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result(s) for
"Schirripa, M"
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BRAF and RAS mutations as prognostic factors in metastatic colorectal cancer patients undergoing liver resection
Background:
Despite major advances in the management of metastatic colorectal cancer (mCRC) with liver-only involvement, relapse rates are high and reliable prognostic markers are needed.
Methods:
To assess the prognostic impact of
BRAF
and
RAS
mutations in a large series of liver-resected patients, medical records of 3024 mCRC patients were reviewed. Eligible cases undergoing potentially curative liver resection were selected.
BRAF
and
RAS
mutational status was tested on primary and/or metastases by means of pyrosequencing and mass spectrometry genotyping assay. Primary endpoint was relapse-free survival (RFS).
Results:
In the final study population (
N
=309)
BRAF
mutant,
RAS
mutant and all wild-type (wt) patients were 12(4%), 160(52%) and 137(44%), respectively. Median RFS was 5.7, 11.0 and 14.4 months respectively and differed significantly (Log-rank,
P
=0.043). At multivariate analyses,
BRAF
mutant had a higher risk of relapse in comparison to all wt (multivariate hazard ratio (HR)=2.31; 95% CI, 1.09–4.87;
P
=0.029) and to
RAS
mutant (multivariate HR=2.06; 95% CI, 1.02–4.14;
P
=0.044). Similar results were obtained in terms of overall survival. Compared with all wt patients,
RAS
mutant showed a higher risk of death (HR=1.47; 95% CI, 1.05–2.07;
P
=0.025), but such effect was lost at multivariate analyses.
Conclusions:
BRAF
mutation is associated with an extremely poor median RFS after liver resection and with higher probability of relapse and death. Knowledge of
BRAF
mutational status may optimise clinical decision making in mCRC patients potentially candidate to hepatic surgery.
RAS
status as useful marker in this setting might require further studies.
Journal Article
European Council of Legal Medicine (ECLM) on-site inspection forms for forensic pathology, anthropology, odontology, genetics, entomology and toxicology for forensic and medico-legal scene and corpse investigation: the Parma form
Further to a previous publication by the European Council of Legal Medicine (ECLM) concerning on-site forensic and medico-legal scene and corpse investigation, this publication provides guidance for forensic medical specialists, pathologists and, where present, coroners’ activity at a scene of death inspection and to harmonize the procedures for a correct search, detection, collection, sampling and storage of all elements which may be useful as evidence, and ensure documentation of all these steps. This ECLM’s inspection form provides a checklist to be used on-site for the investigation of a corpse present at a crime or suspicious death scene. It permits the collection of all relevant data not only for the pathologist, but also for forensic anthropologists, odontologists, geneticists, entomologists and toxicologists, thus supporting a collaborative work approach. Detailed instructions for the completion of forms are provided.
Journal Article
Clinical relevance of EMT and stem-like gene expression in circulating tumor cells of metastatic colorectal cancer patients
Using approved methods, circulating tumor cells (CTCs) are only isolated from blood in 30%-50% of metastatic colorectal cancer (mCRC) patients. We previously validated a technique to isolate circulating tumor cells (CTCs) in a cohort of mCRC patients by combining immunomagnetic enrichment of EpCAM+ /CD45- cells with qRT-PCR amplification of CK20 and survivin expression. Here, we examined the prognostic utility of CTC epithelial-mesenchymal transition (EMT) and stem cell gene expression. An 8 ml blood sample was collected from 78 consecutive mCRC patients before treatment with investigational and standard chemotherapeutics. The mRNA expression of EMT (PI3Kα, Akt-2, Twist1) and stem cell (ALDH1) markers was measured. Associations between CTC gene expression and progression-free survival (PFS) and overall survival (OS) were determined using Cox regression models. Among patients without CK20 or survivin-expressing CTCs (n=17), 55% had expression of ALDH1, PI3Kα and/or Akt-2. Patients with positive CTC Akt-2 expression had a significantly shorter median PFS (3.0 versus 4.0 months) compared with those without CTC Akt-2 expression in univariable (hazard ratio (HR)=1.61; log-rank P=0.034) and multivariable analyses (HR=1.70; adjusted P=0.041). In univariable analysis, CTC ALDH1 expression was associated with shorter OS (10.0 versus 38.6 months; HR=2.04, P=0.021). Patients with CTCs expressing ALDH1, PI3Kα and/or Akt-2 had a significantly inferior PFS (3.0 versus 7.7 months; HR=1.88, P=0.015) and OS (10.0 versus 26.8+ months; HR=2.25, P=0.050) in univariable, but not multivariable, analysis. Conclusions: CTC Akt-2 expression may serve as a clinically useful prognostic marker in mCRC patients and warrants further evaluation in prospective trials.
Journal Article
Histopathologic evaluation of liver metastases from colorectal cancer in patients treated with FOLFOXIRI plus bevacizumab
Background:
The FOLFOXIRI regimen produces a high rate of radiological and histopathological responses. Bevacizumab added to chemotherapy showed an improvement in pathological response and necrosis of colorectal liver metastases (CLMs). FOLFOXIRI plus bevacizumab produced promising early clinical results and is under investigation in several randomised trials, although no data are currently available on its effects on response of CLMs and on liver toxicities.
Methods:
Starting from 499 patients enrolled in first-line phase II/III trials, we selected on the basis of tissue sample availability 18 patients treated with FOLFOXIRI/XELOXIRI and 24 patients treated with FOLFOXIRI plus bevacizumab who underwent secondary resection of CLMs. The 28 untreated patients who underwent primary resection of CLMs were included as control group. Responses of CLMs and chemotherapy-induced toxicities were assessed.
Results:
Among the patients, 63% of those treated with FOLFOXIRI plus bevacizumab, as compared with 28% of those treated with only FOLFOXIRI/XELOXIRI, showed a histopathological response (
P=
0.033). In the two groups, 52% and 12.5%, respectively, showed necrosis ⩾50% (
P
=0.017). The incidence of liver toxicities was not significantly increased in patients treated with FOLFOXIRI plus bevacizumab.
Conclusion:
The addition of bevacizumab to FOLFOXIRI produces high rates of pathologic responses and necrosis of CLM without increasing liver toxicity.
Journal Article
Pharmacodynamic and pharmacogenetic angiogenesis-related markers of first-line FOLFOXIRI plus bevacizumab schedule in metastatic colorectal cancer
Background:
The identification of molecular and genetic markers to predict or monitor the efficacy of bevacizumab (BV) represents a key issue in the treatment of metastatic colorectal cancer (mCRC).
Methods:
Plasma levels of vascular endothelial growth factor (VEGF), placental growth factor (PlGF), soluble VEGF receptor 2 (sVEGFR-2) and thrombospondin-1 (TSP-1) were assessed by ELISA assay at different time points in a cohort of 25 patients enroled in a phase II trial of GONO-FOLFOXIRI plus BV as first-line treatment of mCRC.
VEGF
: −2578A/C, −1498C/T, −1154A/G, −634C/G and 936C/T; and
VEGFR
-2: −604A/G, +1192C/T and +1719A/T, polymorphisms were assessed in a total of 54 patients.
Results:
Treatment with GONO-FOLFOXIRI plus BV determined a prolonged and significant reduction in plasma free, biologically active VEGF concentration. Interestingly, VEGF concentrations remained lower than at baseline also at the time of PD. Conversely, PlGF levels increased during the treatment if compared with baseline, suggesting a possible role in tumour resistance; moreover, sVEGFR-2 increased at the time of PD, as well as TSP-1. No association of assessed polymorphisms with outcome was found.
Conclusion:
Our study suggested the possible mechanisms of resistance to combined therapy in those patients with a progressive disease to be tested in ongoing phase III randomised studies.
Journal Article
Interspecific Interactions May Influence Reef Fish Management Strategies in the Gulf of Mexico
This study highlights the importance of interspecific interactions among marine organisms and the effect that these trophic interactions have on the development of effective, adaptive management strategies for reef fishes in the Gulf of Mexico. To represent the spatially and temporally constrained, interspecific interactions among reef fishes we employ Atlantis (a spatially explicit, biogeochemical ecosystem model) as our simulation tool. Within Atlantis, we evaluate the performance of a two‐point harvest control rule (HCR) that adaptively increases fishing mortality linearly between upper and lower biomass thresholds based on the available biomass of the stocks. This example demonstrated the use of a “blanket” two‐point HCR that assessed the available biomass of several reef fish species (often co‐caught in fishing gear) both simultaneously and objectively. To estimate the impact of reef fish fishing on species abundance and biodiversity in the ecosystem, we examined four “low” and four “high” fishing mortality (F) scaler scenarios. All model projections are forward looking, representing a 50‐year time horizon (2010 to 2060). We evaluated the performance of the two‐point HCRs under the eight fishing mortality scenarios using ecosystem metrics that were previously found to robustly track changes in ecosystem function caused by fishing. We found that the lower F scenarios produced an ecologically distinct ecosystem state compared with the higher F scenarios, where relatively higher levels of fishing mortality (particularly on predators such as the deep Serranidae group) resulted in an increase in prey availability in later years of the simulation. This led to an increase in the overall productivity of the ecosystem over time and higher catch and biomass of most other reef fish groups at equilibrium (year 50). Our results suggest that a better understanding of interspecific interactions among targeted reef fishes and their prey is critical to developing ecosystem‐based management strategies for the Gulf of Mexico.
Journal Article
Prospective study of EGFR intron 1 (CA)n repeats variants as predictors of benefit from cetuximab and irinotecan in chemo-refractory metastatic colorectal cancer (mCRC) patients
The number of
CA
tandem repeats (
CA
)
n
in a highly polymorphic region of
EGFR
(epidermal growth factor receptor) intron 1 may affect gene transcription; the potential impact of allelic variants on the efficacy of cetuximab in metastatic colorectal cancer (mCRC) patients is debated for long. This study aimed at prospectively estimating the impact of
EGFR
intron 1 (
CA
)
n
variants on clinical outcome in
KRAS
exon 2 and
BRAF
wild-type chemo-refractory mCRC patients, receiving cetuximab and irinotecan. Variants presenting
Journal Article
Prospective study of EGFR intron 1 patients
The number of CA tandem repeats [(CA).sub.n] in a highly polymorphic region of EGFR (epidermal growth factor receptor) intron 1 may affect gene transcription; the potential impact of allelic variants on the efficacy of cetuximab in metastatic colorectal cancer (mCRC) patients is debated for long. This study aimed at prospectively estimating the impact of EGFR intron 1 [(CA).sub.n] variants on clinical outcome in KRAS exon 2 and BRAF wild-type chemo-refractory mCRC patients, receiving cetuximab and irinotecan. Variants presenting
Journal Article
The PANDA study: a randomized phase II study of first-line FOLFOX plus panitumumab versus 5FU plus panitumumab in RAS and BRAF wild-type elderly metastatic colorectal cancer patients
Background
Few data are available regarding the treatment of metastatic colorectal cancer elderly patients with anti-EGFR agents in combination with chemotherapy. FOLFOX plus panitumumab is a standard first-line option for
RAS
wild-type metastatic colorectal cancer. Slight adjustments in chemo-dosage are commonly applied in clinical practice to elderly patients, but those modified schedules have never been prospectively tested. Clinical definition of elderly (≥70 years old) patients that may deserve a more or less intensive combination therapy is still debated. Several geriatric screening tools have been developed to predict survival and risk of toxicity from treatment. Among those, the G8 screening tool has been tested in cancer patients showing the strongest prognostic value for overall survival, while the CRASH score can stratify patients according to an estimated risk of treatment-related toxicities.
Methods
The PANDA study is a prospective, open-label, multicenter, randomized phase II trial of first-line therapy with panitumumab in combination with dose-adjusted FOLFOX or with 5-fluorouracil monotherapy, in previously untreated elderly patients (≥70 years) with
RAS
and
BRAF
wild-type unresectable metastatic colorectal cancer.
RAS
and
BRAF
analyses are centralized. Geriatric assessment by means of G8 and CRASH score is planned at baseline and G8 will be re-evaluated at disease progression. The primary endpoint is duration of progression-free survival in both arms. Secondary endpoints include prospective evaluation of the prognostic role of G8 score and the correlation of CRASH risk categories with toxicity.
Discussion
The PANDA study aims at exploring safety and efficacy of panitumumab in combination with FOLFOX or with 5FU/LV in elderly patients affected by
RAS
and
BRAF
wild-type metastatic colorectal cancer, to identify the most promising treatment strategy in this setting. Additionally, this is the first trial in which the prognostic role of the G8 score will be prospectively evaluated. Results of this study will drive further experimental developments for one or both combinations.
Trial Registration
PANDA is registered at
Clinicaltrials.gov
:
NCT02904031
, July 11, 2016. PANDA is registered at EudraCT-No.: 2015–003888-10, September 3, 2015.
Journal Article