the study was the occurrence of a postoperative SSI. We evaluated the economic impact of the intervention.

Results: From January 2017 through February 2018, we randomized 123 patients at the time of closure of the surgical incision. SSI occurred in 9.7% (6/62) of patients in the negative pressure wound therapy group and in 31.1% (19/61) of patients in the standard closure group (relative risk = 0.31; 95% confidence interval, 0.13-0.73; P = 0.003). This corresponded to a relative risk reduction of 68.8%. SSIs were found to independently increase the cost of hospitalization by 23.8%.

Conclusions: The use of negative pressure wound therapy resulted in a significantly lower risk of SSIs. Incorporating this intervention in surgical practice can help reduce a complication that significantly increases patient harm and healthcare costs.
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http://dx.doi.org/10.1097/SLA.0000000000003056DOI Listing
June 2019