BACKGROUND AND OBJECTIVES:Time to worsening in health-related quality of life (HRQoL) is increasingly used in oncology trials. Treatment discontinuation poses a challenge: once discontinued, patients cease HRQoL assessments, precluding outcome observation. Standard survival analyses censor at discontinuation, assuming noninformative censoring-an assumption often violated when discontinuation relates to disease progression or toxicity. Bridging the ICH E9(R1) estimand framework with causal inference methods clarifies how to define and estimate treatment effects in such settings. We reanalyze time to worsening in global health status from the ALTA-1L trial (brigatinib vs crizotinib in ALK + non-small-cell lung cancer), integrating both frameworks. METHODS:Following Young et al's (2020) causal framework for competing events, we defined two estimands structured according to ICH E9(R1): (1) a controlled direct effect under a hypothetical strategy, envisioning a scenario where treatment discontinuation would not occur, estimated using inverse probability of censoring weighted Kaplan-Meier to adjust for informative censoring; and (2) a total effect under a while-on-treatment strategy, with discontinuation as a competing event, estimated using the Aalen-Johansen estimator. Risk ratios (RRs) were estimated at 36 months with bootstrap CIs. RESULTS:The original ALTA-1L analysis reported hazard ratio = 0.69 (95% CI: 0.49, 0.98), censoring at discontinuation and assuming noninformative censoring. Deriving the RR at 36 months from Kaplan-Meier curves yields 0.75 (95% CI: 0.59, 0.97). After adjusting for informative censoring, the controlled direct effect was RR = 0.89 (95% CI: 0.65, 1.26). The total effect was RR = 1.03 (95% CI: 0.76, 1.40), reflecting the competing risk structure: earlier discontinuation in the crizotinib arm (discontinuation RR = 0.54; 95% CI: 0.38, 0.72) reduced observed worsening events. These different estimates illustrate how different estimands address distinct clinical questions. CONCLUSION:This study bridges the ICH E9(R1) estimand framework with causal inference methods for time-to-event HRQoL analysis when discontinuation precludes observation. By quantifying bias from standard approaches, we provide methodological clarity for applied researchers. To facilitate practical implementation, we translate these insights into a decision flowchart for estimand specification and method selection when intercurrent events (ICEs) act as competing events. Future trials should prespecify ICE-handling strategies and consider data collection beyond ICEs to support treatment policy estimation.

Currently there is no established prognostic scoring system for patients with chronic myeloid leukemia (CML) in blast phase (BP). This study aimed to identify prognostic factors of CML-BP in a large cohort of prospectively and retrospectively collected patients and to develop a readily available prognostic scoring system at the onset of BP to enable future comparison between different trials and series. The analyses were based on 275 patients from thirteen countries, collected within the European LeukemiaNet Blast Phase Registry with a median observation time of 45 months and a median OS of 18.9 months. A Cox proportional hazards model for overall survival (OS) was employed, missing values were imputed. The study identified six independent prognostic factors: blast percentage, platelet count, age (all at onset of CML-BP), immunophenotype of BP, extramedullary disease, and previous history of CML. The low-risk group, encompassing 14% of patients, had a median OS of 97 months, the intermediate-risk group (59% of patients) of 22 months, and the high-risk group (27% of patients) of 9 months. Cross-validation demonstrated a good performance of the score, although external validation is strongly recommended. Despite the inherent limitations of registry data, the findings offer robust insights into prognostic factors for CML-BP.

Objective The effects of sex hormones remain largely unexplored in pheochromocytomas and paragangliomas (PPGLs) and gastroenteropancreatic neuroendocrine tumors (GEP-NETs).Methods We evaluated the effects of estradiol, progesterone, Dehydroepiandrosterone sulfate (DHEAS), and testosterone on human patient-derived PPGL/GEP-NET primary culture cell viability (n = 38/n = 12), performed next-generation sequencing and immunohistochemical hormone receptor analysis in patient-derived PPGL tumor tissues (n = 36).Results In PPGLs, estradiol and progesterone (1 mu m) demonstrated overall significant antitumor effects with the strongest efficacy in PPGLs with NF1 (cluster 2) pathogenic variants. Estrogen receptor alpha (ER alpha) positivity was detected in 11/36 PPGLs, including 4/4 head-and-neck paragangliomas (HNPGLs). ER alpha-positive tumors responded with a significant cell viability decrease to estradiol. DHEAS and testosterone (1 mu m) displayed no effects, but higher doses of testosterone (10 mu m) demonstrated significant antitumor effects, including a pheochromocytoma lung metastasis with strong androgen receptor positivity (30%). Driven by the antitumor effects of estrogen, we evaluated G-protein-coupled estrogen receptor (GPER) agonist G-1 as a potential therapeutic option for PPGLs and found strong significant antitumor potential, with the strongest efficacy in tumors with NF1 pathogenic variants. Moreover, we detected sex-related differences-tumors from male patients showed significantly stronger responsivity to G-1 compared with tumors from female patients. In GEP-NETs, sex hormones showed overall no effects, especially no tumor growth-promoting effects.Conclusion We provide novel data on the effects of elevated sex hormone levels, potentially seen during pregnancy or hormone replacement therapy, on PPGL/GEP-NET tumor growth. G-1 might offer a novel therapeutic approach for some PPGLs depending on patient's sex and the individual tumor's genetic/molecular background. All HNPGLs showed ER alpha positivity.

Chronic myeloid leukemia (CML) is a chronic condition with excellent long-term survival under tyrosine kinase inhibitor (TKI) therapy. However, patient priorities regarding treatment goals and quality of life remain insufficiently understood. We conducted a nationwide online survey among German CML patients in collaboration with the German CML Alliance and patient organizations to assess treatment goals at diagnosis, during therapy, and in the treatment-free remission phase. The questionnaire included validated measures of treatment satisfaction, fear of progression, and quality-of-life priorities, supplemented by newly developed items. Between November 2024 and February 2025, 582 patients (median age 56 years, 48.8% female) completed the survey. Overall TKI tolerability was rated positively (median 4/5), particularly in first-line therapy and among patients with shorter disease duration, whereas long-term survivors reported more daily-life limitations. Younger patients ( < 45 years) emphasized fertility, sexuality, and work-related concerns, while older patients prioritized tolerability, independence, and mental health. Treatment history shaped expectations: those with discontinuation experience were more willing to accept adverse effects for the prospect of remission. Overall, patient priorities diverged between achieving deep molecular response and maintaining optimal tolerability. Integrating patient-reported preferences into shared decision-making may enhance satisfaction, adherence, and long-term outcomes of patients with CML.

The IPSS-M was developed to revolutionize the prediction of MDS patients' survival by incorporating molecular data. To compensate for lack of access to molecular analyses, the AIPSS-MDS, a supervised machine learning algorithm exclusively based on clinical and cytogenetic data, was developed by the Spanish MDS Group. We used data of the Düsseldorf MDS Registry and included 207 of more than 8500 registry patients whose IPSS-M-requested complete molecular data were known to compare and validate prognostication regarding OS and LFS of the IPSS-M, IPSS-R and AIPSS-MDS. All three tools reliably prognosticated median OS of patients even in a comparatively small patient cohort. The IPSS-M provided the most accurate prediction of median OS while the frequent lack of molecular data persists as an obstacle in daily clinical practice. Due to these circumstances, the IPSS-R remains the prognostication tool with the widest applicability. Based on our data, prognostication using the AIPSS-MDS is also feasible but less precise.

Prognostic scores are an important tool in medical statistics. In chronic myeloid leukaemia (CML), prognostic models have existed for many years, enabling the classification of patients into groups that can be clearly differentiated in terms of their prognosis. However, over time, the focus of these models has shifted from solely survival outcomes to a broader range of diverse endpoints. This review explores the development and applications of these scores, offering recommendations for their use, and looks ahead to potential future advancements in the field. As the landscape of CML treatment evolves with newer therapeutic options, it is crucial to adapt prognostic models to reflect not only survival rates but also other important clinical milestones such as molecular remission, progression-free survival, and CML-related survival. The continued refinement of these tools, alongside international validation efforts, will be essential in providing clinicians with more accurate and individualized patient prognostication, ultimately improving therapeutic decision-making and patient outcomes.

OBJECTIVE:People with epilepsy (PwE) suffer from progressive brain atrophy, which is reflected as neuroaxonal loss on the retinal level. This study aims to provide initial insight into the longitudinal dynamics of the retinal neuroaxonal loss and possible driving factors. METHODS:PwE and healthy controls (HC; 18-55 years of age) underwent spectral domain optical coherence tomography at baseline and 7.0 ± 1.5 and 6.7 ± 1.0 months later, respectively. The change in retinal thickness/volume and annualized percentage change (APC) were calculated for the peripapillary retinal nerve fiber layer (pRNFL), the macular RNFL (mRNFL), the ganglion cell inner plexiform layer (GCIP), the inner nuclear layer, and the total macular volume (TMV). Group comparisons and multiple linear models with stepwise backward selection were performed to evaluate associations with demographic and clinical parameters. RESULTS:PwE (n = 44, 21 females, mean age = 35.6 ± 10.9 years) revealed a significant decrease in the pRNFL, mRNFL, GCIP, and TMV thickness or volume in the study interval. When compared to HC (n = 56, 37 females, mean age = 32.7 ± 8.3 years), the APC of the pRNFL (-.98 ± 3.13%/year) and the GCIP (-1.24 ± 2.56%/year) were significantly more pronounced in PwE (p = .01 and p = .046, respectively). Of note, atrophy of the mRNFL was significantly influenced by the number of antiseizure medications (ASMs; p = .047) and increasing age of PwE (p = .03). Contradictory results, however, were revealed for the impact of seizures. SIGNIFICANCE:In epilepsy, progression of retinal neuroaxonal loss was already detectable at short-term follow-up. PwE who receive a high number of ASMs seem to be at risk for accelerated neuroaxonal loss, stressing the importance of well-considered and effective antiseizure therapy.

Blast phase (BP) of chronic myeloid leukemia (CML) still represents an unmet clinical need with a dismal prognosis. Due to the rarity of the condition and the heterogeneity of the biology and clinical presentation, prospective trials and concise treatment recommendations are lacking. Here we present the analysis of the European LeukemiaNet Blast Phase Registry, an international collection of the clinical presentation, treatment and outcome of blast phases which had been diagnosed in CML patients after 2015. Data reveal the expected heterogeneity of the entity, lacking a clear treatment standard. Outcomes remain dismal, with a median overall survival of 23.8 months (median follow up 27.8 months). Allogeneic stem cell transplantation (alloSCT) increases the rate of deep molecular responses. De novo BP and BP evolving from a previous CML do show slightly different features, suggesting a different biology between the two entities. Data show that outside clinical trials and in a real-world setting treatment of blast phase is individualized according to disease- and patient-related characteristics, with the aim of blast clearance prior to allogeneic stem cell transplantation. AlloSCT should be offered to all patients eligible for this procedure.

Background Gastric cancer is a leading cause of death from malignant diseases and has been characterized on a molecular level in recent years. In a context of precision medicine, the proposed study aims to describe the three major compartments harboring tumor cells in patients requiring multimodal therapy: peripheral blood, the abdominal cavity, and the local tumor. Unlike tumor tissues and liquid biopsies, the peritoneal space (in terms of ascites and metastatic tumor seeds) is not regularly considered in molecular diagnostics due to difficult access. This study aims to determine circulating tumor DNA in the peritoneum (ptDNA) and in the plasma (ctDNA). It will then be investigated to what extent the detection of ptDNA before and after neoadjuvant therapy correlates with ctDNA. The main goal is to evaluate the relative changes in ptDNA and ctDNA levels after systemic treatment in patients with locally advanced gastric cancer. Hypothesis: We hypothesize that ptDNA in the abdominal cavity reacts differently to chemotherapy than ctDNA in peripheral blood and therefore, peritoneal disease cannot be adequately represented by ctDNA. Patients with elevated initial ptDNA levels, especially those who do not respond to neoadjuvant therapy, might have an increased risk of peritoneal carcinomatosis and consequently require intensified systemic or local (i.e. HIPEC) treatments. Study design: ptDNA and ctDNA will be analyzed at the time of cancer diagnosis (during exploratory laparoscopy according to diagnostics guidelines) and after neoadjuvant therapy (during tumor resection). Subsequently, the determination of ptDNA in gastric cancer patients could allow the identification of a subgroup that will benefit from intensified local treatment options for peritoneal tumor seeding. Finally, the study will attempt to establish the peritoneal space as another compartment for future precision oncology diagnostics and multimodality therapy.

Purpose The Sanders Scoring System has revolutionized the way we assess the remaining growth potential of the skeleton. However, because it involves radiation exposure, it must be used with caution in children. The purpose of the study was to evaluate whether the Sanders skeletal maturity score (SMS) could be accurately determined using ultrasound (U).Methods We took radiographs (R) of the hand and performed U of the thumb and index finger in 115 patients between six and 19 years of age who were undergoing treatment for scoliosis or limb deformities. Paediatric orthopaedic surgeons, a paediatrician, and a paediatric radiologist were evaluated the blinded images. Those classified images are based on the SMS and the Thumb Ossification Composite Index (TOCI).Results Intrarater reliability was high for SMS and slightly weaker for TOCI, but still significant. Interrater reliability was clear for R and weaker for U in both staging systems. Ultimately, SMS 3 and 7 achieved the highest percentage of concordance (P) of 71.7% and 66.0%, respectively, when U was performed. Combining the clinically relevant groups of SMS 3&4 and SMS 7&8 also significantly increased peak scores (SMS 3 and 4 P = 76.7%; SMS 7 and 8 P = 79.7%). The probabilities of peak scores were significantly weaker when the TOCI score was examined.Conclusion Our study shows that U can be used effectively especially to measure stages 3 and 4 and stages 7 and 8 of SMS. The U method is easy to use and therefore may offer advantages in clinical practice without the need for radiation exposure.

The human leukocyte antigen-G (HLA-G) gene encodes a tolerogenic protein known to promote tumor immune-escape. We investigated HLA-G polymorphisms and soluble molecules (sHLA-G) in 68 chronic myeloid leukemia (CML) patients. Patients with G*01:01:01 or G*01:01:02 allele had higher value of sHLA-G compared to G*01:01:03 (109.2 ± 39.5 vs 39.9 ± 8.8 units/ml; p = 0.03), and showed lower event free survival (EFS) (62.3% vs 90.0%; p = 0.02). The G*01:01:03 allele was associated with higher rates and earlier achievement of deep molecular response (MR)4.5 (100% vs 65%, median of 8 vs 58 months, p = 0.001). HLA-G alleles with higher secretion of sHLA-G seem associated with lower EFS, possibly because of an inhibitory effect on the immune system. Conversely, lower levels of sHLA-G promoted achievement of MR4.5, suggesting increased cooperation with immune system.

Abstract Objective Thinning of the peripapillary retinal nerve fiber layer (p‐RNFL), as measured by optical coherence tomography (OCT), was recently introduced as a promising marker for cerebral neuronal loss in people with epilepsy (PwE). However, its clinical implication remains to be elucidated. We thus aimed to (1) systematically characterize the extent of the retinal neuroaxonal loss in a broad spectrum of unselected PwE and (2) to evaluate the main clinical determinants. Methods In this prospective study, a spectral‐domain OCT evaluation was performed on 98 well‐characterized PwE and 85 healthy controls (HCs) (18–55 years of age). All inner retinal layers and the total macula volume were assessed. Group comparisons and linear regression analyses with stepwise backward selection were performed to identify relevant clinical and demographic modulators of the retinal neuroaxonal integrity. Results PwE (age: 33.7 ± 10.6 years; 58.2% female) revealed a significant neuroaxonal loss across all assessed retinal layers (global pRNFL, P = 0.001, Δ = 4.24 μm; macular RNFL, P < 0.001, Δ = 0.05 mm3; ganglion cell inner plexiform layer, P < 0.001, Δ = 0.11 mm3; inner nuclear layer, INL, P = 0.03, Δ = 0.02 mm3) as well as significantly reduced total macula volumes (TMV, P < 0.001, Δ = 0.18 mm3) compared to HCs (age: 31.2 ± 9.0 years; 57.6% female). The extent of retinal neuroaxonal loss was associated with the occurrence and frequency of tonic–clonic seizures and the number of antiseizure medications, and was most pronounced in male patients. Significance PwE presented an extensive retinal neuroaxonal loss, affecting not only the peripapillary but also macular structures. The noninvasive and economic measurement via OCT bears the potential to establish as a practical tool to inform patient management, as the extent of the retinal neuroaxonal loss reflects aspects of disease severity and sex‐specific vulnerability. Plain Language Summary The retina is an extension of the brain and closely connected to it. Thus, cerebral alterations like atrophy reflect also on the retinal level. This is advantageous, as the retina is easily accessible and measureable with help of the optical coherence tomography. Here we report that adults with epilepsy have a significantly thinner retina than healthy persons. Especially people with many big seizures and a lot of medications have a thinner retina. We propose that measurement of the retina can be useful as a marker of disease severity and to inform patient management.

No information is available on long-term survival of tyrosine kinase inhibitor (TKI)- treated patients failing the response milestones as defined by the European LeukemiaNet (ELN). Such information would help with decision making in failing patients when risks associated with comorbidities, drug toxicities or transplantation preclude switching to another TKI or other treatments. To systematically analyze survival after reaching, or not reaching, ELN-response milestones, 1342 imatinib-treated patients from CML-study IV with newly diagnosed CML in chronic phase and regular molecular and cytogenetic tests were studied. Survival was analyzed by landmark analyses at 3, 6, 12 and 24 months and followed up to 14 years. In patients who failed the failure milestones (>10% BCR::ABL1 IS at 6 months, >1% BCR::ABL1 IS at 12 months), 10- to 12-year survival ranged around 70%, 10-20% less than in responding patients. An example is shown in Fig. 1a which depicts survival of patients reaching, or not reaching 1% BCR::ABL1 IS at 12 months. Similar survival curves were observed for the other landmarks that indicate failure. Inbetween response rates of >1%-10% BCR::ABL1 IS at 12 months indicated survival probabilities similar to those of patients failing 1% BCR::ABL1 IS, whereas patients reaching >1%-10% BCR::ABL1 IS at 24 months showed a survival similar to that of patients failing 10% BCR::ABL1 IS. Switching to alternative therapies, mostly to dasatinib and nilotinib, was observed in 372 patients (26.9%) and did not change the main results. Although cytogenetic tests were increasingly replaced by molecular tests in the course of the study, sufficient cytogenetic analyses were available for comparison with molecular analyses. Complete and partial cytogenetic remissions have been shown to be roughly equivalent to 1% and 10% BCR::ABL1 IS, respectively. Wheras reaching, or not reaching cytogenetic and molecular reponse markers at 6 and 12 months was equivalent, not reaching a complete or partial cytogenetic remission at 24 months identified a small subgroup of patients (5.9%) with inferior survival (Fig. 1b). Age (more or less than 60 years) had no major impact on survival differences, but on hazard ratios for early death. Hazard ratios at 10% BCR::ABL1 IS by 6 months were 4.0 (95%CI:2.0-8.1) for the younger patients, but only 0.9 (95% CI: 0.4-1.8) for the elderly. The reasons for early death in the younger patients were mostly CML-related, whereas the elderly primarily died of other reasons. The data show that TKI-treated patients not reaching failure milestones still may derive benefit from continuing TKI-treatment and provide a basis for individualized decisions, if failing patients are confronted with risks of alternative treatments.

The absolute monocyte count (AMC) is associated with mortality in a variety of medical conditions. Its prognostic impact in myelodysplastic syndromes (MDSs) is less well studied. Therefore, we investigated its potential prognostic value in a cohort from the Düsseldorf MDS registry in relationship to the revised international prognostic scoring system (IPSS-R). An AMC below the population's median (<0.2 × 109/L) was associated with several adverse disease features such as lower haemoglobin levels, lower count of neutrophils and platelets, and a higher percentage of blasts in the bone marrow. MDS patients with an AMC < 0.2 × 109/L had a significantly higher risk of progression into acute myeloid leukemia (AML). In a univariate, proportional hazards model the effect of the AMC as a continuous variable was modelled via p-splines. We found a U-shaped effect with the lowest hazard around 0.3 × 109/L. Accordingly, an AMC within the last quartile of the population (0.4 × 109/L) was associated with a reduced overall survival independently of IPSS-R, but not with the risk of secondary AML. Considering monocytopenia as a risk factor for AML progression in MDS may provide an additional argument for allogeneic transplantation or the use of hypomethylating agents in patients who are not clear candidates for those treatments according to current prognostic scoring systems and/or recommendations. Further studies are needed to assess the prognostic impact of the AMC in the context of prognostic scoring systems, considering the molecular risk profile, and to identify the mechanisms responsible for the higher mortality in MDS patients with a subtle monocytosis.

Myelodysplastic syndromes and myeloproliferative neoplasms both represent hematologic diseases associated with bone marrow failure often resulting in anemia. For those patients, transfusion of red blood cell (RBC) units is essential but results in iron overload (IOL) that may affect various organ functions. Therefore, iron chelation therapy plays a major role in anemic patients, not only because it reduces IOL, but also because it may improve hematopoietic function by increasing hemoglobin or diminishing the requirement for RBC transfusions. To assess the utility, efficacy, and safety of the different iron chelation medications approved in Germany, as well as to examine the effect of chelation on hematopoietic insufficiency, a prospective, multicenter, noninterventional study named EXCALIBUR was designed. In total, 502 patients from 106 German hospitals and medical practices were enrolled. A large proportion of patients switched from a deferasirox dispersible tablet to a deferasirox-film-coated tablet, mainly because of more convenient application, which was reflected in the treatment satisfaction questionnaire for medication scores. Iron chelation was effective in lowering serum ferritin levels, with the observed adverse drug reactions being in line with the known safety profile. Hematologic response occurred in a few patients, comparable to other studies that examined hematologic improvement in patients with MDS.

Objective: Titanium particles have been shown in in-vitro studies to lead to the activation of specific pathways, this work aims to systematically review in-vivo studies examining peri-implant and periodontal tissues at the transcriptome, proteome, epigenome and genome level to reveal implant material-related processes favoring peri-implantitis development investigated in animal and human trials.Methods: Inquiring three literature databases (Medline, Embase, Cochrane) a systematic search based on a priori defined PICOs was conducted: '-omics' studies comparing molecular signatures in healthy and infected peri-implant sites and/or healthy and periodontitis-affected teeth in animals/humans. After risk of bias assessments, lists of differentially expressed genes and results of functional enrichment analyses were compiled whenever possible. Results: Out of 2187 screened articles 9 publications were deemed eligible. Both healthy and inflamed peri-implant tissues showed distinct gene expression patterns compared to healthy/diseased periodontal tissues in animal (n = 4) or human studies (n = 5), with immune response, bone metabolism and oxidative stress being affected the most. Due to the lack of available reanalyzable data and inconsistency in methodology of the eligible studies, integrative analyses on differential gene expression were not applicable Conclusion: The differences of transcriptomic signatures in between peri-implant lesions compared to periodontal tissue might be related to titanium particles arising from dental implants and are in line with the in-vitro data recently published by our group. Nevertheless, limitations emerge from small sample sizes of included studies and insufficient publication of re-analyzable data.

Objective: Interdisciplinary-neurovascular-boards (INVB) are deemed to find the patient's optimum treatmentmodality in elective unruptured intracranial aneurysm-repair (EUIAR). If INVB judges risk/success estimation similar for microsurgical/endovascular EUIAR, the choice for either modality is up to the informed patient. However, it is unknown if the patients' decision-making might be biased by the discipline of initial counselling prior to INVB and if INVB's equal risk/success estimation is finally accurate.Methods: We analysed all our patients with EUIAR after INVB-discussion between 2007 and 2017 and identified those patients where INVB-recommendation estimated similar risk/success rates for both treatment-modalities. We investigated the procedural/outcome parameters and determined if the mode of initial counselling prior to INVB influenced the patients' choice of EUIAR and if INVB's equal risk/success estimation was accurate.Results: Within altogether 572 patients with EUIAR during our study period, we identified 99 patients (agemean:58 yrs; m:f=1:2) in whom pre-treatment INVB-discussion estimated risk/success rates for both modalities of EUIAR to be similar. Prior to INVB-discussion, 80 of the 99 patients had been initially counselled in the neurosurgical discipline and 19 patients in the endovascular discipline. The final patients' decision rates for surgical vs. endovascular EUIAR (after secondary consultation of each patient in both disciplines after INVBdiscussion) were 67% vs. 33% in the first and 58% vs. 42% in the latter group (no significant difference: p = 0.345). Uni- and multivariate analysis did not show any hints for a bias in patients' decision-making caused by the discipline of initial counselling prior to INVB/secondary bilateral consultations. Clinical and procedural outcome at last follow-up (median:18mos) did not differ between those 66 patients that eventually decided for microsurgical and those 33 patients that eventually decided for endovascular EUIAR, underlining the high accuracy of INVB's pre-treatment risk/success estimations.