Subgroup Sizes Research Articles

Diagnostic accuracy of CT and PET/CT radiomics in predicting lymph node metastasis in non-small cell lung cancer.

This study evaluates the accuracy of radiomics in predicting lymph node metastasis in non-small cell lung cancer, which is crucial for patient management and prognosis. Adhering to PRISMA and AMSTAR guidelines, we systematically reviewed literature from March 2012 to December 2023 using databases including PubMed, Web of Science, and Embase. Radiomics studies utilizing computed tomography (CT) and positron emission tomography (PET)/CT imaging were included. The quality of studies was appraised with QUADAS-2 and RQS tools, and the TRIPOD checklist assessed model transparency. Sensitivity, specificity, and AUC values were synthesized to determine diagnostic performance, with subgroup and sensitivity analyses probing heterogeneity and a Fagan plot evaluating clinical applicability. Our analysis incorporated 42 cohorts from 22 studies. CT-based radiomics demonstrated a sensitivity of 0.84 (95% CI: 0.79-0.88, p < 0.01) and specificity of 0.82 (95% CI: 0.75-0.87, p < 0.01), with an AUC of 0.90 (95% CI: 0.87-0.92), indicating no publication bias (p-value = 0.54 > 0.05). PET/CT radiomics showed a sensitivity of 0.82 (95% CI: 0.76-0.86, p < 0.01) and specificity of 0.86 (95% CI: 0.81-0.90, p < 0.01), with an AUC of 0.90 (95% CI: 0.87-0.93), with a slight publication bias (p-value = 0.03 < 0.05). Despite high clinical utility, subgroup analysis did not clarify heterogeneity sources, suggesting influences from possible factors like lymph node location and small subgroup sizes. Radiomics models show accuracy in predicting lung cancer lymph node metastasis, yet further validation with larger, multi-center studies is necessary. Radiomics models using CT and PET/CT imaging may improve the prediction of lung cancer lymph node metastasis, aiding personalized treatment strategies. International Prospective Register of Systematic Reviews (PROSPERO), CRD42023494701. This study has been registered on the PROSPERO platform with a registration date of 18 December 2023. https://www.crd.york.ac.uk/prospero/ KEY POINTS: The study explores radiomics for lung cancer lymph node metastasis detection, impacting surgery and prognosis. Radiomics improves the accuracy of lymph node metastasis prediction in lung cancer. Radiomics can aid in the prediction of lymph node metastasis in lung cancer and personalized treatment.

Testing for marginal covariate effect when the subgroup size induced by the covariate is informative.

In many cluster-correlated data analyses, informative cluster size poses a challenge that can potentially introduce bias in statistical analyses. Different methodologies have been introduced in statistical literature to address this bias. In this study, we consider a complex form of informativeness where the number of observations corresponding to latent levels of a unit-level continuous covariate within a cluster is associated with the response variable. This type of informativeness has not been explored in prior research. We present a novel test statistic designed to evaluate the effect of the continuous covariate while accounting for the presence of informativeness. The covariate induces a continuum of latent subgroups within the clusters, and our test statistic is formulated by aggregating values from an established statistic that accounts for informative subgroup sizes when comparing group-specific marginal distributions. Through carefully designed simulations, we compare our test with four traditional methods commonly employed in the analysis of cluster-correlated data. Only our test maintains the size across all data-generating scenarios with informativeness. We illustrate the proposed method to test for marginal associations in periodontal data with this distinctive form of informativeness.

Frequency of Radiation Therapy-Induced Malignancies in Patients With Li-Fraumeni Syndrome and Early-Stage Breast Cancer and the Influence of Radiation Therapy Technique

IntroductionBreast cancer (BC) is the most common malignancy in female patients with Li-Fraumeni Syndrome (LFS), a condition associated with an increased risk of various malignancies, including radiotherapy-induced malignancies (RIM) within previously irradiated areas. Our study aimed to assess the incidence of RIM in LFS patients with early-stage breast cancer (eBC) treated with adjuvant radiotherapy (RT), including the impact of RT dose and technique. MethodsWe examined patients with a germline pathogenic/likely pathogenic TP53 variant diagnosed with eBC and monitored by a Hereditary Cancer Team at a single cancer center. The study endpoints included RIM frequency, the association of RIM with the dose and type of radiotherapy (2D RT, 3D RT, and IMRT), and BC recurrence. ResultsWe analyzed 48 patients with a median age of 39 years (range 21 - 62). A majority (71%) had the TP53 R337H variant, and 87% were unaware of their LFS diagnosis at the time of BC treatment. Treatment modalities included mastectomy (62%), (neo)adjuvant chemotherapy (66%), and RT (62%), with RT being more common after breast-conserving surgery (87% vs. 46% with mastectomy, P=0.010). Among the 30 patients treated with RT, 10% developed RIM in the irradiated field, consisting of three soft tissue malignancies. RT dose (≤40.8 or >40.8 Gy) did not influence RIM occurrence, but the type of RT did. RIM was observed in 100% of cases with 2D RT (2/2), 50% with IMRT (1/2), and 0% with 3D RT (0/16) (P=0.004). ConclusionOur study underscores a concerning rate of RIM following adjuvant RT, emphasizing the importance of a thorough risk-benefit evaluation before recommending RT, with preference for its avoidance if possible. Although subgroup sizes were limited, the risk of RIM appeared to be influenced by the RT technique, with higher rates observed with 2D RT and IMRT compared to 3D RT. Early TP53 testing is essential to guide the BC treatment plan.

Incorporating principal component analysis into Hotelling [formula omitted] control chart for compositional data monitoring

In the manufacturing industry, compositional data (CoDa) is a vital quality characteristic to be monitored. The proposed study has introduced a Hotelling T2 control chart using principal component analysis to monitor CoDa explicitly. The proposed method overcomes the limitations of previous approaches by utilizing isometric log-ratio transformation to map the CoDa into unrestricted real space. A Monte Carlo simulation procedure is employed to evaluate the performance of the proposed multivariate control chart. The simulation involves varying combinations of the number of variables (p) and subgroup sizes to obtain metrics such as the average run length when the process is out-of-control (OOC) and the upper control limit. The article presents a comprehensive analysis of the proposed control chart’s statistical performance. These visual aids facilitate a deeper understanding of the method’s effectiveness in detecting OOC conditions in CoDa. Furthermore, two illustrative examples using synchronous machines and components of electronic scrap are provided to illustrate the practical implementation and effectiveness of the Hotelling T2-based principal component control chart for p=5-part and p=12-part CoDa in real-world scenarios.

Efficacy of dapagliflozin according to geographic regions in patients with heart failure: a patient-level pooled analysis of DAPA-HF and DELIVER

Abstract Background Clinical characteristics and prognosis vary by geographic region in patients with heart failure (HF). Some previous reports suggested the efficacy of certain treatments for HF may be modified by region. However, most analyses based on regions in individual trials are hampered by modest subgroup sizes and small numbers of events and can give unreliable results. Purpose To evaluate the difference in outcomes between regions, and to examine whether the efficacy and safety of dapagliflozin in HF were consistent across regions, using the patient-level pooled data of DAPA-HF and DELIVER. Methods The DAPA-HF (n = 4744) and DELIVER (n = 6263) trials enrolled patients with HF, functional limitation, and elevated natriuretic peptide. The main difference between the trials was that patients with a left ventricular ejection fraction (LVEF) ≤40% were randomized in DAPA-HF and those with a LVEF &amp;gt;40% in DELIVER. In both trials, patients were randomized to dapagliflozin 10 mg daily, or placebo, in addition to standard care. The primary outcome of both trials was the composite of worsening HF or cardiovascular death. Results Of the total 11,007 patients, 5159 patients (46.9%) were enrolled in Europe; 1528 (13.9%) in North America; 1998 (18.2%) in South America; and 2322 (21.1%) in Asia. Patients were younger in Asia and South America and were more often female in South America and Europe. The mean baseline LVEF and median natriuretic peptide level did not vary significantly across regions. Mineralocorticoid receptor antagonists were prescribed less frequently in patients with HF and reduced ejection fraction in North America (46.4%) compared to other regions (70-80%). The rate of the primary outcome (per 100 person-years) was higher in North America [13.9 (95%CI 12.5-15.4)] than in other regions: 10.8 (10.1-11.5) in Europe, 10.0 (9.0-11.1) in South America, and 10.5 (9.5-11.5) in Asia. The rate of the primary outcome increased with decreasing LVEF similarly across all regions studied (Figure 1). The benefit of dapagliflozin on the primary outcome was not modified by region: hazard ratio for dapagliflozin versus placebo 0.85 (95%CI 0.75-0.96) in Europe, 0.75 (0.61-0.93) in North America, 0.72 (0.58-0.89) in South America, and 0.74 (0.61-0.91) in Asia (p-interaction = 0.40). This was the same when evaluated separately for patients with LVEF ≤40% (p-interaction = 0.39) and for those with LVEF &amp;gt;40% (p-interaction = 0.84). In each region, the effect of dapagliflozin was consistent regardless of LVEF (Figure 2). Patients in North America discontinued randomized treatment more frequently than anywhere else (in the placebo group, 21.8% in North America versus 6.4% in South America), but the discontinuation rates did not differ between placebo and dapagliflozin by region. Conclusions The efficacy and safety of dapagliflozin were consistent across global regions despite geographic differences in patient characteristics, background treatment, and event rates.Incidence rate according to regionDapagliflozin effect according to region

Minipuberty in Male Full-term Neonates Appropriate and Small for Gestational Age and in Preterm Babies: Data from a Single Centre

The postnatal activation of the hypothalamic-pituitary-gonadal (HPG) axis is usually known as “minipuberty”. There are still open questions about its biological function and significance depending on sex, gestational age (GA) and birth weight (BW) with few available longitudinal data. A single-centre, longitudinal study to quantify urinary follicle stimulating hormone (uFSH), luteinizing hormone (uLH) and testosterone (uTs) in male neonates. Neonates were enrolled and stratified into three subgroups: full-term boys appropriate for GA (FT AGA); FT boys with BW ≤3rd centile [FT small for gestational age (SGA)]; and preterm (PT) boys ≤33 weeks of GA. Urinary hormones were correlated to simultaneous auxological parameters, linear growth and external genitalia at scheduled time-points. Forty-six boys were recruited, with subgroup sizes FT AGA n=23, FT SGA n=11 and PT n=12. PT boys display a pulsatile pattern of urinary gonadotropins (uGns) with higher levels of uLH and a gradual increase of uTs. Testicular descent started from 29-32 weeks with the peak of uTs. During the first 12-months post-term age (PTA), FT AGA boys displayed a better linear growth (p<0.05). PT showed higher uGns levels until 3-months PTA. PT babies had higher uLH levels than FT AGA, with a peak at 7 and 30 days, during the first 90 days of life (p<0.001) and higher uTs levels. Correlation analysis between penile growth of all neonates and uTs was significant (p=0.04) but not within subgroups. This study investigated postnatal HPG axis activation in term and PT infants. Minipuberty may involve an early window of opportunity to evaluate the functionality of the HPG axis. Further studies with a long-term follow-up are needed with a special focus on possible consequences of GA and BW.

Understanding the Effect of Large Subgroup Sizes on Overdispersion and Using Laney’s P’ Chart to Monitor Overdispersed Data

Background The traditional Shewhart’s P chart is an important statistical process control tool that’s used to monitor processes that yield binary data. However, it has been known for showing a high rate of false alarms (i.e. overdispersion) when handling data with large subgroup sizes. Large subgroup sizes were usually considered to be the cause of overdispersion while no solid evidence actually exists to support this believe. In an effort to manage overdispersion Laney’s P’ chart was proposed in 2002 as a superior alternative to the traditional P chart. And the P chart diagnostic test was also introduced in some software packages to detect any overdispersion in the data and to recommend the suitable chart. Aim In this study we aimed at exploring the effect of large subgroup sizes on the overdispersion of data and we also attempted to test Laney’s P’ chart and the P chart diagnostic test in detecting and handling overdispersed data. Method An Experimental study was conducted using a single set of real data in addition to nine sets of simulated data with variable characteristics. All data sets were used to perform the P chart diagnostic test and to plot Shewhart P chart and Laney’s P’ chart. Results Large subgroup sizes proved to have no effect on binomially distributed data but if the data is not truly binomial, increasing the subgroup sizes will exaggerate overdispersion. In this case using Laney’s P’ chart will successfully resolve the problem. Conclusion The problem of overdispersion is not due to large subgroup sizes rather than it’s due to the false assumption that the data follows a binomial distribution when it frequently doesn’t. An ideal remedy for this problem is to discover a better fitting distribution for the data. Till then Laney’s P’ chart is a practical and capable remedy. Recommendations The P chart diagnostic tool should be used to detect any overdispersion before using Shewhart’s P chart. And if overdispersion is detected Laney’s P’ chart is a recommended alternative. We also recommend Further study of the performance of Laney’s P’ chart and other suggested distributions that can outperform the binomial distribution as a basis for the P chart.

Selective Arterial Embolization of Pseudoaneurysms and Arteriovenous Fistulas after Partial Nephrectomy: Safety, Efficacy, and Mid-Term Outcomes.

The primary objective was to evaluate the clinical success rate after endovascular embolization of iatrogenic vascular lesions caused during partial nephrectomy. The secondary objective was to evaluate the technical success and to assess potential effects on renal function. We retrospectively included consecutive patients from our center who underwent selective embolization to treat iatrogenic renal arterial lesions induced during partial nephrectomy between June 2010 and June 2020. The technical and clinical success rates and renal outcomes were collected. We identified 25 patients with 47 pseudoaneurysms and nine arteriovenous fistulas. Among them, eight were treated by coils only, eight by liquid embolization agents only, and nine by both. The technical success rate was 96% after the first attempt and 100% after the second attempt. The median follow-up was 27.1 ± 24.3 months. Clinical success, defined as no need for further hemostatic surgery during follow-up, was also obtained in 96% and 100% of patients with one and two attempts, respectively. Renal function estimated by the modification of diet in renal disease equation did not change significantly despite a mean 13.8% ± 15.1% decrease in kidney functional volume estimated by angiography. No complications were attributable to the endovascular treatment. No significant difference was found across embolization agents; however, the subgroup sizes were small. Endovascular embolization is safe and effective for treating iatrogenic arterial lesions after partial nephrectomy: success rates are high, complications are infrequent, and renal function is maintained. Recommendations by interventional radiology societies are needed to standardize this treatment.

P-043 Increased paternal age adversely affects live birth rates in oocyte recipient cycles

Abstract Study question To investigate the influence of paternal age on the live birth rates in oocyte recipient cycles Summary answer Increased paternal age appears to have a negative impact on oocyte recipient cycles when adjusted for sperm quality. What is known already While the effect of maternal age on ART outcomes is well established, the effect of paternal age is unclear. Even systematic reviews assessing the impact of paternal age in oocyte recipient cycles have yielded conflicting results. While Morris et al., 2020 could not demonstrate changes in miscarriage rates or live birth rates with increased paternal age, Murugesu et al., 2022 showed an adverse effect of increased paternal age on miscarriages but did not comment on live birth rates. The challenges of systematic reviews are the heterogeneity of the studies and the possible effect of laboratory and clinical practices. Study design, size, duration This retrospective cohort study was conducted at a single centre. A total of 449 IVF/ICSI oocyte recipient cycles performed between January 2015 and June 2022 were examined. Total of 328 cycles resulting in either fresh or frozen-thawed embryo transfers and meeting the inclusion criteria was analysed. The inclusion criteria were donor age ≤35 years, endometrial thickness ≥ 6 mm and a normal endometrial cavity on aqua scan. We excluded cycles with donor sperm or PGT-A. Participants/materials, setting, methods The couples who used donor oocytes because of diminished ovarian reserve, premature ovarian insufficiency, recurrent implantation failure with autologous oocytes or hereditary disease participated. Paternal and recipient ages were grouped according to previous literature to allow for comparability. The primary outcome was the live birth rate and secondary outcomes were clinical pregnancy and miscarriage rates. Simple and multivariate logistic regression analyses were performed. Main results and the role of chance The median recipient and paternal ages were 42 years (interquartile range [IQR] 19–50) and 42 years (IQR 19–76), respectively. The mean age of the donors was 26 years (IQR 18-35). 55.5% [N = 182] of the cycles corresponded to fresh embryo transfers and 44.5% [N = 146] to frozen embryo transfers. Indications for using donor oocytes were diminished ovarian reserve 54.39%, premature ovarian insufficiency 5.7%, recurrent implantation failure with autologous oocytes 37.05% and hereditary disease 2.85%. The overall live birth rate was 155/328 (45.7%). Live birth outcome appeared to be significantly reduced in paternal age over 46 years after adjusting for semen parameters according to WHO 2010 criteria and for recipient age, with an OR 1.5 (95%,0.85 to 1.98, p &amp;lt; 0.002). Clinical pregnancy outcome was significantly reduced in paternal age over 51 years with OR 0.62 (95%, 0.31 to 1.89, p &amp;lt; 0.0001). The overall miscarriage rate was 15/328 (4.57%) and it was not possible to perform subgroup analysis by paternal age group due to the small numbers. When both maternal and paternal age were retained in the multivariate model, the probability of live birth decreased with paternal age over 51 years and maternal age ≥40 years with OR 0.88 [0.40 to 1.38 [N = 37]). Limitations, reasons for caution This study has some limitations. This is a retrospective study and its relatively small subgroup sizes affected the statistical analysis of miscarriage results. In addition, we did not include any effect of sperm DNA fragmentation in the analysis. Wider implications of the findings The overall live birth outcome was positive. Whilst the study can be used to counsel couples with increased paternal age, it should not be used to preclude patients from treatment. Trial registration number IRB-003C02-09-21

Association between pCR, TILs, and Ki-67 at baseline and after 2 weeks in patients with triple-negative breast cancer (TNBC) treated with atezolizumab and chemotherapy +/- a preceding atezolizumab monotherapy window: A translational analysis of the neoMono trial.

595 Background: neoMono randomized patients (pts) with triple negative breast cancer (TNBC) to receive (Arm A) or not to receive (Arm B) 2-week Atezolizumab monotherapy prior to neoadjuvant 24-week Atezolizumab + chemotherapy. In prespecified interim analysis, no difference regarding pathological complete response (pCR) was observed among all pts. However, in regard to pCR rates, pts with PD-L1 positive TNBC seem to benefit from addition of the monotherapy window. Here we analyze the association between central TILs and Ki-67 at baseline (BL) / after 2 weeks (2w) and pCR. Methods: Ki-67 expression (% positive tumor cells) was analyzed using immunohistochemistry. Analysis of stromal TILs was performed according to the International TILs Working Group. Differences from BL at the 2w time point were denoted as Ki-67-diff and TIL-diff, respectively. Associations between pCR and BL/2w measurements were analyzed using logistic regression. Akaike information criterion (AIC) was used to evaluate goodness-of-fit between models. Since the a priori chosen biomarker thresholds ( &lt; = 30% [Ki-67] and &lt; = 60% [TILs]) resulted in very low subgroup sizes, k-means clustering analysis was performed and association of the cluster labels with pCR was then investigated. Results: The analysis included 50 (Arm A) and 51 (Arm B) pts. The threshold of Ki-67 ( &lt; = 30%) was reached in 98% (BL) and 92% (2w), that of TILs ( &lt; = 60%) in 11% (BL) and 18% (2w), respectively. PD-L1 (BL) was &lt; = 1 in 26%. In separate logistic regression models (including BL and change), both BL-Ki-67 and BL-TILs were significantly though moderately associated with pCR. A combined model using both biomarkers yielded the best AIC. BL-Ki-67 and BL-TILs, as well as TIL-diff were highly significantly though again moderately associated with pCR. Cluster analysis I (using BL-Ki-67, Ki-67-diff, and PD-L1) yielded cluster 1 (medium BL-Ki-67 and subsequent increase) with a pCR rate of 50% compared to 77% in cluster 2 (high BL-Ki-67 and decreasing Ki-67). Similarly, cluster analysis II (using BL-TILS, TILS-diff and PD-L1) yielded cluster 3 (low BL-TILs/non-essential TILs change) with a low pCR rate of 55% compared to 84.4% and 85.7% for clusters 4 (low BL-TILs /substantial increase) and 5 (high BL-TILs/non-essential change), respectively. In a combined regression model of all clusters above, clusters 2 and 4 had the highest pCR probability. Conclusions: Our results demonstrate that while BL-Ki-67 and BL-TILs are highly informative of pCR probability, Ki-67-diff and even more so TIL-diff added further significant information. Analysis of the full neoMono dataset will allow us to investigate this association further and to potentially develop a predictive algorithm regarding pCR based on baseline and dynamic biomarkers.

Structure of outpatient urology care in Germany

Although urological specialist practices are central pillars of outpatient care, there is alack of current data on the care structure of these practices. Adescription of the structures in large cities versus rural areas as well as gender effects and generational differences is needed not only as abaseline measure for further studies. The survey includes data from the physician directory of the Stiftung Gesundheit as well as from the German Medical Association and the Federal Statistical Office. Colleagues were divided into subgroups. Based on the different subgroup sizes, statements about the care structure of outpatient urology in Germany can be made. While the majority of urologists in larger cities work in professional practice groups and care for fewer patients on average, in rural areas there is aparticularly high proportion of individual practices with more inhabitants to be cared for per urologist. Female urologists work more frequently in the context of inpatient care. When female urology specialists choose to establish themselves, they are more likely to do so in practice groups and in urban areas. In addition, there is ashift in gender distribution: the younger the age subgroup considered, the higher the proportion of female urologists among all colleagues. This study is the first to describe the current structure of outpatient urology care in Germany. Future trends are already emerging that will significantly influence our way of working and the care of patients in the coming years.

Inequalities for space-bounded Kolmogorov complexity

Finding all linear inequalities for entropies remains an important open question in information theory. For a long time the only known inequalities for entropies of tuples of random variables were Shannon (submodularity) inequalities. Only in 1998 Zhang and Yeung 1998 found the first inequality that cannot be represented as a convex combination of Shannon inequalities, and several other non-Shannon inequalities were found soon after that. It turned out that the class of linear inequalities for entropies is rather fundamental, since the same class can be equivalently defined in terms of subgroup sizes or projections of multidimensional sets (Chan 2001, Chan, Yeung 2002, Romashchenko, Shen, Vereshchagin 2000). The non-Shannon inequalities have interesting applications (e.g., to proofs of lower bounds for the information ratio of secret sharing schemes). Still the class of linear inequalities for entropies is not well understood, though some partial results are known (e.g., Matúš has shown in 2007 that this class cannot be generated by a finite family of inequalities). This class also appears in algorithmic information theory: the same linear inequalities are true for Shannon entropies of tuples of random variables and Kolmogorov complexities of tuples of strings (Hammer et al., 1997). This parallelism started with the Kolmogorov–Levin formula 1968 for the complexity of pairs of strings with logarithmic precision. Longpré proved in 1986 a version of this formula for the space-bounded complexities. In this paper we prove a stronger version of Longpré’s result with a tighter space bound, using Sipser’s trick 1980. Then, using this result, we show that every linear inequality that is true for complexities or entropies, is also true for space-bounded Kolmogorov complexities with a polynomial space overhead, thus extending the parallelism to the space-bounded algorithmic information theory.

P11.35.B The clinical course of long-term survivors after the diagnosis of brain metastasis

Abstract Background To asses demographic and clinical parameters, treatment, and course of disease in patients surviving longer ≥ 5 years after the diagnosis of brain metastasis (BM). Material and Methods We retrospectively identified patients who were treated for BM and survived ≥ 5 years after initial BM diagnosis. We analysed and described clinical and treatment related parameters with respect to histology, time to occurrence and systemic/ BM-specific treatment. Results We included 48 patients with a mean age of 55 years (range 33-81, SD 12) at diagnosis of primary tumor and 58 (range 41-84, SD 20) at initial BM diagnosis. Histology was non-small-cell lung cancer in 18 (37.5%), melanoma in 14 (29.2%), breast cancer in 11 (22.9%), renal carcinoma in 2 (4.2%), and small-cell lung cancer, cancer of unknown primary and gastrointestinal cancer in one case each (2.1%). Treatment for primary tumor included resection (83.3%), chemotherapy (43.8%), radiation (33.3%), interferon therapy (18.8%), and immuno-/targeted therapy (25%). Most patients received a combination of latter. The mean interval between primary tumor and BM diagnosis was 36 months (range -2 to 277; SD 57). At the time of BM diagnosis, 50% of patients presented with systemically stable disease, 66.7% showed BM related symptoms, 92% showed a KPS ≥70. Most patients had 1 BM (72.9%), while 20.9% had 2-3 and 6.3% &amp;gt;3. Initial treatment for BM comprised resection (60.4%), stereotactic radiosurgery (27.2%), whole-brain-radiation therapy (8.4%), and interstitial brachytherapy (4.2%). Approximately half of the patients (52.1%) suffered from ≥1 BM relapse at initial treatment site. At the time of the analysis, 13 (27.1%) patients had died; cause of death was mostly unknown, in two patients each, systemic/cerebral cause was confirmed. The mean overall survival (OS) was 131 months (range 64-344, SD 68) and 95 (range 60-246, SD 36) after diagnosis of primary tumor and BM, respectively. All patients suffering from melanoma who had received interferon therapy (n=8) survived. Neither systemic status at BM diagnosis nor the administration of novel treatment agents or chemotherapy after BM diagnosis showed an impact on OS (p=0.642, p=0.177 and p=0.628, respectively). Further survival analysis was omitted due to subgroup sizes. Conclusion Despite the usually fatal course after BM development, some patients show long-term survival. Whether specific genetic parameters have a particular impact in this subgroup of patients, warrants further investigation.

An exploratory study on support for caregivers of people with vision impairment in the UK.

PurposeMany of the UK's 2.5 million individuals living with vision loss receive support from relatives or friends (so‐called ‘informal caregivers’). However, there is limited understanding of how caregivers of people with visual impairment (PVI) are, or feel, supported by UK healthcare/statutory services and charities. This exploratory study was conducted to explore caregivers' experiences and their suggestions for enhancing support.MethodsParticipants self‐identifying as UK‐based caregivers of PVI (N = 100) volunteered to undertake an online survey, distributed through charity partners. The survey was comprised of the Client Satisfaction Questionnaire‐8 (CSQ‐8, a validated, self‐report measure of satisfaction with support services), Likert‐type questions and two open‐ended, free‐text questions. Interview participants (N = 22) were then selected from survey respondents, and semi‐structured interviews were conducted to focus on caregivers' ideas for improving support. The Framework Method was used for inductive analysis of the free‐text question responses and interview data.ResultsThe mean (SD) CSQ‐8 score was 21.60 (7.2), with no significant differences by demographic, relationship or vision‐related factors, likely limited by the small subgroup sizes. Qualitative data demonstrated the heterogeneity of participating caregivers' experiences, highlighting the importance of personalised support for caregivers. Many participants advocated enhancing informational, practical, emotional and social support for caregivers, and stressed the importance of accessible services and consistent points of contact to turn to for support and advice.ConclusionsAlthough our sample was arguably better connected to support services than the general caregiver population, this study identified concrete suggestions to improve practical, emotional and peer support for caregivers of PVI.

Monitoring multivariate coefficient of variation for high‐dimensional processes

AbstractMultivariate coefficient of variation (MCV) charts are effective tools for monitoring process relative variability. They are developed on the assumption that the process subgroup size available for monitoring the MCV parameter is larger than the number of process characteristics. In such a case, the unbiased estimates of the in‐control mean vector and covariance matrix are used to calculate the chart monitoring statistic. Here, we study the performance of MCV control charts when only a small subgroup size is available for estimating the in‐control mean vector and covariance matrix. We examine the use of a shrinkage estimate of the covariance matrix and propose two one‐sided upward and downward least absolute shrinkage and selection operator (LASSO)‐based MCV charts for detecting upward and downward shifts in the process MCV parameter, respectively. Our simulation study shows that the LASSO‐based MCV charts outperform the classical two one‐sided MCV charts when small subgroup sizes are available for monitoring. The improved performance of the proposed LASSO‐based MCV charts in monitoring shifts in the MCV parameter is demonstrated via an illustrative case study of carbon fiber tube application, where changes are detected earlier than the classical two one‐sided MCV charts.

Proposed tests for location and scale in a nondecreasing ordered alternative

Six nonparametric tests are proposed for the nondecreasing ordered alternative when testing for a difference in either location or scale. The six tests are various combinations of a well-known ordered alternative test for location and a technique that Moses used to convert a scale testing problem into a location testing problem by transforming the data. A simulation study is conducted to determine how well the proposed tests maintain their significance levels. Powers are estimated for the proposed tests under a variety of conditions for three, four and five populations. Several types of variable parameters are considered: when the location parameters are different and the scale parameters are equal; when the location parameters are equal and the scale parameters are different; when the location and scale parameters are both different. Equal and unequal sample sizes of 18 and 30 are considered. Subgroup sizes of 3 and 6 are both used when applying the Moses technique. Recommendations are given.

Abstract P5-05-03: Adipocyte associated methionine domain containing (AAMDC): A nuclear envelope protein with predictive and prognostic potential in luminal breast cancer

Abstract Background Estrogen receptor (ER) positive breast cancers (BCs) are less likely to relapse than other types, due to a lower propensity to disseminate and to sensitivity to anti-estrogen drugs in the adjuvant setting. However, combined analysis of DNA mutation and mRNA expression profiles in BC identifies a number of Integrative Clusters (IntClus), one of which, IntClus2, is characterized by ER positivity but high relpase and mortality. A hallmark of IntClus2 tumours is an amplification of chromosome 11, at the center of which lies the gene for the protein AAMDC. Pre-clinical research shows this protein to drive proliferation, migration, colony formation, switching between glucose and lipid metabolism, folate metabolism and anti-estrogen resistance. We postulated that resultant clinical behaviours could include; high relapse and mortality, anti-estrogen resistance, an interaction with the protective effect on relapse from statins and sensitivity to fluorouracil (FU)-based therapies. Methods The retrospective study cohort comprised 1766 ER positive early BC patients treated 1994-2014. Patient and tumour demographic, statin prescription and treatment data were collated. Primary tumour tissue was available with AAMDC expression data on 419 patients. On noting nuclear (N), cytoplasmic (C) and nuclear envelope (NE) expression, separate intensity scores were attributed to each localization. Intensity score cut-points were based on providing statistically useable sub-group sizes for comparison. Results No significant correlations between BC biology and patterns of AAMDC expression were seen. Cytoplasmic AAMDC weakly linked to some aggressive features, including high grade, luminal B sub-type and progesterone receptor negativity, although less lymph node spread. In contrast, nuclear AAMDC associated with some less aggressive features, being less in high grade and luminal B cancers. Nuclear envelope AAMDC was rarer in the HER2 positive sub-type without other correlates. A trend to higher distant relapse was seen for NE +ive BCs (20 v 14%, p=0.09). Overall mortality was statistically higher for NE expression (54 v 44% mortality, p=0.04) and cytoplasmic expression (56 v 47% mortality, p=0.04) and a trend to lower mortality for nuclear expression (46 v 54%, p=0.06). Looking at combinatorial expression, BC deaths were significantly lower in the nuclear +ive/NE -ive phenotype (4.7%) than the nuclear -ive/NE -ive (19.5%, p=0.013), nuclear -ive/NE +ive (17.6%, p=0.017) or nuclear +ive/NE +ive phenotypes (19.3%, p=0.011).Considering the effects of statins on early BC outcome, overall our patients on statins had notably lower BC return rates (HR 0.31, p=0.004). Considering interactions with AAMDC, in high-risk NE +ive cancers statin protection was high (HR for relapse 0.33, p=0.032), compared to no protection in already low risk NE -ive tumours (HR 0.90, p=0.41). The hypothesis that AAMDC confers sensitivity to FU-based agents was confirmed with a correlation observed for longer responses to FU-based chemotherapy for increasing NE AAMDC expression (R=0.334), whereas no link was seen for other agents or other AAMDC expression sub-locations. The mean times on FU-based therapy for low, moderate and high NE expression were 2.0, 5.7 and 12.2 months respectively (p=0.02). This work indicates that AAMDC expression can BC affect outcome, identifying nuclear envelope located AAMDC as both associating with higher mortality and correlating with superior protection from statins as well as response to FU-based chemotherapies. This could guide metastatic chemotherapy selection for affected patients, implies NE positive BCs might preferentially benefit from adjuvant statins and suggests that AAMDC and NE-associated AAMDC partners may be future therapeutic targets. Citation Format: Indunil Weerasena, Lisa Spalding, Benjamin F Dessauvagie, Emily Golden, Eleanor Woodward, Pilar Blancafort, Andrew Redfern. Adipocyte associated methionine domain containing (AAMDC): A nuclear envelope protein with predictive and prognostic potential in luminal breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-05-03.

Treatment and outcome of intracranial ependymoma after first relapse in the 2nd AIEOP protocol.

More than 40% of patients with intracranial ependymoma need a salvage treatment within 5 years after diagnosis, and no standard treatment is available as yet. We report the outcome after first relapse of 64 patients treated within the 2nd AIEOP protocol. We considered relapse sites and treatments, that is, various combinations of complete/incomplete surgery, if followed by standard or hypofractionated radiotherapy (RT) ± chemotherapy (CT). Molecular analyses were available for 38/64 samples obtained at first diagnosis. Of the 64 cases, 55 were suitable for subsequent analyses. The median follow-up was 147 months after diagnosis, 84 months after first relapse, 5-year EFS/OS were 26.2%/30.8% (median EFS/OS 13/32 months) after relapse. For patients with a local relapse (LR), the 5-year cumulative incidence of second LRs was 51.6%, with a 5-year event-specific probability of being LR-free of 40.0%. Tumor site/grade, need for shunting, age above/below 3 years, molecular subgroup at diagnosis, had no influence on outcomes. Due to variation in the RT dose/fractionation used and the subgroup sizes, it was not possible to assess the impact of the different RT modalities. Multivariable analyses identified completion of surgery, the absence of symptoms at relapse, and female sex as prognostically favorable. Tumors with a 1q gain carried a higher cumulative incidence of dissemination after first relapse. Survival after recurrence was significantly influenced by symptoms and completeness of surgery. Only a homogeneous protocol with well-posed, randomized questions could clarify the numerous issues, orient salvage treatment, and ameliorate prognosis for this group of patients.

Durvalumab After Concurrent Chemoradiotherapy in Elderly Patients With Unresectable Stage III Non–Small–Cell Lung Cancer (PACIFIC)

BackgroundThe PACIFIC trial demonstrated that consolidation durvalumab significantly improved PFS and OS (the primary endpoints) vs. placebo in patients with unresectable, stage III NSCLC whose disease had not progressed after platinum-based, concurrent chemoradiotherapy (CRT). We report exploratory analyses of outcomes from PACIFIC by age. Patients and MethodsPatients were randomized 2:1 (1-42 days post-CRT) to receive 12-months’ durvalumab (10 mg/kg intravenously every-2-weeks) or placebo. We analyzed PFS and OS (unstratified Cox-proportional-hazards models), safety and patient-reported outcomes (PROs: symptoms, functioning, and global-health-status/quality-of-life) in subgroups defined by a post-hoc 70-year age threshold. Data cut-off for PFS was February 13, 2017 and for OS, safety and PROs was March 22, 2018. ResultsOverall, 158 of 713 (22.2%) and 555 of 713 (77.8%) randomized patients were aged ≥70 and <70 years, respectively. Durvalumab improved PFS and OS among patients aged ≥70 (PFS: hazard ratio [HR], 0.62 [95% CI, 0.41-0.95]; OS: HR, 0.78 [95% CI, 0.50-1.22]) and <70 (PFS: HR, 0.53 [95% CI, 0.42-0.67]; OS: HR, 0.66 [95% CI, 0.51-0.87]), although the estimated HR-95% CI for OS crossed one among patients aged ≥70. Durvalumab exhibited a manageable safety profile and did not detrimentally affect PROs vs. placebo, regardless of age; grade 3/4 (41.6% vs. 25.5%) and serious adverse events (42.6% vs. 25.5%) were more common with durvalumab vs. placebo among patients aged ≥70. ConclusionDurvalumab was associated with treatment benefit, manageable safety, and no detrimental impact on PROs, irrespective of age, suggesting that elderly patients with unresectable, stage III NSCLC benefit from treatment with consolidation durvalumab after CRT. However, small subgroup sizes and imbalances in baseline factors prevent robust conclusions.

Maxillary and mandibular dental arch forms in a Jordanian population with normal occlusion

BackgroundEthnic background has been claimed to affect arch form. The purpose of this study was to describe and elucidate the maxillary and mandibular arch forms in Jordanian population and to develop a classification method for these forms which could be employed to construct orthodontic archwires accordingly.MethodsThe sample was comprised of study casts of five hundred and twenty subjects (231 males and 289 females with a mean age of 15.4 ± 1.02 years). All subjects had permanent dentition with normal occlusion. A mathematical method associated with a polynomial function of 6th degree was employed to assess the dental arch forms. The resultant arch forms were classified into 5 groups for both the maxilla and mandible utilizing a computer software with special code designed for this study. Each group was subdivided into 3 subgroup sizes namely: small, medium, and large.ResultsCatenary arch form was found in 47% and 41.2% (p ˂ 0.01) of maxilla and mandible arch forms, respectively. Form 2 (which is halfway between ellipse and U-shaped arch form) was found in 27.7% and 26.7%. Medium size arch form was found in 55.4% of the maxillary and 65.6% of the mandibular arch forms.ConclusionCatenary arch form was the most prevalent arch form, followed by wide elliptical form. The other forms, which included tudor arch, tapered equilateral and quadrangular forms were less frequent. Regarding size, the medium size was the most prevalent among the studied samples.