To identify predictive factors associated with operative morbidity, mortality, and survival outcomes in patients with borderline resectable (BR) or locally advanced (LA) pancreatic ductal ...adenocarcinoma (PDAC) undergoing total neoadjuvant therapy (TNT).
The optimal preoperative treatment sequencing for BR/LA PDA is unknown. TNT, or systemic chemotherapy followed by chemoradiation (CRT), addresses both occult metastases and positive margin risks and thus is a potentially optimal strategy; however, factors predictive of perioperative and survival outcomes are currently undefined.
We reviewed our experience in BR/LA patients undergoing resection from 2010 to 2017 following TNT assessing operative morbidity, mortality, and survival in order to define outcome predictors and response endpoints.
One hundred ninety-four patients underwent resection after TNT, including 123 (63%) BR and 71 (37%) LA PDAC. FOLFIRINOX or gemcitabine along with nab-paclitaxel were used in 165 (85%) and 65 (34%) patients, with 36 (19%) requiring chemotherapeutic switch before long-course CRT and subsequent resection. Radiologic anatomical downstaging was uncommon (28%). En bloc venous and/or arterial resection was required in 125 (65%) patients with 94% of patients achieving R0 margins. The 90-day major morbidity and mortality was 36% and 6.7%, respectively. Excluding operative mortalities, the median, 1-year, 2-year, and 3-year recurrence-free survival (RFS) overall survival (OS) rates were 23.5 (58.8) months, 65 (96)%, 48 (78)%, and 32 (62)%, respectively. Radiologic downstaging, vascular resection, and chemotherapy regimen/switch were not associated with survival. Only 3 factors independently associated with prolonged survival, including extended duration (≥6 cycles) chemotherapy, optimal post-chemotherapy CA19-9 response, and major pathologic response. Patients achieving all 3 factors had superior survival outcomes with a survival detriment for each failing factor. In a subset of patients with interval metabolic (PET) imaging after initial chemotherapy, complete metabolic response highly correlated with major pathologic response.
Our TNT experience in resected BR/LA PDAC revealed high negative margin rates despite low radiologic downstaging. Extended duration chemotherapy with associated biochemical and pathologic responses highly predicted postoperative survival. Potential modifications of initial chemotherapy treatment include extending cycle duration to normalize CA19-9 or achieve complete metabolic response, or consideration of chemotherapeutic switch in order to achieve these factors may improve survival before moving forward with CRT and subsequent resection.
The lack of reliable, noninvasive methods to diagnose early nonalcoholic steatohepatitis (NASH) is a major unmet need. We aimed to determine the diagnostic accuracy of three‐dimensional magnetic ...resonance elastography (3D‐MRE), with shear stiffness measured at 60 Hz, damping ratio at 40 Hz, and magnetic resonance imaging proton density fat fraction (MRI‐PDFF) in the detection of NASH in individuals undergoing bariatric surgery. Obese adults at risk for NASH were enrolled between 2015 and 2017 (prospective cohort, n = 88) and 2010 and 2013 (retrospective cohort, n = 87). The imaging protocol consisted of multifrequency 3D‐MRE (mf3D‐MRE) with shear waves delivered at different frequencies to explore parameters that best correlated with histologic NASH, and MRI‐PDFF to estimate steatosis. The prospective cohort was used to establish the optimal mf3D‐MRE technical parameters for NASH detection. The two cohorts were then combined to derive predictive models of NASH and disease activity by nonalcoholic fatty liver disease activity score (NAS) using the three imaging parameters that correlated with NASH. A total of 175 patients (median age 45, 81% women, and 81 46% with histologic NASH) were used for model derivation. From the complex shear modulus output generated by mf3D‐MRE, the damping ratio at 40 Hz and shear stiffness at 60 Hz best correlated with NASH. The fat fraction obtained from MRI‐PDFF correlated with steatosis (P < 0.05 for all). These three parameters were fit into a logistic regression model that predicted NASH with cross‐validated area under the receiver operating characteristic curve (AUROC) = 0.73, sensitivity = 0.67, specificity = 0.80, positive predictive value = 0.73 and negative predictive value = 0.74, and disease activity by NAS with cross‐validated AUROC = 0.82. Conclusion: The mf3D‐MRE allows identification of imaging parameters that predict early NASH and disease activity. This imaging biomarker represents a promising alternative to liver biopsy for NASH diagnosis and monitoring. The results provide motivation for further studies in nonbariatric cohorts.
Background Outcomes of neoadjuvant systemic therapy versus an upfront operation for clinical, stage III pancreatic adenocarcinoma remain poorly defined. Our aim was to compare survival among patients ...receiving neoadjuvant chemotherapy versus surgery-first with an intention-to-treat analysis. Methods The National Cancer Data Base was reviewed from 2002–2011 for patients with clinical, stage III adenocarcinoma of the head or body of the pancreas. Patients were categorized as neoadjuvant or surgery-first. The intention-to-treat analysis included all neoadjuvant therapy patients in whom a potentially curative operation was planned and all surgery-first patients for whom adjuvant therapy was recommended. Intention-to-treat overall survival was compared by Kaplan-Meier and Cox proportional hazards multivariable regression. Results A total of 593 patients were identified: 377 (63.6%) in the neoadjuvant cohort, wherein 104 (27.6%) experienced preoperative attrition, and 216 (36.4%) in the surgery-first cohort, of whom 30 (13.9%) failed to receive intended adjuvant chemotherapy. Intention-to-treat Kaplan-Meier analysis demonstrated superior survival for neoadjuvant compared to surgery-first (median overall survival 20.7 months vs 13.7 months, log rank P < .001). Intention-to-treat multivariable regression analysis revealed a decreased mortality hazard (hazard ratio = 0.68, 95% confidence interval 0.53–0.86, P = .0012) for neoadjuvant compared to surgery-first. Conclusion Despite preoperative attrition, neoadjuvant therapy in clinical, stage III pancreatic cancer patients is associated with improved overall survival when compared to patients receiving surgery-first.
Global climate and the concentration of atmospheric carbon dioxide (CO2) are correlated over recent glacial cycles. The combination of processes responsible for a rise in atmospheric CO2 at the last ...glacial termination (23,000 to 9,000 years ago), however, remains uncertain. Establishing the timing and rate of CO2 changes in the past provides critical insight into the mechanisms that influence the carbon cycle and helps put present and future anthropogenic emissions in context. Here we present CO2 and methane (CH4) records of the last deglaciation from a new high-accumulation West Antarctic ice core with unprecedented temporal resolution and precise chronology. We show that although low-frequency CO2 variations parallel changes in Antarctic temperature, abrupt CO2 changes occur that have a clear relationship with abrupt climate changes in the Northern Hemisphere. A significant proportion of the direct radiative forcing associated with the rise in atmospheric CO2 occurred in three sudden steps, each of 10 to 15 parts per million. Every step took place in less than two centuries and was followed by no notable change in atmospheric CO2 for about 1,000 to 1,500 years. Slow, millennial-scale ventilation of Southern Ocean CO2-rich, deep-ocean water masses is thought to have been fundamental to the rise in atmospheric CO2 associated with the glacial termination, given the strong covariance of CO2 levels and Antarctic temperatures. Our data establish a contribution from an abrupt, centennial-scale mode of CO2 variability that is not directly related to Antarctic temperature. We suggest that processes operating on centennial timescales, probably involving the Atlantic meridional overturning circulation, seem to be influencing global carbon-cycle dynamics and are at present not widely considered in Earth system models.
Minimally invasive surgical approaches for pancreatic resection have been established as feasible and safe. Whereas widespread application of laparoscopic distal pancreatectomy is in progress, the ...utilization of laparoscopic pancreaticoduodenectomy is still localized to a few centers because of the added complexity and advanced laparoscopic skills required. Comparative studies have demonstrated the typical advantages of minimally invasive approaches for pancreatic resection, namely, less blood loss and shorter hospital stay. Robotic assistance for laparoscopic approaches is gaining interest, but the true value added is still undefined. Significant discussion revolves around the appropriateness of minimally invasive approaches in pancreatic cancer. Although limited data and only short-term follow-up engender ongoing skepticism, the technical feasibility, existing reports in pancreatic cancer, and the lack of negative outcomes in other gastrointestinal cancers spark ongoing clinical evaluation. Minimally invasive surgical approaches have significant potential to improve the outcomes of pancreatic resection especially in pancreatic cancer patients in whom an optimal recovery is important for adjuvant treatment options. Larger experiences are forthcoming, and controlled trials are eagerly awaited; however, the feasibility of such is questionable because of the low incidence of resectable pancreatic cancer and the small number of centers performing minimally invasive pancreatectomy for malignancy.
Background Patient triage in anatomically resectable, early-stage pancreatic ductal adenocarcinoma (PDAC) with elevated carbohydrate antigen 19-9 (CA 19-9) remains unclear. We hypothesized that any ...CA 19-9 elevation indicates biologically borderline resectability. Study Design The National Cancer Data Base (NCDB 2010 to 2012) was reviewed for PDAC patients with reported CA 19-9. Nonsecretors were analyzed separately. Early-stage (I/II) patients were stratified by CA 19-9 above or below normal (37 U/mL). Unadjusted Kaplan-Meier and adjusted Cox proportional hazards survival modeling were performed. Results Of 113,145 patients, only 28,074 (24.8%) had CA 19-9 measured and reported, and this proportion was stage independent. Among early-stage patients (n = 10,806), there were 957 (8.8%) nonsecretors, 2,708 (25.1%) with normal levels, and 7,141 (66.1%) with elevated levels. Demographics and perioperative outcomes were similar between these groups. Survival was worse in all stages in patients with CA 19-9 elevation. Nonsecretors had survival similar to that of patients with normal levels. Early-stage patients with elevated CA 19-9 had decreased survival at 1, 2, and 3 years (56% vs 68%, 30% vs 42%, 15% vs 25%, all p < 0.001) relative to patients with normal levels. Adjusted modeling confirmed this finding (hazard ratio HR 1.26, p < 0.001). Repeat modeling in the neoadjuvant cohort demonstrated this to be the only treatment sequence to completely abrogate increased mortality due to CA 19-9 elevation (p = 0.11). Conclusions The minority of PDAC patients have CA 19-9 measured and reported in NCDB. The CA 19-9 nonsecretors and normal-level patients achieve equivalent survival. Elevation of CA 19-9 is associated with decreased stage-specific survival, with the greatest difference in early stages. Neoadjuvant systemic therapy followed by curative intent surgery best mitigates the increased mortality hazard. Patients with PDAC who have elevated CA 19-9 levels at diagnosis are biologically borderline resectable regardless of anatomic resectability, and neoadjuvant systemic therapy is suggested.
Background EUS can provide access to the main pancreatic duct (MPD) for therapeutic intervention. The long-term clinical success of EUS-guided MPD interventions is unknown. Objective To determine ...technical and clinical success rates, predictors of success, and long-term outcomes of EUS-guided MPD intervention. Design Retrospective, single-center study. Setting Tertiary-care referral center. Patients Forty-five patients. Intervention EUS-guided MPD stent retrieval or placement. Main Outcome Measurements Technical and clinical success rates, adverse events, and long-term clinical outcomes. Results Among the 45 patients, 37 had undergone failed ERCP, and 29 had surgically altered anatomy. Median follow-up after initial EUS-guided intervention was 23 months. Two patients underwent EUS for stent removal, and EUS-guided MPD stent placement was attempted in 43 patients. Technical success was achieved in 32 of 43 patients (74%) with antegrade (n = 18) or retrograde (n = 14) stent insertion. Serious adverse events occurred in 3 patients (6%). Patients underwent a median of 2 (range 1-6) follow-up procedures for revision or removal of stents, without adverse events. Complete symptom resolution occurred in 24 of 29 patients (83%) while stents were in place, including all 6 with nondilated ducts. Stents were removed in 23 patients, who were then followed for an additional median of 32 months; 4 patients had recurrent symptoms. Among the 11 failed cases, most had persistent symptoms or required surgery. Limitations Retrospective study design, individualized patient management. Conclusion EUS-guided MPD intervention is feasible and safe, with long-term clinical success in the majority of patients. EUS provides important treatment options, particularly in patients who would otherwise undergo surgery.
To directly compare the oncologic outcomes of TLPD and OPD in the setting of pancreatic ductal adenocarcinoma.
Total laparoscopic pancreaticoduodenectomy (TLPD) has been demonstrated to be feasible ...and may have several potential advantages over open pancreaticoduodenectomy (OPD), including lower blood loss and shorter hospital stay. Whether potential advantages could allow patients to recover in a timelier manner and pursue adjuvant treatment options remains to be answered.
We reviewed data for all patients undergoing TLPD (N = 108) or OPD (N = 214) for pancreatic ductal adenocarcinoma at our institution between January 2008 and July 2013.
Neoadjuvant therapy, tumor size, node positivity, and margin-positive resection were not significantly different between the 2 groups. Median length of hospital stay was significantly longer in the OPD group (9 days; range, 5-73 days) than in the TLPD group (6 days; range, 4-118 days; P < 0.001). There was a significantly higher proportion of patients in the OPD group (12%) who had a delay of greater than 90 days or who did not receive adjuvant chemotherapy at all compared with that in the TLPD group (5%; P = 0.04). There was no significant difference in overall survival between the 2 groups (P = 0.22). A significantly longer progression-free survival was seen in the TLPD group than in the OPD group (P = 0.03).
TLPD is not only feasible in the setting of pancreatic ductal adenocarcinoma but also has advantages such as shorter hospital stay and faster recovery, allowing patients to recover in a timelier manner and pursue adjuvant treatment options. This study also demonstrated a longer progression-free survival in patients undergoing TLPD than those undergoing OPD.
Background A clinical risk score for pancreatic fistula (CRS-PF) was recently reported to predict postoperative pancreatic fistula (POPF) after pancreatoduodenectomy (PD). An independent external ...validation has not been performed. Our hypothesis was that CRS-PF predicts POPF after both laparoscopic and open PD. Study Design The CRS-PF was calculated from a retrospective review of patients undergoing PD from January 2007 to February 2014. Postoperative pancreatic fistula was graded using International Study Group of Pancreatic Fistula criteria. Grade B and C leaks were defined as clinically significant. Performance was measured based on sensitivity, specificity, positive and negative predictive value, accuracy, and R2. Results There were 808 patients who met inclusion criteria; 539 (66.7%) had open and 269 (33.3%) had laparoscopic PD. The CRS-PF was high risk in 134 patients, intermediate in 492, low in 135, and negligible in 47. Postoperative pancreatic fistula occurred in 191 (23.6%) patients (grade A, 3.8%; B, 14.2%; and C, 5.6%), and it increased with risk category (R2 = 0.935 all, 0.898 open, and 0.968 laparoscopic). High and intermediate risk categories were combined and classified as “test positive,” and negligible and low risk categories were combined and classified “test negative,” resulting in a CRS-PF with a sensitivity of 95% and a negative predictive value of 96% for predicting POPF. Contrary to previous studies, grade A POPF increased with increasing CRS-PF and POPF did not correlate with estimated blood loss (R2 = 0.04). Conclusions The CRS-PF was validated independently by predicting POPF for both laparoscopic and open PD. Predictive performance was at least as good for laparoscopic PD as for open PD. Lack of correlation with estimated blood loss suggests CRS-PF might be tailored for improved performance. The CRS-PF is a clinically useful tool for POPF risk stratification after PD and allows for targeted intra- and postoperative measures to address patients at increased risk.
Background and Aims Among the greatest hurdles to pancreatic cancer (PC) therapy is the limited tissue penetration of systemic chemotherapy because of tumor desmoplasia. The primary study aim was to ...determine the toxicity profile of EUS-guided fine-needle injection (EUS-FNI) with gemcitabine. Secondary endpoints included the ability to disease downstage leading to an R0 resection and overall survival (OS) at 6 months, 12 months, and 5 years after therapy. Methods In a prospective study from a tertiary referral center, gemcitabine (38 mg/mL) EUS-FNI was performed in patients with PC before conventional therapy. Initial and delayed adverse events (AEs) were assessed within 72 hours and 4 to 14 days after EUS-FNI, respectively. Patients were followed for ≥5 years or until death. Results Thirty-six patients with stage II (n = 3), stage III (n = 20), or stage IV (n = 13) disease underwent gemcitabine EUS-FNI with 2.5 mL (.7-7.0 mg) total volume of injectate per patient. There were no initial or delayed AEs reported. Thirty-five patients (97.2%) were deceased at the time of analysis with a median 10.3 months of follow-up (range, 3.1-63.9). OS at 6 months and 12 months was 78% and 44%, respectively. The median OS was 10.4 months (range, 2.7-68). Among patients with stage III unresectable disease, 4 (20%) were downstaged and underwent an R0 resection. Conclusions Our study suggests the feasibility, safety, and potential efficacy of gemcitabine EUS-FNI for PC. Additional data are needed to verify these observations and to determine the potential role relative to conventional multimodality therapy.
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