Familial colorectal cancer type X (FCCX) encompasses a group of families with dominant inheritance pattern of colorectal cancer (CRC) but no alteration in any known CRC susceptibility gene. ...Therefore, the explanation of their susceptibility is a priority to offer an accurate genetic counseling. We screened the 27 coding exons and exon–intron boundaries of BRCA2 in 48 FCCX probands. We identified 29 variants including a frameshift mutation. Deleterious variant c.3847_3848delGT p.(Val1283Lysfs*2) showed cosegregation with disease as well as loss of heterozygosity (LOH) in CRC tumor DNA. This is the first evidence of germline BRCA2 pathogenic mutation associated with CRC risk. Furthermore, missense variants c.502C>A p.(Pro168Thr), c.5744C>T p.(Thr1915Met) and c.7759C>T p.(Leu2587Phe) were proposed as candidate risk alleles based on cosegregation, LOH tumor analysis and in silico testing.
The purpose of this article is to evaluate the safety of two regorafenib dose-escalation approaches in refractory metastatic colorectal cancer (mCRC) patients.
Patients with mCRC and progression ...during or within 3 months following their last standard chemotherapy regimen were randomised to receive the approved dose of regorafenib of 160 mg QD (arm A) or 120 mg QD (arm B) administered as 3 weeks of treatment followed by 1 week off, or 160 mg QD 1 week on/1 week off (arm C). The primary end-point was the percentage of patients with G3/G4 treatment-related adverse events (AEs) in each arm.
There were 299 patients randomly assigned to arm A (n = 101), arm B (n = 99), or arm C (n = 99); 297 initiated treatments (arm A n = 100, arm B n = 98, arm C n = 99: population for safety analyses). G3/4 treatment-related AEs occurred in 60%, 55%, and 54% of patients in arms A, B, and C, respectively. The most common G3/4 AEs were hypertension (19, 12, and 20 patients), fatigue (20, 14, and 15 patients), hypokalemia (11, 7, and 10 patients), and hand–foot skin reaction (8, 7, and 3 patients). Median overall survival was 7.4 (IQR 4.0–13.7) months in arm A, 8.6 (IQR 3.8–13.4) in arm B, and 7.1 (IQR 4.4–12.4) in arm C.
The alternative regorafenib dosing schedules were feasible and safe in patients with mCRC who had been previously treated with standard therapy. There was a higher numerical improvement on the most clinically relevant AEs in the intermittent dosing arm, particularly during the relevant first two cycles.
NCT02835924.
•Feasibility of two dose schedules of regorafenib initial deintensification in Europe.•No improvement on the overall safety profiles was seen.•A reduction in the most relevant AEs was observed (fatigue and HFSR).•Efficacy was sustained across the experimental arms despite dose deintensification.
Background
Persistent alopecia (PA) after docetaxel has been recently described. The aim of our study is to establish the incidence and characteristics of PA following adjuvant docetaxel for breast ...cancer (BC) and to test the ability of scalp cooling in prevention.
Patients and methods
BC patients receiving adjuvant chemotherapy followed or not by endocrine therapy (and a control group receiving only endocrine therapy) were interviewed in a single institution at 1.5 to 5 years following primary diagnosis searching for PA. A confirmatory prevalence study was later performed in other two institutions. Finally, a prevention study using prophylactic scalp cooling (PSC) with ELASTO-GEL hypothermia caps in patients receiving adjuvant docetaxel was performed.
Results
In the initial prevalence study (492 patients), minor forms of PA (grade 1) were recorded with all chemotherapy regimens and aromatase inhibitors. Patients receiving docetaxel regimens at cumulative dose (CD) ≥ 400 mmg/m
2
presented a significantly higher prevalence of grades 1 PA (33–52%) and 2 PA (5–12%). Prevalence of grade 2 PA with docetaxel CD ≥ 400 mmg/m
2
was confirmed in two other institutions. Overall, grade 2 PA was seen in 10.06% (95% CI 7.36–13.61) of 358 patients with docetaxel regimens reaching CD ≥ 400 mmg/m
2
, but not in patients with lower docetaxel CD, other chemotherapy regimens, or endocrine therapy alone. In prevention trial, no grade 2 PA occurred among 116 patients receiving adjuvant docetaxel (≥ 400 mmg/m
2
) and PSC followed-up after a 96 months median time. PSC was well tolerated. No scalp relapses were seen among 30 patients (22% of all inclusions) having disease relapse.
Conclusion
Adjuvant treatment with docetaxel (CD ≥ 400 mmg/m
2
) is associated with a significant rate of grade 2 PA, leading to wearing a wig, in around 10% of patients. This toxicity was completely prevented with scalp cooling. Clinical Trial Reference: NCT00515762.
The bCTC count is a well-established prognostic biomarker in mCRC, as well as in other tumor types. The aim of this analysis was to evaluate the prognostic/predictive role of the bCTC count (≥3 vs. ...<3) in previously untreated mCRC.
The study involved 589 untreated mCRC patients included in the intention-to-treat population of 2 randomized clinical trials (phase III VISNU-1 NCT01640405 and phase II VISNU-2 NCT01640444 studies).
Of the 589 patients, 349 (59.2%) had bCTC≥3 and 240 (40.7%) had bCTC<3. Multivariate analysis showed that the bCTC count is an independent prognostic factor for overall survival (OS) (HR 0.59, 95% CI 0.48-0.72; P = 0.000) and potential for progression-free survival (PFS) (P = 0.0549). Median OS was 32.9 and 19.5 months in patients with bCTC<3 and bCTC≥3 (P <0.001), respectively. This effect was also observed comparing OS in RASwt patients from both studies. Other prognostic factors were: ECOG-PS, primary tumor site, number of metastatic sites and surgery of the primary tumor. Median OS was lower for patients treated with anti-VEGF versus anti-EGFR (22.3 vs. 33.3 months, P <0.0001) while there were no significant differences in PFS according to the targeted treatment received.
This post-hoc analysis of 2 randomized studies confirms the poor prognosis of patients with bCTC≥3 but this is not associated with other adverse independent prognostic factors such as RAS/BRAF mutations.
Baseline circulating tumor cell (bCTC ) enumeration is an established biomarker in metastatic colorectal cancer (mCRC). A total of 589 untreated mCRC patients from 2 randomized clinical trials were included for evaluation of the prognostic/predictive role of the bCTC count (≥3 vs. <3). Our results confirm the poor prognosis of patients with bCTC≥3 but this is not associated with other adverse prognostic factors such as RAS/BRAF mutations.
Neoadjuvant therapy (NAT) is mainly indicated for locally advanced rectal carcinoma. Many reports have shown that regression of the primary tumor is a prognostic factor. However, few reports to date ...have analyzed the potential prognostic significance of lymph node regression in rectal carcinoma. The aim of the present study is to describe the pattern of tumor regression in lymph nodes after NAT for rectal carcinoma and its potential prognostic significance. We have retrospectively reviewed 106 cases of rectal carcinoma treated at a single institution. We have retrieved data from the patients and reviewed the histopathological slides to evaluate tumor regression both of the primary tumor and of LN metastases. Prognosis has been defined both in terms of disease-free survival (DFS) and disease-specific survival (DSS). Of the patients, 16 % showed complete response of the primary tumor, while 24 % showed poor response, according to the CAP regression grading system. Absence of lymph node involvement after therapy was found in 80 % of the patients (ypN0 cases), while 20 % were ypN+. We reviewed 639 LN; 85 were involved by tumor, and 170 showed histological signs of tumor regression. The main pattern of tumor regression in lymph nodes was fibrosis (66.3 %), followed by hystiocytosis (29.1 %) and mucin pools (4.6 %). We found histological signs of regression in 57 % of ypN0 cases and 76 % of ypN+ cases. We found a significant association between regression grade of the primary tumor and of lymph node metastases. For ypN0 patients with persistence of the primary tumor after NAT, the median DFS was significantly shorter in patients showing tumor regression in the LN. In a Cox multivariate survival model for DFS, this prognostic influence was independent of the regression grade of the primary tumor and also of the ypTNM stage. We found no significant association between any factor and DSS. The pattern of tumor regression in lymph nodes was not significantly associated with prognosis. Tumor regression in lymph nodes is an important prognostic factor in rectal carcinoma after NAT and should be specifically looked for and included in pathology reports.
We explored the influence of BRAF and PIK3CA mutational status on the efficacy of bevacizumab or cetuximab plus 5-fluorouracil/leucovorin and irinotecan (FOLFIRI) as first-line therapy in patients ...with RAS wild-type metastatic colorectal cancer (mCRC).
VISNÚ-2 was a multicentre, randomised, phase II study. Patients with RAS wild-type mCRC and <3 circulating tumour cells/7.5 ml blood were stratified by BRAF/PIK3CA status (wild-type versus mutated) and number of affected organs (1 versus >1), and allocated to bevacizumab (5 mg/kg every 2 weeks) or cetuximab (400 mg/m2 then 250 mg/m2 weekly) plus FOLFIRI irinotecan 180 mg/m2, leucovorin 400 mg/m2, 5-fluorouracil 400 mg/m2 (bolus) then 2400 mg/m2 (46-h continuous infusion) every 2 weeks. The primary endpoint was progression-free survival (PFS). All analyses were exploratory.
Two hundred and forty patients with BRAF/PIK3CA wild-type (n = 196) or BRAF- and/or PIK3CA-mutated tumours (n = 44) were enrolled. Median PFS was 12.7 and 8.8 months in patients with BRAF/PIK3CA wild-type and BRAF/PIK3CA-mutated tumours, respectively hazard ratio (HR) = 1.22; 95% confidence interval (CI) 0.80-1.85; P = 0.3602. In the BRAF- and/or PIK3CA-mutated cohort, median PFS was 2.8, 8.8 and 15.0 months in patients with BRAF/PI3KCA-mutated (n = 8), BRAF-mutated/PI3KCA wild-type (n = 16) and BRAF wild-type/PI3KCA-mutated (n = 20) tumours, respectively (P = 0.0002). PFS was similar with bevacizumab plus FOLFIRI versus cetuximab plus FOLFIRI in BRAF/PIK3CA wild-type (HR = 0.99; 95% CI 0.67-1.45; P = 0.9486) and BRAF/PIK3CA-mutated tumours (HR = 1.11; 95% CI 0.53-2.35; P = 0.7820). The most common grade 3/4 treatment-related adverse events were neutropenia, diarrhoea and asthenia in both treatment groups.
BRAF/PIK3CA status influences outcomes in patients with RAS wild-type mCRC but does not appear to assist with the selection of first-line targeted therapy.
•This study examined if BRAF/PIK3CA mutational status can guide therapy in RAS wild-type mCRC.•BRAF mutations were associated with poorer survival outcomes, and were potentiated by PI3KCA mutations.•Bevacizumab-FOLFIRI versus cetuximab-FOLFIRI had similar outcomes in BRAF /PIK3CA wild-type and BRAF /PIK3CA-mutated tumours.•BRAF and PI3KCA mutations have a role as prognostic but not predictive factors.
Energy has an essential role in socio-economic development, particularly in European coal-mining regions undergoing a transition process which implies searching for alternative fuels to coal. ...Forestry wastes provide a large amount of biomass that has the potential to be transformed into biocoal to produce solid biofuels. The present work aims to analyse the feasibility of integrating biocoals as a renewable solid fuel, produced by torrefaction and further mechanical densification, in the currently existing coal-consuming facilities. The methodology proposed evaluates existing forest waste resources and their potential conversion into biocoal pellets for use in thermal and electrical energy production. An analysis of the results indicates a potential overall production of 280 kt/year of torrefied pellets in the seven coal-mining regions in Spain evaluated in the study, with the potential to produce 78 MWe or 470 MWth, respectively, and avoid 582 kt/year of CO2 emissions. The average cost for torrefied pellets production would be 148 €/t and require an emission cost of approximately above 45 €/tCO2 to be cost-competitive with coal for direct use in currently existing energy systems. The use of biocoal is shown from resource to energy management for energy conversion systems in the pathway of the energy transition.
•European coal regions must meet EU targets in renewable energy production.•Bioenergy from torrefaction is a promising source in the energy transition.•Biocoal would avoid 582 kt/year of equivalent CO2 emissions in Spain.•New energy conversion strategies can further develop the bioenergy sector.
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