MINITotal neoadjuvant therapy, or systemic induction chemotherapy followed by chemoradiation, is an optimal preoperative sequencing strategy for patients with borderline resectable or locally ...advanced pancreatic adenocarcinoma. This strategy allows high rate of negative margins despite low frequency of radiologic downstaging with survival dependent on chemotherapy duration and response factors that are potentially modifiable by alteration in initial systemic therapy decisions.This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0
OBJECTIVE: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).
BACKGROUND: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.
METHODS: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.
RESULTS: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.
CONCLUSION: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.This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0
The relationship between primary productivity and diversity has been demonstrated across taxa and spatial scales, but for organisms with biphasic life cycles, little research has examined whether ...productivity of larval and adult environments influence each life stage independently, or whether productivity of one life stage's environment outweighs the influence of the other. Experimental work demonstrates that tadpoles of stream-breeding anurans can exhibit a top-down influence on aquatic primary productivity (APP), but few studies have sought evidence of a bottom-up influence of primary productivity on anuran abundance, species richness and community composition, as seen in other organisms. We examined aquatic and terrestrial primary productivity in two forest types in Borneo, along with amphibian abundance, species richness, and community composition at larval and adult stages, to determine whether there is evidence for a bottom-up influence of APP on tadpole abundance and species richness across streams, and the relative importance of aquatic and terrestrial primary productivity on larval and adult phases of anurans. We predicted that adult richness, abundance, and community composition would be influenced by terrestrial primary productivity, but that tadpole richness, abundance, and community composition would be influenced by APP. Contrary to expectations, we did not find evidence that primary productivity, or variation thereof, predicts anuran richness at larval or adult stages. Further, no measure of primary productivity or its variation was a significant predictor of adult abundance, or of adult or tadpole community composition. For tadpoles, we found that in areas with low terrestrial primary productivity, abundance was positively related to APP, but in areas with high terrestrial primary productivity, abundance was negatively related to APP, suggesting a bottom-up influence of primary productivity on abundance in secondary forest, and a top-down influence of tadpoles on primary productivity in primary forest. Additional data are needed to better understand the ecological interactions between terrestrial primary productivity, aquatic primary productivity, and tadpole abundance.
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.
Understanding variability in species' traits can inform our understanding of their ecology and aid in the development of management and conservation strategies. Monarch butterflies (Danaus plexippus) ...are native to the western hemisphere and are well-known for their long-distance migrations but have experienced significant population declines in recent decades. Here we use a 5-year capture-mark-recapture dataset to compare monarch distributions, mating activity, and larval host plant use between two coastal plain habitats in South Carolina, USA. We observed seasonally specific habitat use, with maritime habitats serving as overwintering areas while nearby inland swamps support significant breeding in spring, summer, and fall seasons due to an abundance of aquatic milkweed (Asclepias perennis). We also observed mating activity by fall migrating monarchs and their use of swallow-wort (Pattalias palustre) in the spring as an important larval host plant in maritime habitats. This phenology and habitat use of monarchs diverges from established paradigms and suggest that a distinct population segment of monarchs may exist, with significance for understanding the conservation status of monarch butterflies and associated habitats in eastern North America. Further research should explore how monarchs along the Atlantic coast of North America relate to other eastern monarch populations.
OBJECTIVE:To directly compare the oncologic outcomes of TLPD and OPD in the setting of pancreatic ductal adenocarcinoma.
BACKGROUND: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.
METHODS: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.
RESULTS: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).
CONCLUSIONS: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 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.
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 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 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
Distant metastases are the strongest predictor of poor prognosis for patients with neuroendocrine tumors (NETs). Cytoreductive hepatectomy (CRH) can relieve symptoms of hormonal excess and ...prolong survival for patients with liver metastases (NETLMs), but long-term outcomes are poorly characterized.
Methods
This retrospective single-institution analysis analyzed patients who underwent CRH for well-differentiated NETLMs from 2000 to 2020. Kaplan-Meier analysis estimated symptom-free interval and overall and progression-free survival. Multivariable Cox regression analysis evaluated factors associated with survival.
Results
The inclusion criteria were met by 546 patients. The most common primary sites were the small intestine (
n
= 279) and the pancreas (
n
= 194). Simultaneous primary tumor resection was performed for 60 % of the cases. Major hepatectomy comprised 27% of the cases, but this rate decreased during the study period (
p
< 0.001). Major complications occurred in 20%, and the 90-day mortality rate was 1.6%. Functional disease was present in 37 %, and symptomatic relief was achieved in 96%. The median symptom-free interval was 41 months (62 months after complete cytoreduction and 21 months with gross residual disease) (
p
= 0.021). The median overall survival was 122 months, and progression-free survival was 17 months. In the multivariable analysis, worse overall survival was associated with age, pancreatic primary tumor, Ki-67, number and size of lesions, and extrahepatic metastases, with Ki-67 as the strongest predictor (odds ratio OR, 1.90 for Ki-67 3–20%;
p
= 0.018 and OR, 4.25 for Ki-67 >20%;
p
< 0.001).
Conclusion
The study showed that CRH for NETLMs is associated with low perioperative morbidity and mortality and excellent overall survival, although the majority will experience recurrence/progression. For patients with functional tumors, CRH can provide durable symptomatic relief.
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