ENGOT-en11/GOG-3053/KEYNOTE-B21: a randomised, double-blind, phase III study of pembrolizumab or placebo plus adjuvant chemotherapy with or without radiotherapy in patients with newly diagnosed, high-risk endometrial cancer.

BACKGROUND: Pembrolizumab plus chemotherapy provides clinically meaningful benefit as first-line therapy for advanced (locoregional extension and residual disease after surgery)/metastatic/recurrent mismatch repair-proficient (pMMR) and mismatch repair-deficient (dMMR) endometrial cancer, with greater magnitude of benefit in the dMMR phenotype. We evaluated the addition of pembrolizumab to adjuvant chemotherapy (with/without radiation therapy) among patients with newly diagnosed, high-risk endometrial cancer without any residual macroscopic disease following curative-intent surgery. METHODS: We included patients with histologically confirmed high-risk [International Federation of Gynecology and Obstetrics (FIGO) stage I/II of non-endometrioid histology or endometrioid histology with p53/TP53 abnormality, or stage III/IVA of any histology] endometrial cancer following surgery with curative intent and no evidence of disease postoperatively, with no prior radiotherapy or systemic therapy. Patients were randomised to pembrolizumab 200 mg or placebo every 3 weeks (Q3W) for six cycles added to carboplatin-paclitaxel followed by pembrolizumab 400 mg or placebo every 6 weeks (Q6W) for six cycles per treatment assignment. Radiotherapy was at the investigator's discretion. The primary endpoints were investigator-assessed disease-free survival (DFS) and overall survival in the intention-to-treat population. RESULTS: A total of 1095 patients were randomised (pembrolizumab, n = 545; placebo, n = 550). At this interim analysis (data cut-off, 4 March 2024), 119 (22%) DFS events occurred in the pembrolizumab group and 121 (22%) occurred in the placebo group [hazard ratio 1.02, 95% confidence interval (CI) 0.79-1.32; P = 0.570]. Kaplan-Meier estimates of 2-year DFS rates were 75% and 76% in the pembrolizumab and placebo groups, respectively. The hazard ratio for DFS was 0.31 (95% CI 0.14-0.69) in the dMMR population (n = 281) and 1.20 (95% CI 0.91-1.57) in the pMMR population (n = 814). Grade ≥3 adverse events (AEs) occurred in 386 of 543 (71%) and 348 of 549 (63%) patients in the pembrolizumab and placebo groups, respectively. No treatment-related grade 5 AEs occurred. CONCLUSIONS: Adjuvant pembrolizumab plus chemotherapy did not improve DFS in patients with newly diagnosed, high-risk, all-comer endometrial cancer. Preplanned subgroup analyses for stratification factors suggest that pembrolizumab plus chemotherapy improved DFS in patients with dMMR tumours. Safety was manageable. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04634877; EudraCT, 2020-003424-17. RESEARCH SUPPORT: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Prognostic Value of En-Block Radical Bowel Resection in Advanced Ovarian Cancer Surgery With HIPEC.

PURPOSE: To identify prognostic factors of survival and recurrence in advanced ovarian cancer patients undergoing radical surgery and HIPEC. METHODS: In a single Department of Surgical Oncology, Peritoneal Surface Malignancy Program, and over a 16-year period, from a total of 274 epithelial ovarian cancer patients, retrospectively, we identified 152 patients undergoing complete (CC-0) or near-complete (CC-1) cytoreduction, including at least one colonic resection, and HIPEC. RESULTS: Mean age of patients was 58.8 years and CC-0 was possible in 72.4%. Rates of in-hospital mortality and major morbidity were 2.6% and 15.7%. Only 122 (80.3%) patients completed Adjuvant Systemic Chemotherapy (ASCH). Rates of metastatic Total Lymph Nodes (TLN), Para-Aortic and Pelvic Lymph Nodes (PAPLN) and Large Bowel Lymph Nodes (LBLN) were 58.7%, 58.5%, and 51.3%, respectively. Median, 5- and 10-year survival rates were 39 months, 43%, and 36.2%, respectively. The recurrence rate was 35.5%. On univariate analysis, CC-1, high Peritoneal Cancer Index (PCI), in-hospital morbidity, and no adjuvant chemotherapy were adverse factors for survival and recurrence. On multivariate analysis, negative survival indicators were the advanced age of patients, extensive peritoneal dissemination, low total number of TLN and no systemic PAPLN. Metastatic LBLN and segmental resection of the small bowel (SIR) were associated with a high risk for recurrence. CONCLUSION: CC-O is feasible in most advanced ovarian cancer patients and HIPEC may confer a survival benefit. Radical bowel resection, with its entire mesocolon, may be necessary, as its lymph nodes often harbor metastases influencing disease recurrence and survival. The role of metastatic bowel lymph nodes has to be taken into account when assessing the impact of systemic lymphadenectomy in this group of patients.

ABREAST: a prospective, real-world study on the effect of nab-paclitaxel treatment on clinical outcomes and quality of life of patients with metastatic breast cancer.

PURPOSE: The efficacy of nab-paclitaxel in patients with metastatic breast cancer (MBC) has been demonstrated in randomized clinical trials. However, real-world evidence on effectiveness remains limited. PATIENTS AND METHODS: The primary objective of this multicenter prospective study was to assess the overall response rate (ORR) of patients with MBC treated with nab-paclitaxel. Secondary objectives included progression-free survival (PFS), overall survival (OS) and quality of life, assessed with the Functional Assessment of Cancer Therapy-Breast (FACT-B) instrument. RESULTS: Eligible patients (N = 150; 36% with de novo MBC presentation) with a median age of 64.5 years were enrolled (86% were ER+, 33.3% (50/150) were ≥ 70 years of age and 53% were treated in the third or later line of treatment). A median of 6 cycles were administered but 26% of patients required dose reduction due to toxicity. The ORR was 26.7% [95% confidence interval (CI) 19.6-33.7], the median PFS was 6.2 months (95% CI 5.2-7.3), and the median OS 21.1 months (95% CI 17.2-not estimable). There was no statistical significant difference in the median PFS of patients < and ≥ 70 years of age. The patients' baseline FACT-B total score remained unchanged. The serious and non-serious adverse event incidence rates were 13% and 48%, respectively. CONCLUSIONS: This prospective study provides further evidence on quality of life, efficacy, and safety of nab-paclitaxel in patients with MBC and sheds more light in special subpopulations such as the elderly and those treated beyond the second line.

Ionospheric response to solar and interplanetary disturbances: a Swarm perspective.

The ionospheric response to solar and interplanetary disturbances has been the subject of intense study for several decades. For 5 years now, the European Space Agency's Swarm fleet of satellites surveys the Earth's topside ionosphere, measuring magnetic and electric fields at low-Earth orbit with unprecedented detail. Herein, we study in situ the ionospheric response in terms of the occurrence of plasma instabilities based on 2 years of Swarm observations. Plasma instabilities are an important element of space weather because they include irregularities like the equatorial spread F events, which are responsible for the disruption of radio communications. Moreover, we focus on three out of the four most intense geospace magnetic storms of solar cycle 24 that occurred in 2015, including the St Patrick's Day event, which is the strongest magnetic storm of the present solar cycle. We examine the associated ionospheric response at Swarm altitudes through the estimation of a Swarm Dst-like index. The newly proposed Swarm derived Dst index may be suitable for space weather applications. This article is part of the theme issue 'Solar eruptions and their space weather impact'.

Haplotype analysis reveals that the recurrent BRCA1 deletion of exons 23 and 24 is a Greek founder mutation.

A recurrent large genomic rearrangement (LGR) encompassing exons 23 and 24 of the BRCA1 gene has been identified in breast-ovarian cancer families of Greek origin. Its breakpoints have been determined as c.5406 + 664_*8273del11052 (RefSeq: NM_007294.3) and a diagnostic polymerase chain reaction (PCR) has been set up for rapid screening. In a series of 2,092 high-risk families completely screened for BRCA1 and BRCA2 germline mutations, we have found the deletion in 35 families (1.68%), representing 7.83% of the mutations identified in both genes and 10.3% of the total BRCA1 mutations. In order to characterize this deletion as a founder mutation, haplotype analysis was conducted in 60 carriers from 35 families, using three BRCA1 intragenic microsatellite markers and four markers surrounding the BRCA1 locus. Our results demonstrate a common shared core disease-associated haplotype of 2.89Mb. Our calculations estimate that the deletion has originated from a common ancestor 1450 years ago, which most probably inhabited the Asia Minor area. The particular (LGR) is the third mutation of such type that is proven to have a Greek founder effect in the Greek population, illustrating the necessity for LGRs testing in individuals of Greek descent.

A hierarchical Bayesian framework for force field selection in molecular dynamics simulations.

We present a hierarchical Bayesian framework for the selection of force fields in molecular dynamics (MD) simulations. The framework associates the variability of the optimal parameters of the MD potentials under different environmental conditions with the corresponding variability in experimental data. The high computational cost associated with the hierarchical Bayesian framework is reduced by orders of magnitude through a parallelized Transitional Markov Chain Monte Carlo method combined with the Laplace Asymptotic Approximation. The suitability of the hierarchical approach is demonstrated by performing MD simulations with prescribed parameters to obtain data for transport coefficients under different conditions, which are then used to infer and evaluate the parameters of the MD model. We demonstrate the selection of MD models based on experimental data and verify that the hierarchical model can accurately quantify the uncertainty across experiments; improve the posterior probability density function estimation of the parameters, thus, improve predictions on future experiments; identify the most plausible force field to describe the underlying structure of a given dataset. The framework and associated software are applicable to a wide range of nanoscale simulations associated with experimental data with a hierarchical structure.

Vascular endothelial growth factor polymorphisms and clinical outcome in patients with metastatic breast cancer treated with weekly docetaxel.

The aim of the study was to evaluate the association of vascular endothelial growth factor (VEGF) genotypes with treatment efficacy in a phase II trial. This study evaluated weekly docetaxel, as first-line treatment for metastatic breast cancer. Existing data from in vitro and animal model experiments suggest that docetaxel at low doses has anti-angiogenic activity. DNA was extracted from blood samples of 86 patients participating in the trial. Genotyping was performed for selected single-nucleotide polymorphisms (SNPs; VEGF-2578, -1498, -1154, and +936). Moreover, due to the highly polymorphic nature of the studied areas, we were able to analyze additional registered SNPs. All candidate genotypes were evaluated for associations with overall survival (OS), progression-free survival (PFS) and response rate. The VEGF-1154 GG genotype was more frequent in patients not responding to treatment compared with responders (42.9% vs 0.0%, P=0.048). Moreover, the VEGF-2578 AA genotype was associated with longer PFS compared with CC (hazard ratio (HR)=0.40; 95% confidence interval (CI) 0.17-0.98; pairwise P=0.0457). Patients with the VEGF-1190 GG genotype demonstrated shorter PFS compared with those with the alternative genotypes (GA and AA) combined (HR=3.85; 95% CI: 1.20-12.50; P=0.0224). In addition, the VEGF-2551/-2534 homozygous del18bp and VEGF-2430/-2425 homozygous ins1bp genotypes were associated with worse PFS compared with no deletion and no insertion, respectively (HR=2.49; 95% CI: 1.02-6.07; pairwise P=0.0442 and HR=2.57; 95% CI: 1.05-6.27; pairwise P=0.0385, respectively). Furthermore, patients with the VEGF-1498 CC genotype exhibited longer median OS compared with those with the alternatives genotypes (CT and TT) combined (HR=0.27; 95% CI: 0.08-0.89; P=0.0311). In multivariate analysis, the VEGF-2578 AA genotype retained its significance (P=0.0220) for PFS. Our results support the association of specific VEGF genotypes with clinical outcome in patients with metastatic breast cancer treated with a potentially anti-angiogenic regimen, such as weekly docetaxel. However, current results should be validated prospectively in larger cohorts.

High MET expression is an adverse prognostic factor in patients with triple-negative breast cancer.

BACKGROUND: The mesenchymal-epithelial transition (MET) pathway is frequently altered in tumours. The purpose of our study was to determine the prognostic value of tumour MET expression levels in patients with triple-negative breast cancer (TNBC), in order to strengthen the rationale for targeted therapy of TNBC using MET inhibitors. METHODS: We determined expression of MET in formalin-fixed paraffin-embedded surgical specimens of TNBC by immunohistochemistry. Recurrence-free and overall survival was analysed with Cox models adjusted for clinical and pathological factors. RESULTS: Immunostaining for MET was classified as high in 89 of 170 (52%) tumours. MET expression was more frequently observed in G3 carcinomas (P=0.02) but was not significantly associated to any of the other clinical or pathological parameters. High MET expression predicted shorter survival of the patients. Multivariate Cox proportional hazards regression analyses identified MET to be an independent prognostic factor for recurrence (adjusted hazard ratio (HR) for recurrence 3.43; 95% confidence interval (CI) 1.65-7.12; P=0.001) and death (adjusted HR for death 3.74; 95% CI 1.65-8.46; P=0.002). CONCLUSION: These results provide further evidence that the MET pathway could be exploited as a target for TNBC.

A test for adequate wastewater treatment based on glutathione S transferase isoenzyme profile.

Discharge to the environment of treated or non-treated municipal wastewater imposes several threats to coastal and estuarine ecosystems which are difficult to assess. In our study we evaluate the use of the isoenzyme profile of glutathione S transferase (GST) in combination with the kinetic characteristics of the whole enzyme and of heme peroxidase, as a test of adequate treatment of municipal wastewater. For this reason, Artemia nauplii were incubated in artificial seawater prepared by wastewater samples, such as secondary municipal effluents produced by a conventional activated sludge unit and advanced treated effluents produced by the employment of coagulation, activated carbon adsorption and chlorination as single processes or as combined ones. Characteristic changes of the isoenzyme pattern and the enzymes' kinetic properties were caused by chlorinated secondary municipal effluent or by secondary non-chlorinated effluent. Advanced treatment by combination of coagulation and/or carbon adsorption resulted to less prominent changes, suggesting more adequate treatment. Our results suggest that GST isoenzyme profile in combination with the kinetic properties of the total enzyme family is a sensitive test for the evaluation of the adequateness of the treatment of reclaimed wastewater and the reduction of potentially harmful compounds. Potentially, it may offer a 'fingerprint' characteristic of a particular effluent and probably of the treatment level it has been subjected.

Protozoans as indicators of sequential batch processes for phenol treatment; an autoecological approach.

The objective of this study was the investigation of the potential use of protistan species as quality indicators of the activated sludge performance in sequential batch processes receiving toxic compounds. Two laboratory scale sequential batch reactors (SBR) were used, a conventional one and a system with plastic biofilm carriers (SBBR), treating wastewater containing phenol at concentrations ranging from 1 up to 40 mg/L. Physicochemical analyses of the samples included the determination of MLSS, effluent suspended solids, BOD5, nitrogen-ammonia, nitrogen-nitrate and phenol. The activated sludge protistan community was identified and enumerated in each reactor. Statistical analyses included Canonical Correspondence Analysis and Indicator Species Analysis of the collected experimental data. Canonical Correspondence Analysis showed inversely proportional relationships between the protozoa and the physicochemical parameters of the effluent as well as protozoan species competition. Indicator species analysis revealed the presence and the prevalence of different species under various phenol influent concentrations. No indicator species were observed for the period of operation under 5 mg/L influent phenol in both reactors, while no indicator species were observed for 20 mg/L influent phenol in the SBR reactor. Carchesium and Epistylis sp. showed the higher values for 1 mg/L phenol in the SBR, while Holophrya sp. showed lower indicator values for the same period in the SBBR. Although several species showed a good correlation to the treatment efficiency of the reactors, Blepharisma sp., could be used as the primary indicator species in both reactors for the operation period under 40 mg/L phenol, as deduced by statistical analysis.

Structure and function of the oncologic boards in Greece. Description of the institutional and scientific frame; objective problems and difficulties.

PURPOSE: Oncology boards should constitute a routine in all hospitals that are dealing with the care of cancer patients. Unfortunately the procedure which should be followed to deal with this health problem has some deficiencies. METHODS: A literature review has recently been attempted, searching Internet databases by using key words such as oncologic board, medical legislation and medical ethics. RESULTS: Current mentality suggests that hiding the truth from the patient is wrong and unethical. However, in the Greek society, this is not the case as it seems not right to adopt foreign practices, i.e. to disclose directly to the patient all information relevant to his health status, the intended therapy and possible outcome. Instead, ambiguous information pass onto relatives who in turn bear the burden of informing the patient. CONCLUSIONS: The best solution would be the integration of the positive elements of the patient's awareness and the beneficial effects of the involvement of the Greek family in the general care of the cancer patient.

A phase I/II study of arfolitixorin and 5-fluorouracil in combination with oxaliplatin (plus or minus bevacizumab) or irinotecan in metastatic colorectal cancer.

BACKGROUND: 5-fluorouracil (5-FU) combined with a folate remains an essential treatment component for metastatic colorectal cancer (mCRC). Leucovorin is the folate most often used, but requires intracellular conversion to a reduced folate, and has high pharmacokinetic variability and limited bioavailability in patients with low folate pathway gene expression. Arfolitixorin is an immediately active form of folate, [6R]-5,10-methylenetetrahydrofolate ([6R]-MTHF), and may improve outcomes. PATIENTS AND METHODS: This open-label, multicenter, phase I/II study in patients with mCRC (NCT02244632) assessed the tolerability and efficacy of first- or second-line arfolitixorin (30, 60, 120, or 240 mg/m2 intravenous) with 5-FU alone, or in combination with oxaliplatin (plus or minus bevacizumab) or irinotecan, every 14 days. Safety, efficacy, and pharmacokinetics were assessed before and after four cycles (8 weeks) of treatment. RESULTS: In 105 treated patients, investigators reported 583 adverse events (AEs) in 86 patients (81.9%), and 256 AEs (43.9%) were potentially related to arfolitixorin and 5-FU. Dose adjustments were required in 16 patients (15.2%). At 8 weeks, 9 out of 57 patients assessed for efficacy achieved an objective response (15.8%), and all 9 achieved a partial response. Six of these nine patients had received arfolitixorin as a first-line treatment. A further 33 patients (57.9%) achieved stable disease. Pharmacokinetics were assessed in 35 patients. The average tmax was 10 min, and area under the plasma concentration-time curve from time 0 to 1 h increased linearly between 30 and 240 mg/m2. No accumulation was observed for [6R]-MTHF following repeated administration, and there were no major pharmacokinetic differences between cycle 1 and cycle 4 at any dose. CONCLUSIONS: Arfolitixorin is a well-tolerated moderator of 5-FU activity. It is suitable for further investigation in mCRC and has the potential to improve treatment outcomes in patients with low folate pathway gene expression. Arfolitixorin can easily be incorporated into current standard of care, requiring minimal changes to chemotherapy regimens.

The prognostic and predictive value of ERCC-1, p53, bcl-2 and bax in epithelial ovarian cancer.

AIM: To evaluate the expression of ERCC-1 in patients with epithelial ovarian cancer (EOC) and to correlate it with the expression of p53, bcl-2 and bax. MATERIALS AND METHODS: Tumor samples from 60 patients with EOC were immunohistochemically investigated for the expression of ERCC1, p53, bcl-2 and bax. RESULTS: ERCC-1 expression was significantly decreased in serous and endometrioid compared to clear cell carcinomas. P53 expression was significantly increased in serous compared to clear cell carcinomas. Bax expression was significantly increased in serous carcinomas as compared to MMTs. High disease stage was correlated with low ERCC-1 and high bcl-2 expression. ERCC-1 expression was associated with increased disease-free interval. CONCLUSION: ERCC-1 status seems to be correlated with disease-free interval, stage and tumor histologic subtype in patients with EOC. Nevertheless, our results indicate that single-gene expressions may be unreliable and thus caution is needed when used as potential prognostic or predictive markers.

Tumor dissemination after laparoscopic surgery for an unsuspected endometrial stromal tumor.

BACKGROUND: The use of laparoscopic surgery in gynecologic oncology might be complicated by unsuspected side-effects for the patient. Experimental data suggest that the risk of tumor dissemination in the non traumatized peritoneum may be higher after pneumoperitoneum than after laparotomy, and they also show the importance of the surgeon's experience and technique. CASES: We present two cases of uterine endometrial stromal tumors which were laparoscopically excised. In both cases, intraperitoneal tumor seedings were identified shortly after the initial operation. The first patient had a low-grade endometrial stromal sarcoma and succumbed from the disease two years after the initial operation, while the second patient who was diagnosed with endometrial stromal tumor remains disease free two years later. CONCLUSIONS: The laparoscopic excision of an endometrial stromal tumor might result in tumor dissemination into the abdominal cavity. A careful second-look examination of the abdomen or a radical surgical approach is proposed.

Combination of osteopontin and activated leukocyte cell adhesion molecule as potent prognostic discriminators in HER2- and ER-negative breast cancer.

BACKGROUND: To analyse the discriminative impact of osteopontin (OPN) and activated leukocyte cell adhesion molecule (ALCAM), combined with human epidermal growth factor 2 (HER2) and oestrogen receptor (ER) in breast cancer. METHODS: Osteopontin, ALCAM, HER2 and ER mRNA expression in breast cancer tissues of 481 patients were analysed (mRNA microarray analysis, kinetic RT-PCR). Hierarchical clustering was performed in training cohort A (N=100, adjuvant treatment) and validation cohorts B (N=200, no adjuvant treatment, low-risk) and C (N=181, adjuvant treatment, high-risk). RESULTS: Negative/low ER and HER2, high OPN and low ALCAM mRNA expression helped to identify patients at particularly high risk, showing shorter DFS, P<0.001, and OAS, P=0.001. Although both validation cohorts showed diverse risk and treatment profiles, this marker constellation was concordantly associated with shorter DFS and OAS (P<0.001 and P=0.075 for cohort B and P=0.043 and P<0.001 for cohort C, respectively). In multivariate analysis, this algorithm was the main independent prognostic factor. Cohort B: DFS, P=0.0065, OAS, not significant; cohort C: DFS, P=0.026, OAS, P<0.001. CONCLUSION: Activated leukocyte cell adhesion molecule and OPN mRNA expression has a strong discriminative impact on survival within cancer patients with low or negative expression of ER and HER2, so called 'high-risk' breast cancers, and might help in identifying patients who could benefit from new treatment approaches like targeted therapies in the adjuvant setting.

Low frequency of somatic mutations in uterine sarcomas: a molecular analysis and review of the literature.

OBJECTIVE: The rarity of uterine sarcomas along with their pathological and molecular heterogeneities render their study particularly challenging. We evaluated a panel of somatic mutations principally centering on the tyrosine kinase gene family and their downstream signaling cascades in an attempt to identify potential candidate markers that may assist in diagnostic or therapeutic decisions in these tumors. METHODS: We performed mutational analysis of 20 exons from 9 genes (EGFR, CDKN2A, MET, KIT, RAS, BRAF, PI3KCA, HER-2 and PDGFR-alpha) on biopsy material from 25 patients who underwent primary surgery for uterine sarcoma between October 1995 and October 2003. Due to the limited number of studies conducted we have also undertaken a literature review of somatic mutations in uterine sarcomas. RESULTS: A total of 3 different somatic mutations were identified: one KRAS (codon G12D) in a carcinosarcoma and two exon 20 PI3KCA mutations (H1047R and H1047Y) both in carcinosarcomas. Mutational status of all mutations was confirmed using germline DNA extracted from peripheral blood. Consistent with the literature data, no other mutations regarding the rest of the genes of the panel were identified. Due to the low number of somatic mutations in our series, we did not perform further clinicopathological correlations. CONCLUSION: The absence of somatic mutations in the majority of genes that are considered critical in neoplastic transformation hampers the identification of potential therapeutic targets in patients with uterine sarcoma.

Molecular markers in epithelial ovarian cancer: their role in prognosis and therapy.

Epithelial cancer of the ovary is the most lethal malignancy of all gynaecological cancers. Various clinical and pathological features of ovarian cancer are used as predictors of clinical outcome. The use of molecular markers in common clinical practice seems promising for the diagnosis and prognostication. The aim of this review article is to describe current theories regarding the pathogenesis and molecular evolution of epithelial ovarian cancer. With respect to the molecules involved, this article focuses on whether they are associated with poor prognosis or not. This evaluation is performed in light of the progress made and the potential usefulness in treatment decisions without overlooking existing controversies that should be further studied. It is tempting to anticipate the gradual integration of molecular profiling in clinical practice.

Novel treatment planning approaches to enhance the therapeutic ratio: targeting the molecular mechanisms of radiation therapy.

Radiation acts not only through cell death but has also angiogenic, immunomodulatory and bystander effects. The realization of its systemic implications has led to extensive research on the combination of radiotherapy with systemic treatments, including immunotherapy and antiangiogenic agents. Parameters such as dose, fractionation and sequencing of treatments are key determinants of the outcome. However, recent high-quality research indicates that these are not the only radiation therapy parameters that influence its systemic effect. To effectively integrate systemic agents with radiation therapy, these new aspects of radiation therapy planning will have to be taken into consideration in future clinical trials. Our aim is to review these new treatment planning parameters that can influence the balance between contradicting effects of radiation therapy so as to enhance the therapeutic ratio.

Long-Term (≥25 Years) Kidney Allograft Survivors: Retrospective Analysis at a Single Center.

INTRODUCTION: Despite great improvements in the short-term patient and kidney graft survival, the long-term morbidity and mortality in kidney transplant recipients still remains a significant problem. The aim of the study was to evaluate the impact of both donor and transplant recipient factors, as well as renal function indices on the very long-term (>25 years) kidney allograft survival. MATERIAL AND METHODS: Retrospective analysis was performed on the data of 41 kidney transplant recipients (KTR), group A: follow-up = 25 years, 20 KTR, 10 male, mean age (mean [M] ± standard deviation [SD]): 34.6 ± 12.6 years, 14 living donors (LD), 6 cadaveric donors (CD); group B: follow-up > 25 years, 21 KTR, 16 male, mean age (M ± SD): 30.86 ± 12.37 years, 14 LD, 7 CD). Kidney graft origin, post-kidney transplantation diabetes mellitus, HLA compatibility, delayed graft function, and acute rejection episodes were also analyzed retrospectively. Statistical analysis with Mann-Whitney test and Kaplan-Meier survival analysis was performed (SPSS 20.0 for Windows). RESULTS: The mean age of CDs was lower than that of LDs: CD mean age (M ± SD): 23.84 ± 16.26 years vs LD mean age: 52.75 ± 12.42 years (P < .001). Cadaveric kidney graft was associated with better renal allograft function 10, 15, and 25 years post kidney transplant. None of the other factors analyzed reached statistical significance between the 2 groups. CONCLUSION: The age of the donor and the kidney graft origin are important co-factors of the very long-term kidney allograft survival.

Randomized multicenter phase II trial of cisplatin and ifosfamide with or without paclitaxel in recurrent or metastatic carcinoma of the uterine cervix: a Hellenic Cooperative Oncology Group (HeCOG) study.

BACKGROUND: We undertook a randomized phase II trial to test whether the addition of paclitaxel (Taxol) to the cisplatin and ifosfamide (IP) combination could improve objective response (OR) rate, progression-free survival (PFS) and overall survival (OS) in patients with recurrent or metastatic cancer of the uterine cervix. PATIENTS AND METHODS: One hundred and fifty-three patients were randomly allocated to receive either the IP regimen (ifosfamide 1.5 g/m(2), daily, on days 1-3 and cisplatin 70 mg/m(2) on day 2) or the same combination with the addition of paclitaxel 175 mg/m(2) on day 1 [ifosfamide, paclitaxel and cisplatinum (ITP) regimen]. Cycles were administered every 4 weeks on an outpatient basis. RESULTS: A modest increase in neurotoxicity was observed with the triplet combination. OR rate was significantly higher in the ITP group (59% versus 33%, P = 0.002). Median PFS was 7.9 and 6.3 months for patients in the ITP and IP arms, respectively (P = 0.023). Median OS was 15.4 months and 13.2 months in the ITP and IP arms, respectively (P = 0.048). In multivariate analysis, the triplet yielded a hazard ratio of 0.70 for relapse or progression (P = 0.046) and 0.75 for death (P = 0.124) compared with the doublet. CONCLUSION: The ITP combination merits further investigation in randomized phase III studies.