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In the last decade, sequencing of primary tumors has clarified the genetic underpinnings of Wilms tumor, yet has not impacted therapy, outcome, or toxicities. We now sharpen our focus on relapse samples from the umbrella AREN03B2 study. We show that over 40% of relapse samples contain mutations in SIX1 or genes of the MYCN network, drivers of progenitor proliferation. Not previously seen in large studies of primary Wilms tumors, DIS3 and TERT are now identified as recurrently mutated. The analysis of primary-relapse tumor pairs suggests that 11p15 loss of heterozygosity (and other copy number changes) and mutations in WT1, MLLT1 typically occur early, however mutations in SIX1, MYCN, and WTX are late developments in some patients. Most strikingly, 75% of relapse samples had gain of 1q, providing strong conceptual support for studying circulating tumor DNA in clinical trials in order to better detect 1q gain earlier and to monitor response.
In IgG4-related disease, the relationship between pathological findings and relapse has not been well established. This study aimed to identify the clinical and pathological predictors of disease relapse in IgG4-RD.
Patients with newly diagnosed IgG4-RD (n = 71) were enrolled between January 2011 and April 2020; all cases were pathologically confirmed. The clinical and pathological features were recorded in a database at baseline and each follow-up visit. Patients were followed up at least once a month via outpatient clinic examinations and telephone calls. Univariate and multivariate Cox regression analyses and receiver operating curve (ROC) analysis were used to identify the predictors of disease relapse and to assess their predictive value.
Although the pathological diagnostic criteria for IgG4-RD have been established [15,16,17,18,19,20,21], the pathological features associated with disease relapse are not known. The aim of this study was to investigate the relationship between pathological manifestations and disease relapse in IgG4-RD and to identify the independent predictors of disease relapse.
Enrolled patients were followed up through outpatient visits and/or telephone calls every month until disease relapse, death, or the end of the study (November 2020). All patients completed at least 6 months of follow-up. Demographic data, clinical features, laboratory examination results, pathological findings, imaging data, medical treatments, and disease outcomes were recorded in a database at baseline and each visit.
Figure 1B shows the cumulative relapse rate in patients with different predictive scores. The 1-year, 2-year, 3-year, and 5-year relapse rates were all significantly different between patients with different prognostic scores (Supplementary Table 6, Additional file 1). The prognostic score showed strong positive correlation with the 1-year, 2-year, 3-year, and 5-year relapse rates. The 3-year relapse rate for patients with 0, 1, 2, and 3 points were 0%, 27.3%, 63.6%, and 100%, respectively. The relationship between the three risk factors and disease relapse at 3 years is further illustrated by the matrix predictive model in Supplementary Table 7, Additional file 1.
Recent studies have investigated whether the 2019 ACR/EULAR classification criteria [34] and the novel clinical phenotypes [35] could predict the relapse of IgG4-RD. However, neither the classification score nor having a specific clinical phenotype of IgG4-RD seem to be associated with the risk of relapse. Further research is needed.
Marked IgG4+ plasma cell infiltration is one of the characteristic pathological manifestations of IgG4-RD. The pathogenesis of IgG4-RD remains unknown. Th2 cytokines (IL-4, IL-5, and IL-13) production can lead to IgG4 hyperproduction in B cell. IL-21-secreting Tfh cells could help germinal center formation and promote the differentiation from B cell to plasma cell. Several studies have demonstrated that the number of plasmablasts is positively correlated with disease activity and that the appearance of distinct plasmablast clones is associated with relapse of IgG4-RD [36, 37]. However, the relationship between the severity of IgG4+ plasma cell infiltration and disease activity or relapse is not well established.
In this study, severe IgG4+ plasma cell infiltration was found to be independently associated with disease relapse. In clinical practice, based on the findings of previous studies, patients with IgG4-RD are considered to have a low risk of relapse if they have single-organ involvement, low serum IgG4 level, and low IgG4-RD RI. However, our results suggest that those with a large number of IgG4+ plasma cells in the biopsied organ should also be considered to be at risk.
In the present study, different from our previous research [8], all patients had pathologically confirmed IgG4-RD. Our focus was on the relationship between the pathological features and relapse; we did not consider the prognostic value of uncommonly evaluated laboratory parameters (e.g., serum cytokine level).
Download our free relapse prevention books. Make Your Last Relapse the Last is a complete, self-paced relapse prevention program. Help Them Succeed guides parents, friends, and family in the steps needed to help your loved one succeed at relapse prevention and rehab. Learn more about the books now:
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Relapse prevention is based on a model that sees relapse as a natural part of the process of change and as an opportunity for people to enhance their understanding of their behaviour. Relapse prevention treatment models include various cognitive and behavioural approaches that address specific steps in the relapse process.
There are four main ideas in relapse prevention. First, relapse is a gradual process with distinct stages. The goal of treatment is to help individuals recognize the early stages, in which the chances of success are greatest [1]. Second, recovery is a process of personal growth with developmental milestones. Each stage of recovery has its own risks of relapse [2]. Third, the main tools of relapse prevention are cognitive therapy and mind-body relaxation, which change negative thinking and develop healthy coping skills [3]. Fourth, most relapses can be explained in terms of a few basic rules [4]. Educating clients in these few rules can help them focus on what is important.
Another goal of therapy at this stage is to help clients identify their denial. I find it helpful to encourage clients to compare their current behavior to behavior during past relapses and see if their self-care is worsening or improving.
These are some of the signs of mental relapse [1]: 1) craving for drugs or alcohol; 2) thinking about people, places, and things associated with past use; 3) minimizing consequences of past use or glamorizing past use; 4) bargaining; 5) lying; 6) thinking of schemes to better control using; 7) looking for relapse opportunities; and 8) planning a relapse.
In bargaining, individuals start to think of scenarios in which it would be acceptable to use. A common example is when people give themselves permission to use on holidays or on a trip. It is a common experience that airports and all-inclusive resorts are high-risk environments in early recovery. Another form of bargaining is when people start to think that they can relapse periodically, perhaps in a controlled way, for example, once or twice a year. Bargaining also can take the form of switching one addictive substance for another.
Clinical experience has shown that occasional thoughts of using need to be normalized in therapy. They do not mean the individual will relapse or that they are doing a poor job of recovery. Once a person has experienced addiction, it is impossible to erase the memory. But with good coping skills, a person can learn to let go of thoughts of using quickly.
Most physical relapses are relapses of opportunity. They occur when the person has a window in which they feel they will not get caught. Part of relapse prevention involves rehearsing these situations and developing healthy exit strategies.
This is also the time to deal with any family of origin issues or any past trauma that may have occurred. These are issues that clients are sometimes eager to get to. But they can be stressful issues, and, if tackled too soon, clients may not have the necessary coping skills to handle them, which may lead to relapse.
Denied users will not or cannot fully acknowledge the extent of their addiction. They cannot imagine life without using. Denied users invariably make a secret deal with themselves that at some point they will try using again. Important milestones such as recovery anniversaries are often seen as reasons to use. Alternatively, once a milestone is reached, individuals feel they have recovered enough that they can determine when and how to use safely. It is remarkable how many people have relapsed this way 5, 10, or 15 years after recovery. 2ff7e9595c
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