Chemotherapy toxicity and activity in patients with pancreatic ductal adenocarcinoma and germline BRCA1-2 pathogenic variants (gBRCA1-2pv): a multicenter survey

Background: Germline BRCA1-2 pathogenic variants (gBRCA1-2pv)-related pancreatic ductal adenocarcinoma (PDAC) showed increased sensitivity to DNA cross-linking agents. This study aimed at exploring safety profile, dose intensity, and activity of different chemotherapy regimens in this setting.Patients and methods: gBRCA1-2pv PDAC patients of any age and clinical tumor stage who completed a first course of chemotherapy were eligible. A descriptive analysis of chemotherapy toxicity, dose intensity, response, and survival outcomes was performed.Results: A total of 85 gBRCA1-2pv PDAC patients treated in 21 Italian centers between December 2008 and March 2021 were enrolled. Seventy-four patients were assessable for toxicity and dose intensity, 83 for outcome. Dose intensity was as follows: nab-paclitaxel 72%, gemcitabine 76% (AG); cisplatin 75%, nab-paclitaxel 73%, capecitabine 73%, and gemcitabine 65% (PAXG); fluorouracil 35%, irinotecan 58%, and oxaliplatin 64% (FOLFIRINOX). When compared with the literature, grade 3-4 neutropenia, thrombocytopenia, and diarrhea were increased with PAXG, and unmodified with AG and FOLFIRINOX. RECIST responses were numerically higher with the three-(81%) or four-drug (73%) platinum-containing regimens that outperformed AG (41%) and oxaliplatin-based doublets (56%). Carbohydrate antigen 19.9 (CA19.9) reduction >89% at nadir was reported in two-third of metastatic patients treated with triplets and quadruplets, as opposed to 33% and 45% of patients receiving oxaliplatin-based doublets or AG, respectively. All patients receiving AG experienced disease progression, with a median progression-free survival (mPFS) of 6.4 months, while patients treated with platinum-containing triplets or quadruplets had an mPFS >10.8 months. Albeit still immature, data on overall survival seemed to parallel those on PFS.Conclusions: Our data, as opposed to figures expected from the literature, highlighted that platinum-based regimens provoked an increased toxicity on proliferating cells, when dose intensity was maintained, or an as-expected toxicity, when dose intensity was reduced, while no change in toxicity and dose intensity was evident with AG. Furthermore, an apparently improved outcome of platinum-based triplets or quadruplets over other regimens was observed

Circulating Cancer Stem Cell-Derived Extracellular Vesicles as a Novel Biomarker for Clinical Outcome Evaluation.

The recent introduction of the "precision medicine" concept in oncology pushed cancer research to focus on dynamic measurable biomarkers able to predict responses to novel anticancer therapies in order to improve clinical outcomes. Recently, the involvement of extracellular vesicles (EVs) in cancer pathophysiology has been described, and given their release from all cell types under specific stimuli, EVs have also been proposed as potential biomarkers in cancer. Among the techniques used to study EVs, flow cytometry has a high clinical potential. Here, we have applied a recently developed and simplified flow cytometry method for circulating EV enumeration, subtyping, and isolation from a large cohort of metastatic and locally advanced nonhaematological cancer patients (N = 106); samples from gender- and age-matched healthy volunteers were also analysed. A large spectrum of cancer-related markers was used to analyse differences in terms of peripheral blood circulating EV phenotypes between patients and healthy volunteers, as well as their correlation to clinical outcomes. Finally, EVs from patients and controls were isolated by fluorescence-activated cell sorting, and their protein cargoes were analysed by proteomics. Results demonstrated that EV counts were significantly higher in cancer patients than in healthy volunteers, as previously reported. More interestingly, results also demonstrated that cancer patients presented higher concentrations of circulating CD31+ endothelial-derived and tumour cancer stem cell-derived CD133 + CD326- EVs, when compared to healthy volunteers. Furthermore, higher levels of CD133 + CD326- EVs showed a significant correlation with a poor overall survival. Additionally, proteomics analysis of EV cargoes demonstrated disparities in terms of protein content and function between circulating EVs in cancer patients and healthy controls. Overall, our data strongly suggest that blood circulating cancer stem cell-derived EVs may have a role as a diagnostic and prognostic biomarker in cancer

Corrigendum to “Circulating Cancer Stem Cell-Derived Extracellular Vesicles as a Novel Biomarker for Clinical Outcome Evaluation”

[This corrects the article DOI: 10.1155/2019/5879616.].Peer Reviewe

Germinal BRCA1-2 pathogenic variants (gBRCA1-2pv) and pancreatic cancer: epidemiology of an Italian patient cohort

Objective: Germline BRCA1-2 pathogenic variants (gBRCApv) increase the risk of pancreatic cancer and predict for response to platinating agents and poly(ADP-ribose) polymerase inhibitors. Data on worldwide gBRCApv incidence among pancreatic ductal adenocarcinoma (PDAC) patients are sparse and describe a remarkable geographic heterogeneity. The aim of this study is to analyze the epidemiology of gBRCApv in Italian patients. Materials and methods: Patients of any age with pancreatic adenocarcinoma, screened within 3 months from diagnosis for gBRCApv in Italian oncologic centers systematically performing tests without any selection. For the purposes of our analysis, breast, ovarian, pancreas, and prostate cancer in a patient’s family history was considered as potentially BRCAassociated. Patients or disease characteristics were examined using the c2 test or Fisher’s exact test for qualitative variables and the Student's t-test or ManneWhitney test for continuous variables, as appropriate. Results: Between June 2015 and May 2020, 939 patients were tested by 14 Italian centers; 492 (52%) males, median age 62 years (range 28-87), 569 (61%) metastatic, 273 (29%) with a family history of potentially BRCA-associated cancers. gBRCA1-2pv were found in 76 patients (8.1%; 9.1% in metastatic; 6.4% in non-metastatic). The gBRCA2/ gBRCA1 ratio was 5.4 : 1. Patients with gBRCApv were younger compared with wild-type (59 versus 62 years, P ¼ 0.01). The gBRCApv rate was 17.1% among patients <40 years old, 10.4% among patients 41-50 years old, 9.2% among patients 51-60 years old, 6.7% among patients aged 61-70 years, and 6.2% among patients >70 years old (none out of 94 patients >73 years old). gBRCApv frequency in 845 patients <74 years old was 9%. Patients with/without a family history of potentially BRCA-associated tumors had 14%/6% mutations. Conclusion: Based on our findings of a gBRCApv incidence higher than expected in a real-life series of Italian patients with incident PDAC, we recommend screening all PDAC patients <74 years old, regardless of family history and stage, due to the therapeutic implications and cancer risk prevention in patients' relatives. Key words: germline BRCA, epidemiology, pancreatic cancer genetics, familial cance

Identification of lenvatinib prognostic index via recursive partitioning analysis in advanced hepatocellular carcinoma

Background: After the advent of new treatment options for advanced hepatocellular carcinoma (HCC), the identification of prognostic factors is crucial for the selection of the most appropriate therapy for each patient. Patients and methods: With the aim to fill this gap, we applied recursive partitioning analysis (RPA) to a cohort of 404 patients treated with lenvatinib. Results: The application of RPA resulted in a classification based on five variables that originated a new prognostic score, the lenvatinib prognostic index (LEP) index, identifying three groups: low risk [patients with prognostic nutritional index (PNI) >43.3 and previous trans-arterial chemoembolization (TACE)]; medium risk [patients with PNI >43.3 but without previous TACE and patients with PNI <43.3, albumin-bilirubin (ALBI) grade 1 and Barcelona Clinic Liver Cancer stage B (BCLC-B)]; high risk [patients with PNI <43.3 and ALBI grade 2 and patients with PNI <43.3, albumin-bilirubin (ALBI) grade 1 and Barcelona Clinic Liver Cancer stage C (BCLC-C)]. Median overall survival was 29.8 months [95% confidence interval (CI) 22.8-29.8 months] in low risk patients (n = 128), 17.0 months (95% CI 15.0-24.0 months) in medium risk (n = 162) and 8.9 months (95% CI 8.0-10.7 months) in high risk (n = 114); low risk hazard ratio (HR) 1 (reference group), medium risk HR 1.95 (95% CI 1.38-2.74), high risk HR 4.84 (95% CI 3.16-7.43); P < 0.0001. The LEP index was validated in a cohort of 127 Italian patients treated with lenvatinib. While the same classification did not show a prognostic value in a cohort of 311 patients treated with sorafenib, we also show a possible predictive role in favor of lenvatinib in the low risk group. Conclusions: LEP index is a promising, easy-to-use tool that may be used to stratify patients undergoing systemic treatment of advanced HCC

Fermi LAT observations of cosmic-ray electrons from 7 GeV to 1 TeV

We present the results of our analysis of cosmic-ray electrons using about 8 million electron candidates detected in the first 12 months on-orbit by the Fermi Large Area Telescope. This work extends our previously-published cosmic-ray electron spectrum down to 7 GeV, giving a spectral range of approximately 2.5 decades up to 1 TeV. We describe in detail the analysis and its validation using beam-test and on-orbit data. In addition, we describe the spectrum measured via a subset of events selected for the best energy resolution as a cross-check on the measurement using the full event sample. Our electron spectrum can be described with a power law $\propto {\rm E}^{-3.08 \pm 0.05}$ with no prominent spectral features within systematic uncertainties. Within the limits of our uncertainties, we can accommodate a slight spectral hardening at around 100 GeV and a slight softening above 500 GeV.Comment: 20 pages, 23 figures, 2 tables, published in Physical Review D 82, 092004 (2010) - contact authors: C. Sgro', A. Moisee

Fermi Large Area Telescope Performance after 10 Years of Operation

The Large Area Telescope (LAT), the primary instrument for the Fermi Gamma-ray Space Telescope (Fermi) mission, is an imaging, wide field-of-view, high-energy gamma-ray telescope, covering the energy range from 30 MeV to more than 300 GeV. We describe the performance of the instrument at the 10 yr milestone. LAT performance remains well within the specifications defined during the planning phase, validating the design choices and supporting the compelling case to extend the duration of the Fermi mission. The details provided here will be useful when designing the next generation of high-energy gamma-ray observatories

Dual PDK1/aurora kinase a inhibitors reduce pancreatic cancer cell proliferation and colony formation

Deregulation of different intracellular signaling pathways is a common feature in cancer. Numerous studies indicate that persistent activation of the phosphoinositide 3-kinase (PI3K) pathway is often observed in cancer cells. 3-phosphoinositide dependent protein kinase-1 (PDK1), a transducer protein that functions downstream of PI3K, is responsible for the regulation of cell proliferation and migration and it also has been found to play a key role in different cancers, pancreatic and breast cancer amongst others. As PI3K is being described to be aberrantly expressed in several cancer types, designing inhibitors targeting various downstream molecules of PI3K has been the focus of anticancer agent development for a long time. In particular, dual inhibitory drugs targeting key signaling molecules in the PI3K pathway have attracted the attention of scientists. Several drugs have progressed to clinical trials, with limited success due to toxicity and bioavailability concerns. Very few anticancer drugs targeting the PI3K pathway have been approved for clinical use and their efficacy is particularly limited towards certain tumors such as pancreatic cancer. Here, we tested two drugs displaying dual inhibitory activity towards PDK1 and Aurora kinase A in a panel of pancreatic cancer cell lines and in two in vivo models of pancreatic cancer. Our data show that both inhibitors are able to impair cell proliferation and clonogenic potential in pancreatic cancer cells. However, the limited activity of both compounds in vivo indicates that further optimization of the pharmacokinetics properties is required

Neoadjuvant treatment (FOLFOX4 plus hypofractionated tomotherapy) for patients with locally advanced rectal cancer: a multicenter phase II trial

Aims: This study aims to evaluate the safety and efficacy of a new neoadjuvant regimen (FOLFOX4 plus hypofractionated tomotherapy) in patients with locally advanced rectal cancer. Methods: Patients with stage II–III rectal cancer were treated with the pre-operative chemoradiotherapy regimen comprising FOLFOX4 (two cycles), TomoTherapy (25 Gy in five consecutive fractions, one fraction per day in 5 days on the clinical target volume at the isodose of 95% of the total dose), FOLFOX4 (two cycles), followed by surgery with total mesorectal excision and adjuvant chemotherapy with FOLFOX4 (eight cycles). The primary endpoint was pathological complete response (pCR). Results: Fifty-two patients were enrolled and 50 patients were evaluable. A total of 46 (92%) patients completed chemoradiotherapy according to the study protocol and 49 patients underwent surgery. Overall, 12 patients achieved a pCR (24.5%, 95% CI 12.5–36.5). The most common grade 3 or more adverse events were neutropenia and alteration of the alvus. Adverse reactions due to radiotherapy, mainly grade 1–2 dermatitis, tenesmus, urinary dysfunction and pain, were tolerable and fully reversible. The most important surgical complications included infection, anastomotic leakage and fistula, all resolved with conservative treatment. Conclusion: FOLFOX and hypofractionated TomoTherapy is effective and safe in patients with locally advanced rectal cancer. Long-term efficacy needs to be further evaluated. Trial registration: ClinicalTrials.gov identifier: NCT02000050 (registration date: 26 November 2013) https://clinicaltrials.gov/ct2/show/NCT02000050