Background
Multidisciplinary discussion of the treatment of patients with colorectal liver metastases (CRLM) is advocated currently. The aim of this study was to investigate medical oncologists' and ...surgeons' assessment of resectability and indication for chemotherapy, and the effect of an educational intervention on such assessment.
Methods
Medical histories of 30 patients with CRLM were presented to ten experienced medical oncologists and 11 surgeons at an initial virtual tumour board meeting (TB1). Treatment recommendations were obtained from each participant by voting for standardized answers. Following lectures on the potential of chemotherapy and surgery, assessment was repeated at a second virtual tumour board meeting (TB2), using the same patients and participants.
Results
Overall, 630 answers (21 × 30) were obtained per tumour board meeting. At TB1, resectability was expected more frequently by surgeons. Participants changed 56·8 per cent of their individual answers at TB2. Assessment shifted from potentially resectable to resectable CRLM in 81 of 161 and from unresectable to (potentially) resectable CRLM in 29 of 36 answers. Preoperative chemotherapy was indicated more often by medical oncologists, and overall was included in 260 answers (41·3 per cent) at TB1, compared with only 171 answers (27·1 per cent) at TB2. Medical oncologists more often changed their decision to primary resection in resectable patients (P = 0·006). Postoperative chemotherapy was included in 51·9 and 52·4 per cent of all answers at TB1 and TB2 respectively, with no difference in changes between medical oncologists and surgeons (P = 0·980).
Conclusion
Resectability and indication for preoperative chemotherapy were assessed differently by medical oncologists and surgeons. The educational intervention resulted in more patients deemed resectable by both oncologists and surgeons, and less frequent indication for chemotherapy.
Judgement of resectability differs substantially
Purpose
Surgery is the standard of care for resectable colorectal liver metastases (CRC-LM). Unfortunately, 60 % of patients develop secondary metastatic recurrence (SMR) after R0-resection of ...CRC-LM. We investigated the impact of surgical re-intervention and chemotherapy (Ctx) on survival in a consecutive series of patients with SMR.
Methods
From 01/2001 to 11/2011, 104 out of 178 consecutive patients with R0-resection of CRC-LM developed SMR and were evaluated. The impact of surgical and Ctx re-interventions on recurrence free (RFS) and cancer-specific survival (CSS) was analyzed. Median follow-up was 28.0 (95 %CI: 19.4–37.4) months.
Results
SMR occurred in 81 patients at a single site (49× liver, 18× lung, 14× other) and in 23 patients at multiple sites. Forty-two patients were scheduled for primary surgery. Fifty-three patients were classified as non-resectable and treated with median 5.0 IQR, 3.0–10.0 cycles of Ctx, combined with an EGFR/VEGF-antibody in 27 patients. Nine patients received best supportive care only. R0/R1 resection could be achieved in 35 patients primarily and even in 8 patients secondarily after Ctx. Surgical morbidity and mortality were 16 and 0 %, respectively. The 5-year RFS rates for patients with R0 versus R1-resection were 22 and 24 % (
p
= 0.948). The 5-year CSS rate for R0/R1-resected patients was 38 % versus 10 % for those patients treated by Ctx alone (
p
< 0.001).
Conclusion
In SMR, surgical re-intervention is feasible and safe in a remarkable number of patients and offers significantly longer CSS compared to patients without resection.
Purpose
Bilobar colorectal liver metastases (CRLM) are often considered incurable or associated with poor prognosis even after R0 resection. In this single-center study, we evaluate the impact of ...CRLM spreading on recurrence-free survival (RFS) and cancer-specific overall survival (CSS) after R0 resection of CRLM with respect to multimodal treatment strategies including perioperative chemotherapy and multistep resections.
Methods
Between January 2001 and December 2010, R0 resection could be achieved in 70 patients with bilobar and 100 with unilobar CRLM. Extent of disease, perioperative chemotherapy, surgical procedures, adjuvant treatment, histopathological workup, RFS, and CSS were compared between both cohorts.
Results
Forty-six (66 %) patients with bilobar and 26 (26 %) patients with unilobar CRLM received preoperative chemotherapy (
p
< 0.001). For bilobar CRLM, more extended and multistep resection including portal vein occlusion were performed (29 % versus 3 %;
p
< 0.001). Morbidity (39 % versus 28 %,
p
= 0.183) and mortality (1 % versus 3 %,
p
= 0.644) rates were comparable in both patients’ cohorts. Postoperative therapy was applied in adjuvant intent to 42 (60 %) versus 51 (51 %) patients (
p
= 0.275). The 5-year RFS and CSS rates were 24 % versus 31 % (
p
= 0.169) and 42 % versus 55 % (
p
= 0.131), respectively.
Conclusions
To our single-center experience, there is no significant effect of CRLM spreading (bilobar versus unilobar) on RFS and CSS rates. Bilobar CRLM are more likely to require extended multimodal efforts to achieve R0 resection.
Abstract
Background/Introduction
Recently published, diverging data of the COAPT and Mitra.fr trials yielded discussion on the impact of the magnitude of mitral valve insufficiency and of left ...ventricular end-diastolic volume index (LVEDVI) in patients with functional mitral regurgitation (FMR) prior to MitraClip intervention on outcome measures.
Purpose
We sought to evaluate the leverage of the effective orifice area (EROA) and LVEDVI on long-term outcome in a real-life cohort.
Methods
We stratified 394 patients (74.4±8.6 years, 60.9% male) that had been treated by MitraClip from 09/2008 to 01/2018 into four subgroups: I (FMR, EROA ≤30mm2 n=76), II (FMR, EROA 30–40mm2 n=87), III (FMR, EROA >40mm2 n=105) and IV (degenerative MR DMR, n=126). Follow-up was conducted at on-site visits 6 months and annually after MC procedure up to 60 months.
Results
At baseline, patients of subgroup IV were oldest (p=0.0011), while subgroups I to III demonstrated significantly higher rates of any cardiomyopathy (I: 78.4%, II: 93.1%, III: 86.7%, IV: 47.6%, p<0.001). The left ventricular ejection fraction (LVEF) differed significantly (I: 38±13%, II: 35±14%, III: 34±14%, IV: 54±12%, p<0.001), as did EuroSCORE values (median, I: 20.4%, II: 24%, III: 23%, IV: 18.4%, p<0.001). Procedural success (placement of ≥1 Clip, residual MR ≤2+) differed significantly (I: 96.1%, II: 96.6%, III: 89.5%, IV: 87.3%, p=0.039).
Up to 60 month follow-up lasting success was noted in 87.5% (I), 81.8% (II), 87.5% (III) and 77.8% (IV) and all subgroups demonstrated a significant improvement in New York Heart Failure Association classification.
In further stratification according to LVEDVI (A: ≤96ml/m2 and B: >96ml/m2), no differences were noted in Kaplan-Meier estimates for death (A: p=0.36 and B: p=53) or in post-hoc comparison of each group (I-IV). Likewise, the combined endpoint of death and cardiac rehospitalization (A: p=0.18, B: p=0.94), MACE (A: p=0.37, B: p=0.54) and MACCE (A: p=0.16, B: p=0.49) and post-hoc comparisons of each group (I-IV) yielded no significant differences in outcome measures.
Conclusions
Despite distinct differences in baseline characteristics of each subgroup, we observed high procedural success rates, long-lasting reductions of MR and beneficial clinical outcome in all patients. In this retrospective analysis of a real-life cohort, EROA and LVEDVI did not influence long-term outcome measures. These results indicate no limitation for MitraClip treatment based on advanced stages of FMR and its underlying pathology, yet mark the necessity for further pre-procedural stratification.
Hematogenous metastasis limits the survival of colorectal cancer (CRC) patients. Here, we illuminated the roles of CD44 isoforms in this process. Isoforms 3 and 4 were predominantly expressed in CRC ...patients. CD44 isoform 4 indicated poor outcome and correlated with epithelial–mesenchymal transition (EMT) and decreased oxidative phosphorylation (OxPhos) in patients; opposite associations were found for isoform 3. Pan‐CD44 knockdown (kd) independently impaired primary tumor formation and abrogated distant metastasis in CRC xenografts. The xenograft tumors mainly expressed the clinically relevant CD44 isoforms 3 and 4. Both isoforms were enhanced in the paranecrotic, hypoxic tumor regions but were generally absent in lung metastases. Upon CD44 kd, tumor angiogenesis was increased in the paranecrotic areas, accompanied by reduced hypoxia‐inducible factor‐1α and CEACAM5 but increased E‐cadherin expression. Mitochondrial genes and proteins were induced upon pan‐CD44 kd, as were OxPhos genes. Hypoxia increased VEGF release from tumor spheres, particularly upon CD44 kd. Genes affected upon CD44 kd in xenografts specifically overlapped concordantly with genes correlating with CD44 isoform 4 (but not isoform 3) in patients, validating the clinical relevance of the used model and highlighting the metastasis‐promoting role of CD44 isoform 4.
Pan‐CD44 knockdown decreases spontaneous metastasis in human colorectal cancer xenograft models. Concurrent intratumoral gene expression alterations significantly correlate with genes differentially regulated among CD44 isoform 4 (but not isoform 3) high vs. low patients (TCGA). The corresponding gene sets and pathways include epithelial–mesenchymal transition, angiogenesis, and OxPhos. CD44 isoform 4 (but not isoform 3) correlates with poor patient outcomes.
The role of fatty acid synthesis in endothelial cells (ECs) remains incompletely characterized. We report that fatty acid synthase knockdown (FASNKD) in ECs impedes vessel sprouting by reducing ...proliferation. Endothelial loss of FASN impaired angiogenesis in vivo, while FASN blockade reduced pathological ocular neovascularization, at >10-fold lower doses than used for anti-cancer treatment. Impaired angiogenesis was not due to energy stress, redox imbalance, or palmitate depletion. Rather, FASNKD elevated malonyl-CoA levels, causing malonylation (a post-translational modification) of mTOR at lysine 1218 (K1218). mTOR K-1218 malonylation impaired mTOR complex 1 (mTORC1) kinase activity, thereby reducing phosphorylation of downstream targets (p70S6K/4EBP1). Silencing acetyl-CoA carboxylase 1 (an enzyme producing malonyl-CoA) normalized malonyl-CoA levels and reactivated mTOR in FASNKD ECs. Mutagenesis unveiled the importance of mTOR K1218 malonylation for angiogenesis. This study unveils a novel role of FASN in metabolite signaling that contributes to explaining the anti-angiogenic effect of FASN blockade.
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•Fatty acid synthase inhibition impairs physiological and pathological angiogenesis•FASN inhibition selectively reduces endothelial cell proliferation, not migration•By elevating malonyl-CoA levels, FASN inhibition promotes mTOR lysine malonylation•The resultant decrease in mTORC1 kinase activity contributes to angiogenic defects
Bruning et al. report that blocking fatty acid synthase (FASN) in endothelial cells (ECs) reduces angiogenesis by impairing EC proliferation. Mechanistically, FASN inhibition elevates the malonyl-CoA substrate pool, thereby increasing post-translational malonylation of mTOR and decreasing the pro-angiogenic mTORC1 activity.
Gnomoniopsis castaneae
is an emerging fungal pathogen currently scored as the major nut rot agent on chestnut, although it is also associated with cankers on both chestnut and hazelnut, as well as ...with necrosis on chestnut galls and leaves. Described for the first time in 2012,
G. castaneae
has been reported in several countries across Europe, Asia and Australasia, often in relation to severe outbreaks. The goal of this review is to provide a comprehensive summary of the state of the art about
G. castaneae
, highlighting the main results achieved by the research and stressing the most relevant knowledge gaps that still need to be filled. This overview includes topics encompassing the taxonomy of the fungal pathogen, its host range and geographic distribution, the symptomatology and the diagnostic methods available for its detection, its impact, biology, ecology and epidemiology. The main interactions between
G. castaneae
and other organisms are also discussed, as well as the possible control strategies. In these past few years, relevant progresses in the knowledge of
G. castaneae
have been achieved, yet the complexity of the challenges that this pathogen poses to chestnut growers and to the scientific community advocates for further advances.
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