Intrahepatic cholangiocarcinoma (ICC)-a rare liver malignancy with limited therapeutic options-is characterised by aggressive progression, desmoplasia and vascular abnormalities. The aim of this ...study was to determine the role of placental growth factor (PlGF) in ICC progression.
We evaluated the expression of PlGF in specimens from ICC patients and assessed the therapeutic effect of genetic or pharmacologic inhibition of PlGF in orthotopically grafted ICC mouse models. We evaluated the impact of PlGF stimulation or blockade in ICC cells and cancer-associated fibroblasts (CAFs) using in vitro 3-D coculture systems.
PlGF levels were elevated in human ICC stromal cells and circulating blood plasma and were associated with disease progression. Single-cell RNA sequencing showed that the major impact of PlGF blockade in mice was enrichment of quiescent CAFs, characterised by high gene transcription levels related to the Akt pathway, glycolysis and hypoxia signalling. PlGF blockade suppressed Akt phosphorylation and myofibroblast activation in ICC-derived CAFs. PlGF blockade also reduced desmoplasia and tissue stiffness, which resulted in reopening of collapsed tumour vessels and improved blood perfusion, while reducing ICC cell invasion. Moreover, PlGF blockade enhanced the efficacy of standard chemotherapy in mice-bearing ICC.
PlGF blockade leads to a reduction in intratumorous hypoxia and metastatic dissemination, enhanced chemotherapy sensitivity and increased survival in mice-bearing aggressive ICC.
Background
The question of the ideal neoadjuvant therapy for locally advanced esophagogastric adenocarcinoma has not been answered to date. Multimodal treatment has become a standard treatment for ...these adenocarcinomas. Currently, perioperative chemotherapy (FLOT) or neoadjuvant chemoradiation (CROSS) is recommended.
Methods
A monocentric retrospective analysis compared long-term survival after CROSS versus FLOT. The study enrolled patients with adenocarcinoma of the esophagus (EAC) or the esophagogastric junction type I or II undergoing oncologic Ivor–Lewis esophagectomy between January 2012 and December 2019. The primary objective was to determine the long-term outcome in terms of overall survival. The secondary objectives were to determine differences regarding the histopathologic categories after neoadjuvant treatment and the histomorphologic regression.
Results
The findings showed no survival advantage for one or the other treatment in this highly standardized cohort. All the patients underwent open (CROSS: 9.4% vs. FLOT: 22%), hybrid (CROSS: 82% vs. FLOT: 72%), or minimally invasive (CROSS: 8.9% vs. FLOT: 5.6%) thoracoabdominal esophagectomy. The median post-surgical follow-up period was 57.6 months (95% confidence interval CI 23.2–109.7 months), and the median survival was longer for the CROSS patients (54 months) than for the FLOT patients (37.2 months) (
p
= 0.053). The overall 5-years survival was 47% for the entire cohort (48% for the CROSS and 43% for the FLOT patients). The CROSS patients showed a better pathologic response and fewer advanced tumor stages.
Conclusion
The improved pathologic response after CROSS cannot be translated into longer overall survival. To date, the choice of which neoadjuvant treatment to use can be made only on the basis of clinical parameters and the patient’s performance status.
Background
So far only trastuzumab, pembrolizumab and ramucirumab have been approved by the FDA for targeted therapy in gastric cancer (GC). Here we report on potential targeted therapy options for ...gastric adenocarcinoma based on a novel analysis of “The Cancer Genome Atlas (TCGA)” database.
Methods
One hundred two FDA-approved targeted cancer drugs were compiled and molecular targets defined. Drugs were considered as potentially effective if targeted genes showed (1) an increase in copy number, (2) gain of function with oncogene activation, (3) specific alterations responsive to approved drugs. Additionally, genetic changes that confer drug resistance and/or sensitivity were evaluated.
Results
Fifty percentage of patients with GC may be treatable with non-GC but FDA-approved targeted cancer therapies. The major drug identified in our in silico study for GC is copanlisib, a PI3K inhibitor. In the TCGA patient database, our genetically based drug response prediction identified more patients with alterations sensitive to copanlisib compared to the already-GC-approved drug trastuzumab (20%, 78 out of 393 patients, vs. trastuzumab: 13%, 52 of 393 patients), which is mainly due to the high incidence of PIK3CA gain of function mutations within mutation hot spots.
Conclusion
Our results demonstrate that various currently FDA-approved drugs might be candidates for targeted therapy of GC. For clinical trials, cancer patients should be selected based on the genomic profile of their tumor.
Background
The impact of total minimally invasive esophagectomy (MIE) on early postoperative outcome and patient’s survival is a matter of recent discussion.
Methods
We performed a 1:2 propensity ...score-matched comparison of 20 patients who underwent 3D-MIE and high intrathoracic esophagogastrostomy with 40 patients who underwent hybrid esophagectomy (HYBRID) with laparoscopic gastric mobilization and open transthoracic esophagectomy and the same anastomosis for esophageal adenocarcinoma in 2014 and 2015. Matching criteria were tumor localization, age, gender, and neoadjuvant treatment.
Results
Both groups did not differ regarding overall postoperative complications (MIE 55% vs. HYBRID 50%,
p
= 0.715) and anastomotic leakage (MIE 15% vs. HYBRID 5%,
p
= 0.186). A significant difference was seen regarding the rate of postoperative pneumonia (MIE 5% vs. HYBRID 27.5%;
p
= 0.040) and the postoperative ICU stay (MIE median 1 day vs. HYBRID median 2 days,
p
< 0.001). The R0-resection rate was 100% in both groups and median number of dissected lymph nodes was 32 for MIE and 35 for HYBRID (
p
= 0.236). Significant differences between both groups were noticed for postoperative number of patients with use of opiate demand medication and numeric rating scale for pain (NRSP maximum pain, median) both in favor of the MIE group (MIE 25%, NRSP 2 vs. HYBRID 60%, NRSP 4;
p
= 0.011,
p
< 0.001). Overall 2-year survival rate was 85% in both groups.
Conclusion
Total minimally invasive esophagectomy is superior to hybrid esophagectomy in regard of postoperative pain and rate of pneumonia. No differences exist for postoperative surgical complications or short-term prognosis.
Esophageal cancer is among the top ten most deadly cancers worldwide with adenocarcinomas of the esophagus showing increasing incidences over the last years. The prognosis is determined by tumor ...stage at diagnosis and in locally advanced stages by response to (radio-)chemotherapy followed by radical surgery. Less than a third of patients with esophageal adenocarcinomas completely respond to neoadjuvant therapies which urgently asks for further strategies to improve these rates. Aiming at the tumor microenvironment with novel targeted therapies can be one strategy to achieve this goal. This review connects experimental, translational, and clinical findings on each component of the esophageal cancer tumor microenvironment involving tumor angiogenesis, tumor-infiltrating immune cells, such as macrophages, T-cells, myeloid-derived suppressor cells, and cancer-associated fibroblasts. The review evaluates the current state of already approved concepts and depicts novel potentially targetable pathways related to esophageal cancer tumor microenvironment.
To date, patients with metastasized pancreatic ductal adenocarcinoma (PDAC M1) are regarded as a uniform collective. We hypothesize the existence of oligometastatic disease (OMD): a state of PDAC M1 ...disease with better tumor biology, limited metastasis, and increased survival.
Data of 128 PDAC M1 patients treated at the University of Cologne between 2008 and 2018 was reviewed. Interdependence between clinical parameter was calculated using the Mann-Whitney U-Test. Survival curves were generated using the Kaplan-Meier method and analyzed using the log-rank test.
Eighty-one (63%) patients had metastases confined to one organ (single organ metastasis, SOG) whereas the remaining 47 (37%) showed multiple metastatic sites (multi-organ metastasis, MOG). Survival analysis revealed a median overall survival (OS) of 12.2 months for SOG vs 4.5 months for MOG (95% CI 5.7-9.8; p < 0.001). We defined limited disease by the presence of ≤4 metastases in liver or lung. Limited disease together with CA 19-9 baseline < 1000 U/ml and response or stable disease after first-line chemotherapy defined OMD. We identified 8 patients with hepatic metastases and 2 with pulmonary metastases matching all OMD criteria. This group of 10 (7.8%) had a median overall survival of 19.4 vs 7.2 months compared to the remaining patients (95% CI 5.7-9.8; p = 0.009).
We propose a definition of oligometastatic disease in PDAC including anatomical criteria and biological criteria reflecting better tumor biology. The 10 OMD patients (7.8%) survived significantly longer and might even benefit from surgical resection in the future.
Residual tumor at the resection margins after surgery for gastric and gastroesophageal junction (GEJ) adenocarcinoma is a known prognostic factor. In this single-center, retrospective cohort study in ...a tertiary referral center, we aimed to evaluate the relevance of intraoperative pathology consultation (IOC) and consecutive extension of surgery on patient survival.
Of 737 consecutive patients undergoing (sub)total gastrectomy for gastric or GEJ adenocarcinoma, 679 cases with curative intent surgery between 05/1996 and 03/2019 were included. Patients were categorized into: i) R0 without further resection (direct R0), ii) R0 after positive IOC and extension of resection (converted R0) and iii) R1.
IOC was performed in 242 (35.6%) patients, in 216 (89.3%) at the proximal resection margin. Direct R0 status was achieved in 598 (88.1%), converted R0 in 26 (3.8%) of 38 (5.6%) patients with positive IOC and R1 in 55 (8.1%) patients. Median follow-up was 29 months for surviving patients. 3-year survival rate (3-YSR) was significantly higher for direct R0 compared to converted R0 with 62.3% compared to 21.8% (hazard ratio (HR)=0.298; 95%CI=0.186-0.477, P<0.001). 3-YSR was similar between converted R0 and R1 (21.8% vs. 13.3%; HR=0.928; 95%CI=0.526-1.636, P=0.792). In multivariate analysis, advanced T (P<0.001), N (P<0.001), R (P=0.003) and M1 status (P<0.001) were associated with worse overall survival (OS).
IOC and consecutive extended resection for positive resection margins in gastrectomy for proximal gastric and gastroesophageal junction does not achieve long-term survival benefits in advanced tumor stages.
Esophageal adenocarcinoma (EAC) is one of the most lethal malignancies, and limits promising treatments. AKR1C3 represents a therapeutic target to combat the resistance in many cancers. However, the ...molecular mechanism of AKR1C3 in the chemotherapy resistance of EAC is still unclear. We found that the mRNA level of AKR1C3 was higher in EAC tumor tissues, and that high AKR1C3 expression might be associated with poor overall survival of EAC patients. AKR1C3 overexpression decreased cell death induced by chemotherapeutics, while knockdown of AKR1C3 attenuated the effect. Furthermore, we found AKR1C3 was inversely correlated with ROS production. Antioxidant NAC rescued chemotherapy-induced apoptosis in AKR1C3 knockdown cells, while the GSH biosynthesis inhibitor BSO reversed a protective effect of AKR1C3 against chemotherapy. AKT phosphorylation was regulated by AKR1C3 and might be responsible for eliminating over-produced ROS in EAC cells. Intracellular GSH levels were modulated by AKR1C3 and the inhibition of AKT could reduce GSH level in EAC cells. Here, we reported for the first time that AKR1C3 renders chemotherapy resistance through controlling ROS levels via AKT signaling in EAC cells. Targeting AKR1C3 may represent a novel strategy to sensitize EAC cells to conventional chemotherapy.
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