Search

A serosurvey of IgG antibodies against SARS-CoV-2 was conducted in Greece between May and August 2020. It was designed as a cross-sectional survey and was repeated at monthly intervals. The leftover sampling methodology was used and a geographically stratified sampling plan was applied. Of 20,110 serum samples collected, 89 (0.44%) were found to be positive for anti-SARS-CoV-2 antibodies, with higher seroprevalence (0.35%) observed in May 2020. The highest seroprevalence was primarily observed in the “30–49” year age group. Females presented higher seroprevalence compared to males in May 2020 (females: 0.58% VS males: 0.10%). This difference reversed during the study period and males presented a higher proportion in August 2020 (females: 0.12% VS males: 0.58%). Differences in the rate of seropositivity between urban areas and the rest of the country were also observed during the study period. The four-month infection fatality rate (IFR) was estimated to be 0.47%, while the respective case fatality rate (CFR) was at 1.89%. Our findings confirm low seroprevalence of COVID-19 in Greece during the study period. The young adults are presented as the most affected age group. The loss of the cumulative effect of seropositivity in a proportion of previous SARS-CoV-2 infections was indicated. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Background: Ramucirumab—an IgG1 vascular endothelial growth factor receptor 2 antagonist—plus docetaxel was previously reported to improve progression-free survival in platinum-refractory, advanced urothelial carcinoma. Here, we report the secondary endpoint of overall survival results for the RANGE trial. Methods: We did a randomised, double-blind, phase 3 trial in patients with advanced or metastatic urothelial carcinoma who progressed during or after platinum-based chemotherapy. Patients were enrolled from 124 investigative sites (hospitals, clinics, and academic centres) in 23 countries. Previous treatment with one immune checkpoint inhibitor was permitted. Patients were randomly assigned (1:1) using an interactive web response system to receive intravenous ramucirumab 10 mg/kg or placebo 10 mg/kg volume equivalent followed by intravenous docetaxel 75 mg/m2 (60 mg/m2 in Korea, Taiwan, and Japan) on day 1 of a 21-day cycle. Treatment continued until disease progression, unacceptable toxicity, or other discontinuation criteria were met. Randomisation was stratified by geographical region, Eastern Cooperative Oncology Group performance status at baseline, and visceral metastasis. Progression-free survival (the primary endpoint) and overall survival (a key secondary endpoint) were assessed in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT02426125; patient enrolment is complete and the last patient on treatment is being followed up for safety issues. Findings: Between July 20, 2015, and April 4, 2017, 530 patients were randomly allocated to ramucirumab plus docetaxel (n=263) or placebo plus docetaxel (n=267) and comprised the intention-to-treat population. At database lock (March 21, 2018) for the final overall survival analysis, median follow-up was 7·4 months (IQR 3·5–13·9). In our sensitivity analysis of investigator-assessed progression-free survival at the overall survival database lock, median progression-free survival remained significantly improved with ramucirumab compared with placebo (4·1 months [95% CI 3·3–4·8] vs 2·8 months [2·6–2·9]; HR 0·696 [95% CI 0·573–0·845]; p=0·0002). Median overall survival was 9·4 months (95% CI 7·9–11·4) in the ramucirumab group versus 7·9 months (7·0–9·3) in the placebo group (stratified HR 0·887 [95% CI 0·724–1·086]; p=0·25). Grade 3 or worse treatment-related treatment-emergent adverse events in 5% or more of patients and with an incidence more than 2% higher with ramucirumab than with placebo were febrile neutropenia (24 [9%] of 258 patients in the ramucirumab group vs 16 [6%] of 265 patients in the placebo group) and neutropenia (17 [7%] of 258 vs six [2%] of 265). Serious adverse events were similar between groups (112 [43%] of 258 patients in the ramucirumab group vs 107 [40%] of 265 patients in the placebo group). Adverse events related to study treatment and leading to death occurred in eight (3%) patients in the ramucirumab group versus five (2%) patients in the placebo group. Interpretation: Additional follow-up supports that ramucirumab plus docetaxel significantly improves progression-free survival, without a significant improvement in overall survival, for patients with platinum-refractory advanced urothelial carcinoma. Clinically meaningful benefit might be restricted in an unselected population. Funding: Eli Lilly and Company. © 2020 Elsevier Ltd

Background: Vascular endothelial growth factor (VEGF) targeting represents the standard first-line therapy for metastatic renal-cell carcinoma (mRCC), while blocking the mammalian target of rapamycin (mTOR) is effective in relapsed disease. Since continuing blockade of VEGF may be of value, we studied the combination of bevacizumab with temsirolimus in mRCC patients relapsing after first-line treatment. Methods: A prospective, phase II study of the combination of bevacizumab (10 mg/kg, every 2 weeks) with temsirolimus (25 mg weekly) in patients with mRCC who failed first-line anti-VEGF treatment. 6-month progression-free survival (PFS) rate was the primary end point. The association of VEGFa, VEGFR2, fibroblast growth factor (FGF) b, platelet-derived growth factor receptor (PDGFR) a and PDGFRb with prognostic factors and outcomes were also studied. Results: 39 patients were enrolled. First-line therapy included: sunitinib (n = 16), bevacizumab/interferon (n = 12), pazopanib (n = 10), sorafenib (n = 1). After a median follow-up of 37 months, 6-month PFS rate was 50.9% [95% confidence interval (CI) 33.8–65.7], median time to progression 6.8 months (95% CI 5.5–9.2) and median overall survival (OS) 18.2 months (95% CI 12.9–27.2). Objective response rate was 27%. The most common AEs were metabolic (33%), renal (8%) and gastrointestinal (GI) (7%). The most common grade 3–5 AEs were GI (18%), infections (14%) and metabolic (25%). Toxicity was the most frequent cause of treatment discontinuation (40%). FGFb levels were associated with OS. Conclusions: In concert with recent data, our study confirms the efficacy of anti-VEGF/anti-mTOR combination in mRCC relapsing after anti-VEGF therapy. Toxicity was considerable leading to high rate of treatment discontinuations. Trial registration: ClinicalTrials.gov: NCT01264341. © 2018, Japan Society of Clinical Oncology.

Background/Aim: KRAS mutations are reported in 20-25% of non-small cell lung cancer (NSCLC) and their prognostic role is unclear. We studied KRAS and EGFR genotyping in Greek NSCLC patients. Patients and Methods: KRAS and EGFR genotypes were centrally evaluated in 421 NSCLC patients (diagnosed September 1998 -June 2013) and associated with clinicopathological parameters. Outcome comparisons were performed in 288 patients receiving first line treatment. Results: Most patients were male (78.6%), >60 years old (63.9%), current smokers (51.1%), with adenocarcinoma histology (63.9%). EGFR and KRAS mutations were found in 10.7% and 16.6% of all histologies, respectively, and in 14.9% and 21.9% of adenocarcinomas. At 4.5 years median follow-up, KRAS status was an independent negative prognostic factor for overall survival (OS, p=0.016). KRAS mutations conferred 80% increased risk of death in patients receiving first-line treatment (p=0.002). Conclusion: The presence of KRAS mutations is an independent negative prognosticator among Greek NSCLC patients and an independent response predictor to first line treatment. © 2019 International Institute of Anticancer Research. All rights reserved.

Aim: The association between two polymorphisms of ERCC1 and treatment outcomes after platinum-based chemotherapy in patients with advanced urothelial cancer (UC) was examined. Materials & methods: Genotyping of 19007C>T and 8092C>A polymorphisms was determined by PCR amplification and RFLP in 113 advanced UC patients, treated with platinum-based chemotherapy. Results: Seventy eight patients (69%) were carriers of the 19007T polymorphic allele: 51 (45%) heterozygotes and 27 (24%) homozygotes. Fifty three (47%) patients were carriers of the 8092A polymorphic allele: the frequencies of C/A and A/A genotypes were 37% and 10%, respectively. The T/T genotype was independently associated with prolonged median cancer-specific survival (not-reached vs 14.8 months; p = 0.026). There was no interaction between T/T or any other genotype with the type of platinum derivative (cisplatin/carboplatin). Conclusion: 19007C>T, especially in its homozygotic state, but not 8092C>A polymorphism, could be a useful prognostic marker in advanced UC treated with platinum-based chemotherapy. Original submitted 17 July 2012; Revision submitted 21 September 2012

Eribulin mesylate is a synthetic derivative of halichondrin B isolated from a marine sponge. Its mechanism of action is through microtubule inhibition, which is different from that of taxanes. Eribulin has been approved for the treatment of metastatic breast cancer and more recently for non-operable or metastatic liposarcoma in patients who have received prior anthracycline chemotherapy. The major side effects of eribulin are bone marrow suppression including neutropenia, leukopenia, anemia, and fatigue/weakness, which can be well managed. In this article, we reviewed evidence from the latest published data on eribulin and its use in the treatment of soft tissue sarcomas. We explored the drug’s mechanism of action, pharmacodynamics, pharmacokinetics, and metabolism. Lastly, we reviewed all preclinical studies as well as clinical trials that investigated eribulin. © 2018 Koliou et al.

Objectives: Linezolid-resistant Staphylococcus epidermidis (LRSE) and linezolid-dependent ST22 strains have been shown to predominate in tertiary care facilities all over Greece.We report herein the dissemination of ST22 but also ST2, ST5 and ST168 linezolid-dependent LRSE clones in four unrelated German hospitals. Methods: Fourteen LRSE clinical isolates recovered during 2012-14 from five distantly located German hospitals were tested by for MIC determination broth microdilution and Etest, PCR/sequencing for cfr and for mutations in 23S rRNA, rplC, rplD and rplV genes, MLST, PFGE and growth curves without and with linezolid at 16 and 32mg/L. Results: Most (11, 78.6%) isolates had linezolid MICs .256 mg/L. Five isolates carried the cfr gene. Eight isolates belonged to ST22, two isolates each to ST168 and ST2 and one isolate each to ST5 and ST23. Ten isolates [seven belonging to ST22 and one to each of ST2, ST5 and ST168; all these STs belong to clonal complex (CC) 5] exhibited linezolid-dependent growth, growing significantly faster in linezolid-containing broth. Four isolates were non-dependent (one belonging to each of ST22, ST2, ST23 and ST168). Four isolates came from three different hospitals, whereas four and six isolates were recovered during outbreaks of LRSE in two distinct hospitals. Conclusions: The multi-clonal dissemination of CC5 linezolid-dependent LRSE throughout German hospitals along with the clonal expansion of ST22 linezolid-dependent LRSE in Greek hospitals is of particular concern. It is plausible that this characteristic is inherent and provides a selective advantage to CC5 LRSE under linezolid pressure, contributing to their dissemination throughout hospitals in these countries. © The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.

This clinical trial assessed the efficacy and toxicity of panitumumab combined with oxaliplatin and capecitabine as first-line treatment in KRAS exon 2 wild-type metastatic colorectal cancer (mCRC) patients. Patients with exon 2 KRAS wild-type mCRC received panitumumab 9 mg/Kg, oxaliplatin 130 mg/m2, and capecitabine 2000 mg/m2 repeated every 3 weeks. The primary endpoint was objective response rate (ORR, minimum 42 responses). We retrospectively assessed mutations in genes implicated in CRC with massively parallel sequencing; ERBB2 and EGFR amplification with fluorescence in situ hybridization, and tumor-infiltrating lymphocyte density. Among 78 patients enrolled, 45 (57.7%) completed 6 cycles. Most common grade 3–4 toxicities were skin rash (19.2%), diarrhea (18%), and neuropathy (6.4%). Among 5 (6.4%) potentially treatment-related deaths, 2 (2.6%) were characterized toxic. Objective response occurred in 43 (55.1%) of the patients (complete 6.4% and partial response 48.7%; stable 17.9% and progressive disease 7.7%), while 3.8% were non-evaluable and 15% discontinued their treatment early. Additional mutations in KRAS/NRAS/BRAF were found in 11/62 assessable (18%) tumors. After 51 months median follow-up, median progression-free (PFS) was 8.1 and overall survival 20.2 months, independently of KRAS/NRAS/BRAF or PI3K-pathway mutation status. Patients with TP53 mutations (n = 34; 55%), as well as those with left colon primary tumors (n = 66; 85%), had significantly better PFS, also confirmed in multivariate analysis. Although the clinical trial met its primary endpoint, according to the current standards, the efficacy and tolerability of the drug combination are considered insufficient. Extended genotyping yielded interesting results regarding the significance of TP53 mutations. ClinicalTrials.gov identifier: NCT01215539, Registration date: Sep 29, 2010. © 2018, Springer Science+Business Media, LLC, part of Springer Nature.

The aim of this study is to investigate the feasibility and determine the pharmacokinetics of low-dose paclitaxel in cancer patients with severe hepatic dysfunction. This was a prospective study. Patients with liver metastases who had either transaminase serum levels higher than 10 times the upper normal limit or bilirubin serum levels higher than 5 times the upper normal limit were eligible. All patients underwent pharmacokinetic evaluation during the first course of treatment. Pharmacokinetics in severe hepatic dysfunction patients were compared with data from a reference group of patients with normal hepatic function who participated in a phase I study. Nine severe hepatic dysfunction patients were treated with paclitaxel 70 mg/m administered as a 1-h infusion every 2 weeks. They received a median three treatment courses (range 1-9) without clinically relevant toxicity. The area under the concentration-time curve of paclitaxel was markedly higher in severe hepatic dysfunction patients when compared with the normal hepatic function control group treated with the same dose (98% increase, P0.1) concentration threshold in the severe hepatic dysfunction patients who received paclitaxel 70 mg/m approximated pharmacokinetics of paclitaxel in patients with normal liver function who received 130 mg/m. Maximum plasma concentration (Cmax) did not differ between the two groups. In conclusion, paclitaxel 70 mg/m was safely delivered every 2 weeks in patients with severe hepatic dysfunction and resulted in adequate plasma concentrations. Paclitaxel at this dosage can be taken as an option for severe hepatic dysfunction patients who are expected to get clinical benefits from taxanes. Anticancer Drugs

The aim of the study was to investigate angiogenesis in patients with advanced-stage ovarian carcinoma. We used paraffin-embedded tumor tissues from 33 patients diagnosed with FIGO III ovarian cancer who had optimal surgery and received platinum-based chemotherapy. The tissue expression of CD34, vascular endothelial growth factor (VEGF), and thrombospondin-1 (TSP-1) was assessed immunohistochemically. CD34 stained hot spot areas were used to evaluate tumor microvessel density (MVD). VEGF and TSP-1 were assessed by semiquantitative methods. The studied molecules were investigated for relationship with standard clinicopathologic parameters. MVD count was high: median value of 39, range 12–143 microvessels/mm2. VEGF was present in all cases and stained strong in 91%. Stroma staining for TSP-1 was weak in 79% of the cases, strong in 6%, and absent in five (15%). We did not find correlations between the three studied markers and histologic type or tumor grade. MVD score did not relate to VEGF or TSP-1. We only observed a trend toward a longer survival in patients with tumors expressing high TSP-1 (60 vs. 36 months, P= 0.1). Proangiogenetic factor VEGF is highly expressed in advanced-stage ovarian carcinomas. The findings of this study may offer support for considering VEGF-targeted therapeutics in ovarian cancer treatment research.

Purpose: We performed a phase I study of two fixed dosing schemes of cisplatin, a DNA cross-linker, with intravenous escalating topotecan, a DNA-topoisomerase I inhibitor. Experimental Design: 40 patients with advanced solid tumors received intravenous cisplatin at a fixed dose of either 25 mg/m2 (schedule A) or 20 mg/m2 (schedule B) daily for 3 days with standard hydration. Topotecan escalation proceeded in 0.75, 0.90, 1.0, 1.15 mg/m2 cohorts in schedule A and 1.0, 1.1, 1.2, 1.3 mg/m2 cohorts in schedule B, administered intravenously at the end of cisplatin infusion daily for 3 days, repeated every 3 weeks. Dose-limiting toxicity (DLT) consisted of protracted grade IV neutropenia, febrile neutropenia, grade IV thrombocytopenia and any grade III/IV non-hematological toxicity. Epoetin and granulocyte colony-stimulating factor support was allowed on severe myeloablation. Endpoints were the identification of maximal tolerated dose (MTD), DLT and other toxicity. Results: The MTD was reached in cohort 25/1.15 mg/m2 in schedule A and 20/1.2 mg/m2 in schedule B. All DLT seen consisted of three episodes of febrile neutropenia and two of grade IV thrombocytopenia in schedule A, with three episodes of febrile neutropenia and one of protracted neutropenia in schedule B. Myelosuppression was substantial in all cohorts despite granulocyte colony-stimulating factor and epoetin support, peaked on the third week of treatment and resulted in administration of chemotherapy at a median of every 4 weeks. Non-hematologic toxicity was mild. The response rate was 51% with seven complete responses occurring in patients with ovarian cancer, small cell and non-small cell lung cancer and cancer of unknown primary. The recommended dose was 20/ 1.1 mg/m2 for cisplatin and topotecan on schedule B, as the number of responses and administered topotecan dose were higher in schedule B recommended dose with lower cisplatin dose, minimizing problems of nephrotoxicity and vomiting. Conclusions: The schedule B daily cisplatin-topotecan × 3 combination with secondary cytokine support is associated with promising activity and schedule convenience. However, substantial myelosuppression undermines its applicability in the palliative setting, stressing the need for less toxic regimens.

Purpose: To investigate the pharmacokinetics of polyethylene glycol-coated liposomal doxorubicin (PLD, Caelyx) when given as a single agent and in combination with the taxanes paclitaxel or docetaxel in humans. Methods: The plasma kinetics of PLD were studied in 19 cancer patients treated with PLD every 4 weeks combined with either paclitaxel (on a weekly basis in seven and as a single infusion in three patients) or docetaxel (weekly in seven and as a single infusion in two). Plasma concentrations of PLD were quantified in two sets of samples per patient to compare the same pharmacokinetic parameters in each subject when treated with single-agent PLD and again with the combination. Total doxorubicin concentrations in plasma were quantified by HPLC. Pharmacokinetics were evaluated by noncompartmental analysis and the data obtained were compared for differences by a matched-pairs nonparametric test. Results: Coadministration of paclitaxel produced a median/mean 54/80% increase in PLD AUCinf (95% confidence interval 23% to 136%, P=0.002). The observed increase was consistent among all subjects. PLD clearance was also decelerated in the presence of paclitaxel (P=0.013) while other pharmacokinetic parameters were affected modestly. A small increase in the AUC of PLD was observed in the docetaxel/PLD arm (mean increase 12%, P=0.039) while PLD clearance decreased marginally and other pharmacokinetic parameters remained unaffected. AUC extrapolated to infinity was below 8% in both arms. Conclusions: This study showed the presence of a pharmacokinetic interaction that led to higher plasma concentrations of PLD when combined with paclitaxel and to a minor extent when combined with docetaxel. This pharmacokinetic information may be of value when planning combination therapies of PLD with taxanes. © Springer-Verlag 2004. 53 5 452 457

Small molecules, mainly tyrosine kinase inhibitors, are currently used in various malignancies. Lapatinib, a dual inhibitor of EGFR/HER2 tyrosine kinases, has demonstrated effectiveness in brain metastases from HER2-overexpressing breast cancer. It also appears to sensitize EGFR-expressing cell lines to radiation. To evaluate the efficacy of lapatinib in combination with whole brain radiotherapy (WBRT) in patients with brain metastases from non-small cell lung cancer (NSCLC) and breast cancer, as assessed by volumetric analysis by MRI. 81 patients were treated with WBRT (30 Gy in ten fractions) in combination with lapatinib 1250 mg once daily, followed by lapatinib 1500 mg once daily for a total 6 weeks. 21 patients had primary breast cancer and 60 patients NSCLC. Pre- and post-treatment MRI scans in a compact disk for central volumetric assessment were available for 43 patients. 27 patients (62.8%) achieved partial response, 15 patients (34.9%) had stable disease and only one patient (2.3%) had disease progression. Response was not associated to EGFR protein expression. All 81 patients were assessed for safety. The large majority of the adverse events were mild. Eight deaths occurred, four of which were considered related to the study drugs but there were also other contributing factors. Nine cases of serious infections were observed in eight patients, but they were also receiving dexamethasone. Lapatinib in combination with WBRT in patients with brain metastases from breast cancer and NSCLC is a feasible approach that can be further studied in larger clinical trials. © 2017, Springer Science+Business Media, LLC.

Background: Epidermal growth factor receptor (EGFR) aberrations have been implicated in the pathogenesis of triple-negative breast cancer (TNBC) but their impact on prognosis and, therefore, druggability, remain controversial. Herein, we studied EGFR aberrations at different molecular levels and assessed their prognostic impact in patients with operable TNBC treated with adjuvant anthracycline-based chemotherapy. Materials and Methods: We evaluated the prognostic impact of EGFR gene status by fluorescent in situ hybridization (FISH), EGFR coding mutations by Sanger and next-generation sequencing, relative EGFR messenger RNA (mRNA) levels by qPCR (upper quartile) and EGFR and p53 protein expression by immunohistochemistry (IHC), in 352 centrally-assessed tumors from an equal number of TNBC patients. Results: Approximately 53.5% of the tumors expressed EGFR, 59.3% p53 and 35.9% both EGFR and p53 proteins; 4.1% showed EGFR gene amplification and 4.4% carried EGFR mutations. The latter were located outside the druggable kinase domain region and presented at low frequencies. Amplification and mutations overlapped only in one case of glycogen-rich carcinoma. EGFR and CEN7 copies were higher in tumors from older patients (p=0.002 and p=0.003, respectively). Patients with amplified tumors (n=11) had excellent prognosis (0 relapses and deaths). Upon multivariate analysis, high EGFR copies conferred significantly favorable disease-free survival (HR=0.57, 95% CI 0.36-0.90, Wald's p=0.017) and high CEN7 copies favorable overall survival (HR=0.49, 95% CI=0.29-0.83, Wald's p=0.008). Patients with EGFR-/p53+ and EGFR+/p53-tumors had significantly higher risk for relapse than those with EGFR-/p53- and EGFR+/p53+ tumors (HR=1.73, 95% CI=1.12-2.67, Wald's p=0.013). Conclusion: EGFR gene amplification and mutations are rare in TNBC, the latter of no apparent clinical relevance. Surrogate markers of EGFR-related chromosomal aberrations and combined EGFR/p53 IHC phenotypes appear to be associated with favorable prognosis in patients with operable TNBC receiving conventional adjuvant chemotherapy.

Purpose: To identify prognostic molecular profiles in patients with mRCC treated with sunitinib, we performed immunohistochemical analysis for VEGF and PI3K/Akt/mTOR pathway components. Methods: The immunohistochemical expression of VEGF, p85α, p110γ, PTEN, p-Akt, p-mTOR, p-4E-BP1 and p-p70S6K was studied in 79 patients with mRCC who received first-line treatment with sunitinib. Expression was correlated with clinicopathological features and survival. Results: VEGF was highly expressed (median H-Score 150), while positivity for the markers of the PI3K/Akt/mTOR pathway was: p85α 43/66 (65 %), p110γ41/60 (68 %), PTEN 32/64 (50 %), p-Akt57/63 (90 %), p-mTOR48/64 (75 %), p-4E-BP1 58/64 (90 %) and p-p70S6K 60/65 (92 %). No single immunohistochemical marker was found to have prognostic significance. Instead, the combination of increased p-mTOR and low VEGF expression was adversely correlated with overall survival (OS) (3.2 vs. 16.9 months, P = 0.001). Conclusion: Immunohistochemistry for VEGF and p-mTOR proteins may discriminate patients refractory to first-line sunitinib with poor prognosis. Prospective validation of our findings is needed. © 2016, Springer-Verlag Berlin Heidelberg.

Background Few treatments with a distinct mechanism of action are available for patients with platinum-refractory advanced or metastatic urothelial carcinoma. We assessed the efficacy and safety of treatment with docetaxel plus either ramucirumab—a human IgG1 VEGFR-2 antagonist—or placebo in this patient population. Methods We did a randomised, double-blind, phase 3 trial in patients with advanced or metastatic urothelial carcinoma who progressed during or after platinum-based chemotherapy. Patients were enrolled from 124 sites in 23 countries. Previous treatment with one immune-checkpoint inhibitor was permitted. Patients were randomised (1:1) using an interactive web response system to receive intravenous docetaxel 75 mg/m2 plus either intravenous ramucirumab 10 mg/kg or matching placebo on day 1 of repeating 21-day cycles, until disease progression or other discontinuation criteria were met. The primary endpoint was investigator-assessed progression-free survival, analysed by intention-to-treat in the first 437 randomised patients. This study is registered with ClinicalTrials.gov, number NCT02426125. Findings Between July, 2015, and April, 2017, 530 patients were randomly allocated either ramucirumab plus docetaxel (n=263) or placebo plus docetaxel (n=267). Progression-free survival was prolonged significantly in patients allocated ramucirumab plus docetaxel versus placebo plus docetaxel (median 4·07 months [95% CI 2·96–4·47] vs 2·76 months [2·60–2·96]; hazard ratio [HR] 0·757, 95% CI 0·607–0·943; p=0·0118). A blinded independent central analysis was consistent with these results. An objective response was achieved by 53 (24·5%, 95% CI 18·8–30·3) of 216 patients allocated ramucirumab and 31 (14·0%, 9·4–18·6) of 221 assigned placebo. The most frequently reported treatment-emergent adverse events, regardless of causality, in either treatment group (any grade) were fatigue, alopecia, diarrhoea, decreased appetite, and nausea. These events occurred predominantly at grade 1–2 severity. The frequency of grade 3 or worse adverse events was similar for patients allocated ramucirumab and placebo (156 [60%] of 258 vs 163 [62%] of 265 had an adverse event), with no unexpected toxic effects. 63 (24%) of 258 patients allocated ramucirumab and 54 (20%) of 265 assigned placebo had a serious adverse event that was judged by the investigator to be related to treatment. 38 (15%) of 258 patients allocated ramucirumab and 43 (16%) of 265 assigned placebo died on treatment or within 30 days of discontinuation, of which eight (3%) and five (2%) deaths were deemed related to treatment by the investigator. Sepsis was the most common adverse event leading to death on treatment (four [2%] vs none [0%]). One fatal event of neutropenic sepsis was reported in a patient allocated ramucirumab. Interpretation To the best of our knowledge, ramucirumab plus docetaxel is the first regimen in a phase 3 study to show superior progression-free survival over chemotherapy in patients with platinum-refractory advanced urothelial carcinoma. These data validate inhibition of VEGFR-2 signalling as a potential new therapeutic treatment option for patients with urothelial carcinoma. Funding Eli Lilly and Company. © 2017 Elsevier Ltd

Liposarcoma (LPS) is a malignancy with extreme heterogeneity and thus optimization towards personalizing patient prognosis and treatment is essential. Here, we evaluated miR-155, miR-21, miR-143, miR-145 and miR-451 that are implicated in LPS, as novel FFPE tissue biomarkers. A total of 83 FFPE tissue specimens from primary LPS and lipomas (LPM) were analyzed. A proteinase K incubation-Trizol treatment coupled protocol was used for RNA isolation. After polyadenylation of total RNA and reverse transcription, expression analysis of 9 candidate reference and 5 target miRNAs was performed by qPCR. Genorm and NormFinder were used for finding the most suitable molecules for normalization. Survival analyses were performed in order to evaluate the prognostic potential of miRNAs. MiR-103 and miR-191 are most suitable for normalization of miRNA expression in LPS. MiR-155 and miR-21 are clearly overexpressed (P < 0.001) in LPS compared with LPM specimens, whereas miR-145 (P < 0.001), miR-143 (P =0.008) and miR- 451 (P=0.037) are underexpressed. MiR-155 (P=0.007) and miR-21 (P=0.029) are differentially expressed between well-differentiated, dedifferentiated, myxoid/round cell and pleomorphic LPs tumor subtypes. MiR-155 represents a novel independent indicator of unfavorable prognosis in LPS (HR = 2.97, 95% CI = 1.23-7.17, P = 0.016).

Purpose: Following the establishment of adjuvant carboplatin in stage I testicular seminoma as a standard, we adopted this treatment for all stage I seminoma patients. We report our 8-year experience and compare these results with our previous adjuvant etoposide/cisplatin (EP) strategy. Patients and methods: Patients with stage I seminoma, treated with adjuvant carboplatin and with a minimum follow-up of 1 year, were included. Two cycles of carboplatin [area under the curve (AUC) 6] were administered. Results: A total of 138 patients with median age of 34 years, treated from September 2003 to December 2011, were selected. There were 5 relapses [5-year relapse-free rate (RFR) 96.8 % (95 % confidence interval 91.6–98.8)]: 3 relapses at retroperitoneal lymph nodes, 1 relapse at the adrenal gland, and 1 isolated brain metastasis. Four patients with relapse were cured with salvage chemotherapy. All patients with relapse had tumor diameter ≥4 cm and/or age ≤34 years. Patients with at least 1 of the above risk factors (n = 111) had a significantly higher relapse rate compared with a similar population (n = 64) treated with 2 cycles of adjuvant EP: 5-year RFR was 95 % (SE 2 %) versus 100 % (SE 0 %), (p = 0.067). Conclusions: Age and tumor diameter were associated with relapse in stage I seminoma treated with adjuvant carboplatin. Although adjuvant carboplatin in patients with age ≤34 and/or tumor diameter ≥4 cm is associated with higher relapse rates than EP, the prognosis of these patients is excellent, and therefore, the use of less toxic treatment is justified. © 2015, Springer-Verlag Berlin Heidelberg.

Relapsed urothelial cancer represents an unmet medical need. Vinflunine is a third-generation antimicrotubuline inhibitor and is currently the only approved drug for secondline treatment across the European Union. We conducted a retrospective analysis assessing the efficacy and safety of vinflunine in 71 Greek patients with relapsed urothelial cancer who were treated between 2005 and 2014. An overall 84% of our patients received vinflunine as second-line treatment, 77% had a performance status of Eastern Cooperative Oncology Group scale 0 or 1, and 30% had liver metastasis at the time of vinflunine administration. A median of four cycles of vinflunine were administered (range 1-16). The most common reported adverse events were constipation, fatigue, and anemia. Median progression-free survival was 6.2 months (95% confidence interval: 4.4-8.8) and overall survival was 11.9 months (95% confidence interval: 7.4-21). Two patients (3%) achieved a complete remission, seven a partial remission (10%), and 22 (31%) had stable disease according to an intention-to-treat analysis. Hemoglobin level less than 10 g/dl and Eastern Cooperative Oncology Group performance status greater than 1 were independent adverse prognostic factors. Stratification according to the Bellmunt risk model was also associated with progression-free survival and overall survival in our population. Vinflunine appears to be a safe and effective treatment modality for relapsed urothelial cancer. More effective therapies and more accurate prognostic algorithms should be sought. © 2015 Wolters Kluwer Health, Inc. All rights reserved.

We characterized the feasibility and toxicity profile of anthracycline-containing adjuvant chemotherapy in women >65 years of age with early breast cancer. Elderly breast cancer patients derive clinical benefit comparable with that of younger patients, mainly at the cost of increased risk of hematological toxicity. Background Intensive chemotherapy confers benefit to patients with high-risk early breast cancer (BC). We characterized the feasibility and toxicity profile of anthracycline-containing adjuvant chemotherapy (ACAC) in older women with early BC. Patients and Methods Available data from women who received ACAC for BC in 3 randomized trials were retrieved. We identified women aged >65 years and we examined differences in tolerability and delivery of chemotherapy, toxicity, and treatment outcome. Results From a total of 2640 patients, we identified 453 patients (17%) as being >65 years old, 89% of whom had tumors that were node-positive, with 77% who were hormone receptor-positive. At least 90% of the planned doses were delivered in 37% of the elderly, compared with 49% in the younger patients (P < .0001). Grade 3 and 4 hematological toxicity was observed in 32% of elderly patients, compared with 21% of the younger (P < .0001). Febrile neutropenia occurred in 4.5% of the elderly patients, as opposed to 2.0% in the younger patients (P < .002). Elderly patients experienced more frequent Grade 3 and 4 fatigue, mucositis, and sensory neuropathy. Relative dose intensities were significantly lower in elderly patients. Treatment discontinuation was not different in the 2 groups. At a median follow-up of 120 months, competing risks analysis showed a significant benefit in disease-free survival for elderly patients. Conclusion Elderly BC patients treated with ACAC derive clinical benefit comparable to that in younger patients, mainly at the cost of increased risk of hematological toxicity. This should be taken into account in decision-making and treatment individualization in high-risk BC patients. © 2015 Elsevier Inc.

The purpose of this study is to investigate whether the outcome of breast cancer (BC) patients treated with adjuvant chemotherapy is affected by co-mutated TP53 and PIK3CA according to stromal tumor-infiltrating lymphocytes (TILs). Paraffin tumors of all clinical subtypes from 1661 patients with operable breast cancer who were treated within 4 adjuvant trials with anthracycline–taxanes chemotherapy were informative for TP53 and PIK3CA mutation status (semiconductor sequencing genotyping) and for stromal TILs density. Disease-free survival (DFS) was examined. TP53 mutations were associated with higher (p

Minimally invasive procedures, which include laparoscopic surgery, use state-of-the-art technology to reduce the damage to human tissue when performing surgery. Minimally invasive procedures require small "ports" from which the surgeon inserts thin tubes called trocars. Carbon dioxide gas may be used to inflate the area, creating a space between the internal organs and the skin. Then a miniature camera (usually a laparoscope or endoscope) is placed through one of the trocars so the surgical team can view the procedure as a magnified image on video monitors in the operating room. Specialized equipment is inserted through the trocars based on the type of surgery. There are some advanced minimally invasive surgical procedures that can be performed almost exclusively through a single point of entry-meaning only one small incision, like the "uniport" video-assisted thoracoscopic surgery (VATS). Not only do these procedures usually provide equivalent outcomes to traditional "open" surgery (which sometimes require a large incision), but minimally invasive procedures (using small incisions) may offer significant benefits as well: (I) faster recovery; (II) the patient remains for less days hospitalized; (III) less scarring and (IV) less pain. In our current mini review we will present the minimally invasive procedures for thoracic surgery. © Annals of Translational Medicine.

Pneumothorax is a situation where air is inserted in the pleural space that separates the lung from the chest wall. Pneumothorax can be primary or secondary. There is also a third type called; tensioned. Based on the concentration of air and type of pneumothorax the proper treatment has to be selected. There are cases where the concentration is minimal and observation is enough and more severe cases where surgery is required. Currently there are many techniques used for the biopsy of lung lesions. The bronchoscope (forceps, fine needle aspiration), fine needle aspiration under computed tomography scan and endobronchial ultrasound (EBUS) are commonly used. However, all these techniques have in common a possible side effect; pneumothorax. In our current issue we will focus on the different minimally invasive techniques of pneumothorax management. Moreover, a presentation will be made for several systems that are being used for air or fluid aspiration. © Annals of Translational Medicine.

A chest tube is a flexible plastic tube that is inserted through the chest wall and into the pleural space or mediastinum. It is used to remove air in the case of pneumothorax or fluid such as in the case of pleural effusion, blood, chyle, or pus when empyema occurs from the intrathoracic space. It is also known as a Bülau drain or an intercostal catheter. Insertion of chest tubes is widely performed by radiologists, pulmonary physicians and thoracic surgeons. Large catheters or small catheters are used based on each situation that the medical doctor encounters. In the current review we will focus on the chest drain systems that are in use. © Annals of Translational Medicine.

The Heimlich valve is a small one-way valve used for chest drainage that empties into a flexible collection device and prevents return of gases or fluids into the pleural space. The Heimlich valve is less than 13 cm (5 inches) long and facilitates patient ambulation. Currently there are several systems in the market. It can be used in many patients instead of a traditional water seal drainage system. The Heimlich chest drainage valve was developed so that the process of draining the pleural cavity could be accomplished in a safe, relatively simple, and efficient manner. This valve system has replaced the cumbersome underwater drainage bottle system. Moreover; the Heimlich valve system connects to chest tubing and allows fluid and air to pass in one direction only. This system functions in any position, and it does not ever need to be clamped, a regulated suction can be attached to it if necessary. The valve drains into a plastic bag that can be held at any level, allowing the patient undergoing chest drainage to be ambulatory simply by carrying the bag. In the current mini review we will present the Heimlich valve system and method of insertion. © Annals of Translational Medicine.

The pneumothorax is an abnormal collection of air or gas in the pleural space that separates the lung from the chest wall. Like pleural effusion where a large abnormal concentration of fluid (>100 mL) is liquid buildup in that space, pneumothorax may interfere with normal breathing. A medical term that it is used is the collapsed lung, although that term may also refer to atelectasis. There are two major types of pneumothorax; there is one that occurs without an apparent cause and in the absence of significant lung disease, while the so called; "secondary" pneumothorax occurs in the presence of existing lung pathology. In a minority of cases, the amount of air in the chest increases markedly when a one-way valve is formed by an area of damaged tissue, leading to a third type of pneumothorax, called "tensioned". © Annals of Translational Medicine.

Purpose: Somatostatin is a peptide with a potent and broad antisecretory action, which makes it an invaluable drug target for the pharmacological management of pituitary adenomas and neuroendocrine tumors. Furthermore, somatostatin (SST) receptors (SSTR1, 2A and B, 3, 4 and 5) belong to the G protein coupled receptor family and are overexpressed in tumors. Since, human small-cell lung cancer overexpresses somatostatin receptors (STTR), they could be legitimate targets for treating SCLC. The aim of this study was the evaluation of cytotoxicity of somatostatin in combination with several anticancer drugs in HTB-175 cell line (Small Cell Lung Cancer Cell line that expresses neuron specific enolase). Methods: Docetaxel, Paclitaxel, Carboplatin, Cisplatin, Etoposide, Gemzar, Navelbine, Fluorouracil, Farmorubicin are the chemotherapeutic drugs that we used for the combination before and after adding somatostatin in SCLC cell culture. HTB-175 cell line was purchased from ATCC LGC Standards. At indicated time-point, 48h after the combination, cell viability and apoptosis were measured with Annexin V staining by flow cytometry. Results: Flow cytometry showed that Docetaxel, Paclitaxel, Gemzar and Cisplatin induced apoptosis more when they were added before somatostatin, whereas etoposide induced apoptosis more after somatostatin treatment. Navelbine alone or in combination with somatostatin showed no differences in apoptosis. Farmorubicin showed equal toxicity in all combinations. Fluorouracil and Carboplatin induced apoptosis more when added alone in HTB-175 cell line. However, increased apoptosis was also observed when Carboplatin was administered before somatostatin in higher concentrations. Conclusion: Our results indicated that depending on the drug, somatostatin treatment before or after chemotherapeutic drugs increased apoptosis in small cell lung cancer cells. We suggest that long acting somatostatin analogues could be used as additive and maintenance therapy in combination to antineoplastic agents in SCLC patients. © 2015 Ivyspring International Publisher.

Metallothioneins (MTs) are a family of cystein-rich metal-binding proteins, which are expressed in normal cells during fetal and postnatal life but also in a variety of human neoplasms. MT expression in human tumors has been linked to resistance to anticancer drugs and differentiation and progression in some types of tumors. This study examined the immunohistochemical expression of MTs in benign, borderline and malignant tumors of ovarian surface epithelium and the possible correlations with clinicopathological parameters and survival. A total of 87 cases with diagnosis of ovarian surface epithelial tumors were included. Specifically, 21 cases of benign cystadenomas (11 serous and 10 mucinous), 14 borderline (low malignant potential tumors, 8 mucinous and 6 serous) and 52 cases of ovarian cancer were analysed. Immunohistochemical expression of MT (cut-off level >10% of tumor cells) was clearly associated with malignancy. A statistically significant correlation was found between the expression of MT in cancer cases and benign tumors (p

BACKGROUND The purpose was to study proteolysis-related molecules, matrix metalloproteinase-2 (MMP-2) and MMP-9 and tissue inhibitor of metalloproteinases-1 (TIMP-1), in carcinoma of unknown primary (CUP). METHODS Paraffin-embedded tumor material from 75 patients diagnosed with CUP was used. Tumor histologies were adenocarcinoma (77%), undifferentiated carcinoma (19%), and squamous cell carcinoma (4%) and patients were categorized into favorable (62%) and unfavorable (38%) subsets. The tissue expression of MMP-2, MMP-9, and TIMP-1 was assessed by use of specific monoclonal antibodies and evaluated by means of a visual staining score. The expression of molecules studied was analyzed against clinicopathological data. RESULTS MMP-2 was found expressed in 69% (strong expression in 49%), MMP-9 in 49% (strong in 36%), and TIMP-1 in 79% (strong in 44%) of studied cases. The expression of MMP-2 correlated positively with MMP-9. TIMP-1 was significantly higher in unfavorable compared with favorable tumors and was associated with a shorter survival of patients (7.5 vs. 12 mos). No other associations were detected. CONCLUSIONS MMP-2, MMP-9, and TIMP-1 are widely expressed in CUP, suggesting an essential role of proteolysis in these tumors. TIMP-1 may be considered a possible marker of poor prognosis in CUP patients. Cancer 2005. © 2005 American Cancer Society.

Therapeutic options for metastatic insular thyroid carcinoma (ITC) are very limited. We present the case of a 39-year-old woman with refractory metastatic ITC who responded to oxaliplatin plus irinotecan chemotherapy. She was initially diagnosed with a locally advanced and metastatic to lung ITC and underwent near-total thyroidectomy. After surgery she was treated and failed to respond first to radioiodine and subsequently to liposomal doxorubicin plus paclitaxel combination chemotherapy and was offered palliative external irradiation for metastases to bone and the brain. Eleven months postdiagnosis the patient became severely dyspnoic as a result of progression of lung metastases and elected to be treated with oxaliplatin plus irinotecan as a second-line chemotherapy. She experienced relief of her dyspnea shortly after treatment initiation and an objective response of her lung metastases was documented after the third course of treatment. Treatment continued for six cycles and tumor remission lasted for 5 months. Toxicity was mild. Confirmatory testing of oxaliplatin-irinotecan combination in case series or single cases of metastatic ITC is warranted. © Mary Ann Liebert, Inc. 15 6 614 617

Carcinoma of unknown primary (CUP) is characterized by dismal patient survival. The outcome of patients with two favourable risk CUP subsets was studied. Eighty patients diagnosed with either midline lymph node metastases (n =33) or peritoneal carcinomatosis (n = 47) were analysed retrospectively. The majority had poorly differentiated adenocarcinoma or undifferentiated carcinoma, treated with platinum-taxane based chemotherapy from 1996 till 2002. Females with peritoneal carcinomatosis also underwent surgical debulking. Objective tumour regression was present in 44% of patients (nodal group 30% versus peritoneal group 53%, p=0.066). Complete responses were seen more often in peritoneal carcinomatosis patients (nodal group 9%, peritoneal group 36%, p = 0.008). At a median follow up of 60 months, median progression-free and overall survival were 5 and 10 months respectively in the nodal group, 7 and 15 months in the peritoneal group. Five-year survival was 7% (nodal group 0% vs. peritoneal group 10%, p = 0.05). Complete responders fared better than non-CR patients. Fewer than four metastatic sites, elevated CA 125, and normal CA 19-9 levels were favourable prognostic factors for survival. Modern combination chemotherapy has satisfactory activity, with a minority of CUP patients enjoying long-term responses. Research efforts towards complete remission consolidation and molecular profiling are imperative. © 2005 Taylor & Francis. 44 2 155 160

Aim: To evaluate the pharmacokinetics of imatinib mesylate (Glivec) and its main metabolite (CGP74588) in a patient with end stage renal disease on hemodialysis and compare it with published data from subjects with normal renal function. Patients and Methods: Serial blood samples were collected over a 2-weeks period in a patient who was receiving daily 400 mg oral imatinib mesylate for the treatment of a gastrointestinal stromal tumor metastatic to the liver while on hemodialysis. Plasma levels of imatinib and CGP74588 were determined by a liquid chromatography-tandem mass spectrometry assay. Results: The pharmacokinetic values for imatinib and CGP74588, respectively, were: maximum concentration (3,340 and 781 ng/ml), time to maximum concentration (2 h), half-life (18.2 and 34.0 h), area under the curve (53.9 and 14.8 μg.h/ml), and trough concentration (1,540 and 508 ng/ml) for at least 24 h. All obtained values fell within the range of values of imatinib and its metabolite obtained in patients with normal renal function. Dialysis courses were not found to intervene with plasma kinetics of the study drug. Conclusions: Our results indicate that the pharmacokinetics of imatinib and its metabolite CGP74588 do not change in patients with end stage renal disease on hemodialysis. Thus, the standard dose of imatinib can be safely administered to patients on hemodialysis, and probably with renal failure, at any stage. © Springer-Verlag 2005. 56 4 358 360