Younger Age Of Onset Research Articles

Maternal family history of urolithiasis is associated with earlier age of onset of stone disease.

To evaluate the impact of detailed family history on the severity of disease and age of onset in patients with urolithiasis. Prospectively collected data from a single institution between October 2015 and December 2020 were analyzed. Our primary endpoint was the number of patients experiencing at least one recurrent stone during the follow-up period. Of 1566 patients analyzed, 603 (39%) reported at least one family member with a history of stones. The percentage of patients experiencing at least one recurrent stone event was higher in patients with a family history of stones (38%) compared to those without a family history of stones (28%) over a median follow-up period of 8months (p = 0.001). On multivariate analysis, the presence of any family history of urolithiasis increased risk of recurrent stone events (odds ratio [OR] 1.62, p < 0.001). The presence of both a first- and a second-degree relative with urolithiasis was associated with higher odds for a recurrent stone event (OR 2.17; p = 0.003) and a younger age of onset for stones, (OR 3.32; < 0.001). A maternal-side relative with stones conferred a higher odds ratio for younger age of first onset of stones (OR 2.93; p < 0.001). Any family history of kidney stone disease imparts an increased risk of recurrent stone event and an earlier age of onset for urolithiasis. The presence of both first- and second-degree relatives or a maternal-side relative with kidney stones may be a predictor for an earlier age of onset for urolithiasis.

Clinical manifestations and prognosis of unexpected uterine sarcoma of uterine fibroids in Tianjin China

BackgroundUterine sarcoma is a rare malignancy of women and fewer uterine sarcomas are detected preoperatively. The reported incidence of preoperatively diagnosed uterine sarcoma (PDUS) was 0.07%. This study aims to identify the prevalence of unexpected uterine sarcoma (UUS) after operation for presumed leiomyoma and compare clinical outcomes after primary therapy.MethodsA retrospective study was performed evaluating all uterine sarcoma diagnosed in Tianjin Central Hospital of Gynecology and Obstetrics between May 2011 and July 2016.We used the χ2 and T tests to assess the incidence and clinical features of patients. The Kaplan–Meier method was used to calculate disease-related survival.ResultsThe study retrospectively analyzed 6625 patients with uterine fibroids and found 45 UUS patients and 21 patients of PDUS. The incidence of UUS is (45/6625) 0.67%. The incidence of UUS in patients undergoing total hysterectomy was higher undergoing tumor resection (P < 0.001); the age of UUS is younger than PDUS (P = 0.046); the differences in menopausal status and primary complaints between the two groups are not statistically significant. The PDUS group had more patients with Stage II and III sarcomas than the UUS group (P < 0.001); the duration of symptoms in the PDUS group was longer than in the UUS group (P = 0.033). The 5-year overall survival (OS) rate of the UUS group (77.7%) is higher than the PDUS group (46.3%) (P < 0.001).ConclusionsThe incidence of UUS is low. UUS has a younger age of onset, shorter history of the disease, earlier clinical stage, and better prognosis.

The Limb-Girdle Muscular Dystrophies

The limb-girdle muscular dystrophies (LGMDs) are a group of inherited muscle disorders with a common feature of limb-girdle pattern of weakness, caused by over 29 individual genes. This article describes the classification scheme, common subtypes, and the management of individuals with LGMD. Advances in genetic testing and next-generation sequencing panels containing all of the LGMD genes have led to earlier genetic confirmation, but also to more individuals with variants of uncertain significance. The LGMDs include disorders with autosomal recessive inheritance, which are often due to loss-of-function mutations in muscle structural or repair proteins and typically have younger ages of onset and more rapidly progressive presentations, and those with autosomal dominant inheritance, which can have older ages of presentation and chronic progressive disease courses. All cause progressive disability and potential loss of ability to walk or maintain a job due to progressive muscle wasting. Certain mutations are associated with cardiac or respiratory involvement. No disease-altering therapies have been approved by the US Food and Drug Administration (FDA) for LGMDs and standard treatment uses a multidisciplinary clinic model, but recessive LGMDs are potentially amenable to systemic gene replacement therapies, which are already being tested in clinical trials for sarcoglycan and FKRP mutations. The dominant LGMDs may be amenable to RNA-based therapeutic approaches. International efforts are underway to better characterize LGMDs, help resolve variants of uncertain significance, provide consistent and improved standards of care, and prepare for future clinical trials.

Factors associated with anxiety disorder comorbidity

BackgroundAnxiety and depressive disorders often co-occur and the order of their emergence may be associated with different clinical outcomes. However, minimal research has been conducted on anxiety-anxiety comorbidity. This study examined factors associated with anxiety comorbidity and anxiety-MDD temporal sequence. MethodsOnline, self-report data were collected from the UK-based GLAD and COPING NBR cohorts (N = 38,775). Logistic regression analyses compared differences in sociodemographic, trauma, and clinical factors between single anxiety, anxiety-anxiety comorbidity, anxiety-MDD (major depressive disorder) comorbidity, and MDD-only. Additionally, anxiety-first and MDD-first anxiety-MDD were compared. Differences in familial risk were assessed in those participants with self-reported family history or genotype data. ResultsAnxiety-anxiety and anxiety-MDD had higher rates of self-reported anxiety or depressive disorder diagnoses, younger age of onset, and higher recurrence than single anxiety. Anxiety-MDD displayed greater clinical severity/complexity than MDD only. Anxiety-anxiety had more severe current anxiety symptoms, less severe current depressive symptoms, and reduced likelihood of self-reporting an anxiety/depressive disorder diagnosis than anxiety-MDD. Anxiety-first anxiety-MDD had a younger age of onset, more severe anxiety symptoms, and less likelihood of self-reporting a diagnosis than MDD-first. Minimal differences in familial risk were found. LimitationsSelf-report, retrospective measures may introduce recall bias. The familial risk analyses were likely underpowered. ConclusionsAnxiety-anxiety comorbidity displayed a similarly severe and complex profile of symptoms as anxiety-MDD but distinct features. For anxiety-MDD, first-onset anxiety had an earlier age of onset and greater severity than MDD-first. Anxiety disorders and comorbidity warrant further investigation and attention in research and practice.

Analysis of the Epigenetic Mechanism and Treatment of Huntington’s Disease

Huntington’s disease (HD) is an irreversible neurodegenerative disorder that is inherited in an autosomal dominant manner. In HD, many regions of the human brain are affected, including the striatum, thalamus, and cortex. The mechanism is by the expansion of CAG repeats, which encode glutamine (Q) in the Huntingtin gene on chromosome 4p16.3. Patients with more CAG repeats tend to have a younger age of onset and a higher risk. Mutant HTT protein, translated from mtHtt, would congregate or interact with other proteins, causing damage to the human body. Patients with HD show symptoms like chorea, which is an involuntary motor disability, cognitive deterioration, and psychiatric disturbances. Except for the genetic pathology of HD, the epigenetic mechanism of this disease has made a lot of progress in recent years. This paper primarily focuses on the alternation of deoxyribonucleic acid (DNA) methylation, histone modification, and non-coding ribonucleic acids (ncRNAs) in HD as well as the advancements of epigenetic therapy and healthcare in HD.

Abstract A001: Clinical-genomic analysis of KRAS wild-type pancreatic cancer confirms alternative targetable drivers and provides insight for age and risk related clinical stratification

Abstract Approximately 8-10% of pancreatic cancers do not harbor mutations in KRAS. Understanding the unique molecular and clinical features of this subset of pancreatic cancer (PC) is important to guide patient stratification for clinical trials of molecularly targeted agents. To this end we investigated a cohort of 795 PC patients from Dana-Farber Cancer Institute who had undergone somatic genomic characterization with OncoPanel, a targeted next-generation sequencing panel with coverage of more than 400 cancer-associated genes. A total of 9.2% (73/795) of cases in our cohort were KRAS WT. The KRAS WT cohort was statistically enriched for MSI-H PC and acinar cell carcinomas (p = 0.0035, p &amp;lt; 0.0001 respectively). Actionable alterations in alternative MAPK drivers were identified in 44% (32/73) of KRAS WT cases. BRAF alterations accounted for 56% (18/32) of detected alternative MAPK drivers, the majority of which (72%) were Class II which exhibit dimer-dependent constitutive activity. Receptor Tyrosine Kinase (RTK) fusion events in BRAF, NTRK1, NRG1, NTRK3, ROS1, and FGFR2 accounted for 25% (8/32) of detected alternative MAPK drivers in KRAS WT tumors. BRAF in-frame deletions showed increased sensitivity to dual pan-RAF and MEK inhibition in organoid models and one patient with a ROS1 fusion received prolonged clinical benefit from targeted therapy. In addition to alternative MAPK drivers, mutations in GNAS (p = 0.0014) and ARID2 (p = 0.045) were significantly enriched in KRAS WT PC, whereas TP53 mutations were significantly less frequent in KRAS WT cases. Interestingly, although not statistically significant, rates of mutation in the other canonical tumor suppressor genes (CDKN2A, SMAD4) were also lower in KRAS WT PC. Clinically, KRAS Mutant (MUT) PC were associated with a decreased overall survival (OS) compared to the KRAS WT cohort [median OS 17.5 vs 24.0 months, HR 1.38, p = 0.036], however this relationship was no longer significant after accounting for other clinical factors. For patients with KRAS WT PC, those with SMAD4 alterations had a significantly decreased OS (HR 6.24, p &amp;lt; 0.001), whereas presence of TP53 or CDKN2A mutations had no significant impact. Lastly, we found that KRAS WT PC was associated with a younger age of onset. Interestingly, we noted that KRAS WT PC patients with a younger age of onset had tumors with few oncogenic alterations whereas no such association was seen in KRAS MUT patients. Validation of this finding in a separate dataset is required and is currently ongoing. In summary, our clinical and genomic characterization of KRAS WT PC identifies a high prevalence of alternative MAPK drivers that are amenable to targeted therapies. Our cohort also recapitulates the previously reported clinical characteristics of KRAS WT PC and identifies the presence of SMAD4 alterations as significantly associated with decreased overall survival in KRAS WT PC. Additional analysis from multiple sources will be critical to risk stratify these patients further and to validate age-related findings. Citation Format: Harshabad Singh, Rachel B. Keller, Kevin S. Kapner, Julien Dilly, Srivatsan Raghavan, Chen Yuan, Eizabeth Cohen, Michael Tolstorukov, Emma Hill, Elizabeth Andrews, Lauren K. Brais, Annacarolina Da Silva, Kimberly Perez, Douglas A. Rubinson, Benjamin L. Schlechter, Michael H. Rosenthal, Jason L. Hornick, Valentina Nardi, Yvonne Li, Hersh Gupta, Andrew Cherniack, Mathew L. Meyerson, James M. Cleary, Jonathan A. Nowak, Brian M. Wolpin, Andrew A. Aguirre. Clinical-genomic analysis of KRAS wild-type pancreatic cancer confirms alternative targetable drivers and provides insight for age and risk related clinical stratification [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A001.

Epidemiological Features and Clinical Outcomes Predicting Risk and Prognosis of Transformed Marginal Zone Lymphoma: A SEER-Based Population Study

Aim: Diffuse large B-cell lymphoma (DLBCL) transformed from marginal zone lymphoma (MZL) is a rare subtype of non-Hodgkin's lymphoma. The clinical outcomes and prognosis of transformed MZL (trMZL) have not been well defined so for. Our study aimed to explore the epidemiology, clinical characteristics and survivals of trMZL with population-based data. Method: A total of 315 cases of trMZL patients diagnosed from 2000 to 2019 were extracted from the Surveillance, Epidemiology, and End Results (SEER) program. Logistic regression was utilized to estimate the risk factors of DLBCL transformation of MZL. Multiple linear regression was conducted to explore the risk factors of early DLBCL transformation in trMZL patients. The least absolute shrinkage and selection operator (LASSO) Cox regression analysis was applied to investigate the epidemiological and clinical factors associated with the overall survival of trMZL patients from diagnosis (OS1) and from transformation (OS2), respectively. Cox proportional hazard regression was further used to determine the independent prognostic factors for OS1 and OS2. Nomograms were developed to predict survival possibilities of 5-, 10- and 15-years OS1. Results: Overall incidence of DLBCL transformation in MZL was 1.58% (315/19675). The 2-, 5-, and 10-years cumulative incidence of DLBCL transformation was 0.41%, 1.13%, and 2.00%, respectively. The median age at diagnosis and at transformation of trMZL patients was 64 years old (range: 25 ~ 89) and 69 years old (range: 34 ~ 91), respectively, with female and White race predominance. Median OS1 and OS2 were 140.0 months (95% CI: 120.5 ~ 159.5) and 53.0 months (95% CI: 35.1 ~ 71.0) respectively, which were significantly worse than that of de novo MZL (median OS 195.0 months [95% CI: 187.77~ 202.3]) and de novo DLBCL (median OS 119.0 months [95% CI: 116.5 ~ 121.5]). Splenic marginal zone lymphoma and Ann Arbor stage III/IV were the risk factors for DLBCL transformation, whereas trMZL patients with older age at diagnosis, non-White race and without radiotherapy may be subjected to early transformation. Multivariate Cox regression demonstrated that five variables were significant prognostic factors associated with superior OS1 (P<0.05), including younger age at diagnosis, female, radiotherapy, surgery, and later DLBCL transformation. With regards to treatment modality, surgery plus radiotherapy could significantly improve patients' OS1 in comparison to chemotherapy-containing treatment regimes. However, only younger age at transformation and female were significantly associated with better OS2 (P<0.05). The nomogram for trMZL was established to predict 5-, 10-, and 15-years OS1 possibility, which was verified by a high concordance index [0.75 (0.73-0.77), P<0.05] and good agreement with the predicted value in calibration plots. Conclusion: The trMCL is a rare neoplasm with a low incidence of DLBCL transformation. Splenic marginal zone lymphoma and advanced stage may increase the risk of DLBCL transformation in MZL patients. Patients with trMCL exhibited distinct clinical features and outcomes. In addition to younger age of onset, use of surgery plus radiotherapy and late DLBCL transformation were associated with favorable prognoses for trMZL patients.

Tumor suppressor DEAR1 regulates mammary epithelial cell fate and predicts early onset and metastasis in triple negative breast cancer

Triple negative breast cancer (TNBC) is a disease of poor prognosis, with the majority classified as the basal-like subtype associated with epithelial-mesenchymal transition and metastasis. Because basal breast cancers originate from proliferative luminal progenitor-like cells upon dysregulation of proper luminal differentiation, genes regulating luminal-basal transition are critical to elucidate novel therapeutic targets to improve TNBC outcomes. Herein we demonstrate that the tumor suppressor DEAR1/TRIM62 is a critical regulator of luminal cell fate. DEAR1 loss in human mammary epithelial cells results in significantly enhanced mammosphere formation that is accelerated in the presence of TGF-β/SMAD3 signaling. Mammospheres formed following DEAR1 loss are enriched for ALDH1A1 and CK5 expression, EpCAM−/CD49f+ and CD44high/24low basal-like epithelial cells, indicating that DEAR1 regulates stem/progenitor cell properties and luminal-basal progenitor transition. We show that DEAR1 maintains luminal differentiation as a novel ubiquitin ligase for SNAI2/SLUG, a master regulator driving stemness and generation of basal-like progenitor populations. We also identify a significant inverse correlation between DEAR1 and SNAI2 expression in a 103 TNBC case cohort and show that low DEAR1 expression significantly correlates with young age of onset and shorter time to metastasis, suggesting DEAR1 could serve as a biomarker to stratify early onset TNBCs for targeted stem cell therapies.

The SOD1-mediated ALS phenotype shows a decoupling between age of symptom onset and disease duration

Superoxide dismutase (SOD1) gene variants may cause amyotrophic lateral sclerosis, some of which are associated with a distinct phenotype. Most studies assess limited variants or sample sizes. In this international, retrospective observational study, we compare phenotypic and demographic characteristics between people with SOD1-ALS and people with ALS and no recorded SOD1 variant. We investigate which variants are associated with age at symptom onset and time from onset to death or censoring using Cox proportional-hazards regression. The SOD1-ALS dataset reports age of onset for 1122 and disease duration for 883 people; the comparator population includes 10,214 and 9010 people respectively. Eight variants are associated with younger age of onset and distinct survival trajectories; a further eight associated with younger onset only and one with distinct survival only. Here we show that onset and survival are decoupled in SOD1-ALS. Future research should characterise rarer variants and molecular mechanisms causing the observed variability.

Epidemiological characteristics and genetic alterations in adult diffuse glioma in East Asian populations.

Understanding the racial specificities of diseases-such as adult diffuse glioma, the most common primary malignant tumor of the central nervous system-is a critical step toward precision medicine. Here, we comprehensively review studies of gliomas in East Asian populations and other ancestry groups to clarify the racial differences in terms of epidemiology and genomic characteristics. Overall, we observed a lower glioma incidence in East Asians than in Whites; notably, patients with glioblastoma had significantly younger ages of onset and longer overall survival than the Whites. Multiple genome-wide association studies of various cohorts have revealed single nucleotide polymorphisms associated with overall and subtype-specific glioma susceptibility. Notably, only 3 risk loci-5p15.33, 11q23.3, and 20q13.33-were shared between patients with East Asian and White ancestry, whereas other loci predominated only in particular populations. For instance, risk loci 12p11.23, 15q15-21.1, and 19p13.12 were reported in East Asians, whereas risk loci 8q24.21, 1p31.3, and 1q32.1 were reported in studies in White patients. Although the somatic mutational profiles of gliomas between East Asians and non-East Asians were broadly consistent, a lower incidence of EGFR amplification in glioblastoma and a higher incidence of 1p19q-IDH-TERT triple-negative low-grade glioma were observed in East Asian cohorts. By summarizing large-scale disease surveillance, germline, and somatic genomic studies, this review reveals the unique characteristics of adult diffuse glioma among East Asians, to guide clinical management and policy design focused on patients with East Asian ancestry.

RF27 | LBSUN361 Understanding The Genetics Of Multiple Endocrine Neoplasia Type 1: The Road Ahead

Abstract Background About 10-30% patients have genotype-negative (GN)-MEN1. Here, we compare our cohort of comprehensively phenotyped GN-MEN1 and genotype-positive (GP)-MEN1 patients. We also investigate somatic mosaicism as a cause of GN-MEN1. Methods GN-MEN1 patients showed no mutations in MEN1 or other primary hyperparathyroidism (PHPT) genes (CASR, RET, CDKN1B, CDC73, AIP, GNA11, AP2S1, GCM2) performed per clinical indication. Index patients (first patient in kindred to be diagnosed with MEN1) or probands (first patient in kindred to be evaluated at our center) from kindreds with GP-MEN1 were identified. All patients underwent testing for tumor biomarkers, imaging and evaluation for Zollinger-Ellison syndrome (ZES). Whole exome sequencing was performed on multiple tumors from 13 GN-MEN1 patients. GP-MEN1 patients were also categorized into high-impact (nonsense, frameshift, splice site, whole or partial gene deletion) or low-impact (missense or in-frame indels) mutation-bearing groups. Results We identified 43 (31 females, 12 males) patients with GN-MEN1 and 160 (102 index, 58 probands) patients with GP-MEN1 (98 females, 62 males). Among GP-MEN1, 97 had high impact and 34 had low-impact mutations. Mean age at last follow-up was 56 (±14) years for GN-MEN1 and 52 (±16) years for GP-MEN1 patients. Among the GN-MEN1 patients, 38/42 developed PHPT - 3/38 (8%) had recurrent disease. In GP-MEN1, 144/149 developed PHPT - 83/144 (58%) with recurrent disease. Median age of index presentation with PHPT significantly differed between the groups (27.5 years in GP-MEN1 vs 53 years in GN-MEN1 (χ2 (1)=5.5: p &amp;lt;0.05)). 33/42 GN-MEN1 patients had a pituitary adenoma (22/33 functioning - 9/22 prolactinomas; 8/22 GH-secreting). In comparison, 94/145 GP-MEN1 patients developed a pituitary adenoma (51 functioning - 37/51 prolactinomas, no GH-secreting tumors). In the GN-MEN1 group, 12/42 (29%) patients developed a gastro-entero-pancreatic (GEP)-NET. In comparison, 86/130 (66%) patients with GP-MEN1 had a GEP-NET. Somatic variants in MEN1, CDC73 or CDKI were observed in six tumors. However, these mutations were not seen in another tumor/s or germline DNA from the patient. All patients with high-impact mutations had PHPT (63% had recurrent disease), 70% had pituitary tumors (35% with macro-adenomas) and 61% developed GEP-NETs (29% with distant metastases). In comparison, 91% patients with low-impact mutations developed PHPT (41% with recurrent disease), 69% developed pituitary tumors (23% with macro-adenomas) and 65% developed GEP-NETs (35% with distant metastases). Conclusion Patients with GP-MEN1 generally experience younger age of onset, greater likelihood of recurrent PHPT and co-occurrence of GEP-NETs in comparison to GN-MEN1. Our findings do not support somatic mosaicism as a cause of GN-MEN1. No apparent correlation in phenotype between high-impact vs. low-impact mutations is noted. Presentation: Monday, June 13, 2022 12:51 p.m. - 12:56 p.m.

Effects of metabolic surgery on islet function in Asian patients with type 2 diabetes

Type 2 diabetes is a high-profile global public health problem, particularly in Asia. The young age of onset, low body mass index, and early appearance of pancreatic islet dysfunction are characteristics of Asian patients with T2DM. Metabolic surgery has become the standard treatment for T2DM patients and can significantly improve T2DM through a variety of mechanisms including modulation of energy homeostasis and reduction of body fat mass. Indeed, restoration of islet function also plays an integral role in the remission of T2DM. After metabolic surgery, islet function in Asian T2DM patients has improved significantly, with proven short-term and long-term effects. In addition, islet function is an important criterion and reference for patient selection prior to metabolic surgery. The mechanism of islet function improvement after metabolic surgery is not clear, but postoperative anatomical changes in the gastrointestinal tract leading to a number of hormonal changes seem to be the potential cause, including glucagon-like peptide-1, gastric inhibitory polypeptide, peptide YY, ghrelin, and cholecystokinin. The authors analyzed the current retrospective and prospective studies on the effect of metabolic surgery on the islet function of Asian T2DM patients with a low BMI and its mechanism, summarized the clinical evidence that metabolic surgery improved islet function in Asian T2DM patients with a low BMI, and discussed its underlying mechanism. It is of great significance for realizing personalized and precise treatment of metabolic surgery and further improving its clinical benefits.

Prevalence of Neurocognitive Impairment for NPC Survivors after Definitive Intensity-Modulated Radiotherapy: A Cross-Sectional Study

<h3>Purpose/Objective(s)</h3> High-dose intensity-modulated radiotherapy (IMRT) has led to excellent prognosis in patients with localized nasopharyngeal carcinoma (NPC). Given the relatively young age of onset and the close anatomic relationship between the nasopharynx and the central nervous system, post-radiation neurocognitive impairment among long-term survivors represents an under-recognized late complication. This study aims to determine the prevalence and the affected cognitive domains in post-IMRT NPC survivors. <h3>Materials/Methods</h3> We undertook a cross-sectional study in a high-volume tertiary oncology center in Hong Kong. NPC survivors who underwent IMRT with a minimal post-radiotherapy interval of 1 year were eligible. All patients underwent an initial screening using the Montreal Cognitive Assessment-Hong Kong (MoCA-HK) test, followed by a 2-hour comprehensive battery of neurocognitive assessments covering 8 distinct domains: intellectual capacity (WAIS-IV), attention span (WAIS-IV digit span, WMS-III Visual Spatial Span), visual memory (WMS-III Visual reproduction span), verbal memory (Auditory Verbal Learning Test), processing speed (Color Trail Test), executive function (Stroop Test), motor dexterity (Grooved Pegboard Test) and language ability (Verbal Fluency Test). Mean percentiles and Z-scores of all neurocognitive assessments were compared with age- and/or education-matched population normative data using one-sample t-tests. Correlation of cognitive outcomes with clinical factors were analyzed using multivariable linear regression. <h3>Results</h3> A total of 182 NPC survivors were enrolled. The median post-radiotherapy interval was 6.9 years, 129 (70.9%) were long-term survivors at least 5 years beyond radiotherapy. The median age was 56 years old, 89% of the enrolled patients had stage III-IVA NPC by AJCC/UICC 8^th Edition, and 87% of patients received chemotherapy. The mean MoCA score was 23.6, 25.8% of patients were considered cognitively impaired. NPC survivors demonstrated significant cognitive impairment in verbal memory (p<0.001), processing speed (p<0.001), executive function (p<0.001), motor dexterity (p<0.001) and language ability (p=0.001). Most significant impairment was observed in executive function, mean z-scores of which were -1.76 to -1.38 below normative data. Post-IMRT interval, disease stage and chemotherapy usage showed no significant association with the degree of neurocognitive impairment. <h3>Conclusion</h3> Post-IMRT neurocognitive impairment was prevalent in NPC survivors. Neurocognitive function was not impaired globally but occurred predominantly in selected domains, particularly executive function. Cognitive assessment and training should be considered a part of survivorship care for NPC patients. Future research on the correlation between neurocognitive function and radiation dosimetry of various brain subsites would be informative.

Effect of diagnosis delay on pulmonary function in children with asthma

BackgroundThe effects of a delayed diagnosis of asthma on lung function in children have not been well investigated. Therefore, a retrospective cohort study was conducted in a children’s hospital to analyse the effect of delayed diagnosis time on lung function in children with asthma.MethodsWe conducted a retrospective cohort study in Jinan Children's Hospital from January 1, 2010, to December 31, 2020. All children were divided into different groups according to the presence or absence of rhinitis, age at first onset (first coughing and wheezing attack) and delayed diagnosis duration (≤ 3 months, 3–12 months, 1–3 years, 3–5 years and > 5 years).ResultsA total of 1,014 children with asthma were included in this study. The median (quartile) delay in asthma diagnosis among all participants was 11 (2, 26) months. The shortest delay in diagnosis time was on the same day of onset, and the longest delay in diagnosis time was 10 years. The median (quartile) duration of delayed diagnosis was 10 (2, 26) months in 307 asthmatic children without rhinitis and 11 (2, 26) months in 707 children with asthma and rhinitis (P < 0.05). The delayed diagnosis time was shorter among female children than among male children (P < 0.05), and the first %predicted forced volume capacity (FVC%pred) results for females were higher than those for males (P = 0.036). The children whose age at first asthma onset was ≤ 3 years had a longer delayed diagnosis duration than those whose age at first onset was > 3 years (P < 0.05). The FVC%pred and %predicted forced expiratory volume in 1 s (FEV1%pred) in the first and second pulmonary function tests were significantly lower in the five delayed diagnosis groups (all P < 0.05). After standardised treatment for 3–6 months, FVC%pred showed a significant difference in the third test among the 5 groups (P < 0.05), but the other pulmonary function indices showed no significant difference. Logistic regression analysis showed that longer delay and young age of onset were associated with lower lung function (P < 0.05), whereas sex, rhinitis and eczema had no significant effects (all P > 0.05) on FVC%pred and FEV1%pred.ConclusionAlthough delayed asthma diagnosis can lead to lung function impairment in children with asthma, lung function can be improved quickly after standardised treatment. Therefore, early asthma diagnosis and standardised treatment are very important.

ISPAD Clinical Practice Consensus Guidelines 2022: Diabetes in adolescence.

ISPAD Clinical Practice Consensus Guidelines 2022: Diabetes in adolescence.

The Prognosis of Diabetic Foot Ulcer is Independent of age? A Comparative Analysis of the Characteristics of Patients with Diabetic Foot Ulcer in Different age Groups: A Cross-Sectional Study from China.

Background: With younger onset age of type 2 diabetes mellitus (T2DM), the incidence of diabetic foot ulcer (DFU) in young and middle-aged adults is also increasing. Elucidating the distinctive characteristics of DFU in different ages and exploring the influence of age on the prognosis of DFU are crucial to the improvement of DFU treatments. Methods: 684 patients hospitalized for DFU in the department of endocrinology were recruited and assigned into the young and middle-aged group (age <65 years old) and the elderly group (age ≥65 years old). Demographic data and clinical features were compared between two groups. Results: Compared with the elderly group, the young and middle-aged group had higher proportion of males (72.3% vs 49.6%, P < .01) and smokers (52.5% vs 35.8%, P < .01), shorter duration of diabetes mellitus (155 months vs 196 months, P < .01), higher levels of glycosylated hemoglobin (9.3% vs 8.7%, P < .01), lower ratio of ankle-brachial index <0.9 (25.8% vs 51.1%, P < .01) and higher levels of c-reactive protein and erythrocyte sedimentation rate (14 mg/L vs 10 mg/L, P < .05; 36 mm/h vs 30 mm/h, P < .05). The prevalence of diabetic peripheral neuropathy and Wagner Grade were similar in two groups. Of note, the prognosis was similar in different age groups, as there were no significant differences in the healing rate (59.7% vs 60.1%, P > .05), healing time (30 days vs 22 days, P > .05) and minor amputation rate (11.9% vs 8.7%, P > .05). Conclusions: We found that no evidence to suggest a better prognosis with younger DFU patients. Compared with elderly ones, young and middle-aged patients were characterized by a higher proportion of smoking, worse glycemic control, higher inflammatory biomarkers but less severe lower limb ischemia, indicating that smoking cessation, strict blood glucose control and early detection of infection were crucial for improving the prognosis of young and middle-aged diabetic DFU patients.

Adherence to NCCN screening guidelines for germline testing of patients with pancreatic cancer at a large academic medical center: A retrospective chart review.

342 Background: Pancreatic ductal adenocarcinoma (PDAC) carries a poor prognosis with an overall 5-year survival rate of 10%. Depending on geographic region, 10-20% of cases are hereditary, with mutations in BRCA1 and BRCA2 being the most common. Contrary to popular belief, clinical risk factors such as family history of cancer and young age of onset are not reliable predictors for which patients may carry one of these predisposing mutations. In 2018, the National Comprehensive Cancer Network (NCCN) recommended that all pancreatic cancer patients should receive germline testing, regardless of family history. In a compliance analysis, we hypothesized that patients diagnosed after the NCCN guideline changes were more likely to be referred for genetic testing than those diagnosed beforehand. Methods: We conducted a retrospective chart review to compare trends in genetic testing of PDAC patients diagnosed from 02/17 - 07/18 versus 08/18 - 01/20, pre- and post-changes to NCCN guidelines, respectively.Family and personal cancer history, referral patterns and results of genetic counseling (GC) were recorded. Data were compared using Chi-square, Fisher’s Exact, and multivariate analyses. Results: There were 268 patients treated for PDAC (128 pre-, 140 post-) at a large academic institution. Demographics across both groups were comparable. A total of 175 were seen by our institution’s medical oncologist (84 pre-, 91 post-). Overall, 52 were referred to GC, 32 attended, 12 at our institution. More PDAC patients were referred to GC following the guideline changes (21% vs. 47%, p= 0.0005, Table). Patients with a family history of cancer were more likely to be referred to genetic testing (51% vs. 19%, p = 0.0002). This was the case for both pre- (odds ratio (OR) = 15.217 (95% CI, 2.725, 286.663)) and post- (OR = 3.353, (95% CI 1.263, 9.435)) eras, but the effect was not statistically significant when compared between eras ( p= 0.2034). Of all patients who underwent genetic testing, 27% were found to have a deleterious germline mutation related to hereditary PDAC. Conclusions: Despite a significant increase in referrals of PDAC patients for genetic testing following the guideline changes, adherence remains inconsistent with more than half of patients still not being referred. As a limitation of this study, we were not able to capture if patients were referred for GC outside of our network. Historically, the medical oncologist places the referral. However, as a possible solution to improve guideline adherence, referral for genetic testing could be initiated after initial diagnosis of PDAC by any provider, regardless of their role on the healthcare team.[Table: see text]

The relationship between eating disorders and OCD symptom dimensions: An explorative study in a large sample of patients with OCD

ObjectivesThis study aimed to describe lifetime and current rates of occurrence of comorbid eating disorders (ED) in a large clinical OCD sample, and to investigate whether comorbid ED in OCD (OCD+ED) are associated with specific demographic, somatic or clinical characteristics. MethodData were obtained from the Netherlands Obsessive Compulsive Disorder Association (NOCDA) study. A sample of 419 participants with lifetime OCD was evaluated on co-occurrence with ED. ResultsLifetime comorbidity with ED occurred in 44 patients (10.5% of the sample), a frequency that exceeds prevalence rates in the normal population. Patients with OCD+ED were on average overweight compared to OCD-ED. The OCD+ED group reported more aggression and checking symptoms and had a younger age of onset of OCD. Further, more comorbidity with MDD, social phobia, PTSD, and depression and anxiety symptoms was reported. ConclusionPatients with OCD+ED seem to clinically represent a sub-group of OCD with more severe psychopathology, and specifically with trauma-related factors and comorbid anxiety and depressive symptoms. Future studies using a longitudinal design should focus on whether patients with OCD+ED differ regarding course characteristics from patients with OCD-ED. Finally, comorbidity with depression, social anxiety and trauma should be taken into account in treatment of patients with OCD+ED.

Relationship between Severity of Disease and Postoperative Neurological Recovery in Patients with Cervical Spondylotic Myelopathy Combined with Developmental Spinal Stenosis.

Objective The study aimed to investigate the correlation between the severity of disease and postoperative neurological recovery in patients with cervical spondylotic myelopathy (CSM) combined with developmental spinal stenosis. Methods A retrospective analysis of the clinical data of 114 CSM patients combined with developmental spinal stenosis admitted to our hospital from June 2019 to June 2020 was performed. All of the patients who underwent posterior cervical unidoor vertebroplasty were divided into the mild, moderate, and severe groups according to the Torg–Pavlov ratio. The clinical data including patients' age, course of spinal cord high signal change, and first onset age were collected. The recovery time, preoperative, and postoperative Japanese Orthopaedic Association (JOA) scores of patients in each group were compared with the calculation of the improvement rate. The correlation between the severity of disease and postoperative neurological recovery in CSM patients combined with developmental spinal stenosis was analyzed by Pearson correlation. The factors influencing postoperative neurological recovery were analyzed using multivariate logistic regression analysis. The receiver operating characteristic curve (AUC) was used to evaluate the value of each influencing factor in predicting postoperative recovery. Results Significant differences were observed in the proportion of linear hyperintensity changes in the spinal cord, the age of first onset, the course of the disease, and the Torg–Pavlov ratio among the mild, moderate, and severe groups (P < 0.05). The postoperative recovery time of the moderate and severe groups was significantly higher than that of the mild group, while the preoperative JOA score was significantly lower than that of the mild group. On the other hand, the postoperative recovery time of the severe group was prominently higher than that of the moderate group, whereas the preoperative JOA score was observably lower than that of the moderate group (P < 0.05). Pearson correlation analysis showed that the postoperative recovery time was significantly negatively correlated with the Torg–Pavlov ratio, age at first onset, and disease course (r = −0.359, −0.502, −0.368, P < 0.05), while it was positively correlated with spinal cord linear high-signal changes (r = 0.641, P < 0.05). Multifactorial logistic regression analysis revealed that the Torg–Pavlov ratio, age at first onset, and disease course were protective factors, while spinal cord linear high-signal alterations were risk factors affecting the recovery time of postoperative neurological function (P < 0.05). The area under the curve (AUC) of the Torg–Pavlov ratio, linear hyperintensity changes in the spinal cord, age at first onset, and disease duration in predicting the postoperative neurological recovery time were 0.794, 0.767, 0.772, and 0.802, respectively. The AUC predicted by the combined detection of each factor was 0.876, which was better than the area under the curve of single prediction. Conclusion Patients with CSM combined with developmental spinal stenosis were characterized by younger age of onset, a short course of the disease, and linear changes in the spinal cord high signal. The degree of developmental spinal stenosis may affect the postoperative recovery time of neurological function in CSM patients but had little effect on postoperative neurological recovery. The Torg–Pavlov ratio, age of first onset, course of the disease, and changes in the spinal cord linear hyperintensity were the factors that affected postoperative neurological recovery, which may provide a basis for reasonably predicting a postoperative neurological recovery in patients with CSM combined with developmental spinal stenosis.

P42 Primary Sjogren’s Syndrome (pSS) in a seronegative adolescent female with family history of BehÇet’s disease: A challenging disease to diagnose Case-based discussion

Introduction/BackgroundSjogren’s Syndrome (SS) is heterogenous chronic autoimmune disease with symptoms ranging from organ-specific to variable non-specific systemic features. It is a rare disease in childhood and can be very difficult to diagnose, especially in seronegative patients, with the absence of any specific diagnostic investigation or criteria. We are presenting a seronegative juvenile Primary Sjogren’s syndrome (pSS) patient with all the challenges we had to confirm the diagnosis and a highlight on the role of MDT as the most sensitive tool.Description/MethodA 14-year-old female patient was first referred to our Paediatric and adolescent rheumatology department at the age of 10 with history of recurrent bilateral painful parotid swellings since the age of 3 with absence of ANA, RF, Anti-SSA-Ro and Anti-SSB-La antibodies repeatedly. From 2016 till 2019 she was under the care of ENT with recurrent complicated bilateral ear infections. Episodes tend to occur every 2-3 weeks and last between a few days to 2 weeks. Her events were associated with fever, fatigue, shivering, joint and leg pain, cervical lymphadenopathy, infrequent folliculitis, and headaches. No history to indicate mouth or eye dryness or significant repeated ulcers. Both of our patient’s mother and maternal grandmother have Behçet’s disease. Further blood investigation only showed mild hypergammaglobulinemia with mildly elevated ESR and CRP, normal LFT, U&Es, complements, muscle enzymes and thyroid function. HIV serology was negative and serum IgG4 subclass was normal. Many USSs confirmed parotitis. Parotid gland biopsy was not specific and indicated chronic parotitis with diffuse infiltration of mature lymphocytes, periductal lymphocytic inflammation and exocytosis of lymphocytes into the ductal epithelium. Focus score nearly reaching 50 cells. Plasma cell staining ruled out IgG4 related disease. Ophthalmic assessment ruled out eye involvement by the appearance of her eyes. The Oral Medicine Team confirmed the appearance of dry mucosa with minimal salivary flow from the parotid ducts, though it has not been subjectively reported to cause any problem before. Failed trial of colchicine, never been off-prednisolone for at least the last 2 years, tried Methotrexate which resulted in significant but not full improvement. Now she is on azathioprine and Hydroxychloquine, but still reporting flares. Escalation in treatment is required though there are some concerns about previous medication compliance, the actual severity of symptoms reported and the lack of current suitable accommodation.Discussion/ResultsDiagnosing pSS is quite challenging especially in seronegative patients due to the possibility of other non-autoimmune diseases causing recurrent parotid gland swellings, especially Recurrent Juvenile Idiopathic Parotitis with very young age of onset. With the persistence of symptoms and lack of an underlying infection, our patient ended up having a parotid biopsy. This was generally not specific, with a focus score close to the 50 mononuclear cells required as evidence of exocrine inflammation. This further added to the challenge of confirming an underlying autoimmune disease. Nine years into the disease course, our patient was confirmed to have objective evidence of dry mucosa and decreased salivary flow from the parotid ducts. This shows how important it is to assess salivary and lacrimal gland dysfunction in a child with suspected pSS, despite the absence of typical xerophthalmia and xerostomia. Considering the non-typical features (sero-negativity and the non-specific histopathology findings), our patient clinical picture was discussed in an MDT meeting including ENT, Histopathology and Rheumatology and the diagnoses of pSS was confirmed. The chronicity of the disease, significant improvement of the flare frequency and severity while on immunosuppressants, the reoccurence of significant flares when the patient was off-treatment (personal decision), and the objective evidence of poor salivary flow all supported the diagnosis of pSS later in the disease course. This case shows us how the typical adult features of pSS should not be strictly applied to the juvenile form of the disease. It also highlights the importance of having an MDT as the most sensitive available tool to confirm the diagnosis.Regarding lack of subjective full response, how do you think we can prove this objectively and what would be the most appropriate next step in treatment escalation?Key learning points/ConclusionA high index of suspicion is crucial to reach the diagnosis and to avoid irreversible damage in children with SS.Quadrable sero-negativity should not be looked at as an absolute exclusion criterion of juvenile pSS.Exclusion of other more common and diverse causes of parotitis is crucial.The typical adult features of SS should not be strictly applied to the juvenile form of the disease.MDT approach is the most sensitive tool to diagnose SS.When there is no subjectively reported ophthalmic or oral dryness, we would advocate sending suspected children of pSS for formal assessment of it- we understand the age-related challenges.Considering its rarity, we need to improve the general awareness of the juvenile form of the disease among the population and the medical practitioners.