Comprehensive molecular screening by next generation sequencing reveals a distinctive mutational profile of KIT/PDGFRA genes and novel genomic alterations: results from a 20-year cohort of patients with GIST from north-western Greece.

INTRODUCTION: Gastrointestinal stromal tumours (GIST) are mesenchymal neoplasms that usually carry an activating mutation in KIT or platelet-derived growth factor receptor alpha (PDGFRA) genes with predictive and prognostic significance. We investigated the extended mutational status of GIST in a patient population of north-western Greece in order to look at geopraphic/genotypic distinctive traits. PATIENT AND METHODS: Clinicopathological and molecular data of 38 patients diagnosed from 1996 to 2016 with GIST in the region of Epirus in Greece were retrospectively assessed. Formalin-fixed paraffin-embedded tumours were successfully analysed for mutations in 54 genes with oncogenic potential. Next generation sequencing was conducted by using the Ion AmpliSeqCancer Hotspot Panel V.2 for DNA analysis (Thermofisher Scientific). RESULTS: Among 38 tumours, 24 (63.16%) and seven (18.42%) of the tumours harboured mutations in the KIT and PDGFRA genes, respectively, while seven (18.42%) tumours were negative for either KIT or PDGFRA mutation. No mutations were detected in five (13.16%) cases. Concomitant mutations of BRAF and fibroblast growth factor receptor 3 (FGFR3) genes were observed in two patients with KIT gene mutation. Two patients with KIT/PDGFRA wild-type GIST had mutations in either KRAS or phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) genes. There was no significant survival difference regarding the exonic site of mutation in either KIT or PDGFRA gene. The presence of a mutation in pathway effectors downstream of KIT or PDGFRA, such as BRAF, KRAS or PIK3CA, was associated with poor prognosis. Adverse prognosticators were also high mitotic index and the advanced disease status at diagnosis. CONCLUSIONS: We report comparable incidence of KIT and PDGFRA mutation in patients with GIST from north-western Greece as compared with cohorts from other regions. Interestingly, we identified rare mutations on RAS, BRAF and PIK3CA genes in patients with poor prognosis.

"Juvenile" oncology--a missing subspecialty. The experience of a reference cancer centre.

INTRODUCTION: Despite unique tumor epidemiology and a higher cancer incidence compared to pediatric patients, adolescents and young adults have not been receiving specialized, multidisciplinary, centralized care. In an effort to emphasize this need, we present outcome and toxicity data from a reference centre. METHODS: Cohort of 150 patients aged 15-30 treated for malignant tumors of lymphoid and solid organs from 1986 to 2002. RESULTS: Patients aged 15-19 commonly had lymphomas, germ cell tumors and pediatric sarcomas, whereas those aged 20-30 experienced germ cell tumors, lymphomas, melanomas and epithelial tumors more often. Overall 5- and 10-year survival was 80%, whereas 5-year and 10-year time to treatment failure was 68% and 43.5% respectively. 24% of patients experienced persistent, late treatment-related toxicities that interfered with their normal lifestyle. CONCLUSION: Despite the need for specialized care, psychosocial support and enrollment in clinical trials, youngsters have not been recognized as a patient group with distinct needs. Development of "Juvenile" oncology is required.

Elderly patients with squamous lung carcinoma: faring better or worse?

INTRODUCTION: Nonsmall cell lung cancer is increasingly diagnosed at an advanced age and squamous cell carcinoma is the commonest histological type encountered in older patients. The clinical course, management, and outcome of squamous lung cancer in the elderly have not been thoroughly studied to date. PATIENTS AND METHODS: We retrospectively analyzed 236 squamous cell lung cancer patients diagnosed in two reference hospitals and compared key epidemiological, clinical, and management features between elderly (>70 years) and younger patients. Sixty-four were aged more than 70 years at diagnosis while 172 were up to 70 years of age. RESULTS: There were no differences between the two groups in gender or stage distribution. No differences were observed in the nature or duration of presenting symptoms, the appearance of pleurisy, atelectasis or vascular invasion, the incidence of distant metastatic spread, or the response to combination chemotherapy. Elderly patients were less fit (performance status 2/3 30 vs 20%, p=0.03), developed hemoptysis more often (56 vs 42%, p=0.04), and presented with smaller tumor primaries (median 4 vs 8 cm, p=0.004). When metastases were present, older patients exhibited a tropism for bony (64 vs 29%, p=0.03) and rarity of brain (5 vs 14%, p=0.03) deposits. Though elderly subjects received chemotherapy (63 vs 82%, p=0.003) or radiotherapy (29 vs 48%, p=0.009) less often than their younger counterparts, they tolerated it well and achieved comparable median time to treatment failure and overall survival (median 17 vs 18 months, log-rank p=0.22). Platinum-based chemotherapy and potentially curative management were applied less often in older patients. CONCLUSIONS: Older patients are less fit, develop bony but not brain metastases, receive antineoplastic treatment less often, and survive as long as younger patients. Squamous lung carcinoma may follow a more indolent clinical course in the elderly, a hypothesis worth validating by case-cohort studies and molecular profiling, with the hope to rationally individualize patient treatment.

Survivin and glycodelin transcriptional activity in node-positive early breast cancer: mRNA expression of two key regulators of cell survival.

INTRODUCTION: Glycodelin and survivin are key polypeptide regulators of cellular proliferation, apoptosis and angiogenesis. In view of contradictory reports on their functional role in tumors, we studied their transcriptional levels in localized breast cancer. PATIENTS AND METHODS: Glycodelin and survivin messenger ribonucleic acid (mRNA) was isolated and amplified by quantitative reverse-trancription PCR from paraffin-embedded breast carcinomas of 275 women. A normalized score was calculated by the use of GAPDH, RPL37A reference genes and was correlated with clinicopathologic/molecular parameters and patient outcome. RESULTS: A total of 272 patients were eligible, most harbored stage III node-positive breast carcinomas larger than 2 cm. Glycodelin mRNA was expressed in 68 patients (25%), more frequently in premenopausal women (P = 0.01) and those with HER2 mRNA-positive tumors (P = 0.02). Survivin mRNA was present in 263 tumors (97%) and its levels correlated significantly with high nuclear grade, VEGF mRNA and p53 mRNA presence (P < 0.05). At a median follow-up of 64 months, neither glycodelin nor survivin mRNA expression demonstrated prognostic utility for overall or disease-free survival at univariate and multivariate analysis. CONCLUSIONS: Glycodelin and survivin transcriptional activity are associated with adverse clinicopathologic and molecular characteristics of node-positive primary breast cancer but do not predict patient outcome. Further study is needed for illumination of their functional roles in tumorigenesis.

Metastatic breast carcinoma confined to bone: portrait of a clinical entity.

BACKGROUND: The current study was performed to study metastatic breast carcinoma that remains confined to bone. METHODS: The medical notes of 2514 breast carcinoma patients who were treated in 2 academic units over a 20-year period were screened and patients who fulfilled the following criteria were selected: 1) clinical manifestation and imaging confirmation of bone metastases, and 2) metastatic disease remaining confined to bone for a minimum of 24 months. Available clinical and pathologic data were recorded and analyzed. The objective of the current study was to describe this clinical entity and investigate possible correlations between clinicopathologic parameters and clinical outcome. RESULTS: A total of 104 patients (4% of the total screened patient population) fulfilled the study criteria. The majority of patients were postmenopausal, with a median age of 58 years; 44 of the patients were found to have metastases at the time of presentation (M1) and 60 patients developed metastases at a median of 38 months (range, 8-160 months) after surgery for the primary tumor. Metastases remained confined to bone for a median of 50 months. Survival after the diagnosis of bony metastases was 72 months and was similar in the 2 groups (66 months vs. 78 months). Of the patients treated, 80% responded to hormonal therapy, and 76.5% responded to chemotherapy. There was no association noted between survival and tumor grade, anatomic distribution, or disease extension. CONCLUSIONS: Bone-confined metastatic breast carcinoma has an indolent clinical course that alleviates the need for vigorous follow-up and calls into question aggressive therapeutic approaches in these patients. Translational studies are warranted to map the molecular profile, leading to the development of targeted therapies in this group of patients.