Germline Predisposition and Copy Number Alteration in Pre-stage Lung Adenocarcinomas Presenting as Ground-Glass Nodules.

Objective: Synchronous multiple ground-glass nodules (SM-GGNs) are a distinct entity of lung cancer which has been emerging increasingly in recent years in China. The oncogenesis molecular mechanisms of SM-GGNs remain elusive. Methods: We investigated single nucleotide variations (SNV), insertions and deletions (INDEL), somatic copy number variations (CNV), and germline mutations of 69 SM-GGN samples collected from 31 patients, using target sequencing (TRS) and whole exome sequencing (WES). Results: In the entire cohort, many known driver mutations were found, including EGFR (21.7%), BRAF (14.5%), and KRAS (6%). However, only one out of the 31 patients had the same somatic missense or truncated events within SM-GGNs, indicating the independent origins for almost all of these SM-GGNs. Many germline mutations with a low frequency in the Chinese population, and genes harboring both germline and somatic variations, were discovered in these pre-stage GGNs. These GGNs also bore large segments of copy number gains and/or losses. The CNV segment number tended to be positively correlated with the germline mutations (r = 0.57). The CNV sizes were correlated with the somatic mutations (r = 0.55). A moderate correlation (r = 0.54) was also shown between the somatic and germline mutations. Conclusion: Our data suggests that the precancerous unstable CNVs with potentially predisposing genetic backgrounds may foster the onset of driver mutations and the development of independent SM-GGNs during the local stimulation of mutagens.

Long-term therapy with bevacizumab in a young patient affected by NF-2: a case report and review of the literature.

Neurofibromatosis type 2 (NF-2) is an autosomal dominant inherited disease caused by heterozygous mutations in the NF-2 tumor suppressor gene. It is characterized by the development of multiple benign tumors in the central nervous system. A majority of these tumors can be treated with surgery or radiotherapy in the case of the symptomatic disease. Cytotoxic chemotherapy has no established role in the treatment of NF-2. Vascular endothelial growth factor (VEGF) is a critical mediator of tumor angiogenesis and vessel permeability. VEGF and its receptor VEGFR-1 have been detected in schwannomas, and increased levels of these factors correlate with increased rates of tumor growth. The use of bevacizumab has made many progresses in recent years in NF-2 patients. We report a case of a young patient treated with more than 100 administration of bevacizumab, with clinical and instrumental benefits.

Should age impact breast cancer management in young women? Fine tuning of treatment guidelines.

Despite breast cancer being uncommon in young women, it is still the most frequent cancer diagnosed in women aged 15-39 years, and the leading cause of death in this age group in high-income countries, after accidents and self-injury. The present review summarizes the most recent guidelines and offers an expert perspective on the many challenges associated with treatment of young women with breast cancer. We will especially focus on early breast cancer, exploring the specificities of the diagnostic process, imaging techniques, locoregional and systemic treatments, and the added value of dedicated multidisciplinary teams. Specific differences in adjuvant treatment between premenopausal and postmenopausal women, especially regarding endocrine therapy, will be addressed in detail. Research questions and current gaps in important fields, such as the paucity of age-specific data regarding antihuman epidermal growth factor receptor 2 (anti-HER2) therapy and gene panels such as OncotypeDX or MAMMAPRINT will be highlighted. A consistent part of this review is dedicated to the issues defining 'young women', such as fertility preservation, managing long-term side effects of oncological treatments and genetic counselling, by detailing current strategies and future perspectives.

Hypoxia and tumor angiogenesis in the era of hepatocellular carcinoma transarterial loco-regional treatments.

This review focuses upon interactions and potential therapeutic targets in the 'vicious cycle' between hypoxia and neoangiogenesis following treatment of hepatocellular carcinoma with transarterial loco-regional therapies. Biomarkers correlated with angiogenesis have been studied by many authors as prognostic determinants following transarterial intrahepatic therapy. According to these results future therapies directed toward specific factors related to angiogenesis could play a significant role in preventing local tumor recurrence and remote metastasis.

Biopsy and re-biopsy in lung cancer: the oncologist requests and the role of endobronchial ultrasounds transbronchial needle aspiration.

As the leading cause of death worldwide, lung cancer has proven itself incurable in the advanced stages. For early stages, endobronchial ultrasounds transbronchial needle aspiration (EBUS-TBNA) is now considered the standard to assess mediastinal lymph node, to define the multimodality therapeutic approach. In recent years, EBUS-TBNA has extended its use also in the metastatic and locally recurrent disease. New molecules, with specific mutations that give resistance to current target therapies, have made re-biopsy at disease progression an important assessment, with therapeutic and clinical implication. Here we present the oncologist's point of view on EBUS-TBNA in the staging process, at recurrence and progression.

Targeted therapy for thymic epithelial tumors: a new horizon? Review of the literature and two cases reports.

Surgical resection remains the cornerstone of therapy for early-stage thymic epithelial tumors (TETs), while in advanced or recurrent forms, a multimodality approach incorporating radiation and chemotherapy is required. Given the absence of effective treatment options for metastatic/refractory TETs and the poor related prognosis, there is a compelling need to identify promising 'drugable' molecular targets. Initial reports of activity from targeted agents in TETs derived from anecdotal cases have been often associated with specific activating mutations. Only in recent years, several agents have been formally investigated into prospective clinical trials, with varying success rates. We reviewed the literature on targeted therapy in TETs along with two cases of thymoma achieving striking responses to sorafenib in combination with lapatinib.

Phase I pharmacokinetic and pharmacodynamic study of lapatinib in combination with sorafenib in patients with advanced refractory solid tumors.

BACKGROUND: The epidermal growth factor receptor (EGFR) and ERBB2 (HER2) pathways and vascular endothelial growth factor (VEGF)-dependent angiogenesis have a pivotal role in cancer pathogenesis and progression. Robust experimental evidence has shown that these pathways are functionally linked and implicated in acquired resistance to targeted therapies making them attractive candidates for joined targeting. We undertook this phase I trial to assess the safety, the recommended dose for phase II trials (RPTD), pharmacokinetics (PK), pharmacodynamics (PD), and the preliminary antitumour activity of the combination of lapatinib and sorafenib in patients with advanced refractory solid tumours. METHODS: Four cohorts of at least three patients each received lapatinib once daily and sorafenib twice daily together on a continuous schedule. Doses of lapatinib and sorafenib were escalated based on dose-limiting toxicities (DLTs) in the first treatment cycle following a traditional 3+3 design until the RPTD was reached. Additional patients were treated at the RPTD to characterise PK profiles of this combination and to investigate the potential interaction between lapatinib and sorafenib. Serum samples were collected at baseline and then prospectively every two cycles to assess changes in PD parameters. This trial is registered with ClinicalTrials.gov, number NCT00984425. FINDINGS: Thirty patients with advanced refractory solid tumours were enroled. DLTs were grade three fatigue and grade 3 atypical skin rash observed at dose levels 3 and 4, respectively. The higher dose level explored (lapatinib 1250mg/day and sorafenib 400mg twice daily) represented the RPTD of the combination. The most common drug-related adverse events were fatigue (68%), hypocalcemia (61%), diarrhoea (57%), lymphopaenia (54%), anorexia (50%), rash (50%), and hypophosphatemia (46%). PK analysis revealed no significant effect of sorafenib on the PK profile of lapatinib. Of the 27 assessable patients for clinical activity, one achieved a confirmed complete response, four (15%) had a partial response, and 12 (44%) achieved disease stabilisation. The disease control rate overall was 63%. INTERPRETATION: Combination treatment with lapatinib and sorafenib was feasible with promising clinical activity and without significant PK interactions. Long term tolerability seems to be challenging.