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The primary analysis of IMvigor130 showed a significant progression-free survival benefit with first-line atezolizumab plus platinum-based chemotherapy (group A) versus placebo plus platinum-based chemotherapy (group C) in patients with locally advanced or metastatic urothelial cancer. However, this finding did not translate into significant overall survival benefit for group A versus group C at the final analysis, precluding formal statistical testing of outcomes with atezolizumab monotherapy (group B) versus group C. Here we report the final overall survival results for group B versus group C; this report is descriptive and should be considered exploratory due to the study's statistical design. In this global, partially blinded, randomised, controlled, phase 3 study, patients (aged ≥18 years) who had locally advanced or metastatic urothelial cancer previously untreated in the metastatic setting and Eastern Cooperative Oncology Group performance status of 0–2 were enrolled at 221 hospitals and oncology centres in 35 countries. Patients were randomly assigned (1:1:1), using a permuted block method (block size of six) and an interactive voice and web response system, stratified by PD-L1 status, Bajorin score, and investigator's choice of platinum-based chemotherapy, to receive either atezolizumab plus platinum-based chemotherapy (group A), atezolizumab alone (group B), or placebo plus platinum-based chemotherapy (group C). Sponsors, investigators, and patients were masked to assignment to atezolizumab or placebo in group A and group C; atezolizumab monotherapy in group B was open label. For groups B and C, atezolizumab (1200 mg) or placebo was administered intravenously every 3 weeks. Chemotherapy involved 21-day cycles of gemcitabine (1000 mg/m2 body surface area on day 1 and day 8 of each cycle) plus the investigator's choice of carboplatin (area under the curve 4·5 mg/mL per min or 5 mg/mL per min) or cisplatin (70 mg/m2 body surface area), administered intravenously. Co-primary endpoints were progression-free survival and overall survival in group A versus group C, and overall survival in group B versus group C, tested hierarchically, in the intention-to-treat (ITT) population, and then the populations with high PD-L1 tumour expression (immune cell [IC] expression score of IC2/3) if the results from group A versus group C were significant. Here, we report the co-primary endpoint of overall survival for group B versus group C in the ITT and IC2/3 populations. The ITT population for this analysis comprised concurrently enrolled patients in groups B and C who were randomly assigned to treatment. For the safety analysis, all patients enrolled in group B and group C who received any study treatment were included. The trial is registered with ClinicalTrials.gov , NCT02807636 , and is active but no longer recruiting. Between July 15, 2016, and July 20, 2018, 1213 patients were enrolled and randomly assigned to treatment, of whom 362 patients were assigned to group B and 400 to group C, of whom 360 and 359, respectively, were enrolled concurrently (ITT population). 543 (76%) of 719 patients were male, 176 (24%) were female, and 534 (74%) were White. As of data cutoff (Aug 31, 2022), after a median follow-up of 13·4 months (IQR 6·2–30·8), median overall survival was 15·2 months (95% CI 13·1–17·7; 271 deaths) in group B and 13·3 months (11·9–15·6; 275 deaths) in group C (stratified hazard ratio 0·98 [95% CI 0·82–1·16]). The most common grade 3–4 treatment-related adverse events were anaemia (two [1%] in patients who received atezolizumab monotherapy vs 133 [34%] in those who received placebo plus chemotherapy), neutropenia (one [<1%] vs 115 [30%]), decreased neutrophil count (0 vs 95 [24%]), and decreased platelet count (one [<1%] vs 92 [24%]). Serious adverse events occurred in 163 (46%) patients versus 196 (50%). Treatment-related deaths occurred in three (1%; n=1 each, pneumonia, interstitial lung disease, large intestinal obstruction) patients who received atezolizumab monotherapy and four (1%; n=1 each, diarrhoea, febrile neutropenia, unexplained death, toxic hepatitis) who received placebo plus chemotherapy. The final analysis from IMvigor130 did not show a significant improvement in overall survival with first-line atezolizumab monotherapy compared with platinum-based chemotherapy in the intention-to-treat population. The safety profile of atezolizumab monotherapy remained acceptable after extended follow-up, with no new safety signals. F Hoffmann-La Roche. [ABSTRACT FROM AUTHOR]

A European group of experts produced the first consensus statements on oligometastatic bladder cancer (OMBC). On the basis of the evidence available, up to three metastatic sites that can be radically resected or irradiated after a favourable response to systemic therapy was proposed as a definition of OMBC. This definition can assist standardisation of future research to provide guidance on patient selection for OMBC management options. In contrast to other cancers, the concept of oligometastatic disease (OMD) has not been investigated in bladder cancer (BC). To develop an acceptable definition, classification, and staging recommendations for oligometastatic BC (OMBC) spanning the issues of patient selection and the roles of systemic therapy and ablative local therapy. A European consensus group of 29 experts, led by the European Association of Urology (EAU), the European Society for Radiotherapy and Oncology (ESTRO), and the European Society of Medical Oncology (ESMO), and including members from all other relevant European societies, was established. A modified Delphi method was used. A systematic review was used to build consensus questions. Consensus statements were extracted from two consecutive surveys. The statements were formulated during two consensus meetings. Agreement levels were measured to determine if consensus was achieved (≥75% agreement). The first survey included 14 questions and the second survey had 12. Owing to a considerable lack of evidence, which was the major limitation, definition was limited in the context of de novo OMBC, which was further classified as synchronous OMD, oligorecurrence, and oligoprogression. A maximum of three metastatic sites, all resectable or amenable to stereotactic therapy, was proposed as the definition of OMBC. Pelvic lymph nodes represented the only "organ" not included in the definition of OMBC. For staging, no consensus on the role of 18F-fluorodeoxyglucose positron emission tomography/computed tomography was reached. A favourable response to systemic treatment was proposed as the criterion for selection of patients for metastasis-directed therapy. A consensus statement on the definition and staging of OMBC has been formulated. This statement will help to standardise inclusion criteria in future trials, potentiate research on aspects of OMBC for which consensus was not achieved, and hopefully will lead to the development of guidelines on optimal management of OMBC. As an intermediate state between localised cancer and disease with extensive metastasis, oligometastatic bladder cancer (OMBC) might benefit from a combination of systemic treatment and local therapy. We report the first consensus statements on OMBC drawn up by an international expert group. These statements can provide a basis for standardisation of future research, which will lead to high-quality evidence in the field. [ABSTRACT FROM AUTHOR]

Since the late 1990s, tumor necrosis factor alpha (TNF-α) inhibitors (anti-TNFs) have revolutionized the therapy of immune-mediated inflammatory diseases (IMIDs) affecting the gut, joints, skin and eyes. Although the therapeutic armamentarium in IMIDs is being constantly expanded, anti-TNFs remain the cornerstone of their treatment. During the second decade of their application in clinical practice, a large body of additional knowledge has accumulated regarding various aspects of anti-TNF-α therapy, whereas new indications have been added. Recent experimental studies have shown that anti-TNFs exert their beneficial effects not only by restoring aberrant TNF-mediated immune mechanisms, but also by de-activating pathogenic fibroblast-like mesenchymal cells. Real-world data on millions of patients further confirmed the remarkable efficacy of anti-TNFs. It is now clear that anti-TNFs alter the physical course of inflammatory arthritis and inflammatory bowel disease, leading to inhibition of local and systemic bone loss and to a decline in the number of surgeries for disease-related complications, while anti-TNFs improve morbidity and mortality, acting beneficially also on cardiovascular comorbidities. On the other hand, no new safety signals emerged, whereas anti-TNF-α safety in pregnancy and amid the COVID-19 pandemic was confirmed. The use of biosimilars was associated with cost reductions making anti-TNFs more widely available. Moreover, the current implementation of the "treat-to-target" approach and treatment de-escalation strategies of IMIDs were based on anti-TNFs. An intensive search to discover biomarkers to optimize response to anti-TNF-α treatment is currently ongoing. Finally, selective targeting of TNF-α receptors, new forms of anti-TNFs and combinations with other agents, are being tested in clinical trials and will probably expand the spectrum of TNF-α inhibition as a therapeutic strategy for IMIDs. [ABSTRACT FROM AUTHOR]

Arterial thromboembolism has been associated with cancer or its treatment. Unlike venous thromboembolism, the incidence and risk factors have not been extensively studied. Here, we investigated the incidence of arterial thromboembolic events (ATEs) in an institutional series of advanced urinary tract cancer (aUTC) treated with cytotoxic chemotherapy. The ATE definition included peripheral arterial embolism/thrombosis, ischemic stroke and coronary events. A total of 354 aUTC patients were analyzed. Most patients (95.2%) received platinum-based chemotherapy. A total of 12 patients (3.4%) suffered an ATE within a median time of 3.6 months from the start of chemotherapy. The most frequent ATE was ischemic stroke (n = 7). Two ATEs were fatal. The 6-month and 24-month incidence were 2.1% (95% confidence interval [CI]: 0.9–4.1) and 3.6% (95% CI: 1.9–6.2), respectively. Perioperative chemotherapy increased the risk for ATE by 5.55-fold. Tumors other than UTC and pure non-transitional cell carcinoma histology were also independent risk factors. No association with the type of chemotherapy was found. Overall, ATEs occur in 4.6% of aUTC patients treated with chemotherapy and represent a clinically relevant manifestation. Perioperative chemotherapy significantly increases the risk for ATE. The role of prophylaxis in high-risk groups should be prospectively studied. [ABSTRACT FROM AUTHOR]

Background: Optimization of treatment with biologics is currently an unmet need for patients with ulcerative colitis (UC). Real-world studies provide neutral estimates of drug efficacy and safety within unselected patient populations and allow for the recognition of specific characteristics that affect response to therapy. Aims: We aimed to depict the efficacy of vedolizumab in patients with UC in a real-world setting and identify prognosticators of improved outcomes. Methods: Patients with active UC who commenced treatment with vedolizumab were prospectively followed up. Patient-reported outcomes (PROs) and clinical/endoscopic-reported outcomes were recorded at baseline and at weeks 14 and 54. Predefined endpoints of early and persistent efficacy were analyzed against clinical characteristics to identify prognostic factors for response. Results: We included 96 patients (anti-TNF-exposed = 38.5%). At week 14, 73 patients (76%) had clinical response and 54 (56.3%) clinical remission. At week 54, the primary endpoint of vedolizumab persistence was met by 72 patients (75%), whereas steroid-free clinical remission by 59.4%. Among patients who had endoscopy, rates for mucosal healing (Mayo endoscopic score of 0) were 29.8% at week 14 and 44.6% at week 54, respectively. Vedolizumab treatment led to significant improvements in quality of life. Corticosteroid-refractory or anti-TNF-refractory disease, articular manifestations, and high baseline UC-PRO2 were associated with decreased efficacy of vedolizumab in the primary and secondary outcomes. Conclusions: Vedolizumab is characterized by high efficacy and long-term treatment persistence in UC. More aggressive disease, as indicated by refractoriness to steroids or anti-TNFs and elevated baseline PROs, may predict suboptimal response and help pre-treatment prognostic stratification of patients. [ABSTRACT FROM AUTHOR]

We previously showed that ERCC1 19007 C>T polymorphism was associated with cancerspecific survival (CSS) after platinum-based chemotherapy in patients with advanced urothelial cancer (aUC). We aimed to confirm this association in a different cohort of patients. Genotyping of the 19007C>T polymorphism was carried out by polymerase chain reaction (PCR) amplification and restriction fragment length polymorphism (RFLP) in 98 aUC patients, treated with platinum-based chemotherapy. Median age of the patients was 68.8, 13.3% of them were female, 90.8% had ECOG PS of 0 or 1, and 48% received cisplatin-based chemotherapy. In addition to chemotherapy, 32.7% of the patients received immunotherapy, and 19.4% vinflunine. Eighty-one patients (82.7%) were carriers of the 19007T polymorphic allele: 46 (46.9%) were heterozygotes, and 35 (35.7%) were homozygotes. The ERCC1 polymorphism was not associated with CSS, progression-free (PFS), or overall (OS) survival in the total population. Nevertheless, there was a significant interaction between the prognostic significance of ERCC1 polymorphism and the use of modern immunotherapy: the T allele was associated with worse outcome in patients who received chemotherapy only, while this association was lost in patients who received both chemotherapy and immune checkpoint inhibitors. Our study suggests that novel therapies may influence the significance of ERCC1 polymorphism in patients with aUC. Its determination may be useful in the changing treatment landscape of the disease. [ABSTRACT FROM AUTHOR]

Objective: To investigate the efficacy of alternating cycles of sunitinib and everolimus vs standard sequential treatment of sunitinib followed by everolimus in first‐line metastatic renal cell carcinoma (mRCC), as alternating blockade of vascular endothelial growth factor receptor (VEGFR) and mammalian target of rapamycin (mTOR) pathways could potentially prevent the occurrence of resistance to anti‐VEGFR therapy in mRCC. Patients and Methods: SUNRISES, a randomised open‐label Phase II study, investigated the efficacy of alternating cycles of sunitinib and everolimus vs standard sequential treatment of sunitinib followed by everolimus upon progression. Treatment‐naïve patients with clear‐cell mRCC were included. Alternating treatment consisted on 12 weeks of sunitinib, followed by 12 weeks of everolimus. The primary endpoint was the progression‐free survival (PFS) rate at 1 year. The secondary endpoints included the median PFS, overall survival (OS), response rate, and safety. Results: Accrual was low due to the advent of new‐generation therapies, and the study was stopped prematurely. Only 41 patients out of the planned 102 patients were accrued, and randomised in a 2:1 ratio (15 patients to the control arm, 26 to the experimental arm). In all, 60.9% of patients had performance status (PS) 0 and 39% PS 1; 63% had a favourable prognostic risk profile, while 36% were intermediate risk. The primary endpoint was not met. The 1‐year PFS rate was 49.7% (experimental arm) vs 84.62% (control arm; P = 0.11). There was a trend towards fewer Grade ≥3 adverse events with the alternating approach (50% vs 73.3%; P = 0.14). The median OS was similar in both treatment arms. The other secondary endpoints favoured the control arm. Conclusions: The study failed to show any benefit of alternating cycles of sunitinib and everolimus in patients with mRCC. The alternating approach using an mTOR inhibitor does not seem to prevent the occurrence of resistance to VEGFR blockade. [ABSTRACT FROM AUTHOR]

• Real-world data confirm activity and safety of vinflunine within its approved use. • Immunotherapy is a new standard for relapsed advanced urothelial cancer. • Immunotherapy offers long-term responses to only 25% of patients. • Vinflunine represents a useful option in patients not responding to immunotherapy. Vinflunine (VFL) is approved in Europe as second-line treatment of metastatic urothelial cancer after failure of platinum-containing therapy. We performed a systematic review and meta-analysis of real-world data (RWD) to assess utilization, efficacy and safety of VFL. We performed a MEDLINE search for the period of 1/1/2000-31/8/2017. Full-length articles providing post-marketing RWD on VFL in patients failing previous chemotherapy were eligible. Interventional clinical trials were excluded. Ten studies with 797 patients were identified. According to pooled REs analysis, overall response rate was 19%, most frequent, all-grade toxicities were fatigue (41%), constipation (39%), nausea/vomiting (25%), and most prevalent Grade 3–4 toxicities were neutropenia (13%), anaemia (9%), fatigue (8%). Median OS was comparable to results reported in recent randomized studies. Our findings confirm the efficacy and safety of VFL in an unselected population and support the use of VFL in the changing treatment paradigm of relapsed mUC. [ABSTRACT FROM AUTHOR]

• GLI transcription factors are frequently expressed in various lung cancer types. • Both canonical Hedgehog signaling and other pathways activate GLI in lung cancer. • Activation of the Hedgehog pathway often occurs upon development of resistance. • Clinical trials of Smoothened inhibitors in Small-Cell Lung Cancer were negative. • Further research is required with new agents in molecularly defined subgroups. Inhibitors of the hedgehog pathway are effective in patients with basal cell carcinoma and a subgroup of patients with medulloblastoma with active hedgehog signaling. Despite preclinical work suggesting otherwise, clinical trials in solid tumors of epithelial origin have not shown added benefit with these drugs. Here, we review the preclinical and clinical data of hedgehog pathway inhibition in the most common histologic types of lung cancer. We focus on highlighting areas of uncertainty, where further research might define a niche for hedgehog pathway inhibition in patients with lung cancer. [ABSTRACT FROM AUTHOR]

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 [ABSTRACT FROM AUTHOR]

Several statements in the article describe A2780 cell results and/or compare A2780 versus A2780/C30 results, yet many of the A2780 cell results described were not reported in the article or public dataset. (A2780/C30 data corresponding to results shown in Fig 2C) Typical comet assay images of A2780/C30 cells treated with cisplatin (0-150 g/ml) for 3h or carboplatin (0-300 g/ml) for 24h and analyzed at the end of the treatment. [Extracted from the article]

Background: Cisplatin-based combination chemotherapy is the standard treatment of advanced urinary tract cancer (aUTC), but 50% of patients are ineligible for cisplatin according to recently published criteria. We used a multinational database to study patterns of chemotherapy utilization in patients with aUTC and determine their impact on survival. Patients and methods: This was a retrospective study of patients with: UTC (bladder, renal pelvis, ureter or urethra); advanced disease (stages T4b and/or N+ and/or M+); urothelial, squamous or adenocarcinoma histology. Primary objective was overall survival (OS). Eligibility-for-cisplatin was defined by Eastern Cooperative Oncology Group performance status≤1, creatinine clearance≥60 ml/min, no hearing loss, no neuropathy and no heart failure. Cox regression multivariate analyses were used to establish independent associations of cisplatin versus noncisplatin-based chemotherapy on OS. Results: About 1794 patients treated between 2000 and 2013 at 29 centers were analyzed. Median follow-up was 29.1 months. About 1333 patients (74%) received first-line chemotherapy: the use of first-line chemotherapy was associated with longer OS: [hazard ratio (HR): 1.91, 95% confidence interval (CI): 1.67-2.20]. Type of first-line chemotherapy received was: cisplatin-based 669 (50%), carboplatin-based 399 (30%) and other 265 (20%). Cisplatin use was an independent favorable prognostic factor (HR: 1.54, 95% CI: 1.35-1.77). This benefit was independent of baseline characteristics or comorbidities but was associated with eligibility-for-cisplatin: eligible patients treated with cisplatin lived longer than those who were not (HR: 1.74, 95% CI: 1.36-2.21), while such benefit was not observed among ineligible patients. About 26% of patients who did not receive cisplatin were eligible for this agent. Median OS of ineligible patients was poor irrespective of the chemotherapy used. Conclusions: The importance of applying published criteria of eligibility-for-cisplatin was confirmed in a multinational, realworld setting in aUTC. The reasons for deviations from these criteria set targets to improve adherence. Effective therapies for cisplatin-ineligible patients are needed. [ABSTRACT FROM AUTHOR]

Osteonecrosis of the jaw ( ONJ) is a severe complication of therapy with antiresorptive agents (e.g. bisphosphonates and denosumab), which are used to manage bone metastases from cancer, to reduce the incidence of skeletal-related events. Available data indicate that 0-27, 5% of patients exposed to antiresorptive agents may develop ONJ, depending on the number of infusions and the duration of therapy. Besides antiresorptive therapy, a number of risk factors for osteonecrosis have been identified. Oral surgical procedures, tooth extractions and infection to the jawbones are considered the main risk factors for developing ONJ, when receiving antiresorptive therapy. However, a growing number of patients develop ONJ without apparent risk factors, raising concern for other predisposing factors. Jaw bone necrosis may be irreversible, resulting in a chronic disease with negative impact on the quality of patients' lives. The role of risk reduction strategies like meticulous dental screening and optimal oral hygiene is fundamental for preventing development of ONJ. ONJ is usually treated conservatively to relieve the symptoms and manage jaw bone necrosis. In certain cases, surgical intervention is required. Future research should emphasize individual predisposition to ONJ, more effective preventive measures and more efficient therapeutic procedures. [ABSTRACT FROM AUTHOR]

Background: In the open-label randomized phase III AURELIA trial, adding bevacizumab to chemotherapy for platinumresistant ovarian cancer (PROC) significantly improved progression-free survival and response rate versus chemotherapy alone, but not overall survival (OS). We explored the effect of bevacizumab use after disease progression (PD) in patients randomized to chemotherapy alone. Patients and methods: In AURELIA, 361 women with PROC were randomized to chemotherapy alone or with bevacizumab. Patients initially randomized to chemotherapy were offered bevacizumab after PD. Post hoc analyses assessed efficacy and safety in three subgroups: chemotherapy alone, chemotherapy followed by bevacizumab after PD, and chemotherapy plus bevacizumab at randomization. Results: Of the 182 patients randomized to chemotherapy alone, 72 (40%) received bevacizumab after PD and 110 (60%) never received bevacizumab. There were no significant differences in patient and disease characteristics between these subgroups at baseline or the time of PD. Compared with patients never receiving bevacizumab, the risk of death was significantly reduced in patients receiving bevacizumab either upfront with chemotherapy [hazard ratio (HR)=0.68, 95% confidence interval (CI) 0.52-0.90] or after PD (HR=0.60, 95% CI 0.43-0.86). The tolerability of bevacizumab was similar with administration upfront or after PD. Conclusions: Post-PD bevacizumab use may have confounded OS results in AURELIA. In these exploratory analyses of nonrandomized subgroups, bevacizumab use, either with chemotherapy or after PD on chemotherapy alone, improved OS compared with no bevacizumab. Combining bevacizumab with chemotherapy at first appearance of platinum resistance maximises the likelihood of patients receiving this active treatment for PROC. ClinicalTrials.gov: NCT00976911. [ABSTRACT FROM AUTHOR]

Anti-CTL4-A therapy is associated with development of colitis. We characterized ipilimumab-associated colitis in nine melanoma patients (6 male, mean age: 55.3-yrs). Median value for diarrhea grade was 2, number of ipilimumab doses 2, and interval since last administration 3-wks. Endoscopic characteristics resembled inflammatory bowel disease and histology revealed predominance of plasmacytes or CD4+ T-cells. We observed significant upregulation of Th1 and Th17 effector pathways (>10-fold increase for IFN-γmRNA, >5-fold for IL-17A, p < 0.01 vs. controls). Significant elevation of FoxP3 was also detected. In conclusion, ipilimumab administration results in elevations of effector lymphocytes and pro-inflammatory mediators in the gut lamina propria. [ABSTRACT FROM AUTHOR]

TNF-like cytokine 1A (TL1A) is expressed on APCs and provides costimulatory signals to activated lymphocytes that bear its functional receptor, death receptor 3 (DR3). TL1A/DR3 signaling is involved in the pathogenesis of human and experimental inflammatory bowel disease. In the current study, we investigated the role of this cytokine/receptor pair in acute intestinal injury/repair pathways. We demonstrate that intact DR3 signaling protected mice from acute dextran sodium sulfate colitis because DR3-/- mice showed more severe mucosal inflammation and increased mortality. DR3-/- mice were compromised in their ability to maintain adequate numbers of CD4+CD25+Foxp3+ regulatory T cells in response to acute mucosal damage. This defect in immune regulation led to a nonspecific upregulation of effector proinflammatory pathways, which was most prominent for the Th17 immunophenotype. TL1A-/- mice were similarly more susceptible to dextran sodium sulfate colitis, although without mortality and with delayed kinetics compared with DR3-/- mice, and also displayed significantly reduced numbers of regulatory T cells. Infection of DR3-/- mice with Salmonella typhimurium was associated with defective microbial clearance and elevated bacterial load. Taken together, our findings indicate a novel protective role for the TL1A/DR3 axis in the regulation of mucosal homeostasis during acute intestinal injury/repair, which contrasts with its known pathogenic function during chronic intestinal inflammation. [ABSTRACT FROM AUTHOR]

Transurethral resection of bladder tumor ( TURBT), radiotherapy, chemotherapy, or combinations can be used in patients with muscle-invasive bladder cancer ( MIBC) not undergoing cystectomy. Nevertheless, unfitness for cystectomy is frequently associated with unfitness for other therapeutic modalities. We report the outcome of patients with MIBC who did not undergo cystectomy and did not receive cisplatin-based chemotherapy. Selection criteria for the study were nonmetastatic MIBC, no cystectomy, no cisplatin-based chemotherapy. Chemotherapy and/or radiotherapy should have been used aside from TURBT. Forty-nine patients (median age 79), managed between April 2001 and January 2012, were included in this analysis. Median Charlson Comorbidity Index was 5, while 76% were unfit for cisplatin. Treatment included radiotherapy ( n = 7), carboplatin-based chemotherapy ( n = 25), carboplatin-based chemotherapy followed by radiotherapy ( n = 10), and radiochemotherapy ( n = 7). Five-year event-free rate was 26% (standard error [ SE] = 7) for overall survival, 23% ( SE = 7) for progression-free survival, and 30 ( SE = 8) for cancer-specific survival ( CSS). Patients who were treated with combination of radiotherapy and chemotherapy had significantly longer CSS compared to those treated with radiotherapy or chemotherapy only (5-year CSS rate: 16% [ SE 8] vs. 63% [ SE 15], P = 0.053). Unfit-for-cystectomy patients frequently receive suboptimal nonsurgical treatment. Their outcome was poor. Combining chemotherapy with radiotherapy produced better outcomes and should be prospectively evaluated. [ABSTRACT FROM AUTHOR]

Background Bacterial translocation (BT) commonly occurs in cirrhosis. Reliable biomarkers for BT are currently lacking. Human beta defensin-1 (hBD-1) is a member of the family of natural antimicrobial peptides produced by epithelial cells and participates in the mucosal defensive mechanisms that prevent BT. Th e aim of the present study was to examine the local and systemic expression of hBD-1 in patients with cirrhosis. Methods Plasma concentrations of hBD-1 and of soluble CD14 (sCD14) proteins were measured by ELISA in patients with chronic viral hepatitis, cirrhosis, and healthy controls. Relative mRNA expression of various natural antimicrobial peptides was determined by real-time PCR in biopsies from the terminal ileum and colon. Results We found signifi cant upregulation of hBD-1 and sCD14 in the peripheral blood of patients with cirrhosis compared to patients with chronic viral hepatitis and healthy controls. Th e etiology of cirrhosis did not aff ect the concentration of either protein. Th e levels of hBD-1 protein correlated signifi cantly with the levels of sCD14 in blood collected from hepatic veins of cirrhotic patients. In contrast, no signifi cant diff erences were observed in the intestinal mucosal mRNA expression of the Paneth cell specifi c defensin A5 or hBD-1 between patients with cirrhosis and healthy controls. Conclusions hBD-1 is upregulated in patients with cirrhosis and highly correlates with the lipopolysaccharide-induced protein sCD14. hBD-1 may serve as a biomarker of BT in patients with cirrhosis. [ABSTRACT FROM AUTHOR]

Inflammatory bowel diseases, ulcerative colitis and Crohn׳s disease are characterized by chronic relapsing inflammation of the gastrointestinal tract of unknown etiology that seems to be the consequence of a genetically driven dysregulated immune response against various local and environmental triggers through a defective epithelial barrier. During the last decades, a large number of animal experimental models of intestinal inflammation have been generated and provided valuable insights into the mechanisms that either maintain mucosal homeostasis or drive intestinal inflammation. Their study enabled the identification of various treatment targets and the development a large pipeline of new drugs, mostly biologics. Safety and therapeutic efficacy of these agents have been evaluated in a large number of clinical trials but only a minority has reached the clinic so far. Translational successes but mostly translational failures have prompted to re-evaluate results of efficacy and safety generated by pre-clinical testing and to re-examine the way to interpret experimental in vivo data. This review examines the contribution of the most popular experimental colitis models to our understanding of the pathogenesis of human inflammatory bowel diseases and their translational input in drug development and discusses ways to improve translational outcome. [ABSTRACT FROM AUTHOR]

Ovarian carcinoma (OC) is the most lethal gynecological malignancy. Despite the advances in the treatment of OC with combinatorial regimens, including surgery and platinum-based chemotherapy, patients generally exhibit poor prognosis due to high chemotherapy resistance. Herein, we tested the hypothesis that DNA damage response (DDR) pathways are involved in resistance of OC patients to platinum chemotherapy. Selected DDR signals were evaluated in two human ovarian carcinoma cell lines, one sensitive (A2780) and one resistant (A2780/C30) to platinum treatment as well as in peripheral blood mononuclear cells (PBMCs) from OC patients, sensitive (n = 7) or resistant (n = 4) to subsequent chemotherapy. PBMCs from healthy volunteers (n = 9) were studied in parallel. DNA damage was evaluated by immunofluorescence γH2AX staining and comet assay. Higher levels of intrinsic DNA damage were found in A2780 than in A2780/C30 cells. Moreover, the intrinsic DNA damage levels were significantly higher in OC patients relative to healthy volunteers, as well as in platinum-sensitive patients relative to platinum-resistant ones (all P<0.05). Following carboplatin treatment, A2780 cells showed lower DNA repair efficiency than A2780/C30 cells. Also, following carboplatin treatment of PBMCs ex vivo, the DNA repair efficiency was significantly higher in healthy volunteers than in platinum-resistant patients and lowest in platinum-sensitive ones (t1/2 for loss of γH2AX foci: 2.7±0.5h, 8.8±1.9h and 15.4±3.2h, respectively; using comet assay, t1/2 of platinum-induced damage repair: 4.8±1.4h, 12.9±1.9h and 21.4±2.6h, respectively; all P<0.03). Additionally, the carboplatin-induced apoptosis rate was higher in A2780 than in A2780/C30 cells. In PBMCs, apoptosis rates were inversely correlated with DNA repair efficiencies of these cells, being significantly higher in platinum-sensitive than in platinum-resistant patients and lowest in healthy volunteers (all P<0.05). We conclude that perturbations of DNA repair pathways as measured in PBMCs from OC patients correlate with the drug sensitivity of these cells and reflect the individualized response to platinum-based chemotherapy. [ABSTRACT FROM AUTHOR]

LINKED CONTENT This article is linked to Almradi et al paper. To view this article, visit https://doi.org/10.1111/apt.16248 [ABSTRACT FROM AUTHOR]

Background:Accurate prediction of outcome for metastatic renal cell carcinoma (mRCC) patients receiving targeted therapy is essential. Most of the available models have been developed in patients treated with cytokines, while most of them are fairly complex, including at least five factors. We developed and externally validated a simple model for overall survival (OS) in mRCC. We also studied the recently validated International Database Consortium (IDC) model in our data sets.Methods:The development cohort included 170 mRCC patients treated with sunitinib. The final prognostic model was selected by uni- and multivariate Cox regression analyses. Risk groups were defined by the number of risk factors and by the 25th and 75th percentiles of the model's prognostic index distribution. The model was validated using an independent data set of 266 mRCC patients (validation cohort) treated with the same agent.Results:Eastern Co-operative Oncology Group (ECOG) performance status (PS), time from diagnosis of RCC and number of metastatic sites were included in the final model. Median OS of patients with 1, 2 and 3 risk factors were: 24.7, 12.8 and 5.9 months, respectively, whereas median OS was not reached for patients with 0 risk factors. Concordance (C) index for internal validation was 0.712, whereas C-index for external validation was 0.634, due to differences in survival especially in poor-risk populations between the two cohorts. Predictive performance of the model was improved after recalibration. Application of the mRCC International Database Consortium (IDC) model resulted in a C-index of 0.574 in the development and 0.576 in the validation cohorts (lower than those recently reported for this model). Predictive ability was also improved after recalibration in this analysis. Risk stratification according to IDC model showed more similar outcomes across the development and validation cohorts compared with our model.Conclusion:Our model provides a simple prognostic tool in mRCC patients treated with a targeted agent. It had similar performance with the IDC model, which, however, produced more consistent survival results across the development and validation cohorts. The predictive ability of both models was lower than that suggested by internal validation (our model) or recent published data (IDC model), due to differences between observed and predicted survival among intermediate and poor-risk patients. Our results highlight the importance of external validation and the need for further refinement of existing prognostic models. [ABSTRACT FROM AUTHOR]

Abstract: Interactions between TNF-like Cytokine 1A (TL1A) and its receptors, death receptor-3 (DR3) and decoy receptor-3 (DcR3) may be important in atherogenesis. We hypothesized that dysregulation of this system predicts formation of new atheromatic plaques in rheumatoid arthritis (RA). Forty-five patients were prospectively followed up for 40.5±3.6months. Serum concentrations of TL1A and DcR3 were measured at baseline and carotid and femoral arteries examined by ultrasound at baseline and at the end of follow-up. Individual serum levels of TL1A correlated with the progression of carotid atheromatic plaque height (Spearman rho=0.550, p=0.003). Patients with low TL1A and undetectable DcR3 serum levels at baseline showed significantly fewer newly formed carotid plaques during the next 3.5years than the remaining patients (P=0.016). Univariate analysis showed that a “low TL1A/DcR3” immunophenotype predicted a preserved atherosclerosis profile in carotid (P=0.026), or carotid and/or femoral arteries (P=0.022). Dysregulated TL1A-induced signaling may be associated with risk for accelerated atherosclerosis in RA. [Copyright &y& Elsevier]

Background The combinations of methotrexate, vinblastine, Adriamycin, cisplatin (Pharmanell, Athens, Greece) (MVAC) or gemcitabine, cisplatin (GC) represent the standard treatment of advanced urothelial cancer (UC). Dose-dense (DD)-MVAC has achieved longer progression-free survival (PFS) than the conventional MVAC. However, the role of GC intensification has not been studied. We conducted a randomized, phase III study comparing a DD-GC regimen with DD-MVAC in advanced UC. Patients and methods One hundred and thirty patients were randomly assigned between DD-MVAC: 66 (M 30 mg/m2, V 3 mg/m2, A 30 mg/m2, C 70 mg/m2 q 2 weeks) and DD-GC 64 (G 2500 mg/m2, C 70 mg/m2 q 2 weeks). The median follow-up was 52.1 months (89 events). Results The median overall survival (OS) and PFS were 19 and 8.5 months for DD-MVAC and 18 and 7.8 months for DD-GC (P = 0.98 and 0.36, respectively). Neutropenic infections were less frequent for DD-GC than for DD-MVAC (0% versus 8%). More patients on DD-GC received at least six cycles of treatment (85% versus 63%, P = 0.011) and the discontinuation rate was lower for DD-GC (3% versus 13%). Conclusions Although DD-GC was not superior to DD-MVAC, it was better tolerated. DD-GC could be considered as a reasonable therapeutic option for further study in this patient population. Clinical Trial Number ACTRN12610000845033, www.anzctr.org.au. [ABSTRACT FROM PUBLISHER]

Objective. To determine the expression of soluble TNF-like cytokine 1A (sTL1A), a new member of the TNF superfamily, in patients with AS.Methods. Seventy-five consecutive patients with AS [61 males, mean (s.d.) age: 47.2 (15.5) years, disease duration: 20.3 (13.9) years] were included in this study. Forty-four patients were anti-TNF treatment naïve, whereas the remaining patients were on infliximab (n = 21), adalimumab (n = 3) or etanercept (n = 7). The patients’ perceived disease activity was recorded by BASDAI and AS DAS using serum CRP levels (ASDAS-CRP), whereas functional status was assessed by BASFI and measurements of spinal mobility (AS Metrology). Serum concentrations of TL1A were measured by ELISA. Twenty-five age- and sex-matched healthy individuals served as controls.Results. Anti-TNF treatment-naïve patients demonstrated a 2.6-fold higher sTL1A average value [mean (s.e.m.) 581 (157.5) pg/ml] compared with healthy controls [226.7 (48.24) pg/ml, P = 0.042]. The sTL1A levels of anti-TNF-treated patients [178 (42)] were significantly lower than anti-TNF treatment-naïve patients (3.3-fold decrease, P = 0.0038) and comparable to those of healthy controls. No significant association was found between sTL1A level and functional status (BASFI score, AS Metrology parameters) or CRP measured in the same sera; however, a positive correlation was observed between individual levels of sTL1A and both BASDAI (P = 0.008) and ASDAS-CRP (P = 0.058) scores suggesting that sTL1A levels may reflect disease activity in patients with AS.Conclusion. TL1A is up-regulated in AS, associates with disease activity and is influenced by anti-TNF treatment, suggesting that TL1A may be of pathogenic and potentially of therapeutic importance in AS patients. [ABSTRACT FROM PUBLISHER]

Objective: The prognosis for patients with platinum-resistant advanced ovarian cancer remains poor. The impact of approved agents on survival has not been clarified during the last decade. We studied survival trends during the last 15 years in platinum-resistant patients treated with cytoreductive surgery followed by paclitaxel/platinum chemotherapy. Methods: Patients with epithelial ovarian, fallopian or peritoneal cancer, stages III/IV and platinum-resistant disease after first-line chemotherapy with paclitaxel/platinum were included. They were grouped according to the period of chemotherapy: group A 31/3/1995-31/12/2001 (n = 56) and Group B 1/1/2002-24/12/2008 (n = 57). In order to compensate for the difference in follow-up between the 2 groups, we performed minimum follow-up (MFU) analyses by considering as cases only women who had an event within 3 years of follow-up. Patients with no events for up to 3 years were censored at that time. Results: MFU analyses showed that median overall survival (OS) was significantly longer in group B: 12.3 vs. 17.5 months (p = 0.012). This was due to a doubling of the median OS after relapse: 5.7 vs. 10.9 months (p = 0.0180). Multivariate Cox regression indicated group and histology as factors statistically significantly associated with OS. Following relapse, patients in group B were predominantly treated with liposomal doxorubicin and gemcitabine, and patients in group A were treated with platinum compounds, docetaxel and oral etoposide (p < 0.001). Conclusions: The introduction of novel agents without cross-resistance to platinum or taxanes has improved the prognosis of platinum-resistant patients. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: Ovarian cancer is the leading cause of death from gynecological cancers. Primary treatment of advanced ovarian cancer (FIGO stages III and IV) until recently consisted of cytoreductive surgery and paclitaxel/carboplatin chemotherapy. The results of two randomized studies, showing prolongation of progression-free survival (PFS) by the addition of the anti-VEGF monoclonal antibody, bevacizumab, led to the approval of this agent for first-line treatment of this disease and indicate that angiogenesis is a promising therapeutic target. Angiogenesis is essential for oncogenesis but also the viability and expansion of ovarian cancer. Specifically, VEGF is involved in the formation of ascites and has a direct effect on ascites tumor cells as well as an immunosuppressive function. Apart from VEGF, PDGF, FGF and angiopoietins present a therapeutic interest. We are reviewing the results of published clinical studies using anti-angiogenic factors in advanced ovarian cancer. [Copyright &y& Elsevier]

Abstract: In addition to their well-known role in acute injury and chronic inflammation, “innate” cytokines play an important role in health and the maintenance of normal immune homeostasis. This group includes the prototypic cytokines IL-1 and TNFα, as well as several other members belonging to the IL-1 and TNF family, such as IL-18, IL-33, IL-36–38, and TL1A. The dichotomous role of these cytokines has been best characterized in the intestine where innate cytokines may play both a protective and a pro-inflammatory role, depending upon the immmunological status of the host or the type and phase of the inflammatory process. This new information has produced novel pathogenetic hypotheses that have important translational implications both in regard to the prevention and treatment of chronic intestinal inflammation, including Crohn’s disease and ulcerative colitis, the two major forms of inflammatory bowel disease. This review will discuss and summarize current data regarding the role of IL-1, TNFα, and their family members in regulating gut mucosal homeostasis and chronic intestinal inflammation. [Copyright &y& Elsevier]

Abstract: Aim: Ovarian carcinomas have been classified into types I and II according to the hypothesised mode of carcinogenesis and molecular characteristics. The prognostic significance of this classification has not been studied. Patients and methods: Five hundred and sixty-eight patients with histologically confirmed, ovarian, fallopian tube or peritoneal carcinomas, international federation of gynecology and obstetrics (FIGO) stages IIC–IV, treated with paclitaxel/platinum following cytoreductive surgery, were included in this analysis. Type I included low-grade serous, mucinous, endometrioid and clear-cell and type II high-grade serous, unspecified adenocarcinomas and undifferentiated carcinomas. Results: Median overall survival (OS) was 49months for type I versus 45 for type II (p =0.576). In contrast to type II, there was considerable prognostic heterogeneity among the subtypes included in type I. Cox regression analysis showed that cell-type classification: low-grade serous, mucinous, endometrioid, clear-cell, type II (high-grade serous, unspecified adenocarcinomas, undifferentiated carcinoma) was an independent predictor of survival (respective median OS 121 versus 15 versus 64 versus 29 versus 45months, p =0.003). On the contrary, histopathological subtype or tumour type (I versus II) did not offer additional prognostic information. Conclusion: The proposed model of ovarian tumourigenesis does not reflect tumour behaviour in advanced disease. Tumour-cell type is the most relevant histopathological prognostic factor in advanced ovarian cancer treated with platinum/paclitaxel. [Copyright &y& Elsevier]

Objective: We investigated the efficacy of risk-adapted adjuvant paclitaxel/carboplatin chemotherapy in early-stage ovarian carcinoma. Methods: Fifty-three patients were treated according to the risk of relapse: patients with stages IA or IB or with grade 1 (low risk) received 4 cycles of paclitaxel and carboplatin; patients with IC/IIA and grade 2 or 3 (high risk) received 6 cycles of chemotherapy. The outcome was compared with that of 95 patients who were all treated with 4 cycles. Results: Median follow-up was 88, 113 and 42 months for the whole cohort, non-risk-adapted and risk-adapted treatment, respectively. Five-year relapse-free and disease-specific survival was 86 and 93% for the whole population, 96 and 97% for low-risk and 81 and 91% for high-risk patients. Risk classification was the only significant prognostic factor for relapse-free (p = 0.011) and disease-specific survival (p = 0.039). Among high-risk patients, the administration of 6 cycles was associated with a significantly lower relapse rate after censoring events, which occurred beyond 2 years (3 vs. 18%; p = 0.013), but this difference was diminished at 5 years (23 vs. 25%; p = 0.797). Conclusions: Six cycles of chemotherapy reduced the risk of relapse within 2 years, but the benefit from two additional cycles beyond this time is questionable. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: Objective: Early-stage epithelial ovarian cancer represents a prognostically heterogenous group. We studied prognostic factors in patients treated with adjuvant paclitaxel/carboplatin chemotherapy. Methods: Data was extracted from 147 patients with FIGO stage IA/IB, grade 2/3 or stage IC/IIA (any grade) who underwent primary surgery followed by paclitaxel/carboplatin chemotherapy. Results: Median follow-up was 88months. Ten-year relapse-free (RFS) and disease-specific survival (DSS) were: 81% (95% confidence interval [CI]: 73–89) and 81% (95% CI: 73–89). On multivariate analysis, non serous histology was associated with reduced risk for RFS (0.294, 95% CI: 0.112–0.577, p=0.001) and DSS (0.194, 95% CI: 0.075–0.504, p=0.001), while high-risk category (stage IC/IIA and grade 2/3) with increased risk for RFS (3.989, 95% CI: 1.189–13.389, p=0.009) and DSS (3.989, 95% CI: 1.064–16.386, p=0.038). The combination of histology and grade identified 3 groups with distinctly different 10-year RFS and DSS rates (p<0.001): grade 1 (100% and 100%), non-serous grade 2/3 (83% and 86%) and serous grade 2/3 (60% and 60%). Conclusions: Serous histology is an adverse prognostic factor in early-stage ovarian cancer treated with adjuvant paclitaxel/carboplatin. Risk stratification according to histology and grade is a useful discriminator of prognosis and can be used in the design of future studies. [Copyright &y& Elsevier]

TNF is critically involved in the pathogenesis of psoriasis. TL1A is a TNF-like cytokine, which, after binding to death domain receptor DR3, provides costimulatory signals to lymphocytes, amplifies Th1- and Th17-mediated immune responses and induces apoptotic cell death. These functions are inhibited when TL1A associates to decoy receptor DcR3. In the present study, we investigated the expression profiles for TL1A, DR3 and DcR3 in the normal skin and in psoriatic skin lesions. By use of immunohistochemistry, we were able to demonstrate constitutive cutaneous expression of DR3 and DcR3 but not of TL1A in healthy skin. On the other hand, in patients with active psoriasis, we observed abundant immunostaining for TL1A and significant upregulation of its receptors ( P < 0.05 in comparison to healthy skin). TL1A, DR3 and DcR3 proteins, as well as mRNA transcripts reflecting in situ production of TL1A and DcR3, were also specifically increased in lesional as compared to non-lesional skin from patients with psoriasis ( P < 0.05). These proteins were upregulated in cell populations that are critically involved in the pathogenesis of chronic skin inflammation, such as keratinocytes, macrophages in deep dermis and cells at the perivascular/endothelial area. Finally, we provide evidence for the existence of nuclear localization of TL1A in inflammatory cells from psoriatic lesions. This was also observed in inflamed synovia from patients with rheumatoid arthritis, but not in neoplastic TL1A-expressing cell lines. We conclude that interactions between TL1A and its two receptors may be involved in the pathogenesis of chronic skin inflammation that takes place in psoriasis. [ABSTRACT FROM AUTHOR]

Abstract: Aim: Hypertension (HT) complicates treatment with antiangiogenic agents, including the tyrosine kinase inhibitor (TKI) sunitinib. To prospectively evaluate the prevalence and management of HT in patients with advanced renal cell carcinoma (RCC) receiving sunitinib we used 24-h ABPM and we treated HT according to guidelines of the Joint National Committee on Prevention, Detection and Evaluation and the Treatment of High Blood Pressure (JNC7). Patients and methods: Normal 24-h ABPM at the baseline and at 2, 4 and 6weeks of the first cycle was ensured with the successive use of hydrochlorothiazide+irbesartan, nebivolol and amlodipine. Office BP measurements were used in subsequent cycles to monitor HT. Sunitinib dose was modified only if BP was not controlled with four anti-hypertensive agents. Results: Forty patients were included in this analysis. Twenty-one patients (53%) had baseline HT, while 12 of 14 (84%) normotensive patients required anti-HT treatment during the 1st cycle of sunitinib. HT was infrequent in subsequent cycles and increase of anti-HT medication was required in only 2 cases. Two patients permanently discontinued sunitinib due to HT. The remaining 34 (94%) required no dose modifications for HT. One cardiac event (2.8%) was observed. There was no correlation of HT with sunitinib efficacy. Conclusion: Sunitinib-associated HT is more frequent than previously reported. The use of 24-h ABPM for diagnosis and tailoring of HT according to JNC7 guidelines may achieve uninterrupted, full dose therapy in most patients. The substitution of such protocols for currently used Toxicity Criteria may be warranted. [Copyright &y& Elsevier]

Renal cancer comprises 2% of all cancer, with 210,000 new cases being reported every year worldwide, and in the last 20 years it has shown an increase of 30%. During the last 5 years, significant progress has been made in the therapeutic approach to advanced/metastatic renal cancer. The drugs involved in the treatment of advanced/metastatic renal cancer are classified according to their molecular action. The most significant categories are the tyrosine kinase inhibitors (sorafenib, sunitinib), cytokines (IF?-α, IL-2), mTOR inhibitors (temsirolimus, everolimus) and VEGF inhibitors (pazopanib, axitinib, bevacizumab). Sunitinib, prescribed as a first line treatment, has doubled the median progression free survival compared with IFN-α, and has decreased the risk of death or progression of the disease. Sorafenib has achieved longer overall improvement in both progression free survival and in symptom worsening compared with placebo. Bevacizumab, when co-administered with IF?-α, has doubled progression free survival and significantly increased the response of the tumor to treatment, compared with monotherapy with IF?-α. mTOR inhibitors are indicated in patients with poor prognosis and those resistant to the first line targeted therapeutic approach. Other drugs used in renal cancer have shown promising results without producing significant or prohibitive side effects, but comparative trials are needed in order to establish their superiority over the standard first line regimes. The side effects of all the drugs studied are not specific and are those commonly seen in clinical medicine. Physicians should be aware of the possible side effects, in order to attribute them to the drugs and not to an underlying disease. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: Stage I testicular nonseminomatous germ-cell tumors (NSGCT) are highly curable. Following orchidectomy surveillance, adjuvant chemotherapy and retroperitoneal lymph node dissection can be applied. Certain factors are used to select patients in high-risk for relapse. We report the outcome and safety of a risk-adapted strategy by the Hellenic Cooperative Oncology Group. Methods: Between 1994 and 2004, 142 patients with stage I NSGCT and 1 of the following risk factors: lymphovascular invasion (LVI), invasion of tunica vaginalis, spermatic cord, rete testis or scrotal wall, embryonal component >50% of the total tumor, were prospectively included in a protocol of adjuvant chemotherapy consisting of two 3-week courses of bleomycin 15 IU, etoposide 120 mg/m2, and cisplatin 40 mg/m2 for 3 consecutive days with G-CSF support. Results: Median follow-up was 79 months and 138 patients have been followed for at least 2 years. Seventy-seven patients (54%) had LVI and 74 (52%) had >50% embryonal component. There was 1 relapse, which was cured with chemotherapy and surgery. Another patient died due to disease-unrelated causes and 1 patient developed a new primary of the remaining testicle, which was cured with surgery. Conclusion: Two cycles of bleomycin/etoposide/cisplatin is an effective and safe form of adjuvant therapy in high-risk stage I NSGCT. [Copyright &y& Elsevier]

Immunosuppressive drugs are commonly used for the treatment of inflammatory bowel disease. Patients receiving immunosuppressants are susceptible to a variety of infections with opportunistic pathogens. We present a case of skin infection with Mycobacterium chelonae in a 60-year-old Caucasian woman with ulcerative colitis who had been treated with corticosteroids and azathioprine. The disease manifested with fever and rash involving the right leg. Infliximab was administered due to a presumptive diagnosis of pyoderma gangrenosum, leading to worsening of the clinical syndrome and admission to our hospital. Routine cultures from various sites were all negative. However, Ziehl-Neelsen staining of pus from the lesions revealed acid-fast bacilli, and culture yielded a rapidly growing mycobacterium further identified as M. chelonae. The patient responded to a clarithromycinbased regimen. Clinicians should be aware of skin lesions caused by atypical mycobacteria in immunocompromised patients with inflammatory bowel disease. Furthermore, they should be able to thoroughly investigate and promptly treat these conditions. [ABSTRACT FROM AUTHOR]

Abstract: Decoy receptor-3 (DcR3) is a member of the TNF receptor superfamily of proteins, which has been implicated in anti-apoptotic and anti-inflammatory pathways, via binding to TL1A, LIGHT and Fas-L. The role of the TL1A/DcR3 ligand/receptor pair in ulcerative colitis (UC) has not been studied. We investigated the systemic (peripheral blood) and local (large intestine) expression of DcR3 and TL1A in 64 patients with UC and 56 healthy controls. DcR3 serum concentrations were highly elevated in patients with active UC (P <0.0001 vs. healthy controls). This elevation was clearly related to the presence of intestinal inflammation as it was less frequently observed in patients in remission (P =0.003 vs. active UC) whereas effective treatment resulted in disappearance or significant decrease of serum DcR3 (P =0.006 vs. pre-treatment). Furthermore, DcR3 mRNA transcripts were significantly elevated in inflamed areas of the colon (P =0.002 vs. non-affected of the same patient). In addition to DcR3 elevation, we found increased circulating levels of TL1A in patients with either active or inactive UC in comparison to healthy controls (P <0.001 for both). We conclude that elevated serum DcR3 may serve as an indicator of active colonic inflammation in patients with UC. TL1A/DcR3-mediated pathways may participate in the pathogenesis of UC. [ABSTRACT FROM AUTHOR]

The optimal adjuvant treatment for gastric cancer remains controversial. We compared the efficacy of a docetaxel and platinum adjuvant chemotherapy regimen, in patients with high-risk gastric cancer, with that of the same chemotherapy plus radiation therapy (RT). In addition, we evaluated the prognostic and/or predictive value of a panel of molecular markers. Patients with histologically proven, radically resected gastric cancer, stage ≥T3 and/or N+ were randomized to 6 cycles of docetaxel with cisplatin, both at 75 mg/m2 every 3 weeks (arm A) or the same treatment with RT (arm B; 45 Gy). Due to excessive nausea and vomiting, cisplatin was substituted by carboplatin at AUC (area under the curve) of 5 after the first 45 patients (22 group A, 23 group B). The prognostic value of EGFR, ERCC1, HER2, MET/HGFR, MAP-Tau, and PTEN expression was also studied in a subset of 67 patients using immunohistochemistry on tissue microarrays (TMAs). A total of 147 patients were randomized. After a median follow-up of 53.7 months, no differences in overall (OS) and disease-free survival (DFS) were found between the two arms. The most common grade 3/4 toxicities for arms A and B (excluding alopecia) were non-febrile neutropenia (11 and 17%, respectively), febrile neutropenia (9 and 7%) and diarrhea (7 and 4%, respectively). Patients with ERCC1 positive tumors had significantly longer median DFS (33.1 vs. 11.8 months, Wald P = 0.016) and OS (63.2 vs. 18.8 months, Wald P = 0.046). Our results indicate that the addition of RT to platinum/docetaxel adjuvant chemotherapy does not appear to improve survival in high-risk, radically resected gastric cancer. However, the possibility that a benefit by the addition of RT was not detected due to decreased power of the study should not be excluded. [ABSTRACT FROM AUTHOR]

The article reports on the study which examined the link of mucinous and clear cell histology to adverse prognosis in ovarian carcinomas. It notes that subject patients with advanced stage carcinoma were treated with combined Paclitaxel-Platinum chemotherapy. It implies that mucinous but not clear histology was linked to the significant worse prognosis in patients with advanced ovarian cancer.

Background: The treatment paradigm in advanced renal cell carcinoma (RCC) has changed in the recent years. Sunitinib has been established as a new standard for first-line therapy. We studied the prognostic significance of baseline characteristics and we compared the risk stratification with the established Memorial Sloan Kettering Cancer Center (MSKCC) model. Methods: This is a retrospective analysis of patients treated in six Greek Oncology Units of HECOG. Inclusion criteria were: advanced renal cell carcinoma not amenable to surgery and treatment with Sunitinib. Previous cytokine therapy but no targeted agents were allowed. Overall survival (OS) was the major end point. Significance of prognostic factors was evaluated with multivariate cox regression analysis. A model was developed to stratify patients according to risk. Results: One hundred and nine patients were included. Median follow up has been 15.8 months and median OS 17.1 months (95% CI: 13.7-20.6). Time from diagnosis to the start of Sunitinib (≤ 12 months vs. >12 months, p = 0.001), number of metastatic sites (1 vs. >1, p = 0.003) and performance status (PS) (≤ 1 vs >1, p = 0.001) were independently associated with OS. Stratification in two risk groups ("low" risk: 0 or 1 risk factors; "high" risk: 2 or 3 risk factors) resulted in distinctly different OS (median not reached [NR] vs. 10.8 [95% confidence interval (CI): 8.3- 13.3], p < 0.001). The application of the MSKCC risk criteria resulted in stratification into 3 groups (low and intermediate and poor risk) with distinctly different prognosis underlying its validity. Nevertheless, MSKCC model did not show an improved prognostic performance over the model developed by this analysis. Conclusions: Studies on risk stratification of patients with advanced RCC treated with targeted therapies are warranted. Our results suggest that a simpler than the MSKCC model can be developed. Such models should be further validated. [ABSTRACT FROM AUTHOR]

We evaluated an intensified therapeutic strategy in order to optimize treatment outcomes while maintaining acceptable toxicity in patients with advanced seminoma. Fifty-two patients with advanced pure seminoma were retrospectively evaluated. Patients with low-risk advanced seminoma, according to the International Germ Cell Cancer Collaborative Group Consensus Classification criteria, had received four cycles of the BEP regimen either in the 5-day or the alternative 3-day schedule, while patients with intermediate-risk advanced seminoma had received four cycles of the IBEP regimen. Forty-two patients (80.7%) had testicular seminoma while ten patients (19.3%) presented with primary extragonadal (mediastinal or retroperitoneal) tumor. Forty-seven (90.8%) patients belonged to the low-risk group and five patients (9.2%) to the intermediate-risk group. Treatment-related toxicity was moderate, with febrile neutropenia being the most prevalent (13.5%). Twenty patients (38.5%) achieved a complete response to chemotherapy. Twenty-three from the remaining 32 patients had residual masses more than 3 cm and were submitted to surgery (2 patients), FDG-PET scan (8 patients) or surveillance (13 patients). After 69 months of follow-up there were three recurrences that were successfully treated with high-dose or salvage chemotherapy. No death by any cause was recorded. Intensified cisplatin-based chemotherapy for patients with advanced seminoma does not confer evidence of superiority over radiotherapy alone or the standard BEP regimen. Patients with low-volume abdominal disease (clinical stage IIA and IIB) can be cured by four cycles of BEP instead of radiotherapy at the cost of a substantial increase in chemotherapy exposure and the resulting toxicity. [ABSTRACT FROM AUTHOR]

Abstract: TL1A is a novel TNF-like cytokine, which provides co-stimulatory and Th1-polarizing signals to activated lymphocytes, via binding to death-domain receptor 3 (DR3). These functions are inhibited when TL1A associates to decoy receptor 3 (DcR3). We investigated the serum expression of TL1A and DcR3 in 81 patients with RA and 51 healthy controls. TL1A concentrations were elevated in patients by 5-fold (P <0.00001). This increase was more prominent in RFactor-positive patients and correlated with clinical activity in this subgroup. DcR3 was detected more frequently and in significantly higher values in RA-derived sera, correlated strongly with TL1A, and was present in inflammatory synovial fluid. Severe RA stage was associated with highly elevated TL1A and DcR3 serum levels. Treatment with an anti-TNF agent significantly decreased TL1A serum levels. We conclude that TL1A may serve as an inflammatory marker in RA. Interactions between TL1A and its receptors may be important in the pathogenesis of RA. [Copyright &y& Elsevier]

Abstract: The primary objective was to compare the 3-year survival of rectal cancer patients randomised postoperatively to irinotecan (IRI), Leucovorin (LV) and bolus 5-fluorouracil (5FU) or LV-bolus 5FU with radiotherapy. Secondary objectives included disease-free survival, local relapse and toxicity. The study included 321 eligible patients. The treatment consisted of weekly administration of IRI 80mg/m2 intravenously (IV), LV 200mg/m2 and 5FU 450mg/m2 bolus (arm A) versus LV 200mg/m2 and 5FU 450mg/m2 IV bolus (arm B). One cycle included four infusions and treatment was continued for a total of six cycles. The first cycle was followed by pelvic irradiation plus 5FU. There were no differences between the arms in 3-year overall, disease-free and local relapse-free survival. Grades 3 and 4 toxicity was similar in both the arms with the exception of leucopaenia, neutropaenia and alopecia, which were higher in the IRI arm. IRI added to adjuvant radiochemotherapy with LV and bolus 5FU was not shown to improve survival, whereas the incidence of severe leucopaenia was significantly higher in the IRI arm. [Copyright &y& Elsevier]

Abstract: Objectives: To investigate potential prognostic and predictive factors in patients with androgen-independent prostate cancer (AIPC) treated with docetaxel chemotherapy. Methods: This analysis included 94 consecutive AIPC patients who were treated between March 2001 and May 2006 with biweekly docetaxel 45mg/m2 (day 2) and estramustine 140mg three dimes daily (days 1–3). Results: Prostate-specific antigen (PSA) responses were observed in 45 of 84 evaluable patients (53%), whereas objective responses were observed in 16 of 40 patients with measurable disease (40%). Median survival (OS) was 16.2 mo (95% confidence interval [CI], 12.9–19.4) and median time to PSA progression (TTP) 5.0 mo (95%CI, 3.6–7.1). OS was independently associated with pain score baseline PSA and weight loss. Patients with only extraosseous disease had higher PSA response rate (87% vs. 49%, p =0.014) and superior TTP compared with patients with bone metastases with or without extraosseous disease (7.3 vs. 4.3 vs. 4 mo, p =0.002). Concurrent bone and extraosseous metastases were associated with worse prognosis compared with each site alone (median OS: 12.3 vs.19 vs.18.3 mo, p =0.007). Conclusions: Among patients with AIPC treated with biweekly docetaxel and estramustine, baseline PSA >100, existence of pain, weight loss, and simultaneous extraosseous and bone disease were associated with worse prognosis. Extraosseous metastases seem to be more sensitive than bone disease to this chemotherapy. [Copyright &y& Elsevier]

Abstract: Background: Several cytokines have been associated with immune regulation and prognosis in ovarian cancer. CD4+CD25+ Tregs and CD3+CD56+ NK-like T cells are involved in the immune response against the tumor. We have investigated the association of cytokines in the ascites from patients with ovarian cancer with these populations, the platinum resistance and the prognosis of these patients. Patients and methods: Ascites from 64 patients with ovarian cancer was analysed. Forty-two patients were studied at diagnosis (FIGO stage III in 40 cases) and were treated with cytoreductive surgery and platinum-based chemotherapy. Ascites from 9 patients with cirrhosis was used as control. Vascular endothelial growth factor (VEGF), tumor necrosis factor-α (TNFα), interferon-gamma (IFNγ), inteleukin-10 (IL10) and interleukin-12 (IL12) in ascites and serum were measured by enzyme-linked immunosorbent assay (ELISA), while lymphocytic populations were studied with three-colour flow cytometry. Results: VEGF ascites levels were inversely correlated with CD3+CD56+ cells (rho=−0.316, p =0.012), while a similar correlation was observed between TNFα ascites levels and CD4+CD25+(hi) cells (rho=−0.332, p =0.041). Among patients receiving first-line chemotherapy, VEGF levels <1900 pg/ml and TNFα levels >35 pg/ml were associated with platinum sensitivity (p =0.021 and p =0.028, respectively) and improved progression-free survival (PFS) (p =0.007 and p =0.045, respectively). Low VEGF levels were also associated with improved overall survival (p =0.026). Conclusion: VEGF and TNFα ascites levels are associated with prognosis in advanced ovarian cancer. Their prognostic significance may be due to their association with immunologically important populations, namely the NK T-like CD3+CD56+ cells and the Tregs CD4+CD25+(hi) cells. [Copyright &y& Elsevier]

Abstract: Objective. : Taxane-based chemotherapy has been recently introduced as an effective therapeutic option in recurrent or metastatic endometrial carcinoma (RMEC). The aim of the study was to determine the prognostic factors in RMEC after taxane-based chemotherapy. Methods. : One hundred ten patients who received paclitaxel-containing regimen for RMEC were retrospectively evaluated. Potential prognostic factors for overall survival were identified with the Kaplan–Meier method in univariate and the Cox regression model in multivariate analysis. Results. : Performance status (PS) and relapse within the field of previous external radiation were independent prognostic factors for overall survival (p =0.007 and p =0.026 respectively). Non-endometriod histology was associated with a shorter median survival compared to endometriod adenocarcinoma (14.46 vs. 17.57 months, p =0.093), but histology was not an independent prognostic factor (HR=1.43, 95% CI: 0.82–2.48, p =0.21). Stratification according to PS and relapse within the irradiation field identified three risk groups with distinctly different prognosis (median survival 27.36, 16.71, and 11.33 months for the group of favorable, intermediate, and unfavorable prognosis respectively, p <0.001). Within the favorable prognosis group, 34% of patients had a probability of 5-year survival. Conclusion. : PS at diagnosis and relapse within the irradiated area may constitute a valid prognostic model in RMEC patients who receive taxane-based chemotherapy and are able to identify long-term survivors. [Copyright &y& Elsevier]

Objectives: Adjuvant carboplatin is used as adjuvant therapy in Stage I testicular seminoma. Although cure is the rule, relapses still occur, especially in high-risk populations. We report the results of a risk-adapted strategy by the Hellenic Cooperative Oncology Group. Methods: From 1996 to 2003, 64 patients with Stage I seminoma and one of two risk factors (maximal tumor diameter greater than 4 cm and/or age younger than 34 years) were prospectively included in a protocol of adjuvant chemotherapy. Treatment consisted of two 3-week courses of etoposide 120 mg/m2 and cisplatin 40 mg/m2 for three consecutive days with granulocyte colony-stimulating factor support. Results: Of the 64 patients, 43 (67%) were younger than 34 years and 55 (86%) had a tumor diameter greater than 4 cm. Neutropenia and nausea and vomiting were the most frequent grade 3 or 4 toxicities (16.5% and 9.5%, respectively), apart from alopecia. After a median follow-up of 60 months (range 7 to 118), no disease relapses have occurred. A metachronous testicular carcinoma has been reported. One patient died of causes unrelated to his disease. Conclusions: The results of our study have shown that two cycles of etoposide and cisplatin is an effective and safe form of adjuvant therapy for Stage I testicular seminoma. Risk factors can be used to identify patients who could benefit from etoposide and cisplatin treatment. [Copyright &y& Elsevier]