Several studies associating single nucleotide polymorphisms (SNPs) frequencies with tumors outcome have been conducted, nevertheless malignant melanoma literature data are inconclusive.Therefore we ...evaluate the impact of different genotypes for phosphoinositide-3-kinase (PI3K) and vitamin D3 nuclear receptor (VDR) SNPs on melanoma patients' outcome.
Genomic DNA of 88 patients was extracted from blood and tumor samples. SNPs were determined by PCR using TaqMan assays. We selected polymorphisms of the regulatory and catalytic subunit of PI3K (PIK3R1 and PIK3CA genes, respectively), analyzing rs2699887C>T of
and rs3730089G>A of
SNPs. Furthermore we considered the following
SNPs: rs2228570A>G (Fok1), rs731236A>G (Taq1) and rs1544410C>T (Bsm1).Progression free survival (PFS) and overall survival (OS) were estimated with the Kaplan-Meier method and with Mantel-Haenszel log-rank test.
The statistical analysis for Fok1 of
showed a significant difference in PFS after the first line therapy (median PFS= 21.2 months in the homozygous recessive genotype group vs. 3.3 months of homozygous dominant and heterozygous ones,
= 0.03). In particular, in homozygous recessive patients for Fok1 SNPs of
a high rate of histological regression and BRAF (B- Rapidly Accelerated Fibrosarcoma gene) mutation were observed. Furthermore, more efficacy of BRAF +/- MEK (MAPK-ERK-Kinase) inhibitors therapies in homozygous recessive patients vs. homozygous dominant and heterozygous ones was shown.
Our study showed a significant correlation between homozygous recessive genotype of Fok1 SNPs of VDR gene and an increased PFS in patients who underwent a first line therapy with BRAF inhibitors.
We previously showed that selected single-nucleotide-polymorphisms (SNPs) of genes involved in angiogenesis influence the aggressiveness of thymic epithelial tumors (TETs). This study analyzes their ...role in TETs and in thymic benign lesions, in order to investigate potential correlation with risk and outcome.
Genomic DNA was extracted from paraffin-embedded tissue of 92 patients, undergoing surgery at our Institution. We investigated by Real-Time PCR the SNPs of the following genes: platelet-derived growth factor receptor
α (
α), hypoxia-inducible factor-1α (
α), vascular endothelial growth factor
(
), vascular endothelial growth factor receptor-2 and 3 (
), excision repair cross-complementation group-1 (
).
Fifty-seven TETs and 35 thymic benign lesions were included into the study. Frequency of SNPs was as follows: rs2057482 C, rs11158358 C and rs11549465 C polymorphisms of
: thymomas < general population (P=0.008, P=0.007, and P=0.044 respectively).
alleles: general population > study groups, rs1951795C SNP (P=0.026 for benign lesions and P=0.0007 for thymomas), rs10873142T SNP (P=0.008 and P=0.001 respectively), rs12434438 A SNP (P=0.034 and P=0.0007) and rs2301113A SNP (P=0.027 and P=0.010). rs699947C polymorphism of VEGF-A: benign lesions > general population (P=0.012).
This is the first study investigating the angiogenetic polymorphisms in thymic benign lesions and TETs. SNPs analysis may represent a further asset in identification of patients who could benefit from anti-angiogenetic therapy.
Gastro-entero-pancreatic tumors (GEP-NETs) are rare neoplasms often characterized by an overexpression of somatostatin receptors. Thus, radiolabeled somatostatin analogues have showed an increasing ...relevance both in diagnosis and treatment, especially in low- and intermediate-differentiated GEP-NETs. These evidences have led to a growing development of new functional imaging techniques as 68Ga-DOTATATE positron emission tomography/computed tomography (PET/CT) proved useful in the management of these neoplasms. However these tumors have a heterogeneous behavior also modifying their aggressiveness through time. Therefore sometimes 18F-fluorodeoxyglucose PET/CT appears to be more appropriate to obtain a better assessment of the disease. According to these considerations, the combination of different functional imaging techniques should be considered in the management of GEP-NETs patients allowing clinicians to choose the tailored therapeutic approach among available options.
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Background: Patients (pts) presenting with persistent moderate to severe stomatitis or cutaneous toxicity during everolimus may need of treatment discontinuation or a dose ...reduction. We assessed the correlation between stomatitis or cutaneous toxicity associated with either everolimus discontinuation or dose reduction and clinical outcome pts with metastatic renal cell cancer (mRCC). Methods: We retrospectively reviewed the clinical data of pts with mRCC treated with everolimus in two Italian Centers. Clinical evidence of stomatitis or cutaneous toxicity toxicity inducing a treatment discontinuation or a dose reduction were considered stomatitis-cutaneous toxicity events (SCTE). SCTE were evaluated and corresponding clinical data were reviewed for response and clinical outcome. Response was evaluated according to Response Evaluation Criteria in Solid Tumours (RECIST) criteria. Results: Seventy-nine mRCC pts treated with everolimus (57 male, 22 female; median age 69 years, range 44–88) were evaluated. Fifty-two pts (66%) received everolimus as second-line therapy, while 27 (34%) as third-line. SCTE were observed in 20/79 pts (25%) at a median of 30.5 days on everolimus treatment (range 10–270 days). Tumor response was evaluable in 77 of 79 patients (19 of 20 SCTE pts and 58 of 59 non-SCTE). Partial response or stable disease was achieved in 15 of 19 pts with SCTE (79%) compared to 28 of 58 (48%) with no SCTE (p=0.03). After a median follow up of 19 months (range, 1 to 39), the median progression-free survival (PFS) was 5.5 months (95% CI 3.4-7.7) and the median overall survival (OS) was 17.2 months (95% CI 13.2-24.4). A significant difference was found in the median PFS equal to 7.5 months (95% CI 3.4-24.4) in SCTE pts vs. 3.7 months (95% CI 2.7-7.5) in non-SCTE, p = 0.047, and in the median OS equal to 30.6 months (95% CI 14.8-not reached) in SCTE pts vs. 14.0 months (95% CI 9.9-17.7) in non-SCTE, p=0.004. Conclusions: These data suggest that SCTE may be a predictive marker of favorable outcome in mRCC pts treated with everolimus.
Abstract Thymic malignancies represent a wide range of clinical, histological and molecular entities, with probably considerable heterogeneity even among tumors of the same histotype. Systemic ...chemotherapy with cisplatin-based regimens continues to represent the standard of care in metastatic or inoperable refractory/recurrent diseases and ADOC regimen (including cisplatin, doxorubicin, vincristine and cyclophosphamide) demonstrated the longer overall response rate and median survival in the first line setting, although no randomized trial is available; and there is still a lack of standard treatment after first-line failure. To date research efforts are focused on translational studies on molecular pathways involved in thymic tumors carcinogenesis, aimed to better understand and predict the efficacy of chemotherapy and targeted therapy. Recent molecular characterization includes identification of a number of oncogenes, tumor suppressor genes, chromosomal aberrations, angiogenic factors, and tumor invasion factors involved in cellular survival and proliferation and in tumor growth. The use of biologic drugs is currently not recommended in a routine practice because there are limited data on their therapeutic role in thymic epitelial tumors. Because of the lack of data from adequate-sized, prospective trials are required for validation and the enrolment of patients with advanced disease into available clinical trials has to be encouraged.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The aim of the study was to determine the potential role of occupational exposures to chromium (Cr) in the onset of extragonadal germinal embryonal carcinoma. The first two cases of workers in a ...company with Cr exposure are reported. The published scientific literature regarding the topic in peer-reviewed journals including MEDLINE and CancerLit databases was extensively reviewed. Two young patients who were coworkers in the same company, exposed to Cr, developed extragonadal germinal embryonal carcinomas. One of them also developed angiosarcoma of the mediastinum. To the best of our knowledge these are the first two cases of germinal embryonal carcinoma in patients with occupational exposure to Cr.
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BFBNIB, GIS, IJS, KISLJ, NUK, PNG, UL, UM, UPUK
Abstract Background In clinical practice, discontinuation or dose reduction of everolimus may be induced not only by grade 3-4 toxicites, but also by prolonged grade 2 toxicities, as stomatitis ...and/or cutaneous toxicity, which share some pathogenetic mechanisms. We assessed the correlation between either everolimus discontinuation or dose reduction induced by stomatitis-cutaneous toxicity events (SCTE) and clinical outcome of patients with metastatic renal cell cancer (mRCC). Patients and Methods We retrospectively reviewed the clinical data of patients with mRCC treated with everolimus in two Italian Centers. Clinical evidence of SCTE was evaluated and corresponding clinical data were reviewed for response and clinical outcome. Results Seventy-nine mRCC patients treated with everolimus (57 male, 22 female; median age 66 years, range 44–88) were evaluated. SCTE were observed in 20/79 patients (25%) at a median of 30.5 days on everolimus treatment (range 10–270 days). Partial response or stable disease was achieved in 15 of 19 evaluable patients with SCTE (79%) compared to 28 of 58 (48%) with no SCTE (p = 0.03). At a median follow-up of 19 months, a significant difference was found in the median PFS equal to 7.8 months (95% CI 2.8-24.4) in SCTE pts vs 4.3 months (95% CI 2.7-7.5) in non-SCTE, p = 0.029, and in the median OS equal to 30.6 months (95% CI 19.6-not reached) in SCTE pts vs 13.5 months (95% CI 9.9-17.7) in non-SCTE, p = 0.0007. Conclusion These data suggest that SCTE may be a predictive marker of favorable outcome in mRCC patients treated with everolimus.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Aims and background
Although worldwide use of asbestos has decreased, the incidence of malignant pleural mesothelioma (MPM) is expected to increase over the next few decades. A number of scoring ...systems has been proposed to assess clinicopathologic features and to predict the prognosis. We assessed the relationship between patients’ features and disease evolution in order to choose the best treatment able to prolong overall survival (OS) and progression-free survival (PFS).
Methods
We retrospectively analyzed patients with locally advanced or metastatic MPM, treated at the Department of Medical Oncology, Università Politecnica Marche, Italy, from January 2003 to September 2013. Data on age, sex, smoking history, asbestos exposure, performance status, tumor stage, histology, type of treatment, and routine laboratory tests including complete blood count panel, date of death, or censored status were collected. The OS and PFS were estimated using Kaplan-Meier method and Cox analysis was performed to analyze the prognostic relevance of clinical parameters.
Results
We enrolled a total of 62 patients. Univariate analysis showed that histologic type, performance status, response to first-line therapy, pretreatment hemoglobin levels, and plasmatic Ca125 were significant prognostic factors. Conversely, no significant correlation was found between age, sex, smoking history, reported exposure to asbestos, stages at diagnosis, treatments, and OS and PFS.
Conclusions
Our results showed that anemia and increased Ca125 might be considered negative prognostic parameters in MPM patients and confirmed the prognostic role of histotype, performance status, and response to first-line chemotherapy.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
Since the introduction of targeted therapies, prognosis in human epidermal growth factor receptor (HER) 2-positive metastatic breast cancer (MBC) has radically changed. The addition of Pertuzumab to ...Trastuzumab and standard chemotherapy has further increased patients' overall survival (OS). However, there is no agreement regarding the optimal duration of trastuzumab therapy in selected patients achieving long-term complete remission. In addition, no potential factors of long-term benefit have been identified yet. In the present study, we report the case of a MBC woman who was successfully treated with trastuzumab for over 10 years. At the time of diagnosis (February 2005), she revealed lung, nodal and bone metastases. Therefore, a first-line chemotherapy with Epirubicine and Docetaxel was administered for 6 cycles and then the patient started Trastuzumab plus hormonal therapy until reaching a sensible reduction of mammary lump and disappearance of distant metastases. Following a multidisciplinary evaluation, in November 2006, the patient underwent radical mastectomy and axillary dissection, achieving a complete remission. She continued Trastuzumab until September 2015 (for a total of 156 cycles) when a pleural diffusion was demonstrated. Long-term survival during anti-HER2 treatment remains a rare and optimal situation. Currently, no data exist to support trastuzumab interruption in this setting and collaborative efforts to better analyze the characteristics of long-responder patients are needed. Data regarding prognostic factors in this setting are relatively confusing. Our review reveals that hormonal receptor (HR)-positive disease is associated with a better prognosis, whereas the role of visceral spread differs by single or dual target anti HER2-inhibition. The introduction of Pertuzumab is raising concerns in terms of toxicity and its cost effectiveness. While waiting for novel molecular data and randomized trials, available evidence advocates continuous use of anti-HER2 therapies until disease progression or development of side effects.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Abstract
Background: Thymic Hyperplasia refers to an enlargement of the thymus, while thymomas display significant heterogeneity from morphologic point of view, clinical behaviour, expression of ...immunohistochemical markers and molecular profiling. Therefore improving our understanding of the molecular biology of thymic disorders represents a key challenge in the treatment of these rare diseases.
Methods:
The genomic DNA of 93 consecutive patients undergoing total thymectomy at our Institution was extracted from paraffin-embedded tissue.
We selected the following SNPs: Hypoxia Inducible Factor-1 alpha (HIF1a: rs2057482T>C, rs1951795A>C, rs2301113C>A, rs10873142C>T, rs11158358G>C, rs12434438G>A, rs11549465C>T, rs11549467G>A), Vascular Endothelial Growth Factor-A (VEGF-A: rs2010963G>C, rs699947A>C), VEGF Receptor 2 (VEGFR-2: rs2305948C>T, rs1870377T>A), VEGFR-3 (rs307826T>C, rs307821C>A), Platelet-Derived Growth Factor-A (PDGFR-A: rs35597368C>T).
Gene polymorphisms were determined by Real-Time PCR using TaqMan assays.
Results:
93 patients were included into the study, 58 females and 35 males.
The patients underwent surgery: 43 for thymomas, 14 for thymic carcinomas, 36 for thymic hyperplasia.
The frequency of PDGFRa rs35597368T (95.24%) was significantly higher in thymic malignancies if compared with data available for population (86%, p=0.012), thus suggesting that it may represent a risk factor for this type of disease. On the other hand, the frequency of several HIF-1a polymorphisms (rs2057482C, rs11549465C, rs1951795C, rs2301113A, rs10873142T, rs11158358C, rs12434438A) resulted lower in our study than in the general population (p<0.05). In particular, frequencies of HIF1a rs1951795C, rs2301113A, rs12434438A were significantly lower in thymic malignancy than in thymic hyperplasia and moreover these were lower than population, according to available literature data on other types of tumors, suggesting a protective role.
Furthermore, VEGFR3 rs307821C polymorphism was higher in thymoma than in thymic carcinoma (79.5% vs 72%, p=0.0371), and therefore it seems to be related to a lower grade of malignancy.
Finally, the following factors were significantly correlated with a better overall survival: VEGFR-3 rs307826C, VEGFR-2 rs1870377A, PDGFR-A rs35597368T/C, HIF1a rs2301113C, rs2057482C/T, rs1951795C, rs11158358G/C and rs10873142T/C (p<0.05).
Conclusion: To the best of our knowledge this is the largest monocentric study analyzing the angiogenetic variants in thymic hyperplasia and tumors representing a further asset in the definition of high-risk patients after curative resection, also driving the selection of more aggressive adjuvant treatment in this subgroup of patients. The selection tool deriving from this analysis may allow an optimal use of innovative treatment strategies in thymic malignancies including targeted agents such as sunitinib, sorafenib or pazopanib.
Citation Format: Rossana Berardi, Silvia Pagliaretta, Alessandro Brunelli, Vittorio Paolucci, Gaia Goteri, Majed Refai, Cecilia Pompili, Agnese Savini, Giulia Marcantognini, Mariangela Torniai, Michela Tiberi, Consuelo Ferrini, Francesca Morgese, Miriam Caramanti, Silvia Rinaldi, Azzurra Onofri, Antonio Zizzi, Paola Mazzanti, Stefano Cascinu. Impact of single-nucleotide polymorphisms (SNPs) on thymic hyperplasia and tumors outcome. abstract. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2220. doi:10.1158/1538-7445.AM2014-2220
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