The quest for improving treatment of cancer of unknown primary (CUP) through molecularly-driven treatments: a systematic review

Background: Carcinomas of unknown primary (CUP) account for 3-5% of all malignancy and, despite a reduction in incidence, the overall survival has not improved over the last decade. Chemotherapy regimens have not provided encouraging results. New diagnostic technologies, such as next generation sequencing (NGS), could represent a chance to identify potentially targetable genomic alterations in order to personalize treatment of CUP and provide insights into tumor biology. Methods: A systematic review of studies of patients with CUP, whose tumor specimen was evaluated through a NGS panel, has been performed on June 10th, 2019 according to PRISMA criteria from PubMed, ASCO meeting library and Clinicaltrial.gov. We have identified potentially targetable alterations for which approved/off-label/in clinical trials drugs are available. Moreover, we have included case reports about CUP patients treated with targeted therapies driven by NGS results in order to explore the clinical role of NGS in this setting. Results: We have evaluated 15 publications of which eleven studies (9 full-text articles and 2 abstracts) have analyzed the genomic profiling of CUPs through NGS technology, with different platforms and with different patients cohorts, ranging from 16 to 1,806 patients. Among all these studies, 85% of patients demonstrated at least one molecular alteration, the most frequent involving TP53 (41.88%), KRAS (18.81%), CDKN2A (8.8%), and PIK3CA (9.3%). A mean of 47.3% of patients harbored a potentially targetable alteration for which approved/off-label/in clinical trials drugs were available. Furthermore, we have identified 4 case reports in order to evaluate the clinical relevance of a specific targeted therapy identified through NGS. Conclusions: NGS may represent a tool to improve diagnosis and treatment of CUP by identifying therapeutically actionable alterations and providing insights into tumor biology

Silicon photomultipliers: On ground characterizations and modelling for use in front-end electronics aimed to space-borne experiments

Abstract Silicon Photomultipliers (Si-PM) consist of an array of semiconductor photodiodes joint on the common substrate and operating in limited geiger mode. A new generation of Si-PM is currently under test in INFN Rome Tor Vergata facilities: they consist of a 5625 element, 3 * 3 mm 2 array with an improved light response. These elements have been characterized. Furthermore, a functional model of the Si-PM has been developed to be used in a VLSI development of front-end electronics

Does a SLAP lesion affect shoulder muscle recruitment as measured by EMG activity during a rugby tackle?

Background: The study objective was to assess the influence of a SLAP lesion on onset of EMG activity in shoulder muscles during a front on rugby football tackle within professional rugby players. Methods: Mixed cross-sectional study evaluating between and within group differences in EMG onset times. Testing was carried out within the physiotherapy department of a university sports medicine clinic. The test group consisted of 7 players with clinically diagnosed SLAP lesions, later verified on arthroscopy. The reference group consisted of 15 uninjured and full time professional rugby players from within the same playing squad. Controlled tackles were performed against a tackle dummy. Onset of EMG activity was assessed from surface EMG of Pectorialis Major, Biceps Brachii, Latissimus Dorsi, Serratus Anterior and Infraspinatus muscles relative to time of impact. Analysis of differences in activation timing between muscles and limbs (injured versus non-injured side and non injured side versus matched reference group). Results: Serratus Anterior was activated prior to all other muscles in all (P = 0.001-0.03) subjects. In the SLAP injured shoulder Biceps was activated later than in the non-injured side. Onset times of all muscles of the noninjured shoulder in the injured player were consistently earlier compared with the reference group. Whereas, within the injured shoulder, all muscle activation timings were later than in the reference group. Conclusions: This study shows that in shoulders with a SLAP lesion there is a trend towards delay in activation time of Biceps and other muscles with the exception of an associated earlier onset of activation of Serratus anterior, possibly due to a coping strategy to protect glenohumeral stability and thoraco-scapular stability. This trend was not statistically significant in all cases

High Circulating Methylated DNA Is a Negative Predictive and Prognostic Marker in Metastatic Colorectal Cancer Patients Treated With Regorafenib

Background: Regorafenib improves progression free survival (PFS) in a subset of metastatic colorectal cancer (mCRC) patients, although no biomarkers of efficacy are available. Circulating methylated DNA (cmDNA) assessed by a five-gene panel was previously associated with outcome in chemotherapy treated mCRC patients. We hypothesized that cmDNA could be used to identify cases most likely to benefit from regorafenib (i.e., patients with PFS longer than 4 months). Methods: Plasma samples from mCRC patients were collected prior to (baseline samples N = 60) and/or during regorafenib treatment (N = 62) for the assessment of cmDNA and total amount of cell free DNA (cfDNA). Results: In almost all patients, treatment with regorafenib increased the total cfDNA, but decreased cmDNA warranting the normalization of cmDNA to the total amount of circulating DNA (i.e., cmDNA/ml). We report that cmDNA/ml dynamics reflects clinical response with an increase in cmDNA/ml associated with higher risk of progression (HR for progression = 1.78 [95%CI: 1.01-3.13], p = 0.028). Taken individually, high baseline cmDNA/ml (above median) was associated with worst prognosis (HR for death = 3.471 [95%CI: 1.83-6.57], p < 0.0001) and also predicted shorter PFS (<16 weeks with PPV 86%). In addition, high cmDNA/ml values during regorafenib treatment predicted with higher accuracy shorter PFS (<16 weeks with a PPV of 96%), therefore associated with increased risk of progression (HR for progression = 2.985; [95%CI: 1.63-5.46; p < 0.0001). Conclusions: Our data highlight the predictive and prognostic value of cmDNA/ml in mCRC patients treated with regorafenib

KRAS codon 61, 146 and BRAF mutations predict resistance to cetuximab plus irinotecan in KRAS codon 12 and 13 wild-type metastatic colorectal cancer

BACKGROUND: KRAS codons 12 and 13 mutations predict resistance to anti-EGFR monoclonal antibodies (moAbs) in metastatic colorectal cancer. Also, BRAF V600E mutation has been associated with resistance. Additional KRAS mutations are described in CRC. METHODS: We investigated the role of KRAS codons 61 and 146 and BRAF V600E mutations in predicting resistance to cetuximab plus irinotecan in a cohort of KRAS codons 12 and 13 wild-type patients. RESULTS: Among 87 KRAS codons 12 and 13 wild-type patients, KRAS codons 61 and 146 were mutated in 7 and 1 case, respectively. None of mutated patients responded vs 22 of 68 wild type (P = 0.096). Eleven patients were not evaluable. KRAS mutations were associated with shorter progression-free survival (PFS, HR: 0.46, P = 0.028). None of 13 BRAF-mutated patients responded vs 24 of 74 BRAF wild type (P = 0.016). BRAF mutation was associated with a trend towards shorter PFS (HR: 0.59, P = 0.073). In the subgroup of BRAF wild-type patients, KRAS codons 61/146 mutations determined a lower response rate (0 vs 37%, P = 0.047) and worse PFS (HR: 0.45, P = 0.023). Patients bearing KRAS or BRAF mutations had poorer response rate (0 vs 37%, P = 0.0005) and PFS (HR: 0.51, P = 0.006) compared with KRAS and BRAF wild-type patients. CONCLUSION: Assessing KRAS codons 61/146 and BRAF V600E mutations might help optimising the selection of the candidate patients to receive anti-EGFR moAbs. British Journal of Cancer (2009) 101, 715-721. doi: 10.1038/sj.bjc.6605177 www.bjcancer.com Published online 14 July 2009 (C) 2009 Cancer Research U

PAMELA - A Payload for Antimatter Matter Exploration and Light-nuclei Astrophysics

The PAMELA experiment is a satellite-borne apparatus designed to study charged particles in the cosmic radiation with a particular focus on antiparticles. PAMELA is mounted on the Resurs DK1 satellite that was launched from the Baikonur cosmodrome on June 15th 2006. The PAMELA apparatus comprises a time-of-flight system, a magnetic spectrometer, a silicon-tungsten electromagnetic calorimeter, an anticoincidence system, a shower tail catcher scintillator and a neutron detector. The combination of these devices allows antiparticles to be reliably identified from a large background of other charged particles. This paper reviews the design, space qualification and on-ground performance of PAMELA. The in-orbit performance will be discussed in future publications.The PAMELA experiment is a satellite-borne apparatus designed to study charged particles in the cosmic radiation with a particular focus on antiparticles. PAMELA is mounted on the Resurs DK1 satellite that was launched from the Baikonur cosmodrome on June 15th 2006. The PAMELA apparatus comprises a time-of-flight system, a magnetic spectrometer, a silicon-tungsten electromagnetic calorimeter, an anticoincidence system, a shower tail catcher scintillator and a neutron detector. The combination of these devices allows antiparticles to be reliably identified from a large background of other charged particles. This paper reviews the design, space qualification and on-ground performance of PAMELA. The in-orbit performance will be discussed in future publications

Epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of non-small-cell lung cancer: results and open issues

The medical treatment of non-small-cell lung cancer (NSCLC) has progressively changed since the introduction of “targeted therapy”. The development of one of these molecular drug categories, e. g., the epidermal growth factor receptor (EGFR) tyrosine-kinase (TK) selective inhibitors, such as the orally active gefitinib and erlotinib, offers an interesting new opportunity. The clinical response rates obtained with their employment in unselected patient populations only account for approximately 10%. Because of this, over the last two years numerous studies have been performed in order to identify the patient subsets that could better benefit from these agents. Not only patient characteristics and clinical-pathological features, such as never-smoking status, female gender, East Asian origin, adenocarcinoma histology, bronchioloalveolar subtype, but also molecular findings, such as somatic mutations in the EGFR gene, emerge as potentially useful prognostic and predictive factors in advanced NSCLC. Further, specifically designed clinical trials are still needed to completely clarify these and other open issues that are reviewed in this paper, in order to clarify all the interesting findings available in the clinical practice