Background
Neoadjuvant chemotherapy (NAC) is an integral part of preoperative treatment for patients with borderline resectable/locally advanced (BR/LA) pancreatic ductal adenocarcinoma (PDAC). The ...identification of a chemotherapeutic regimen that is both effective and tolerable is critical for NAC to be of oncologic benefit. After initial first-line (FL) NAC, some patients have lack of response or therapeutic toxicities precluding further treatment with the same regimen; optimal decision making regarding this patient population is unclear. Chemotherapy switch (CS) may allow for a larger proportion of patients to undergo curative-intent resection after NAC.
Methods
We reviewed our surgical database for patients undergoing combinatorial NAC for BR/LA PDAC. Variant histologic exocrine carcinomas, intraductal papillary mucinous neoplasm-associated PDAC, and patients without research consent were excluded.
Results
Overall, 468 patients with BR/LA PDAC receiving FL chemotherapy were reviewed, of whom 70% (329/468) continued with FL chemotherapy followed by surgical resection. The remaining 30% (139/468) underwent CS, with 72% (100/139) of CS patients going on to curative-intent surgical resection. Recurrence-free survival (RFS) and overall survival (OS) were not significantly different between the resected FL and CS cohorts (30.0 vs. 19.1 months,
p
= 0.13, and 41.4 vs. 36.4 months,
p
= 0.94, respectively) and OS was significantly worse in those undergoing CS without subsequent resection (19 months,
p
< 0.0001). On multivariable analysis, carbohydrate antigen (CA) 19-9 and pathologic treatment responses were predictors of RFS and OS.
Conclusion
CS in patients undergoing NAC for BR/LA pancreatic cancer does not incur oncologic detriment. The incorporation of CS into NAC treatment sequencing may allow a greater proportion of patients to proceed to curative-intent surgery.
The Hippo pathway effector, Yes-associated protein (YAP), is a transcriptional coactivator implicated in cholangiocarcinoma (CCA) pathogenesis. YAP is known to be regulated by a serine/threonine ...kinase relay module (MST1/2-LATS1/2) culminating in phosphorylation of YAP at Serine 127 and cytoplasmic sequestration. However, YAP also undergoes tyrosine phosphorylation, and the role of tyrosine phosphorylation in YAP regulation remains unclear. Herein, YAP regulation by tyrosine phosphorylation was examined in human and mouse CCA cells, as well as patient-derived xenograft (PDX) models. YAP was phosphorylated on tyrosine 357 (Y357) in CCA cell lines and PDX models. SRC family kinase (SFK) inhibition with dasatinib resulted in loss of YAPY357 phosphorylation, promoted its translocation from the nucleus to the cytoplasm, and reduced YAP target gene expression, including cell lines expressing a LATS1/2-resistant YAP mutant in which all serine residues were mutated to alanine. Consistent with these observations, precluding YAPY357 phosphorylation by site-directed mutagenesis (YAPY357F) excluded YAP from the nucleus. Targeted siRNA experiments identified LCK as the SFK that most potently mediated YAPY357 phosphorylation. Likewise, inducible CRISPR/Cas9-targeted LCK deletion decreased YAPY357 phosphorylation and its nuclear localization. The importance of LCK in CCA biology was demonstrated by clinical observations suggesting LCK expression levels were associated with early tumor recurrence following resection of CCA. Finally, dasatinib displayed therapeutic efficacy in PDX models.
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Background
Surgical portosystemic shunts are rare. We reviewed indications, operative details, and outcomes of patients undergoing surgical portosystemic shunt procedures.
Methods
We retrospectively ...reviewed clinical data of consecutive patients between 1997 and 2018 from a single institution. Clinical characteristics and outcomes were compared between two groups: patients with portomesenteric venous thrombosis (PMVT) vs those with cirrhosis. Endpoints included 30-day mortality, shunt-related complications, patency, and survival.
Results
There were 99 patients, 45 male and 54 female, with a mean age of 46 ± 18 years, enrolled in the study. There were 63 patients (63%) with PMVT and 36 patients (36%) with cirrhosis. Both groups had similar demographics, cardiovascular risk factors, and aneurysm extent, except for more diabetes among those with cirrhosis (
p
< 0.05). There were no significant differences in procedural metrics and intra-procedure complications between groups, except that patients with PMVT underwent more non-selective shunts than those with cirrhosis (63% vs. 30%,
p
< 0.001). There were two 30-day deaths (2%), with no difference in mortality and MAEs between groups. On univariate analysis, cholangiopathy and PMVT were associated with graft thrombosis (HR = 9.22, 95% CI 1.22–70.27) while race, smoking, cardiac comorbidity, type of operative shunt, configuration of the shunt, and use of conduit were not (
p
> 0.05). Patients with PMVT had significantly lower 1-, 5-, and 10-year primary (77%, 71%, and 71% vs. 97%,
p
= 0.009) and secondary patency (88%, 76%, and 72% vs. 96%,
p
= 0.027) compared with those with cirrhosis. The 1-, 5-, and 10-year survival rates were 94%, 84%, and 61% for patients with PMVT compared with 88%, 58%, and 26% for those with cirrhosis (non-adjusted HR 0.40, 95% CI 0.19–0.84,
p
= 0.01, age-adjusted HR 0.51, 95% CI 0.24–1.09,
p
= 0.08). The survival of patients with PMVT without liver disease trended higher than those with liver disease; however, when adjusted for age, the survival gap narrowed, and the difference was not statistically significant (
p
= 0.19), survival being lowest for those with PMVT and liver disease.
Conclusions
Surgical portosystemic shunts are safe and effective for symptom relief in selected patients with portal hypertension. The odds of graft thrombosis is 9 times higher in patients with PMVT. Overall survival is similar in patients with PMVT or cirrhosis.
Resection margin status has been recognized as an independent prognostic factor on overall survival in pancreatic cancer patients undergoing surgical resection. However, its impact after neoadjuvant ...treatment remains uncertain.
We analyzed 305 patients with resectable or borderline resectable pancreatic cancer treated with neoadjuvant therapy and pancreatoduodenectomy at 3 tertiary referral centers between 2010 and 2017. Positive resection margin was defined as 1 or more cancer cells at any margin. Overall survival was measured from the date of surgery until death or last follow-up.
One hundred and seventy-eight patients received neoadjuvant chemotherapy and 127 received neoadjuvant chemoradiotherapy. The median overall survival was 29.8 months. The 1-, 3-, and 5-year overall survival rates were 79.2%, 44.0%, and 23.5%, respectively. Negative margin was achieved in 275 (90.2%) patients. Negative margin resection patients had a significantly longer overall survival than positive resection margin patients (31.3 vs 16.3 months, P < .001). In univariate analyses, overall survival was associated with age, margin status, histologic grade, ypT, number of positive lymph nodes, perineural invasion, treatment effect, postoperative carbohydrate antigen 19-9, and adjuvant therapy. Positive margin resection, poorly differentiated carcinoma, treatment effect score of 3, postoperative carbohydrate antigen 19-9 of 37 U/mL or higher, and lack of adjuvant therapy were predictive of poor overall survival in multivariate Cox regression analysis.
Margin status was an independent predictor of overall survival in patients treated with neoadjuvant therapy and pancreatoduodenectomy, supporting the use of a negative margin resection as a surrogate of adequate oncological resection in this setting. Our findings may also have significant implications for patient stratification in future randomized trials.
Abstract Perioperative anemia is common, yet detrimental, in surgical patients. However, red blood cell transfusions (RBCTs) used to treat anemia are associated with significant postoperative risks ...and worse oncologic outcomes. Perioperative iron has been suggested to mitigate perioperative anemia. This meta-analysis examined the impact of perioperative iron compared to no intervention on the need for RBCT in gastrointestinal surgery. We systematically searched Medline, Embase, Web of Science, Cochrane Central, and Scopus to identify relevant randomized controlled trials (RCTs) and nonrandomized studies (NRSs). We excluded studies investigating autologous RBCT or erythropoietin. Two independent reviewers selected the studies, extracted data, and assessed the risk of bias using the Cochrane tool and Newcastle-Ottawa scale. Primary outcomes were proportion of patients getting allogeneic RBCT and number of transfused patient. Secondary outcomes were hemoglobin change, 30-day postoperative morbidity and mortality, length of stay, and oncologic outcomes. A meta-analysis using random effects models was performed. The review was registered in PROSPERO (CRD42013004805). From 883 citations, we included 2 RCTs and 2 NRSs (n = 325 patients), all pertaining to colorectal cancer surgery. Randomized controlled trials were at high risk for bias and underpowered. One RCT and 1 NRS using preoperative oral iron reported a decreased proportion of patients needing RBCT. One RCT on preoperative intravenous iron and 1 NRS on postoperative PO iron did not observe a difference. Only 1 study revealed a difference in number of transfused patients. One RCT reported significantly increased postintervention hemoglobin. Among 3 studies reporting length of stay, none observed a difference. Other secondary outcomes were not reported. Meta-analysis revealed a trend toward fewer patients requiring RBCT with iron supplementation (risk ratio, 0.66 0.42, 1.02), but no benefit on the number of RBCT per patient (weighted mean difference, − 0.91 − 1.61, − 0.18). Although preliminary evidence suggests that it may be a promising strategy, there is insufficient evidence to support the routine use of perioperative iron to decrease the need for RBCT in colorectal cancer surgery. Well-designed RCTs focusing on the need for RBCT and including long-term outcomes are warranted.
Background
In gastric cancer, the utility of sentinel lymph node (SLN) biopsy has not been established. SLN may be a good predictor of the pathological status of other lymph nodes and thus the ...necessity for more extensive surgery or lymph node dissection. We aimed to identify and synthesize findings on the performance of SLN biopsies in gastric cancer.
Methods
Electronic literature searches were conducted using Medline, EMBASE, and the Cochrane Central Register of Controlled Trials from 1998 to 2009. Titles and abstracts were independently rated for relevance by a minimum of two reviewers. Techniques, detection rates, accuracy, sensitivity, specificity, and false-negative rates (FNRs) were analyzed. Analysis was performed based on the FNR.
Results
Twenty-six articles met our inclusion criteria. SLN detection using the dye method (DM) was reviewed in 18 studies, the radiocolloid method (RM) was used in 12 studies, and both dye and radiocolloid methods (DUAL) were used in 5 studies. The DM had an overall calculated FNR of 34.7% (95% confidence interval CI 21.2, 48.1). The RM had an overall calculated FNR of 18.5% (95% CI 9.1, 28.0). DUAL had an overall calculated FNR of 13.1% (95% CI −0.9, 27.2).
Conclusion
Application of the SLN technique may be practical for early gastric cancer. The use of DUAL for identifying SLN may yield a lower FNR than either method alone, although statistical significance was not met.
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