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.
.
.
OBJECTIVE:The aim of the study was to identify the survival of patients with locally advanced pancreatic cancer (LAPC) and assess the effect of surgical resection after neoadjuvant therapy on patient ...outcomes.
BACKGROUND:An increasing number of LAPC patients who respond favorably to neoadjuvant therapy undergo surgical resection. The impact of surgery on patient survival is largely unknown.
MATERIALS AND METHODS:All LAPC patients who presented to the institutional pancreatic multidisciplinary clinic (PMDC) from January 2013 to September 2017 were included in the study. Demographics and clinical data on neoadjuvant treatment and surgical resection were documented. Primary tumor resection rates after neoadjuvant therapy and overall survival (OS) were the primary study endpoints.
RESULTS:A total of 415 LAPC patients were included in the study. Stratification of neoadjuvant therapy in FOLFIRINOX-based, gemcitabine-based, and combination of the two, and subsequent outcome comparison did not demonstrate significant differences in OS of 331 non-resected LAPC patients (P = 0.134). Eighty-four patients underwent resection of the primary tumor (20%), after a median duration of 5 months of neoadjuvant therapy. FOLFIRINOX-based therapy and stereotactic body radiation therapy correlated with increased probability of resection (P = 0.006). Resected patients had better performance status, smaller median tumor size (P = 0.029), and lower median CA19-9 values (P < 0.001) at PMDC. Patients who underwent surgical resection had significant higher median OS compared with those who did not (35.3 vs 16.3 mo, P < 0.001). The difference remained significant when non-resected patients were matched for time of neoadjuvant therapy (19.9 mo, P < 0.001).
CONCLUSIONS:Surgical resection of LAPC after neoadjuvant therapy is feasible in a highly selected cohort of patients (20%) and is associated with significantly longer median overall survival.
OBJECTIVE:The purpose of this study is to determine preoperative factors that are predictive of malignancy in patients undergoing pancreatic resection for intraductal papillary mucinous neoplasms ...(IPMN).
SUMMARY BACKGROUND DATA:IPMN of the pancreas may be precursor lesions to pancreatic cancer (PC) and represent a target for early diagnosis or prevention. While there has been much effort to define preoperative risk factors for malignant pathology, guidelines are ever-changing and controversy remains surrounding which patients would benefit most from resection.
METHODS:We performed a retrospective analysis of 901 consecutive patients obtained from two tertiary referral centers who underwent pancreatic resection for histologically proven IPMN between 2004 and 2017. Collected data included patient demographic characteristics, preoperative symptoms, radiological findings, and laboratory data.
RESULTS:Main pancreatic duct (MPD) dilatation was the only variable that was significantly associated with increased probability of malignancy (defined high-dysplasia or invasion) on both univariate and multivariate analysis. Even middle-range MPD dilatation from 5 mm to 9.9 mm (n = 286) was associated with increased odds of HG-IPMN (OR = 2.74; 95% CI = 1.80–4.16) and invasion (OR = 4.42; 95% CI = 2.55–7.66). MPD dilatation >10 mm (n = 150) had even greater odds of HG-IPMN (OR = 6.57; 95% CI = 3.94–10.98) and invasion (OR = 15.07; 95% CI = 8.21–27.65). A cutoff of 5 to 7 mm MPD diameter was determined to be the best predictor to discriminate between malignant and benign lesions.
CONCLUSIONS:In agreement with current IPMN management guidelines, we found MPD dilatation, even low levels from 5 mm to 9.9 mm, to be the single best predictor of HG-IPMN or invasion, highlighting the critical role that MPD plays in the selection of surgical candidates.
To establish an evidence-based cut-off to differentiate between early and late recurrence and to compare clinicopathologic risk factors between the two groups.
A clear definition of "early ...recurrence" after pancreatic ductal adenocarcinoma resection is currently lacking.
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.
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.
A recurrence-free interval of 12 months is the optimal threshold for differentiating between early and late recurrence, based on subsequent prognosis.
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.
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.
.
.
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.
Full text
Available for:
EMUNI, FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
OBJECTIVES:Previous retrospective studies demonstrated that circulating tumor cells (CTCs) subtypes correlate with overall survival in patients with pancreatic ductal adenocarcinoma (PDAC). Herein, ...we report results of a prospective observational study on CTCs dynamics to assess their clinical significance.
METHODS:The CLUSTER study is a prospective longitudinal study on PDAC CTCs dynamics (NCT02974764). Multiple peripheral blood samples were collected from 200 consecutively enrolled patients with presumed PDAC diagnosis. CTCs were isolated and characterized by immunofluorescence.
RESULTS:Two major CTCs subtypes were identified in PDAC patientsepithelial CTCs (eCTCs) and epithelial/mesenchymal CTCs (mCTCs). Patients who received neoadjuvant chemotherapy had significantly lower total CTCs (tCTCs, P = 0.007), eCTCs (P = 0.007), and mCTCs (P = 0.034), compared with untreated patients eligible for upfront resection. Surgical resection of the primary tumor resulted in significant reduction, but not disappearance, of CTCs burden across all cell subtypes (P < 0.001). In multivariable logistic regression analysis, preoperative numbers of all CTCs subpopulations were the only predictors of early recurrence within 12 months from surgery in both chemo-naive and post-neoadjuvant patients (odds ratio 5.9 to 11.0). Alterations in CTCs were also observed longitudinally, before disease recurrence. A risk assessment score based on the difference of tCTCs increase accurately identified disease recurrence within the next 2 months, with an accuracy of 75% and 84% for chemo-naive and post-neoadjuvant patients, respectively.
CONCLUSION:We report novel findings regarding CTCs from a large prospective cohort of PDAC patients. CTCs dynamics reflect progression of disease and response to treatment, providing important information on clinical outcomes, not available by current tumor markers and imaging.
Background Attrition from general surgery residency remains constant at approximately 20% despite nearly a decade of work-hour reform and studies aiming to identify common risk factors. High rates of ...attrition from training have a wide impact, from the overall quality of trainees produced to implications on public health and the broader surgical work force. We set out to evaluate a novel character trait, grit, defined as passion and perseverance for long-term goals, as a marker and potential risk factor for resident attrition. Methods Twelve Accreditation Council for Graduate Medical Education–approved general surgery residency programs participated in a prospective, multi-institutional, survey-based analysis of grit and attrition during the 2012–2013 academic year. Participating individuals were blinded with regards to the primary outcome of the study. Participating institutions were blinded to the responses of their trainees. Participating residency programs were located in a variety of settings, from university-based health systems to community hospitals. Results Sixty-eight percent (68%) of residents (180 of 265) at participating institutions completed the study. The primary end point for this study was attrition from residency as a function of grit. Secondary end points included an evaluation of the utility of the grit score in surgical residents, variability of grit according to postgraduate year, sex, measurements of resident satisfaction with current program, lifestyle, and career goals. Finally, the study included an analysis of key resident support strategies. The attrition rate across 12 institutions surveyed was approximately 2% (5 residents). Of those five, three participated in our study. All three had below-median levels of grit. Those residents with below-median grit were more likely to contemplate leaving surgical residency. Given the low attrition rate, no variable surveyed reached statistical significance in our analysis. Key support strategies for residents responding included family, friends outside of residency, co-residents, and formal mentorship through their particular residency. Conclusion In this preliminary underpowered study, grit appears to be a promising marker and risk factor for attrition from surgical residency. In an effort to retain residents, programs should consider screening for grit in current residents and directing support to those residents with below-median values, with a focus on building family, friend, and formal mentor relationships.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
PDF
