Bladder‐sparing, combined‐modality approach for muscle‐invasive bladder cancer

AbstractBACKGROUND.The authors evaluated their long‐term experience with combined‐modality, conservative treatment in patients with muscle‐invasive bladder cancer.METHODS.In total, 121 patients with T2, T3, or T4 bladder cancer (mean age, 63 years; ratio of men to women, 3:1) underwent induction by transurethral resection (TUR) of the tumor and received 2 cycles of neoadjuvant chemotherapy followed by radiotherapy (RT) (n = 43 patients) or radiochemotherapy (RCT) (n = 78 patients). Six weeks after RT or RCT, responses were evaluated by restaging TUR. Patients who achieved a complete response (CR) were observed at regular intervals. In patients who had persistent or recurrent invasive tumor, further treatment was recommended.RESULTS.Local response evaluation by restaging TUR was possible in 119 patients, and 102 of those patients (85.7%) achieved a CR. After a median follow‐up of 66 months (range, 6–182 months), no local or distant disease recurrences were observed in 67 of 102 complete responders (65.7%), 17 of 102 complete responders (16.7%) experienced superficial local disease recurrence, and 18 of 102 complete responders (17.6%) had a muscle‐invasive relapse. The 5‐year tumor‐specific, overall, and bladder‐intact survival rates were 73.5%, 67.7%, and 51.2%, respectively. Treatment modality, tumor classification, and resection status after initial TUR had an impact on survival rates (P = .04, P = .02, and P = .02, respectively).CONCLUSIONS.The current results indicated that conservative combined treatment is a reasonable alternative to radical cystectomy in selected patients with muscle‐invasive bladder cancer. Cancer 2008. © 2007 American Cancer Society

REducing INFectiOns thRough Cardiac device Envelope: insight from real world data. The REINFORCE Project

Background: Infections resulting from cardiac implantable electronic device (CIED) implantation are severely impacting on patients' and on health care systems. The use of TYRXTM absorbable antibiotic-eluting envelope has proven to decrease major CIED infections within 12 months of CIED surgery. Aims: to evaluate the impact of the envelope use on infection-related clinical events in a real-world contemporary patient population. Methods: Data on patients undergoing CIED surgery were collected prospectively by participating centers of the One Hospital ClinicalService project. Patients were divided into two groups according to whether TYRXTM absorbable antibiotic-eluting envelope was used or not. Results: Out of 1819 patients, 872 (47.9%) were implanted with an absorbable antibiotic-eluting envelope and included in the Envelope group and 947 (52.1%) patients who did not receive an envelope were included in the Control group. Compared to control, patients in the Envelope group had higher thrombo-embolic or hemorrhagic risk, higher BMI, lower LVEF and more comorbidities. During a mean follow-up of 1.4 years, the incidence of infection-related events was significantly higher in the control compared to the Envelope group (2.4% vs 0.8%, p = 0.007). The 5-year cumulative incidence of infection-related events was 8.1% in the control and 2.1% in the Envelope group (HR: 0.34, 95%CI: 0.14-0.80, p = 0.010). Conclusions: In our analysis, the use of an absorbable antibiotic-eluting envelope in the general CIED population was associated with a lower risk of systemic and pocket infection

Phase 1/2 study of valproic acid and short-course radiotherapy plus capecitabine as preoperative treatment in low-moderate risk rectal cancer-V-shoRT-R3 (Valproic acid--short Radiotherapy--rectum 3rd trial).

BACKGROUND: Locally advanced rectal cancer (LARC) is a heterogeneous group of tumors where a risk-adapted therapeutic strategy is needed. Short-course radiotherapy (SCRT) is a more convenient option for LARC patients than preoperative long-course RT plus capecitabine. Histone-deacetylase inhibitors (HDACi) have shown activity in combination with RT and chemotherapy in the treatment of solid tumors. Valproic acid (VPA) is an anti-epileptic drug with HDACi and anticancer activity. In preclinical studies, our group showed that the addition of HDACi, including VPA, to capecitabine produces synergistic antitumour effects by up-regulating thymidine phosphorylase (TP), the key enzyme converting capecitabine to 5-FU, and by downregulating thymidylate synthase (TS), the 5-FU target. METHODS/DESIGN: Two parallel phase-1 studies will assess the safety of preoperative SCRT (5 fractions each of 5 Gy, on days 1 to 5) combined with (a) capecitabine alone (increasing dose levels: 500-825 mg/m2/bid), on days 1-21, or (b) capecitabine as above plus VPA (oral daily day -14 to 21, with an intra-patient titration for a target serum level of 50-100 microg/ml) followed by surgery 8 weeks after the end of SCRT, in low-moderate risk RC patients. Also, a randomized phase-2 study will be performed to explore whether the addition of VPA and/or capecitabine to preoperative SCRT might increase pathologic complete tumor regression (TRG1) rate. A sample size of 86 patients (21-22/arm) was calculated under the hypothesis that the addition of capecitabine or VPA to SCRT can improve the TRG1 rate from 5% to 20%, with one-sided alpha = 0.10 and 80% power.Several biomarkers will be evaluated comparing normal mucosa with tumor (TP, TS, VEGF, RAD51, XRCC1, Histones/proteins acetylation, HDAC isoforms) and on blood samples (polymorphisms of DPD, TS, XRCC1, GSTP1, RAD51 and XRCC3, circulating endothelial and progenitors cells; PBMCs-Histones/proteins acetylation). Tumor metabolism will be measured by 18FDG-PET at baseline and 15 days after the beginning of SCRT. DISCUSSION: This project aims to improve the efficacy of preoperative treatment of LARC and to decrease the inconvenience and the cost of standard long-course RT. Correlative studies could identify both prognostic and predictive biomarkers and could add new insight in the mechanism of interaction between VPA, capecitabine and RT.EudraCT Number: 2012-002831-28. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT01898104

18F-FDG PET/CT Is an Early Predictor of Pathologic Tumor Response and Survival to Preoperative Radiochemotherapy with Bevacizumab in High Risk Locally Advanced Rectal Cancer.

There is an unmet need for predictive biomarkers of the clinical benefit of anti-angiogenic drugs.The aim of the present study was to prospectively evaluate the value of FDG-PET/CT performed during and after preoperative radiochemotherapy (CRT) with bevacizumab for the prediction of complete pathologic tumor regression and survival in magnetic resonance imaging (MRI)-defined high-risk locally advanced rectal cancer (LARC) patients Methods: Sixty-one patients treated in a non-randomized phase II study (BRANCH) with concomitant or sequential (4 days before CRT) administration of bevacizumab with preoperative CRT were included. 18F-FDG PET/CT was performed at baseline, 11 days after the beginning of the CRT (early) and before surgery (late). Metabolic changes were compared with pathological complete (TRG1) vs incomplete (TRG2-5) tumor regression, progression-free survival (PFS), cancer specific survival (CSS) and overall survival (OS). Receiver operating characteristic (ROC) curves were calculated for those FDG-PET/CT parameters that significantly correlated with TRG1. Results: Early total lesion glycolysis (TLG-early) and its percent change compared to baseline (ΔTLG-early %) could discriminate TRG1 from TRG2-5. Only ROC analysis of ΔTLG-early % showed an AUC > 0.7 (0.76), with an optimal cutoff at 59.5% (80% sensitivity, 71.4 specificity) for identifying TRG1. Late metabolic assessment could not discriminate between the two groups. After a median follow-up of 98 months (range 77-132) metabolic responders (ΔTLG-early % ≥ 59.5 %) demonstrated a significantly higher 10-year PFS (89.3 vs 63.6 %, P = 0.02) and CSS (92.9 vs 72.6 %, P = 0.04) compared to incomplete metabolic responders . Conclusion: Our results suggest that early metabolic response can act as a surrogate marker of the benefit of antiangiogenic therapy and provide further support for the use of early -FDG-PET/CT evaluation to predict pathological response and survival in the preoperative treatment of patients with LARC. ΔTLG-early% showed the best accuracy in predicting TRG and may be particularly useful in guiding treatment modifying decisions during preoperative CRT based on expected response

Convergent Sets of Data from In Vivo and In Vitro Methods Point to an Active Role of Hsp60 in Chronic Obstructive Pulmonary Disease Pathogenesis

BACKGROUND: It is increasingly clear that some heat shock proteins (Hsps) play a role in inflammation. Here, we report results showing participation of Hsp60 in the pathogenesis of chronic obstructive pulmonary diseases (COPD), as indicated by data from both in vivo and in vitro analyses. METHODS AND RESULTS: Bronchial biopsies from patients with stable COPD, smoker controls with normal lung function, and non-smoker controls were studied. We quantified by immunohistochemistry levels of Hsp10, Hsp27, Hsp40, Hsp60, Hsp70, Hsp90, and HSF-1, along with levels of inflammatory markers. Hsp10, Hsp40, and Hsp60 were increased during progression of disease. We found also a positive correlation between the number of neutrophils and Hsp60 levels. Double-immunostaining showed that Hsp60-positive neutrophils were significantly increased in COPD patients. We then investigated in vitro the effect on Hsp60 expression in bronchial epithelial cells (16HBE) caused by oxidative stress, a hallmark of COPD mucosa, which we induced with H\u2082O\u2082. This stressor determined increased levels of Hsp60 through a gene up-regulation mechanism involving NFkB-p65. Release of Hsp60 in the extracellular medium by the bronchial epithelial cells was also increased after H\u2082O\u2082 treatment in the absence of cell death. CONCLUSIONS: This is the first report clearly pointing to participation of Hsps, particularly Hsp60, in COPD pathogenesis. Hsp60 induction by NFkB-p65 and its release by epithelial cells after oxidative stress can have a role in maintaining inflammation, e.g., by stimulating neutrophils activity. The data open new scenarios that might help in designing efficacious anti-inflammatory therapies centered on Hsp60 and applicable to COP

Outcomes of pregnancies after kidney transplantation: lessons learned from CKD. A comparison of transplanted, nontransplanted chronic kidney disease patients and low-risk pregnancies: a multicenter nationwide analysis.

BACKGROUND: Kidney transplantation (KT) may restore fertility in CKD. The reasons why materno-foetal outcomes are still inferior to the overall population are only partially known. Comparison with the CKD population may offer some useful insights for management and counselling.Aim of this study was to analyse the outcomes of pregnancy after KT, compared with a large population of non-transplanted CKD patients and with low-risk control pregnancies, observed in Italy the new millennium. METHODS: We selected 121 live-born singletons after KT (Italian study group of kidney in pregnancy, national coverage about 75%), 610 live-born singletons in CKD and 1418 low-risk controls recruited in 2 large Italian Units, in the same period (2000-2014). The following outcomes were considered: maternal and foetal death; malformations; preterm delivery; small for gestational age baby (SGA); need for the neonatal intensive care unit (NICU); doubling of serum creatinine or increase in CKD stage. Data were analysed according to kidney diseases, renal function (staging according to CKD-EPI), hypertension, maternal age, partity, ethnicity. RESULTS: Materno-foetal outcomes are less favourable in CKD and KT as compared with the low-risk population. CKD stage and hypertension are important determinants of results. KT patients with e-GFR >90 have worse outcomes compared with CKD stage 1 patients; the differences level off when only CKD patients affected by glomerulonephritis or systemic diseases ('progressive CKD') are compared with KT. In the multivariate analysis, risk for preterm and early-preterm delivery was linked to CKD stage (2-5 versus 1: RR 3.42 and 3.78) and hypertension (RR 3.68 and 3.16) while no difference was associated with being a KT or a CKD patient. CONCLUSIONS: The materno-foetal outcomes in patients with kidney transplantation are comparable with those of nontransplanted CKD patients with similar levels of kidney function impairment and progressive and/or immunologic kidney diseas