mstate: An R Package for the Analysis of Competing Risks and Multi-State Models

Multi-state models are a very useful tool to answer a wide range of questions in survival analysis that cannot, or only in a more complicated way, be answered by classical models. They are suitable for both biomedical and other applications in which time-to-event variables are analyzed. However, they are still not frequently applied. So far, an important reason for this has been the lack of available software. To overcome this problem, we have developed the mstate package in R for the analysis of multi-state models. The package covers all steps of the analysis of multi-state models, from model building and data preparation to estimation and graphical representation of the results. It can be applied to non- and semi-parametric (Cox) models. The package is also suitable for competing risks models, as they are a special category of multi-state models. This article offers guidelines for the actual use of the software by means of an elaborate multi-state analysis of data describing post-transplant events of patients with blood cancer. The data have been provided by the EBMT (the European Group for Blood and Marrow Transplantation). Special attention will be paid to the modeling of different covariate effects (the same for all transitions or transition-specific) and different baseline hazard assumptions (different for all transitions or equal for some).

Flexible (Polyactive®) versus rigid (hydroxyapatite) dental implants

In a beagle dog study, the peri-implant bone changes around flexible (Polyactive®) and rigid hydroxyapatite (HA) implants were investigated radiographically by quantitative digital subtraction analysis and by assessment of marginal bone height, with the aid of a computerized method. A loss of approximately 1 mm of marginal bone height was observed for both the dense Polyactive and the HA implants, after 6 months of loading. This value appeared to be stable from 12 weeks of loading onward. Along the total length of the implant during the first 6 weeks of loading, both the flexible (dense Polyactive) and the rigid (HA) implants showed a decrease in density. However, after this 6-week period, the bone density around the implants increased, and after 18 weeks the original bone density was reached. The flexible Polyactive implants provoked less decrease in density than the rigid HA implants, although not to a statistically significant level. This finding sustains the hypothesis that flexible implant materials may transfer stresses to the surrounding bone more favorably

Corrigendum to “Authors’ reply—Does the RAPIDO trial suggest a benefit of post-operative chemotherapy after preoperative chemoradiation in rectal cancer? No, it does not”: [ESMO Open 8 (2023) 101645]

The authors regret that in the original publication reference 1 was given in correctly. The correct reference is as follows: 1. J. Socha, W. Michalski, K. Bujko, Does the RAPIDO trial suggest a benefit of post-operative chemotherapy after preoperative chemoradiation in rectal cancer? No, it does not., ESMO Open, Volume 8, Issue 5, 2023, 101644, https://doi.org/10.1016/j.esmoop.2023.101644The authors would like to apologise for any inconvenience caused.</p

The impact of loco-regional recurrences on metastatic progression in early-stage breast cancer: a multistate model

To study whether the effects of prognostic factors associated with the occurrence of distant metastases (DM) at primary diagnosis change after the incidence of loco-regional recurrences (LRR) among women treated for invasive stage I or II breast cancer. The study population consisted of 3,601 women, enrolled in EORTC trials 10801, 10854, or 10902 treated for early-stage breast cancer. Data were analysed in a multivariate, multistate model by using multivariate Cox regression models, including a state-dependent covariate. The presence of a LRR in itself is a significant prognostic risk factor (HR: 3.64; 95%-CI: 2.02-6.5) for the occurrence of DM. Main prognostic risk factors for a DM are young age at diagnosis (</=40: HR: 1.79; 95%-CI: 1.28-2.51), larger tumour size (HR: 1.58; 95%-CI: 1.35-1.84) and node positivity (HR: 2.00; 95%-CI: 1.74-2.30). Adjuvant chemotherapy is protective for a DM (HR: 0.66; 95%-CI: 0.55-0.80). After the occurrence of a LRR the latter protective effect has disappeared (P = 0.009). The presence of LRR in itself is a significant risk factor for DM. For patients who are at risk of developing LRR, effective local control should be the main target of therapy

Testing Inflation with Large Scale Structure: Connecting Hopes with Reality

The statistics of primordial curvature fluctuations are our window into the period of inflation, where these fluctuations were generated. To date, the cosmic microwave background has been the dominant source of information about these perturbations. Large scale structure is however from where drastic improvements should originate. In this paper, we explain the theoretical motivations for pursuing such measurements and the challenges that lie ahead. In particular, we discuss and identify theoretical targets regarding the measurement of primordial non-Gaussianity. We argue that when quantified in terms of the local (equilateral) template amplitude $f_{\rm NL}^{\rm loc}$ ($f_{\rm NL}^{\rm eq}$), natural target levels of sensitivity are $\Delta f_{\rm NL}^{\rm loc, eq.} \simeq 1$. We highlight that such levels are within reach of future surveys by measuring 2-, 3- and 4-point statistics of the galaxy spatial distribution. This paper summarizes a workshop held at CITA (University of Toronto) on October 23-24, 2014.Comment: 27 pages + reference

Reducing Zero-point Systematics in Dark Energy Supernova Experiments

We study the effect of filter zero-point uncertainties on future supernova dark energy missions. Fitting for calibration parameters using simultaneous analysis of all Type Ia supernova standard candles achieves a significant improvement over more traditional fit methods. This conclusion is robust under diverse experimental configurations (number of observed supernovae, maximum survey redshift, inclusion of additional systematics). This approach to supernova fitting considerably eases otherwise stringent mission calibration requirements. As an example we simulate a space-based mission based on the proposed JDEM satellite; however the method and conclusions are general and valid for any future supernova dark energy mission, ground or space-based.Comment: 30 pages,8 figures, 5 table, one reference added, submitted to Astroparticle Physic

Frequency and prognosis of associated malignancies in 504 patients with lymphomatoid papulosis

Contains fulltext : 218179.pdf (Publisher’s version ) (Open Access)BACKGROUND: Lymphomatoid papulosis (LyP) can be associated with other haematological malignancies (HM), but reported percentages vary from 20% to over 50%. OBJECTIVE: To evaluate the frequency and prognostic significance of associated HM and non-HM in LyP patients. METHODS: In this multicentre cohort study, the complete Dutch LyP population was included from the Dutch Cutaneous Lymphoma Registry between 1985 and 2018. Clinical and histopathological information was retrieved from every individual patient. RESULTS: After a median follow-up of 120 months (range, 6-585), an associated HM was observed in 78/504 (15.5%) patients. Most common associated HM were mycosis fungoides (MF; n = 31) and anaplastic large-cell lymphoma (ALCL; n = 29), while 19 patients had another HM of B-cell (n = 14) or myeloid origin (n = 5). Even after a 25-year follow-up period, percentages of associated HM did not exceed 20%. Thirty-nine of 465 patients (8.4%) without a prior or concurrent associated HM developed an associated HM during follow-up, after a median of 68 months (range of 3-286 months). Nine of 78 patients died of associated HM, including 6/22 patients developing extracutaneous ALCL, while all patients with associated MF or skin-limited ALCL had an excellent prognosis. Compared with the general population, LyP patients showed an increased risk (relative risk, 2.8; 95% confidence intervals, 2.4-3.3) for non-HM, in particular cutaneous squamous cell carcinoma, melanoma and intestinal/lung/bladder cancer. CONCLUSIONS: An associated HM was reported in 15.5% of the LyP patients, particularly MF and ALCL. Although the frequency of associated HM is lower than suggested and the prognosis of most patients with associated HM is excellent, a small subgroup will develop aggressive disease, in particular extracutaneous ALCL. Furthermore, LyP patients have a higher risk of developing other malignancies. Clinicians should be aware of these risks, and LyP patients require close monitoring