Exploring WebRTC Potential for DICOM File Sharing.

This paper explores the potential use of WebRTC set of protocols for DICOM file exchange. We have developed a simple proof-of-concept peer-to-peer DICOM file-sharing web application based on a set of WebRTC protocols. Application performance is compared with contemporary DICOM applications and transfer protocols which showed that WebRTC has its place in the DICOM file-sharing domain.

Association of Inherited Pathogenic Variants in Checkpoint Kinase 2 (CHEK2) With Susceptibility to Testicular Germ Cell Tumors.

IMPORTANCE: Approximately 50% of the risk for the development of testicular germ cell tumors (TGCTs) is estimated to be heritable, but no mendelian TGCT predisposition genes have yet been identified. It is hypothesized that inherited pathogenic DNA repair gene (DRG) alterations may drive susceptibility to TGCTs. OBJECTIVE: To systematically evaluate the enrichment of germline pathogenic variants in the mendelian cancer predisposition DRGs in patients with TGCTs vs healthy controls. DESIGN, SETTING, AND PARTICIPANTS: A case-control enrichment analysis was performed from January 2016 to May 2018 to screen for 48 DRGs in 205 unselected men with TGCT and 27 173 ancestry-matched cancer-free individuals from the Exome Aggregation Consortium cohort in the discovery stage. Significant findings were selectively replicated in independent cohorts of 448 unselected men with TGCTs and 442 population-matched controls, as well as 231 high-risk men with TGCTs and 3090 ancestry-matched controls. Statistical analysis took place from January to May 2018. MAIN OUTCOMES AND MEASURES: Gene-level enrichment analysis of germline pathogenic variants in individuals with TGCTs relative to cancer-free controls. RESULTS: Among 205 unselected men with TGCTs (mean [SD] age, 33.04 [9.67] years), 22 pathogenic germline DRG variants, one-third of which were in CHEK2 (OMIM 604373), were identified in 20 men (9.8%; 95% CI, 6.1%-14.7%). Unselected men with TGCTs were approximately 4 times more likely to carry germline loss-of-function CHEK2 variants compared with cancer-free individuals from the Exome Aggregation Consortium cohort (odds ratio [OR], 3.87; 95% CI, 1.65-8.86; nominal P = .006; q = 0.018). Similar enrichment was also seen in an independent cohort of 448 unselected Croatian men with TGCTs (mean [SD] age, 31.98 [8.11] years) vs 442 unselected Croatian men without TGCTs (at least 50 years of age at time of sample collection) (OR, >1.4; P = .03) and 231 high-risk men with TGCTs (mean [SD] age, 31.54 [9.24] years) vs 3090 men (all older than 50 years) from the Penn Medicine Biobank (OR, 6.30; 95% CI, 2.34-17.31; P = .001). The low-penetrance CHEK2 variant (p.Ile157Thr) was found to be a Croatian founder TGCT risk variant (OR, 3.93; 95% CI, 1.53-9.95; P = .002). Individuals with the pathogenic CHEK2 loss-of-function variants developed TGCTs 6 years earlier than individuals with CHEK2 wild-type alleles (5.95 years; 95% CI, 1.48-10.42; P = .009). CONCLUSIONS AND RELEVANCE: This multicenter case-control analysis of men with or without TGCTs provides evidence for CHEK2 as a novel moderate-penetrance TGCT susceptibility gene, with potential clinical utility. In addition to highlighting DNA-repair deficiency as a potential mechanism driving TGCT susceptibility, this analysis also provides new avenues to explore management strategies and biological investigations for high-risk individuals.

JavaScript Access to DICOM Network and Objects in Web Browser.

Digital imaging and communications in medicine (DICOM) 3.0 standard provides the baseline for the picture archiving and communication systems (PACS). The development of Internet and various communication media initiated demand for non-DICOM access to PACS systems. Ever-increasing utilization of the web browsers, laptops and handheld devices, as opposed to desktop applications and static organizational computers, lead to development of different web technologies. The DICOM standard officials accepted those subsequently as tools of alternative access. This paper provides an overview of the current state of development of the web access technology to the DICOM repositories. It presents a different approach of using HTML5 features of the web browsers through the JavaScript language and the WebSocket protocol by enabling real-time communication with DICOM repositories. JavaScript DICOM network library, DICOM to WebSocket proxy and a proof-of-concept web application that qualifies as a DICOM 3.0 device were developed.

Review of recent advances in segmentation of the breast boundary and the pectoral muscle in mammograms.

This paper presents a review of recent advances in the development of methods for segmentation of the breast boundary and the pectoral muscle in mammograms. Regardless of improvement of imaging technology, accurate segmentation of the breast boundary and detection of the pectoral muscle are still challenging tasks for image processing algorithms. In this paper, we discuss problems related to mammographic image preprocessing and accurate segmentation. We review specific methods that were commonly used in most of the techniques proposed for segmentation of mammograms and discuss their advantages and disadvantages. Comparative analysis of the methods reported on is made difficult by variations in the datasets and procedures of evaluation used by the authors. We attempt to overcome some of these limitations by trying to compare methods which used the same dataset and have some similarities in approaches to the breast boundary segmentation and detection of the pectoral muscle. In this paper, we will address the most often used methods for segmentation such as thresholding, morphology, region growing, active contours, and wavelet filtering. These methods, or their combinations, are the ones most used in the last decade by the majority of work published in this image processing domain.

Serum metallothionein in patients with testicular cancer.

PURPOSE: Metallothioneins (MTs) have been disclosed as a useful diagnostic factor for tumour progression and drug resistance in a variety of malignancies. Increased levels of MT in blood serum have been found in patients with several types of cancer, but there is no available information on serum MT levels in patients with testicular germ cell tumour (TGCT). The aim of the study was to determine MT levels in serum of patients with TGCT and to evaluate the portion of platinum (Pt) that binds to MT after cisplatin administration since MTs could be involved in drug resistance. METHODS: Concentration of total MT was determined in serum of 25 men with newly diagnosed TGCT by differential pulse voltammetry. The fractionation of serum was carried out by size exclusion high-performance liquid chromatography (SE-HPLC), while concentration of Pt in collected fractions was determined by inductively coupled plasma mass spectrometry. RESULTS: Concentration of serum MT was significantly higher in TGCT patients than in healthy volunteers. The results of SE-HPLC analysis showed that only a small amount of Pt was bound to proteins in the area of MT elution. CONCLUSIONS: Significant increase in MT levels in individuals with TGCT indicates certain health problem and, in combination with other commonly used diagnostic tools, could improve early diagnosis.

Use of volumetric features for temporal comparison of mass lesions in full field digital mammograms.

PURPOSE: Temporal comparison of lesions might improve classification between benign and malignant lesions in full-field digital mammograms (FFDM). The authors compare the use of volumetric features for lesion classification, which are computed from dense tissue thickness maps, to the use of mammographic lesion area. Use of dense tissue thickness maps for lesion characterization is advantageous, since it results in lesion features that are invariant to acquisition parameters. METHODS: The dataset used in the analysis consisted of 60 temporal mammogram pairs comprising 120 mediolateral oblique or craniocaudal views with a total of 65 lesions, of which 41 were benign and 24 malignant. The authors analyzed the performance of four volumetric features, area, and four other commonly used features obtained from temporal mammogram pairs, current mammograms, and prior mammograms. The authors evaluated the individual performance of all features and of different feature sets. The authors used linear discriminant analysis with leave-one-out cross validation to classify different feature sets. RESULTS: Volumetric features from temporal mammogram pairs achieved the best individual performance, as measured by the area under the receiver operating characteristic curve (Az value). Volume change (Az = 0.88) achieved higher Az value than projected lesion area change (Az = 0.78) in the temporal comparison of lesions. Best performance was achieved with a set that consisted of a set of features extracted from the current exam combined with four volumetric features representing changes with respect to the prior mammogram (Az = 0.90). This was significantly better (p = 0.005) than the performance obtained using features from the current exam only (Az = 0.77). CONCLUSIONS: Volumetric features from temporal mammogram pairs combined with features from the single exam significantly improve discrimination of benign and malignant lesions in FFDM mammograms compared to using only single exam features. In the comparison with prior mammograms, use of volumetric change may lead to better performance than use of lesion area change.

Genome damage in testicular seminoma patients seven years after radiotherapy.

PURPOSE: Testicular seminoma cancer incidence has significantly increased over the last few decades, and although it is successfully treated by radiotherapy, long-term health risks are still unclear. The aim of the study was to show long-term genome damage in patients with seminoma after radiotherapy. MATERIALS AND METHODS: Chromosome aberration (CA) and micronucleus (MN) assays seven years after radiotherapy with a total dose of 25 Gy were conducted in 10 testicular seminoma patients aged 23-49 years and results were compared with 10 healthy control subjects matched for age and smoking status. RESULTS: Although mean CA frequency did not deviate from control values, significantly increased frequencies of dicentrics, double minutes, and ring chromosomes were detected in seminoma patients. MN frequency in binuclear lymphocytes of patients was similar to controls (4.60/1000 vs. 5.82/1000, respectively). Significantly higher MN frequency was detected in mononuclear lymphocytes of patients than in controls (2.55/1000 vs. 0.73/1000, respectively). Average percentage of centromere-positive MN was 62.6% in seminoma patients. CONCLUSION: This study shows the persistence of unstable CA in seminoma patients seven years after radiotherapy and the relevance of long-term follow up. MN frequency in mononuclear lymphocytes was shown to be relevant biomarker of long-term genome damage.

[Clinical guidelines for diagnosing, treatment and monitoring patients with testicular cancer--Croatian Oncology Society and Croatian Urology Society, Croatian Medical Association]. / Klinicke upute za dijagnostiku, lijecenje i pracenje bolesnika oboljelih od raka testisa Hrvatskoga Onkoloskog Drustva i Hrvatskoga Uroloskog Drustva Hrvatskoga Lijecnickog Zbora.

Testicular tumors are the most common solid tumors in men between 15 and 34 years of age. The worldwide incidence of these tumors has doubled in the past 40 years. Germ cell tumors comprise 95% of malignant tumors arising in the testes and they are classified either as seminoma or nonseminoma. Testicular cancers have a high cure rates even in disseminated stage of the disease. The chemotherapy mostly contributed to these results but surgery is an inevitable part of successful treatment. In a significant number of these patients treatment algorithms with minimum side effects are designed with the intention to maintain same cure rates as previously used, more aggressive therapy. The following text presents the clinical guidelines in order to standardize the procedures and criteria for diagnosis, management, treatment and follow-up of patients with testicular cancer in Republic of Croatia.

[Clinical guidelines for diagnosing, treatment and monitoring patients with bladder cancer--Croatian Oncology Society and Croatian Urology Society, Croatian Medical Association]. / Klinicke upute za dijagnostiku, lijecenje i pracenje bolesnika oboljelih od raka mokracnog mjehura Hrvatskoga Onkolokog Drustva i Hrvatskoga Uroloskog Drustva Hrvatskoga Lijecnickog Zbora.

Urothelial cancer is the most common bladder cancer. Hematuria is the most common presenting symptom in patients with bladder cancer. The most common diagnostics of bladder cancer is performed by transurethral resection of bladder after which pathohistological diagnosis is set. It is necessary to determine whether the cancer penetrated in muscle layer (muscle-invasive cancer) or not (muscle-noninvasive cancer). Decision on therapeutic modality depends on the clinical stage of disease and on prognostic and risk factors. For muscle non-invasive bladder cancer transurethral resection is preferred with or without intravesical instillation of Bacillus Calmette-Guérin (BCG). For invasive cancer the method of choice is radical cystectomy. Radiotherapy is used in radical and palliative purposes. Metastatic disease is most frequently treated by chemotherapy metotrexate/vinblastine/doxorubicine/cisplatin (MVAC) or gemcitabine/cisplatin (GC). The purpose of this article is to present clinical recommendations to set standards of procedures and criteria in diagnostics, treatment and follow up of patients with bladder cancer in the Republic of Croatia.

[Clinical guidelines for diagnosing, treatment and monitoring patients with prostate cancer--Croatian Oncology Society and Croatian Urology Society, Croatian Medical Association]. / Klinicke upute za dijagnostiku, lijecenje i pracenje bolesnika oboljelih od raka prostate Hrvatskoga Onkoloskog Drustva i Hrvatskoga Uroloskog Drustva Hrvatskoga Lijecnickog Zbora.

Prostate adenocarcinoma is the second most common solid neoplasm in male population in Croatia. It rarely causes symptoms unless it is advanced. The finding of PSA rise is the most common reason for diagnostic workout. Treatment plan is based on TNM classification, Gleason score and PSA. Clinically localized disease is successfully treated by radical prostatectomy or radiotherapy with or without hormonal therapy. Locally advanced disease is treated with radiotherapy and hormonal therapy. Metastatic disease can be controlled for many years by androgen deprivation. For castration resistant disease appropriate treatment is chemotherapy or secondary hormonal therapy. The following paper presents the clinical guidelines in order to standardize procedures and criteria for the diagnosis, management, management, treatment and monitoring of patients with prostate cancer in the Republic of Croatia.

Replication of genetic susceptibility loci for testicular germ cell cancer in the Croatian population.

Genome-wide association studies in patients with testicular germ-cell tumors (TGCT) from Great Britain and the United States have identified six susceptibility loci in or near biologically plausible candidate genes. However, these loci have not been replicated in an independent European sample. We performed a genetic replication study of previously identified TGCT susceptibility loci in a Croatian case-control sample and performed additional analyses as concerning histological subtypes or tumor staging. We analyzed six single-nucleotide polymorphisms [rs2900333 (ATF7IP), rs210138 (BAK1), rs755383 (DMRT1), rs995030 (KITLG), rs4624820 (SPRY4), and rs4635969 (TERT/CLPTM1L)], each representing one of the published susceptibility loci/genes. Five susceptibility loci were found to be also associated in the Croatian population with P-values between 2.1e-10 (rs995030; odds ratio [OR] 3.08) and 0.01739 (rs4635969; OR 1.37), which remained statistically significant after correction for multiple testing. Although rs2900333 near ATF7IP just showed borderline association with all-TGCT (OR 1.24, P = 0.062), it showed significant association with the more aggressive forms of the tumor (OR 1.51, P = 0.0067)-a clinically interesting finding, which however has to be replicated in an independent sample. Assessment of cumulative risks revealed that men with at least seven risk alleles have a more than 2.5-fold increased disease risk (OR = 2.73, 95% confidence interval = 1.98-3.79). In summary, we independently replicated the majority of TGCT susceptibility loci identified previously in a Croatian sample and suggested a possible role of genetic variation near ATF7IP in regulating disease progression.

Side effects of adjuvant radiotherapy in men with testicular seminoma stage I.

In this study we followed up the side effects of adjuvant radiotherapy in patients with testicular seminoma stage I over a period from 13 to 84 months (median 28 months). The most frequent side effects during radiotherapy were gastrointestinal (nausea/vomiting), psychological, cognitive, and minor sexual problems.The reported side effects were treated by antiemetics and anxiolytics. After radiotherapy, the side effects persisted in 6 % of patients, but only a few of them required additional treatment. Healthy children were born to 76 % of patients in the 18 to 39 years age group. This study shows that adjuvant radiotherapy of the para-aortic lymph nodes with the total dosage of 24 Gy in 16 daily fractions administered to testicular seminoma patients causes acceptable side effects, does not adversely affect quality of life and fertility, if the approach to treatment is individual and family consulting is provided. This makes adjuvant radiotherapy of the para-aortic lymph nodes an acceptable treatment for testicular seminoma stage I patients.

Long-term follow-up study of genome damage elimination in patients with testicular seminoma exposed to ionising radiation during radiotherapy.

The rate of genome damage elimination after therapeutic exposure to ionising radiation was estimated in stage I testicular seminoma patients monitored over a seven-year follow-up. DNA damage elimination in peripheral lymphocytes of ten subjects was analysed by the chromosome aberration assay. Seven years after the end of radiotherapy, significantly increased frequency of ring and dicentric chromosomes was still detected in comparison with baseline values. These results indicate the induction of genome instability. Long-term follow-up studies of cancer patients after radiotherapy could give us valuable information on the rate of genome damage elimination after exposure to ionising radiation and about the duration and manifestation of genome instability. This may be used in health risk assessment related to the possible development of secondary neoplasia. Studies such as this could have a great value both for oncology and radiation protection management protocols, especially after accidental overexposures.

Cytogenetic follow-up in testicular seminoma patients exposed to adjuvant radiotherapy.

Early stage testicular seminoma is a radiosensitive tumor. Its incidence has significantly increased during the last decade especially in the young population. Although the therapy for testicular seminoma gives very satisfying results, the evaluation of genome damage caused by the therapy is of a great importance in order to recognize possible related health risks. The present study was performed on ten patients diagnosed with seminoma stage I; pT1/2N0M0S0, treated with adjuvant radiotherapy (a radiation dose of 25 Gy divided in 16 fractions) after orchidectomy. To assess the possible existence of an increased baseline DNA/chromosome damage in patients we also selected the appropriate control group often healthy men. The levels of primary DNA/chromosome damage in peripheral blood lymphocytes, as well as the dynamics of their repair were studied using the alkaline comet assay, chromosome aberration and cytokinesis-block micronucleus assay. Altogether four blood samples per patient were collected in the course of the therapy: before and after receiving the first dose of radiotherapy, in the middle of the radiotherapy cycle, and after the last dose of radiotherapy. Other two follow-up blood samples were collected six and twelve months after the cessation of therapy. As observed, the administration of the first radiation dose significantly increased the levels of DNA damage in almost all patients compared to their baseline values. Specific patterns of DNA damage were recorded in samples analyzed in the middle of radiotherapy and after receiving the last dose, indicating the possibility of an adaptive response in some patients. The levels of chromosomal aberrations and the incidence of micronuclei also increased in the course of therapy but gradually declined during the follow-up period. Our results confirmed the existence of post-irradiation damage in peripheral blood lymphocytes (and possibly in other non-target cells) of cancer patients which may represent a risk for the secondary cancer development. Considering that the majority of patients with testicular cancer are of a younger age, they represent a population deserving special attention. As cytogenetic screening may detect high-risk individuals, it might be useful in regular medical monitoring of seminoma patients after the successful therapy.

DNA and cytogenetic damage in white blood cells of postmenopausal breast cancer patients treated with radiotherapy.

The primary and residual genome damage and its elimination rate were evaluated in peripheral blood lymphocytes of breast cancer patients treated with adjuvant radiotherapy after surgical removal of the tumor by mastectomy or quadrantectomy. The levels of DNA/chromosome damage were estimated before, throughout, as well as after six months, respectively one year after the radiotherapy, using the alkaline comet assay, the chromosome aberration analysis and the cytokinesis-block micronucleus assay. The marked individual differences in the baseline genome damage were observed in patients, which additionally increased until the end of the radiotherapy cycle. The levels of DNA/cytogenetic damage slowly declined during post-irradiation period; although in the majority of subjects they did not return to pre-therapy levels. In addition to the well-established comet parameters, the long-tailed nuclei were also proved as a useful indicator of individual DNA damage and response to radiation. One of the most important observation was that older breast cancer patients, irradiated after mastectomy, had higher values of almost all parameters evaluated. We found positive correlations between the comet assay parameters and the cytogenetic biomarkers that confirmed their complementary value in the assessment of the radiation sensitivity/susceptibility in elderly breast cancer patients. The specific patterns of DNA damage observed in the majority of subjects after a prolonged exposure to ionizing radiation indicate the possibility of adaptive response. Such results may also be linked to the hormesis theory and support previous observations, but the underlying mechanisms should be further investigated on a much larger population.

Loss of heterozygosity of selected tumor suppressor genes in human testicular germ cell tumors.

Human testicular germ cell tumors (TGCTs) are histologically heterogenous neoplasms with a variable malignant potential. Two main groups of germ cell tumors occur in men: seminomas and nonseminomas. In the present study, a set of four tumor suppressor genes was investigated in testicular cancers. CDH1, APC, p53, and nm23-H1 genes were tested for loss of heterozygosity (LOH). Thirty-eight testicular germ cell tumors (17 seminomas and 21 nonseminomas) were analyzed by PCR using restriction fragment length polymorphism or the dinucleotide/tetranucleotide repeat polymorphism method. An allelic loss of p53 at exon 4 was detected in five nonseminomas, whereas LOH of p53 at intron 6 occurred in one of the seminoma and two of the nonseminoma samples. Allelic losses of the APC gene were present in three seminomas and one nonseminoma, whereas one seminoma and three nonseminomas showed LOH of CDH1. The analysis of allelic losses showed no common structural genetic alterations in tumor tissues, although a different pattern of LOH was observed between the two main histological groups of TGCTs.

Ureteral metastasis as the first and sole manifestation of gastric cancer dissemination.

BACKGROUND: Isolated ureteral metastasis from gastric cancer is extremely rare. CASE REPORT: We describe a 50 year old man with a history of subtotal gastrectomy who presented 4 years later with an ureteral metastasis. He was asymptomatic and diagnostic tests were performed due to the elevated creatinine level disclosed incidentally. The partial resection of distal right ureter as well as the resection of the right ureterovesical junction was performed with the implantation of double J stent. Histopathology revealed a metastasis of the adenocarcinoma that matched perfectly a tumour specimen from the gastric cancer surgery. It was first and isolated manifestation of gastric cancer dissemination. CONCLUSIONS: Although rare, the ureteral metastasis from gastric cancer can be the first, sole and asymptomatic manifestation of gastric cancer dissemination after a period of time.

Genome damage in oropharyngeal cancer patients treated by radiotherapy.

AIM: To estimate genome damage in oropharyngeal cancer patients before, during, and after radiotherapy and to measure the persistence of caused genome damage relevant in the evaluation of secondary cancer risk. METHODS: DNA damage was evaluated in peripheral blood lymphocytes of 10 oropharyngeal cancer patients using alkaline comet assay, analysis of structural chromosome aberrations, and micronucleus assay. Blood samples were taken 2 hours before irradiation on day 1 of the first radiotherapy cycle, 2 hours after the application of the first dose, in the middle of the radiotherapy cycle, within 2 hours after the last received radiotherapy dose, and after 6 and 12 months after radiotherapy. RESULTS: In most participants, the highest level of primary DNA damage was recorded in blood samples collected after the administration of first radiation dose (mean tail length 25.04+/-6.23 mum). Most patients also had increased frequency of comets with long tail-nucleus (LTN comets) after the administration of the first radiation dose (mean, 10.50+/-7.71 per 100 comets), which remained increased in the middle of radiotherapy (mean, 18.30+/-27.62 per 100 comets). Later on, the levels of primary DNA damage as recorded by the comet assay, slightly diminished. The frequency of structural chromosome aberrations in lymphocytes gradually increased during the radiation cycle (26.50+/-27.72 per 100 metaphases at the end of the therapy), as well as the frequency of micronuclei (mean total number of micronuclei 167.20+/-35.69 per 1000 binuclear cells). CONCLUSION: Oropharyngeal cancer patients had relatively high levels of primary DNA damage in their peripheral blood lymphocytes even before therapy. The frequency of complex structural chromosome aberrations and the frequency of micronuclei increased with the progression of the radiation cycle and the doses delivered. As the frequency of chromosomal aberrations a year after radiotherapy mostly did not return to pre-therapy values, it represents an important risk factor related to the onset of second cancer.

Cisplatin and gemcitabine first-line chemotherapy followed by maintenance gemcitabine or best supportive care in advanced non-small cell lung cancer: a phase III trial.

PURPOSE: The primary objective of this randomized phase III study was to show significant difference in median time to progression (TTP) in patients with advanced NSCLC treated with single-agent gemcitabine maintenance therapy versus best supportive care following gemcitabine plus cisplatin initial first-line therapy. PATIENTS AND METHODS: Chemonaive patients with stage IIIB/IV NSCLC received gemcitabine 1,250 mg/m(2) (days 1 and 8) plus cisplatin 80 mg/m(2) (day 1) every 21 days. Patients achieving objective response or disease stabilization following initial gemcitabine plus cisplatin therapy were randomized (2:1 fashion) to receive maintenance gemcitabine (1,250 mg/m(2) on days 1 and 8 every 21 days) plus best supportive care (GEM arm), or best supportive care only (BSC arm). RESULTS: Between November 1999 and November 2002, we enrolled 352 patients (median age: 57 years; stage IV disease: 74%; Karnofsky performance status (KPS) >80: 41%). Following initial therapy, 206 patients were randomized and treated with gemcitabine (138) or best supportive care (68). TTP throughout the study period was 6.6 and 5 months for GEM and BSC arms, respectively, while values for the maintenance period were 3.6 and 2.0 months (for p < 0.001 for both). Median overall survival (OS) throughout study was 13.0 months for GEM and 11.0 months for BSC arms (p = 0.195). The toxicity profile was mild, with neutropenia being most common grade 3/4 toxicities. CONCLUSION: Maintenance therapy with gemcitabine, following initial therapy with gemcitabine plus cisplatin, was feasible, and produced significantly longer TTP compared to best supportive care alone. Further studies are warranted to establish the place of maintenance chemotherapy in patients with advanced NSCLC.

Gemcitabine, epirubicin, and paclitaxel versus fluorouracil, epirubicin, and cyclophosphamide as first-line chemotherapy in metastatic breast cancer: a Central European Cooperative Oncology Group International, multicenter, prospective, randomized phase III trial.

BACKGROUND: The objectives of this phase III trial were to compare the time to progressive disease (TtPD), overall response rate (ORR), overall survival, and toxicity of gemcitabine, epirubicin, and paclitaxel (GET) versus fluorouracil (FU), epirubicin, and cyclophosphamide (FEC) as first-line therapy in patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: Female patients aged 18 to 75 years with stage IV and measurable MBC were enrolled and randomly assigned to either gemcitabine (1,000 mg/m(2), days 1 and 4), epirubicin (90 mg/m(2), day 1), and paclitaxel (175 mg/m(2), day 1) or FU (500 mg/m(2), day 1), epirubicin (90 mg/m(2), day 1), and cyclophosphamide (500 mg/m(2), day 1). Both regimens were administered every 21 days for a maximum of eight cycles. RESULTS: Between October 1999 and November 2002, 259 patients (GET, n = 124; FEC, n = 135) were enrolled. Baseline characteristics were well balanced across treatment arms. After a median of 20.4 months of follow-up, median TtPD was 9.1 months and 9.0 months in the GET and FEC arms, respectively (P = .557). The ORR was 62.3% in the GET arm (n = 114) and 51.2% in the FEC arm (n = 129; P = .093). Grade 3 and 4 toxicities, including neutropenia, thrombocytopenia, anemia, stomatitis, neurosensory toxicity, and allergy, occurred significantly more often in the GET arm. CONCLUSION: No significant differences in terms of TtPD and ORR were observed between the two treatment arms. Treatment-related toxicity was higher in the GET arm.