HAROW: the first comprehensive prospective observational study comparing treatment options in localized prostate cancer

Purpose

To collect data on primary treatment decision and follow-up in patients with diagnosed, histologically confirmed localized (T1a–T2c/N0/M0) prostate cancer (PCa) for up to 5 years in a prospective observational non-interventional study.

Methods

Patients were non-randomly allocated to one of the five treatment strategies: hormone therapy, active surveillance, radiation, operation, or watchful waiting.

Results

A total of 3169 patients were included by 259 participating sites; 2957 patients had at least one follow-up visit. 54.8 % of tumors at baseline were staged as T1c, 38 % as T2a–T2c, and 7.1 % as T1a or T1b (missing: 0.2 %). 38.9, 32.6 and 26.6 % of patients were classified as low risk, intermediate risk, and high risk according to d’Amico, respectively (missing: 1.8 %). 56.6 % of patients underwent prostatectomy as primary therapy, 16.4 % received radiation, 6.9 % HT, 15.8 and 4.3 % decided for AS or WW. Mean follow-up was 28.4 months. Progression rates were between 8.6 % (RT) and 33.1 % (AS).

Conclusion

Whereas RP remains the main treatment option of localized PCa, active surveillance appears to become an accepted and selectively employed treatment option. Careful selection of patients is documented by the highest proportion of patients with low risk (82.5 %), PSA density <0.2 ng/ml/ml (77.5 %), T1 staging (83.6 %), Gleason score ≤6 (92.5 %), ≤2 positive biopsies (79.4 %), and lowest mean PSA (5.8 ng/ml) in the AS group. The relatively high progression rate in the AS group has to be considered in the context of treatment changes; 71/155 patients had a documented change of treatment and 62 of them with a follow-up period of >3 months.

     

Evaluation of stair motion contributes to new insights into hip osteoarthritis‐related motion pathomechanics

Stair motion in the presence of hip osteoarthritis (OA) has received less attention than level walking. Its more strenuous aspect may shed the light on different locomotor strategies when compared to walking. We, therefore, aimed to define stair motion features associated to hip OA and to evaluate whether these specific features would differ from level walking and better characterize the hip pathological condition. Principal component and linear discriminant analyses were, respectively, used as data reduction and classification techniques. Our study highlighted that most of stair motion features associated to hip OA were similar to the ones of walking. Stair descent presented with the lowest misclassification error rate, ranging from 12% to 19% (estimated by cross‐validation). But, features that may be considered as a mechanism to reduce demand on the hip abductors were found to be more important in the stair ascent condition. This was reflected by both, greater importance in the classification rule and variance compared with walking, that is, decreased hip internal rotation moment at mid‐stance (72.50% vs. 57.63%) and increased trunk lateroflexion toward affected side (56.43% vs. 29.37%). This study emphasized the importance of investigating stair motion in hip osteoarthritic population by highlighting specific locomotor strategies. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:187–196, 2016.     

Impact of Mucinous Histology on the Prognosis of Stage I–III Adenocarcinomas of the Appendix: a Population-Based,Propensity Score-Matched Analysis

Background

Whereas the poor prognosis of signet ring cell adenocarcinomas of the appendix is well known, the significance of mucinous histology remains unclear. The aim of this population-based study was to evaluate if mucinous histology is an independent prognostic factor in appendiceal adenocarcinomas.

Methods

Patients with stage I–III adenocarcinoma of the appendix who underwent surgery between 2004 and 2012 were identified in the Surveillance, Epidemiology, and End Results database. Overall survival (OS) and cancer-specific survival (CSS) were assessed using risk-adjusted Cox proportional hazards regression models and propensity score methods.

Results

Overall, 980 patients with appendix cancer were included, of which 449 (45.8 %) had a mucinous histology. In an unadjusted analysis, the 5-year OS and CSS in patients with a mucinous adenocarcinoma (MC) was 76.8 % (95 % confidence interval (95 %CI): 72.1–81.7 %) and 81.0 % (95 %CI: 76.6–85.6 %), respectively, compared with 70.0 % (95 %CI: 65.1–75.3 %) and 76.2 % (95 %CI: 71.5–81.2 %) in patients with non-mucinous adenocarcinoma (NMC) (P?=?0.082 and P?=?0.368). In multivariable analysis, no impact on survival was observed for OS (HR?=?1.22, 95 %CI: 0.89–1.68, P?=?0.208) and CSS (HR?=?1.21, 95 %CI: 0.84–1.74, P?=?0.296). After propensity score matching, nearly identical survival rates were observed (OS: HR?=?1.03, 95 %CI: 0.71–1.49, P?=?0.881 and CSS: HR?=?1.05, 95 %CI: 0.70–1.59, P?=?0.803).

Conclusions

The present population-based, propensity score matched analysis shows that mucinous histology does not affect survival in stage I–III appendiceal adenocarcinoma patients. Therefore, the same treatment strategies can be applied for patients with NMC and MC of the appendix.

     

Oxidatively damaged DNA in aging dyslipidemic ApoE-/- and wild-type mice

The free radical theory of aging depicts an accumulation of cellular oxidatively damaged DNA. In this study, we investigated this theory in mice with knocked-out apolipoprotein E gene (ApoE(-/-)), which develops atherosclerosis and wild-type counterparts. The level of oxidatively damaged DNA was investigated as strand breaks, endonuclease III- and formamidopyrimidine DNA glycosylase-sensitive sites by the comet assay. The level of DNA damage was mainly increased with age in the liver of ApoE(-/-) mice, whereas no increase was observed in the aorta or lung of the mice. This suggests that the accumulation of oxidized DNA in the liver of dyslipidemic ApoE(-/-) mice could be secondary to dysfunction of the lipid metabolism. Visually, the aortas of the ApoE(-/-) mice were clearly atherosclerotic as indicated by rigid texture and yellowish in color. However, the unaltered levels of oxidized DNA in severely atherosclerotic aortas of old ( approximately 70 weeks) ApoE(-/-) mice indicate that oxidative stress may not be a generalized phenomenon, but rather related locally to the individual plaques. In conclusion, the results of this study suggest that dyslipidemic ApoE(-/-) mice suffer from hepatic oxidative stress in terms of oxidized DNA, and this effect could be due to the dysfunction of lipid metabolism.     

Nanoparticulate vaccine inhibits tumor growth via improved T cell recruitment into melanoma and huHER2 breast cancer

Nanoparticulate vaccines are promising tools to overcome cancer immune evasion. However, a deeper understanding on nanoparticle–immune cell interactions and treatments regime is required for optimal efficacy. We provide a comprehensive study of treatment schedules and mode of antigen-association to nanovaccines on the modulation of T cell immunity in vivo, under steady-state and tumor-bearing mice. The coordinated delivery of antigen and two adjuvants (Monophosphoryl lipid A, oligodeoxynucleotide cytosine-phosphate-guanine motifs (CpG)) by nanoparticles was crucial for dendritic cell activation. A single vaccination dictated a 3-fold increase on cytotoxic memory-T cells and raised antigen-specific immune responses against B16.M05 melanoma. It generated at least a 5-fold increase on IFN-γ cytokine production, and presented over 50% higher lymphocyte count in the tumor microenvironment, compared to the control. The number of lymphocytes at the tumor site doubled with triple immunization. This lymphocyte infiltration pattern was confirmed in mammary huHER2 carcinoma, with significant tumor reduction.     

Monocytes give rise to mucosal, but not splenic, conventional dendritic cells

The mononuclear phagocyte (MP) system is a body-wide macrophage (MPhi) and dendritic cell (DC) network, which contributes to tissue homeostasis, inflammation, and immune defense. The in vivo origins of MPs remain poorly understood. Here, we use an adoptive precursor cell transfer strategy into MP-depleted mice to establish the in vivo differentiation sequence from a recently identified MPhi/DC-restricted bone marrow (BM) precursor (MDP) via BM and blood intermediates to peripheral MPhis and DCs. We show that MDPs are in vivo precursors of BM and blood monocytes. Interestingly, grafted Gr1high "inflammatory" blood monocytes shuttle back to the BM in the absence of inflammation, convert into Gr1low monocytes, and contribute further to MP generation. The grafted monocytes give rise to DCs in the intestinal lamina propria and lung, but not to conventional CD11chigh DCs in the spleen, which develop during homeostasis from MDPs without a monocytic intermediate.