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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EMUNI, FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background
Prognosis in pancreatic ductal adenocarcinoma (PDAC) remains poor despite improved systemic therapies and surgical techniques. The identification of biomarkers to advance insight in tumor ...biology and achieve better individualized prognostication could help improve outcomes. Our aim was to elucidate the prognostic role of the four main driver mutations (
KRAS
,
TP53
,
SMAD4
,
CDKN2A
) and their combinations in resected PDAC.
Patients and Methods
A retrospective analysis was conducted utilizing the cBioPortal database and National Cancer Institute’s Cancer Genomic Atlas (TCGA) on patients in whom next-generation sequencing was performed on upfront resected PDAC from 2012 to 2020. Multivariable Cox regression was implemented to elucidate risk-adjusted predictors of overall (OS) and recurrence-free survival (RFS). Results were validated employing a Johns Hopkins Hospital (JHH) cohort.’
Results
In the discovery cohort (
n
= 587), increased number of mutated driver genes was associated with worse OS (
p =
0.047). Specifically, patients with mutations in ≥ 2 driver genes had worse OS than ≤ 1 mutated gene (18.2 versus 32.3 months,
p =
0.033). Co-occurrence of mutant (mt)
KRAS
p
.
G12D with mt
TP53
(median OS, 25.9 months) conferred better prognosis than co-occurrence of other mt
KRAS
variants (p.G12V/R/other) with mt
TP53
(median OS, 16.9 months,
p =
0.038). The findings were validated using a JHH cohort. Multivariable risk-adjustment found co-occurrence of mt
KRAS
p.G12D with mt
TP53
to be an independent predictor of beneficial OS and RFS HR (95% CI): 0.18 (0.03–0.81) and 0.31 (0.11–0.89) respectively.
Conclusion
In chemo-naïve resected PDAC, combinations of mutations in the four driver genes are associated with prognosis. In patients with combined mt
KRAS
and mt
TP53
,
KRAS
p.G12D variant confers a better OS and RFS.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background
Pancreatic ductal adenocarcinoma (PDAC) has a high propensity for systemic dissemination. Ovarian metastases are rare and poorly described.
Methods
We identified PDAC cases with ovarian ...metastasis from a prospectively maintained registry. We reported on the association between outcomes and clinicopathologic factors. Recurrence-free (RFS) and overall survival (OS) were calculated using Kaplan–Meier analysis.
Results
Twelve patients with PDAC and synchronous or metachronous ovarian metastases were identified. Nine patients (75%) underwent pancreatectomy for localized PDAC and developed metachronous ovarian recurrence. The median OS for all patients was 25.4 (IQR:15.4–82.9) months. For the nine patients with metachronous ovarian metastasis, the median RFS and OS were 14.2 (IQR:7.2–58.3) and 44.6 (IQR:18.6–82.9) months, respectively. Nodal disease, poor grade, vascular invasion in the pancreatic primary, and bilateral ovarian disease tended to confer worse outcomes.
Conclusion
Patients with resected PDAC and ovarian recurrence tend to have a comparable disease course to more common patterns of recurrence. Primaries with nodal disease, poorer grade, vascular invasion, and bilateral ovarian disease were indicative of more aggressive disease biology. The ideal management remains largely unknown, and future collaborative efforts should optimize therapeutic strategies.
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EMUNI, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background
Postoperative chemotherapy following pancreatic cancer resection is the standard of care. The utility of postoperative chemotherapy for patients who receive neoadjuvant therapy (NAT) is ...unclear.
Methods
Patients who underwent pancreatectomy after NAT with FOLFIRINOX or gemcitabine-based chemotherapy for non-metastatic pancreatic adenocarcinoma (2015–2019) were identified. Patients who received less than 2 months of neoadjuvant chemotherapy or died within 90 days from surgery were excluded.
Results
A total of 427 patients (resectable, 22.2%; borderline resectable, 37.9%; locally advanced, 39.8%) were identified with the majority (69.3%) receiving neoadjuvant FOLFIRINOX. Median duration of NAT was 4.1 months. Following resection, postoperative chemotherapy was associated with an improved median overall survival (OS) (28.7 vs. 20.4 months,
P
= 0.006). Risk-adjusted multivariable modeling showed negative nodal status (N0), favorable pathologic response (College of American Pathologists score 0 & 1), and receipt of postoperative chemotherapy to be independent predictors of improved OS. Regimen, duration, and number of cycles of NAT were not significant predictors. Thirty-four percent (60/176) of node-positive and 50.1% (126/251) of node-negative patients did not receive postoperative chemotherapy due to poor functional status, postoperative complications, and patient preference. Among patients with node-positive disease, postoperative chemotherapy was associated with improved median OS (27.2 vs. 10.5 months,
P
< 0.001). Among node-negative patients, postoperative chemotherapy was not associated with a survival benefit (median OS, 30.9 vs. 36.9 months;
P
= 0.406).
Conclusion
Although there is no standard NAT regimen for patients with pancreatic cancer, postoperative chemotherapy following NAT and resection appears to be associated with improved OS for patients with node-positive disease.
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EMUNI, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
To define frequencies, pattern of progression (invasive vs noninvasive), and risk factors of progression of resected noninvasive intraductal papillary mucinous neoplasms (IPMNs).
There is a risk of ...progression in the remnant pancreas after resection of IPMNs.
Four hundred forty-nine consecutive patients with resected IPMNs from 1995 to 2018 were included to the study. Patients with invasive carcinoma or with follow-up <6 months were excluded. Noninvasive progression was defined as a new IPMN, increased main pancreatic duct size, and increased size of an existing lesion (5 mm compared with preoperative imaging). Invasive progression was defined as development of invasive cancer in the remnant pancreas or metastatic disease.
With a median follow-up of 48.9 months, progression was identified in 124 patients (27.6%); 108(24.1%) with noninvasive and 16(3.6%) with invasive progression. Median progression follow-up was longer for invasive progression (85.4 vs 55.9 months; P = 0.001). Five-and 10-year estimates for a cumulative incidence of invasive progression were 6.4% and 12.9% versus 26.9% and 41.5% for noninvasive progression. After risk adjustment, multifocality (HR 4.53, 95% CI 1.34-15.26; P = 0.02) and high-grade dysplasia (HGD) in the original resection (HR 3.60, 95% CI 1.13-11.48; P = 0.03) were associated with invasive progression.
Progression to invasive carcinoma can occur years after the surgical resection of a noninvasive IPMN. HGD in the original resection is a risk factor for invasive progression but some cases of low-grade dysplasia also progressed to cancer. Patients with high-risk features such as HGD and multifocal cysts should be considered for more intensive surveillance and represent an important cohort for future trials such as anti-inflammatory or prophylactic immunotherapy.
Pancreatic ductal adenocarcinoma (PDAC) frequently presents with metastasis, but the molecular programs in human PDAC cells that drive invasion are not well understood. Using an experimental pipeline ...enabling PDAC organoid isolation and collection based on invasive phenotype, we assessed the transcriptomic programs associated with invasion in our organoid model. We identified differentially expressed genes in invasive organoids compared with matched noninvasive organoids from the same patients, and we confirmed that the encoded proteins were enhanced in organoid invasive protrusions. We identified 3 distinct transcriptomic groups in invasive organoids, 2 of which correlated directly with the morphological invasion patterns and were characterized by distinct upregulated pathways. Leveraging publicly available single-cell RNA-sequencing data, we mapped our transcriptomic groups onto human PDAC tissue samples, highlighting differences in the tumor microenvironment between transcriptomic groups and suggesting that non-neoplastic cells in the tumor microenvironment can modulate tumor cell invasion. To further address this possibility, we performed computational ligand-receptor analysis and validated the impact of multiple ligands (TGF-β1, IL-6, CXCL12, MMP9) on invasion and gene expression in an independent cohort of fresh human PDAC organoids. Our results identify molecular programs driving morphologically defined invasion patterns and highlight the tumor microenvironment as a potential modulator of these programs.
Abstract Background and Aim Intraductal papillary mucinous neoplasm (IPMN)‐derived pancreatic ductal adenocarcinoma (PDAC) management is generally extrapolated from pancreatic intraepithelial ...neoplasia (PanIN)‐derived PDAC guidelines. However, these are biologically divergent, and heterogeneity further exists between tubular and colloid subtypes. Methods Consecutive upfront surgery patients with PanIN‐derived and IPMN‐derived PDAC were retrospectively identified from international centers (2000–2019). One‐to‐one propensity score matching for clinicopathologic factors generated three cohorts: IPMN‐derived versus PanIN‐derived PDAC, tubular IPMN‐derived versus PanIN‐derived PDAC, and tubular versus colloid IPMN‐derived PDAC. Overall survival (OS) was compared using Kaplan–Meier and log‐rank tests. Multivariable Cox regression determined corresponding hazard ratios (HR) and 95% confidence intervals (95% CI). Results The median OS (mOS) in 2350 PanIN‐derived and 700 IPMN‐derived PDAC patients was 23.0 and 43.1 months ( P < 0.001), respectively. PanIN‐derived PDAC had worse T‐stage, CA19‐9, grade, and nodal status. Tubular subtype had worse T‐stage, CA19‐9, grade, nodal status, and R1 margins, with a mOS of 33.7 versus 94.1 months ( P < 0.001) in colloid. Matched ( n = 495), PanIN‐derived and IPMN‐derived PDAC had mOSs of 30.6 and 42.8 months ( P < 0.001), respectively. In matched ( n = 341) PanIN‐derived and tubular IPMN‐derived PDAC, mOS remained poorer (27.7 vs 37.4, P < 0.001). Matched tubular and colloid cancers ( n = 112) had similar OS ( P = 0.55). On multivariable Cox regression, PanIN‐derived PDAC was associated with worse OS than IPMN‐derived (HR: 1.66, 95% CI: 1.44–1.90) and tubular IPMN‐derived (HR: 1.53, 95% CI: 1.32–1.77) PDAC. Colloid and tubular subtype was not associated with OS ( P = 0.16). Conclusions PanIN‐derived PDAC has worse survival than IPMN‐derived PDAC supporting distinct outcomes. Although more indolent, colloid IPMN‐derived PDAC has similar survival to tubular after risk adjustment.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The liver plays a key role in amino acid metabolism. In former studies, a ratio between branched-chain and aromatic amino acids (Fischer's ratio) revealed associations with hepatic encephalopathy. ...Furthermore, low concentrations of branched-chain amino acids were linked to sarcopenia in literature. Encephalopathy and sarcopenia are known to dramatically worsen the prognosis. Aim of this study was to investigate a complex panel of plasma amino acids in the context of mortality in patients with end-stage liver disease.
166 patients evaluated for orthotopic liver transplantation were included. 19 amino acids were measured from citrated plasma samples using mass spectrometry. We performed survival analysis for plasma amino acid constellations and examined the relationship to established mortality predictors.
33/166 (19.9%) patients died during follow-up. Lower values of valine (p<0.001), Fischer's ratio (p<0.001) and valine to phenylalanine ratio (p<0.001) and higher values of phenylalanine (p<0.05) and tyrosine (p<0.05) were significantly associated with mortality. When divided in three groups, the tertiles discriminated cumulative survival for valine (p = 0.016), phenylalanine (p = 0.024) and in particular for valine to phenylalanine ratio (p = 0.003) and Fischer's ratio (p = 0.005). Parameters were also significantly correlated with MELD and MELD-Na score.
Amino acids in plasma are valuable biomarkers to determine increased risk of mortality in patients with end-stage liver disease. In particular, valine concentrations and constellations composed of branched-chain and aromatic amino acids were strongly associated with prognosis. Due to their pathophysiological importance, the identified amino acids could be used to examine individual dietary recommendations to serve as potential therapeutic targets.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The association of circulating sphingosine-1-phosphate (S1P), a bioactive lipid involved in various cellular processes, and related metabolites such as sphinganine-1-phosphate (SA1P) and sphingosine ...(SPH) with mortality in patients with end-stage liver disease is investigated in the presented study. S1P as a bioactive lipid mediator, is involved in several cellular processes, however, in end-stage liver disease its role is not understood.
The study cohort consisted of 95 patients with end-stage liver disease and available information on one-year outcome. The median MELD (Model for end-stage liver disease) score was 12.41 (Range 6.43-39.63). The quantification of sphingolipids in citrated plasma specimen was performed after methanolic protein precipitation followed by hydrophilic interaction liquid chromatography and tandem mass spectrometric detection.
S1P and SA1P displayed significant correlations with the MELD score. Patients with circulating S1P levels below the lowest tertile (110.68 ng/ml) showed the poorest one-year survival rate of only 57.1%, whereas one-year survival rate in patients with S1P plasma levels above 165.67 ng/ml was 93.8%. In a multivariate cox regression analysis including platelet counts, concentrations of hemoglobin and MELD score, S1P remained a significant predictor for three-month and one-year mortality.
Low plasma S1P concentrations are highly significantly associated with prognosis in end-stage liver disease. This association is independent of the stage of liver disease. Further studies should be performed to investigate S1P, its role in the pathophysiology of liver diseases and its potential for therapeutic interventions.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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