Статті в журналах з теми "536.2.083, 662.711"

Aim This study aimed to investigate the relationship between sarcopenia and change in bone mineral density (BMD) and functional outcome in hip arthroplasty patients. Methods: Among the 221 patients who had undergone hip arthroplasty, 147 patients were enrolled. All patients were divided into 2 groups according to presence of sarcopenia. Bone mineral density (BMD) at hospitalization and 1-year after surgery and Barthel index was measured at the time of before injury, hospitalization, 3 months and 1-year after surgery. Results: BMD at hospitalization showed .627 ± .082 (g/cm2) in Sarcopenia and .726 ± .059 (g/cm2) in Non-sarcopenia at femur (total) site ( P < .001), .531 ± .085 (g/cm2) vs .629 ± .057 (g/cm2) at femur neck site (P=.002), .715 ± .084 (g/cm2) vs .807 ± .058 (g/cm2) at lumbar (L1-L4) site ( P < .001). BMD at 1-year follow-up period, Sarcopenia showed .626 ± .082 (g/cm2) and Non-sarcopenia showed .725 ± .060 (g/cm2) at femur (total) site ( P < .001), .530 ± .085 (g/cm2) vs .629 ± .058 (g/cm2) at femur neck site ( P < .001), .715 ± .084 (g/cm2) vs .806 ± .058 (g/cm2) at lumbar (L1-L4) site ( P < .001). Change of BMD showed −.01 ± .25% for Sarcopenia and −.15 ± .47% for Non-sarcopenia in femur (total) site (P=.089), −.08 ± .63% vs −.01 ± 1.01% in femur neck site ( P = .058), .00 ± .09% vs −.12 ± .33% for each group in lumbar (L1-L4) site ( P = .052). Barthel index score showed 79.94 ± 5.66 for Sarcopenia and 84.74 ± 5.36 for Non-sarcopenia at pre-injury status ( P < .001), 33.89 ± 4.94 vs 33.87 ± 5.36 at the time of hospitalization ( P = .977), 57.42 ± 7.19 vs 60.06 ± 5.39 at 3 months follow up ( P = .015), 73.86 ± 5.94 vs 80.71 ± 4.81 for each group at 1-year follow up ( P < .001). Conclusions: Our study found that the sarcopenia showed lower BMD than the non-sarcopenia, but there was no significant difference of BMD change in the follow-up period. In addition, the sarcopenia showed poor functional results at all points except at the time of hospitalization.

Zusammenfassung Ziel: Kostenanalyse und Evaluation der Vergütung durch GKV und PKV der 10 häufigsten angiografischen Verfahren an einem Universitätsklinikum. Material und Methoden: Retrospektive Auswertung aller angiografischen Eingriffe des Jahres 2010 und Evaluation der 10 am häufigsten durchgeführten (Port-, Dialysekatheter, PTA von Ober- (OS) und Unterschenkel (US), TACE, Stents (Becken, viszeral, supraaortal), SIRT, zerebrale Coilembolisation). Berechnung der DRG-Anteile und Analyse, ob die Interventionen die DRGs modifizierten und Mehreinnahmen erzeugten. Kalkulation der Vergütung gemäß GOÄ für stationäre und ambulante Patienten. Berechnung von Material-, Personal- und Sachkosten für die Interventionen. Ergebnisse: Folgende Werte (in €) wurden errechnet [Gesamt-, Material-, Personalkosten, DRG-Anteil, GOÄ (stat., amb.)]: Portkatheter: 375, 266, 59, 328, 260, 612; Dialysekatheter 456, 349, 59, 272, 343, 807; PTA OS: 595, 445, 99, 1 240, 425, 1 077; PTA US: 732, 552, 129, 1 082, 425, 1 184; Stent Becken: 1 523, 1 338, 135, 1 323, 815, n/a; Stent viszeral: 2 124, 1 875, 199, 1 326, 912, n/a; Stent supraaortal: 1 901, 1 713, 138, 6 705, 1 138, n/a; TACE: 1 359, 1 120, 188, 2 588, 598, n/a; SIRT: 1 251, 1 054, 147, 2 289, 1 107, n/a; Coiling zerebral: 6 684, 6 367, 266, 6 531, n/a, n/a. Es konnte keine Abhängigkeit der DRGs von den durchgeführten Interventionen nachgewiesen werden. Schlussfolgerung: Die Auswertungen ergaben bei Analyse der DRG-Anteile ein Mischbild aus Verlusten (Port- und Dialysekatheter, Stent Becken und viszeral) und rechnerischen Mehreinnahmen (PTA OS/US, Stent supraaortal, TACE, SIRT). Das Coiling erscheint wirtschaftlich neutral. Eine reine Abrechnung nach GOÄ führt lediglich im ambulanten Sektor zu Gewinnen. Einschränkend muss jeder radiologische Eingriff natürlich ebenfalls als Teil der gesamten DRG gesehen werden.

High temperatures can be harmful to the competence of cumulus–oocyte complexes and to embryo development (Al-Katanani et al. 2002 J. Dairy Sci. 85, 390–396). The aim of this study was to evaluate the effect of maternal heat stress on in vitro embryo yield. Ten multiparous nonlactating Gir (Bos indicus) cows were kept in tie stalls for an adaptive period of 28 days [pre-heat-stress period (PRE-HS)/Days -28 to -1]. Cows were subjected to 2 OPU (ovum pickup) sessions (Days -14 and -7). In the heat-stress period (HS; Days 0 to 28), cows were divided into control (C: n = 5) and heat-stressed (HS: n = 5) groups. During this period, OPU sessions were performed once a week from Days 0 to 28. The C group remained in a thermo-neutral environment, and the HS group was kept in a climatic chamber with controlled temperature and humidity (38�C and 80% during the day and 30�C and 80% during the night). In the post-heat-stress period (POST-HS; Days 28 to 147), all cows returned to thermo-neutral conditions. Then 17 OPU sessions were performed once a week from Days 35 to 147. In all periods, blood samples were collected weekly for progesterone (P4) analysis, and ovarian follicles were counted, measured, and aspirated. The COCs were evaluated and selected for the IVF procedure. Data were analyzed by ANOVA (PROC MIXED of SAS) and a chi-squared test. The luteal phase was defined as the period between 2 samples with P4 below 1.0 ng mL-1. A handling accident caused the exclusion of an HS cow after the sixth session. The C and HS groups were subjected to 125 and 107 OPU sessions, respectively. Means � SEM for the C vs. HS groups, in the PRE-HS, HS, and POST-HS periods, respectively, were visualized follicles: 25.5 � 2.5 vs. 28.5 � 2.8, 24.2 � 1.1 vs. 24.0 � 1.9, and 15.3 � 0.6 vs. 15.8 � 0.8; largest follicle diameter: 12.1 � 1.5 vs. 11.1 � 1.7, 13.3 � 0.8 vs. 13.0 � 0.6, and 11.4 � 0.4b vs. 14.0 � 0.4a; P &lt; 0.05; 2nd largest follicle diameter: 6.2 � 1.3 vs. 6.0 � 1.2, 5.9 � 0.6 vs. 7.1 � 0.8, and 6.3 � 0.3b vs. 8.7 � 0.5a; recovered COCs: 11.2 � 2.8 vs. 14.3 � 2.5, 9.6 � 1.0 vs. 11.0 � 1.3, and 8.6 � 0.7 vs. 7.9 � 0.6; COCs selected for IVF: 69/112 (61.6%)b vs. 108/143 (75.5%)a, 164/241 (68%) vs. 172/265 (64.9%), and 426/712 (59.8%) vs. 305/535 (75.0%); cleavage: 44/59 (74.5%) vs. 87/105 (82.9%), 72/101 (71.3%) vs. 74/121 (61.2%), and 226/317 (71.3%) vs. 159/230 (69.1%); embryos per cow/OPU: 2.1 � 1.1y vs. 4.1 � 1.0x, 0.4 � 0.3 vs. 0.5 � 0.3, and 0.9 � 0.2x vs. 0.4 � 0.1y; P &lt; 0.1; and blastocyst yield: 16/59 (27.1%) vs. 33/105 (31.5%), 11/31 (35.5%) vs. 13/52 (25.0%), and 76/279 (27.2%)a vs. 25/188 (13.3%)b. In conclusion, maternal heat stress increased the percentage of short estrous cycles, decreased the P4 concentrations, and decreased the number of embryos produced by Bos indicus cows, mainly from 28 to 147 days post-heat-stress, showing long-term deleterious effects on blastocyst development.

Bovine in vitro production is highly relevant for dairy systems in Brazil, and the main breeds used as oocyte donors are Gyr (G) and Holstein (H). This study aimed to evaluate the ovarian follicular dynamics of G and H oocyte donors kept under tropical conditions to detect differences that could guide improvement of follicular wave synchronization protocols for ovum pickup. Fourteen cyclic cows (6 H and 8 G), assessed twice each (after a 14-day interval), had their oestrus cycle synchronized by the use of 1.0 g of progesterone via intravaginal device (Ourofino, Brazil) and administration of 2 mg of oestradiol benzoate (EB; Day 0). Withdrawal of progesterone device was followed by 7.6 mg of cloprostenol administration (Day 7); EB (1 mg) was administered after 24 h (Day 8, 0 h), and the animals were evaluated every 12 h by ultrasound for 6 days (0–132 h). All evaluations are reported regarding EB administration (0 h). Videos from each ovary were stored and processed using the ImageJ software (http://rsb.info.nih.gov/ij), by measuring the diameter of each visualised follicle. All procedures were approved by local ethics committee. Ovulation time (G = 42.0 ± 8.3; H = 42.5 ± 6.2), ovulatory follicle (F1) diameter (G = 11.5 ± 1.8; H = 12.4 ± 2.0), and F2 diameter (G = 7.2 ± 1.9; H = 7.4 ± 2.7) did not differ (P > 0.05) between breeds. Growth rate (mm day–1) after ovulation was similar (P > 0.05) between breeds for each follicle (F1 = G: 0.6 ± 0.2, H: 0.8 ± 0.1; F2 = G: 0.5 ± 0.1 H: 0.4 ± 0.1, F3 = G: 0.2 ± 0.1, H: 0.3 ± 0.1). In H group, the F1 growth rate was higher (P < 0.05) than F2 and F3, but there was no difference (P > 0.05) in G group. Follicle deviation was identified 120 h after EB in the G group (~78 h after ovulation) and 132 h in the H group (~90 h after ovulation), and at that time F1, F2, and F3 follicle diameters were 8.0 ± 0.3, 6.6 ± 0.5, and 5.3 ± 0.3 for G (120 h), respectively; 8.8 ± 0.7, 7.2 ± 0.4, and 6.2 ± 0.3 for H (132 h), respectively. There was no difference between the size of F1, F2, and F3 between breeds at any time, except at 132 h, when H F3 was higher (P < 0.05) than G F3. Regarding the follicular population, follicles smaller than 3 mm were more numerous in G animals at all evaluated moments, and differed at 0 (G = 7.1 ± 1.1; H = 2.5 ± 0.5) and 132 h (G = 5.6 ± 0.8; H = 1.5 ± 0.3). Number of follicles between 3 and 8 mm increased in H compared to G at 24 (14.4 ± 1.0), 36 (15.7 ± 1.3), and 132 h (18.3 ± 1.4). Comparing 3- and 8-mm follicles in G between times, an increase (P < 0.05) in number was detected from 36 h onwards, comparedto 0 h (0 h: 9.2 ± 1.0; 36 h: 13.6 ± 1.4). This increase was not significant in H group (0 h: 13.7 ± 1.1; 132 h: 18.3 ± 1.4). The main findings of this study are that the moment of deviation and the population of follicles smaller than 3 mm and between 3 and 8 mm differs from Gyr and Holstein oocyte donors. Those observations suggest ovum pickup is better performed slightly later in Holstein donors than in Gyr, and can contribute to improvement of follicular wave synchronization protocols for each of the breeds in tropical conditions. Study supported by FAPERJ, Embrapa and CNPq.

Abstract Background: BC remains the most commonly diagnosed cancer for women. TNBC is an aggressive form with a poorer prognosis compared with other subtypes. Neoadjuvant therapy (NAT) is the standard-of-care approach to shrink tumors in the breast and axilla and to improve patient outcomes. Few RW studies exist of US patients with early BC (eBC); this study aimed to describe clinical parameters by receipt of systemic therapy and to assess overall survival (OS) and progression-free survival (PFS) after NAT and adjuvant therapy (AT) in women with early HR+/HER2− or TNBC using RW evidence in the US. Methods: This retrospective observational study used the Flatiron Health nationwide electronic health record-derived de-identified database, including women ([pts], age ≥18 years) diagnosed with early HR+/HER2− BC or TNBC between 01/01/2011 and 05/31/2018. The primary outcome was to describe pt demographics, clinical characteristics, and treatment patterns. Secondary outcomes included OS and PFS. Results: Of the pts identified for inclusion (N = 5,299), 13.3% (n = 707) were diagnosed with early TNBC and 86.7% (n = 4,592) with HR+/HER2− eBC, of whom 34.7% (n = 245) and 10.9% (n = 502), respectively, did not receive systemic therapy (Table). Systemically treated pts with TNBC vs HR+/HER2− tended to be younger (59.0 years vs 64.0 years); were represented by a higher proportion of Black women (18.0% vs 7.2%); had a greater proportion presenting with invasive ductal carcinoma (IDC) (91.6% vs 78.2%); had a higher proportion with progression to metastasis (19.0% vs 5.7%) and presented with a more aggressive disease (Grade 3) at diagnosis (79.0% vs 18.4%). Most pts (98.4%) received surgery, predominantly breast-conserving surgery (BCS; unilateral lumpectomy: 62.8%); however, 17.8% received bilateral mastectomies. Overall, 9.1% of pts received NAT. More pts with TNBC vs HR+/HER2− received NAT (34.0% vs 7.9%) and achieved a pathologic complete response (pCR; 36.3% vs 6.2%). Consistent with treatment guidelines, pts with TNBC were treated with chemotherapy (CT)-doublet or single-agent regimens and pts with HR+/HER2− received hormone and CT-based regimens. Duration of NAT was similar for both subtypes (3.3 months) but was shorter for AT in pts with TNBC vs HR+/HER2− (3.4 vs 38.2 months). From initial diagnosis, the 36-month survival probability [standard error] was lower for systemically treated pts with TNBC vs HR+/HER2− (85.7% [1.8%] vs 95.6% [0.3%]) and from start of therapy by line setting (NAT: 80.6% [3.5%] vs 91.9% [1.7%]; AT: 84.7% [2.2%] vs 95.8% [0.4%]). Similarly, the 36-month PFS probability was lower for pts with TNBC vs HR+/HER2− from diagnosis (77.9% [2.1%] vs 93.3% [0.4%]) and from start of therapy by line setting (NAT: 68.7% [4.1%] vs 85.2% [2.1%]; AT: 79.5% [2.5%] vs 93.5% [0.4%]). Conclusion: This analysis of US RWE further confirms early TNBC to be a particularly aggressive form of BC, with poorer survival compared with pts with HR+/HER2− eBC. While these RW data indicate BCS is becoming more routine, almost one-fifth of pts still receive bilateral mastectomies. Overall, these data confirm there remains a high unmet need to reduce the need for aggressive treatments while further improving outcomes in pts with early TNBC and HR+/HER2− BC. Table: Patient demographics, clinical characteristics, OS and PFSPatient selection criteriaNumber of patients, n (%)SubgroupsEarly HR+/HER2− BC4,592 (86.7)Patients who received systemic therapy4,090 (89.1)Early TNBC707 (13.3)Patients who received systemic therapy462 (65.3)All patients [1] (N = 5,299), n (%)Systemically treated patients with early HR+/HER2− BC (n = 4,090), n (%)Systemically treated patients with early TNBC (n = 462), n (%)Patient demographicsMedian age (years)64.064.059.0RaceBlack or African American449 (8.5)294 (7.2)83 (18.0)White3,602 (68.0)2,835 (69.3)283 (61.3)Asian139 (2.6)111 (2.7)9 (1.9)Hispanic or Latino15 (0.3)12 (0.3)1 (0.2)Clinical characteristicsHistology at initial diagnosisIDC4,222 (79.7)3,197 (78.2)423 (91.6)ILC684 (12.9)612 (15.0)7 (1.5)Infiltrating ductal mixed and infiltrating lobular mixed132 (2.5)108 (2.6)3 (0.6)Mucinous adenocarcinoma97 (1.8)88 (2.2)0 (0.0)Other [2]122 (2.3)63 (1.5)26 (5.6)Unknown/ND42 (0.8)22 (0.5)3 (0.6)Tumor grade at initial diagnosisGrade 11,350 (25.5)1,161 (28.4)5 (1.1)Grade 22,462 (46.5)2,098 (51.3)88 (19.0)Grade 31,374 (25.9)752 (18.4)365 (79.0)Unknown/ND113 (2.1)79 (1.9)4 (0.9)Surgery at initial diagnosisYes5,215 (98.4)4,032 (98.6)450 (97.4)Surgery type [3]Unilateral lumpectomy3,277 (62.8)2,568 (63.7)241 (53.6)Unilateral mastectomy1,168 (22.4)883 (21.9)128 (28.4)Bilateral lumpectomy75 (1.4)61 (1.5)5 (1.1)Bilateral mastectomy927 (17.8)713 (17.7)89 (19.8)Treatment line settingNumber of patients who received NAT481 (9.1)324 (7.9)157 (34.0)Number of patients who received AT4,263 (80.4)3,949 (96.6)314 (68.0)pCR to NATAchieved pCR77 (16.0)20 (6.2)57 (36.3)OSFrom initial diagnosis: survival probability at Month 36, % (SE)94.0 (0.4)95.6 (0.3)85.7 (1.8)From NAT: survival probability at Month 36, % (SE)88.3 (1.6)91.9 (1.7)80.6 (3.5)From AT: survival probability at Month 36, % (SE)94.9 (0.4)95.8 (0.4)84.7 (2.2)PFSFrom initial diagnosis: progression-free probability at Month 36, % (SE)91.3 (0.4)93.3 (0.4)77.9 (2.1)From NAT: progression-free probability at Month 36, % (SE)79.9 (2.0)85.2 (2.1)68.7 (4.1)From AT: progression-free probability at Month 36, % (SE)92.5 (0.4)93.5 (0.4)79.5 (2.5)Duration of treatment, Months (n)Median duration of NAT3.3 (481)3.3 (324)3.3 (157)Median duration of AT35.3 (4263)38.2 (3,949)3.4 (314)[1] All patients includes both patients systemically treated and systemically untreated. [2] Other includes Inflammatory, Papillary, Metaplastic, Medullary and Tubular histologies. [3] Patient may have received more than one surgery. AT, adjuvant therapy; IDC, invasive ductal carcinoma; NAT, neoadjuvant therapy; ND, not documented; SE, standard error. Citation Format: Anagha Gogate, Amanda Crosbie, Trong Kim Le, Ying Zhang, Rolee Das, Catherine Davis. Clinical characteristics, treatment patterns, and survival outcomes in women with early triple-negative (TN) or hormone receptor-positive/human epidermal growth factor receptor-2 negative (HR+/HER2−) breast cancer (BC) in the real-world (RW) setting [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 P3-12-15.

Aims/Objectives/BackgroundGlobally, injuries cause more than 5 million deaths annually. Children and young people are a particularly vulnerable group and injuries are the leading cause of death in people aged 5–24 years globally and a leading cause of disability.In most low and middle-income countries where the majority of global child injury burden occurs, systems for routinely collecting injury data are limited. There is a continuing need for better data on childhood injuries and for injury surveillance.The aim of our study was to introduce a hospital-based injury surveillance tool – the first of its kind in Nepal and explore its feasibility. We undertook prospective collection of data on all injuries/trauma presenting to 2 hospital emergency departments to describe the epidemiology of paediatric hospital injury presentations and associated risk factors.Methods/DesignA new injury surveillance system for use in emergency departments in Nepal was designed and used to collect data on patients presenting with injuries. Data were collected prospectively in two hospitals 24 h a day over 12 months (April 2019 - March 2020) by trained data collectors using tablet computers.Abstract 432 Table 1Socio-demographic profile and characteristics of injury among children attending emergency of hospitals in Makwanpur district, Nepal, April 2019 – March 2020 (N=2696)CharacteristicsFrequencyGender Male 1778 Female 918 Age groups 0–4 years 653 5–9 years 866 10–14 years 680 15–17 years 497 Median year (IRQ) 8 (5 – 13) Ethnicity/caste Janajati 1384 Brahmin/Chhetri 892 Dalit 148 Madhesi 146 Muslim 74 Others 50 Unknown 2 Place where injury occurred Home/Compound 1576 Highway/road/street 636 School 233 Recreational area 138 Workplace 76 Other 37 Activities at the time injury occurred Leisure/Play 1889 Travelling (other than to/from school/work) 296 Work 202 Travelling (to/from school/work) 184 Education 42 Organised sports 11 Other 52 Unknown 20 Intent of injury Unintentional 2560 Intentional (self-harm) 61 Intentional (assault) 75 Unintentional (n=2560) Fall 912 Animal or insect related 728 Road traffic injury 356 Injured by a blunt force 201 Stabbed, cut or pierced 176 Fire, burn or scald 65 Poisoning 52 Suffocation/choking 36 Electrocution 12 Drowning and submersion 7 Other 13 Unknown 2 Self-harm (n=61) Poisoning 38 Hanging, strangulation, suffocation 12 Stabbed, cut or pierced 6 Injured by blunt object 4 Other 1 Assault (n=75) Bodily force (physical violence) 43 Injured by blunt object 18 Stabbed, cut or pierced 8 Pushing from a high place 2 Poisoning 2 Sexual assault 1 Other 1 Nature of injury (one most severe) Cuts, bites or open wound 1378 Bruise or superficial injury 383 Fracture 299 Sprain, strain or dislocation 243 Internal injury 124 Head Injury/Concussion 83 Burns 67 Other 115 Unknown 2 Not recorded 2 Severity of injury No apparent injury 125 Minor 1645 Moderate 813 Severe 111 Not recorded 2 Disposition Discharged 2317 Admitted to hospital 164 Transferred to another hospital 179 Died 21 Leave Against Medical Advice (LAMA) 11 Unknown 2 Not recorded 2 Note:Not recorded = missing cases95% CI calculated using one proportion test and normal approximation method in Minitab.Abstract 432 Table 2Distribution of injuries by age-group, sex and mechanism of injury among children attending emergency of hospitals in Makwanpur district, Nepal, April 2019 – March 2020Age groups & Sex0 - 4 years5 - 9 years10–14 years15–17 yearsMaleFemaleTotalIntent & mechanismsn (%)n (%)n (%)n (%)n (%)n (%)n (%)Unintentional Fall 239 (26.2) 328 (36.0) 249 (27.3) 96 (10.5) 636 (69.7) 276 (30.3) 912 (100) Animal or insect related 175 (24.0) 260 (35.7) 190 (26.1) 103 (14.1) 470 (64.6) 258 (35.4) 728 (100) Road traffic injury 49 (13.8) 108 (30.3) 86 (24.2) 113 (31.7) 223 (62.6) 133 (37.4) 356 (100) Injured by a blunt force 54 (26.9) 74 (36.8) 49 (24.4) 24 (11.9) 150 (74.6) 51 (25.4) 201 (100) Stabbed, cut or pierced 20 (11.4) 56 (31.8) 49 (27.8) 51 (29.0) 127 (72.2) 49 (27.8) 176 (100) Fire, burn or scald 42 (64.6) 10 (15.4) 9 (13.8) 4 (6.2) 27 (41.5) 38 (58.5) 65 (100) Poisoning 33 (63.5) 6 (11.5) 5 (9.6) 8 (15.4) 26 (50.0) 26 (50.0) 52 (100) Suffocation/choking 24 (66.7) 5 (13.9) 2 (5.6) 5 (13.9) 20 (55.6) 16 (44.4) 36 (100) Electrocution 2 (15.7) 0 (0.0) 3 (25.0) 7 (58.3) 10 (83.3) 2 (16.7) 12 (100) Drowning and submersion 1 (14.3) 1 (14.3) 3 (42.9) 2 (28.6) 3 (42.9) 4 (57.1) 7 (100) Other 6 (46.2) 4 (30.8) 3 (23.1) 0 (0.0) 10 (76.9) 3 (23.1) 13 (100) Unknown 2 (100) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 2 (100) 2 (100) Total 647 (25.3) 852 (33.3) 648 (25.3) 413 (16.1) 1702 (66.5) 858 (33.5) 2560 (100) Self-harm Poisoning 0 (0.0) 0 (0.0) 6 (15.8) 32 (84.2) 7 (18.4) 31 (81.6) 38 (100) Hanging 0 (0.0) 0 (0.0) 3 (25.0) 9 (75.0) 4 (33.3) 8 (66.7) 12 (100) Stabbed, cut or pierced 0 (0.0) 0 (0.0) 2 (33.3) 4 (66.7) 1 (16.7) 5 (83.3) 6 (100) Injured by blunt object 0 (0.0) 2 (50.0) 2 (50.0) 0 (0.0) 4 (100) 0 (0.0) 4 (100) Other 0 (0.0) 0 (0.0) 0 (0.0) 1 (100) 1 (100) 0 (0.0) 1 (100) Total 0 (0.0) 2 (3.3) 13 (21.3) 46 (75.4) 17 (27.9) 44 (72.1) 61 (100) Assault Bodily force (physical violence) 3 (7.0) 1 (2.3) 11 (25.6) 28 (65.1) 37 (86.0) 6 (14.0) 43 (100) Injured by blunt object 2 (11.1) 8 (44.4) 4 (22.2) 4 (22.2) 13 (72.2) 5 (27.8) 18 (100) Stabbed, cut or pierced 1 (12.5) 0 (0.0) 2 (25.0) 5 (62.5) 7 (87.5) 1 (12.5) 8 (100) Pushing from a high place 0 (0.0) 1 (50.0) 1 (50.0) 0 (0.0) 1 (50.0) 1 (50.0) 2 (100) Poisoning 0 (0.0) 1 (50.0) 0 (0.0) 1 (50.0) 1 (50.0) 1 (50.0) 2 (100) Sexual assault 0 (0.0) 0 (0.0) 1 (100) 0 (0.0) 0 (0.0) 1 (100) 1 (100) Other 0 (0.0) 1 (100) 0 (0.0) 0 (0.0) 0 (0.0) 1 (100) 1 (100) Total 6 (8.0) 12 (16.0) 19 (25.3) 38 (50.7) 59 (78.7) 16 (21.3) 75 (100) Abstract 432 Table 3Association of injury location, nature and severity with age among children attending emergency of hospitals in Makwanpur district, Nepal, April 2019 – March 2020Age groups0 – 4 years5 – 9 years10–14 years15–17 yearsTotalChi-SquareInjury characteristicsn (%)n (%)n (%)n (%)n (%)P valueLocation of injury sustained Home/Compound 537 (34.1) 504 (32.0) 319 (20.2) 216 (13.7) 1576 (100) <0.001 Highway/road/street 85 (13.4) 196 (30.8) 190 (29.9) 165 (25.9) 636 (100) School 15 (6.4) 107 (45.9) 85 (36.5) 26 (11.2) 233 (100) Recreational area 9 (6.5) 44 (31.9) 55 (39.9) 30 (21.7) 138 (100) Workplace 1 (1.3) 4 (5.3) 19 (25.0) 52 (68.4) 76 (100) Other 6 (16.2) 11 (29.7) 12 (32.4) 8 (21.6) 37 (100) Total 653 (24.2) 866 (32.1) 680 (25.2) 497 (18.4) 2696 (100) Nature of injury Cuts, bites or open wound 328 (23.8) 506 (36.7) 314 (22.8) 230 (16.7) 1378 (100) <0.001 Bruise or superficial injury 81 (21.1) 99 (25.8) 118 (30.8) 85 (22.2) 383 (100) Fracture 48 (16.1) 101 (33.8) 112 (37.5) 38 (12.7) 299 (100) Sprain, strain or dislocation 48 (19.8) 78 (32.1) 72 (29.6) 45 (18.5) 243 (100) Internal injury 44 (35.5) 8 (6.5) 18 (14.5) 54 (43.5) 124 (100) Head Injury/Concussion 18 (21.7) 26 (31.3) 18 (21.7) 21 (25.3) 83 (100) Burns 42 (62.7) 9 (13.4) 10 (14.9) 6 (9.0) 67 (100) Other 41 (35.7) 38 (33.0) 18 (15.7) 18 (15.7) 115 (100) Unknown 2 (100) 0 (0.0) 0 (0.0) 0 (0.0) 2 (100) Total 652 (24.2) 865 (32.1) 680 (25.2) 497 (18.4) 2694 (100) Severity of injury No apparent injury 39 (31.2) 45 (36.0) 26 (20.8) 15 (12.0) 125 (100) <0.001 Minor 419 (25.5) 535 (32.5) 406 (24.7) 285 (17.3) 1645 (100) Moderate 171 (21.0) 262 (32.2) 225 (27.7) 155 (19.1) 813 (100) Severe 23 (20.7) 23 (20.7) 23 (20.7) 42 (37.8) 111 (100) Total 652 (24.2) 865 (32.1) 680 (25.2) 497 (18.4) 2694 (100) Abstract 432 Table 4Association of injury location, nature and severity with sex among children attending emergency of hospitals in Makwanpur district, Nepal, April 2019 – March 2020SexMaleFemaleTotalChi-SquareInjury characteristicsn (%)n (%)n (%)P valueLocation of injury sustained Home/Compound 979 (62.1) 597 (37.9) 1576 (100) <0.001 Highway/road/street 421 (66.2) 215 (33.8) 636 (100) School 176 (75.5) 57 (24.5) 233 (100) Recreational area 111 (80.4) 27 (19.6) 138 (100) Workplace 62 (81.6) 14 (18.4) 76 (100) Other 29 (78.4) 8 (21.6) 37 (100) Total 1778 (65.9) 918 (34.1) 2696 (100) Nature of injury Cuts, bites or open wound 959 (69.6) 419 (30.4) 1378 (100) <0.001 Bruise or superficial injury 246 (64.2) 137 (35.8) 383 (100) Fracture 200 (66.9) 99 (33.1) 299 (100) Sprain, strain or dislocation 154 (63.4) 89 (36.6) 243 (100) Internal injury 50 (40.3) 74 (59.7) 124 (100) Head Injury/Concussion 59 (71.1) 24 (28.9) 83 (100) Burns 27 (40.3) 40 (59.7) 67 (100) Other 79 (68.7) 36 (31.3) 115 (100) Unknown 2 (100) 0 (0.0) 2 (100) Total 1776 (65.9) 918 (34.1) 2694 (100) Severity of injury No apparent injury 81 (64.8) 44 (35.2) 125 (100) 0.048 Minor 1102 (67.0) 543 (33.0) 1645 (100) Moderate 533 (65.6) 280 (34.4) 813 (100) Severe 60 (54.1) 51 (45.9) 111 (100) Total 1776 (65.9) 918 (34.1) 2694 (100) Abstract 432 Table 5Distribution of injuries by outcome and mechanism of injury among children attending emergency of hospitals in Makwanpur district, Nepal, April 2019 – March 2020Outcome of injuryDischargedAdmittedTransferredDiedLAMAUnknownTotalIntent & mechanismsn (%)n (%)n (%)n (%)n (%)n (%)n (%)Unintentional Fall 787 (86.5) 65 (7.1) 53 (5.8) 0 (0.0) 4 (0.4) 1 (0.1) 910 (100) Animal/insect bite/sting 704 (96.7) 3 (0.4) 19 (2.6) 0 (0.0) 1 (0.1) 1 (0.1) 728 (100) Road traffic injury 260 (73.0) 47 (13.2) 44 (12.4) 5 (1.4) 0 (0.0) 0 (0.0) 356 (100) Injured by a blunt force 190 (94.5) 4 (2.0) 6 (3.0) 0 (0.0) 1 (0.5) 0 (0.0) 201 (100) Stabbed, cut or pierced 165 (93.8) 8 (4.5) 3 (1.7) 0 (0.0) 0 (0.0) 0 (0.0) 176 (100) Fire, burn or scald 52 (80.0) 12 (18.5) 1 (1.5) 0 (0.0) 0 (0.0) 0 (0.0) 65 (100) Poisoning 30 (57.7) 4 (7.7) 16 (30.8) 1 (1.9) 1 (1.9) 0 (0.0) 52 (100) Suffocation/choking/asphyxia 24 (66.7) 4 (11.1) 6 (16.7) 1 (2.8) 1 (2.8) 0 (0.0) 36 (100) Electrocution 7 (58.3) 2 (16.7) 2 (16.7) 1 (8.3) 0 (0.0) 0 (0.0) 12 (100) Drowning and submersion 4 (57.1) 0 (0.0) 0 (0.0) 3 (42.9) 0 (0.0) 0 (0.0) 7 (100) Other 12 (92.3) 1 (7.7) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 13 (100) Unknown 2 (100) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 2 (100) Total 2237 (87.5) 150 (5.9) 150 (5.9) 11 (0.4) 8 (0.3) 2 (0.1) 2558 (100) Self-harm Poisoning 5 (13.2) 8 (21.1) 23 (60.5) 0 (0.0) 2 (5.3) 0 (0.0) 38 (100) Hanging 1 (8.3) 0 (0.0) 1 (8.3) 10 (83.3) 0 (0.0) 0 (0.0) 12 (100) Stabbed, cut or pierced 6 (100) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 6 (100) Injured by blunt object 4 (100) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 4 (100) Other 1 (100) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (100) Total 17 (27.9) 8 (13.1) 24 (39.3) 10 (16.4) 2 (3.3) 0 (0.0) 61 (100) Assault Bodily force (physical violence) 34 (79.1) 5 (11.6) 3 (7.0) 0 (0.0) 1 (2.3) 0 (0.0) 43 (100) Injured by blunt object 18 (100) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 18 (100) Stabbed, cut or pierced 6 (75.0) 1 (12.5) 1 (12.5) 0 (0.0) 0 (0.0) 0 (0.0) 8 (100) Pushing from a high place 2 (100) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 2 (100) Poisoning 1 (50) 0 (0.0) 1 (50.0) 0 (0.0) 0 (0.0) 0 (0.0) 2 (100) Sexual assault 1 (100) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (100) Other 1 (100) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (100) Total 63 (84.0) 6 (8.0) 5 (6.7) 0 (0.0) 1 (1.3) 0 (0.0) 75 (100) Abstract 432 Figure 1Seasonal variation of injuries identified by the injury surveillance system over a year among children attending emergency of hospitals in Makwanpur district, Nepal, April 2019 – March 2020Results/ConclusionsThe total number of ED patients with injury in the study was 10,154.2,696 were patients aged <18 years. Most injuries in children were unintentional and over half of children presenting with injuries were <10 years of age. Falls, animal bites/stings and road traffic injuries accounted for nearly 75% of all injuries with some (drowning, poisonings and burns) under-represented. Over half of injuries were cuts, bites and open wounds. The next most common injury types were superficial injuries (14.2%); fractures (11.1%); sprains/dislocations (9.0%). Child mortality was 1%.This is the biggest prospective injury surveillance study in a low or middle country in recent years and supports the use of injury surveillance in Nepal for reducing child morbidity and mortality through improved data.CHILD PAPER: RESULTS SECTIONTotal number of ED patients: 33046Total number of ED patient with injury: 10154 (adult=7458 & children=2696)8.2% (n=2696) patients with injury were children aged <18 yearsHetauda hospital: 2274 (84.3%)Chure hill hospital: 422 (15.7%)

Introduction: Emergency department (ED) opioid prescribing has been linked to long-term use and dependence. Anecdotally, significant opioid practice variability exists between physicians and institutions, but this is poorly defined. Our objective was to collate and analyze multicenter data looking at predictors of ED opioid use and to identify potential areas for opioid stewardship. Methods: We linked administrative and computerized physician order entry (CPOE) data from all four ED's within our municipality over a one-year period. Eligible patients included those with a Canadian Triage and Acuity Scale (CTAS) pain complaint or an arrival numeric rating scale (NRS) pain score of greater than 3/10. Patients with missing demographic or chief complaint data were excluded. Multiple imputation was used for missing NRS pain scores. We performed descriptive analyses of opioid-treated and non-treated patients, followed by a multivariable logistic regression to identify predictors of ED opioid administration. Results: A total of 129,547 patients were studied. The mean age was 47.4 years and 55.4% were female. The median pain score was 6.6 in the no-opioid group and 8 in the opioid group. The most common pain categories were abdominal pain (23%), trauma (18.2%) and chest pain (15.3%). Overall, opioids were prescribed to 34% of patients. The most common CTAS score was CTAS 3 (44%), CTAS 1-2 42%) and CTAS 4-5 (13.9%). Multivariable predictors of opioid-use included the need for admission (adjusted OR 6.57; CI = 6.34-6.79), NRS pain score (aOR 1.24 per unit increase, CI 1.23-1.25), higher numerical CTAS score (aOR 0.89 per unit increase, CI 0.87-0.91), and chief complaints of back (aOR 7.69, CI 7.1-8.1), abdominal (aOR 5.9, CI 5.6-6.2), and flank pain (OR 3.8, CI 3.5-4). Oral opioids were prescribed in 39.8% of back pain presentations and 18.5% received IV opioids. Increasing age was a predictor but sex was not. There were significant institutional differences in opioid prescribing rates, with Hospital B being the least likely to prescribe opioids (aOR 0.82, CI 0.80-0.85) followed by Hospital C (aOR 0.83, CI 0.79-0.86) compared to the reference standard of Hospital A. Hospital D was most likely to prescribe opioids (aOR 1.32, CI 1.27-1.37). Conclusion: Predictors of ED opioid use were characterized using multicenter administrative data. Future research should seek to describe the physician- and site-level factors driving regional variation in opioid-based pain treatment.

Abstract Background: Obesity is associated with an increased risk of breast cancer recurrence and poor survival. Obesity rate in adults in the city of Philadelphia is high, with non-Hispanic blacks and Hispanics having the highest rates. We sought to evaluate changes in body mass index (BMI) in breast cancer survivors within the first 2 years from initial encounter for a breast cancer (BC) diagnosis (dx), and investigate factors that may correlate with a change in BMI. Methods: We identified 5,423 BC patients (pts) in our electronic medical record, (1/2015-present), using ICD-10 code C50.X. We then selected pts with BMI values at the three-time points: baseline, 1 year and 2 year intervals from baseline. The closest BMI value before the 1st encounter within 6 months prior to BC dx was considered as the baseline BMI. BMI at 1 year +/- 3 months after the BC dx was considered 1-year interval BMI. BMI at 2 years +/- 6 months after the BC dx was considered 2-year interval BMI. Subjects needed baseline BMI and at least 1 year or 2 year follow-up BMI for inclusion. After all BMI exclusions, 630 pts were included in the study cohort. We used a mixed effects model to predict BMI changes as a linear function of association with time, sex, race and ethnicity, age at BC dx, baseline BMI, treatments (i.e., chemotherapy [CT], endocrine therapy [ET], or immunotherapy [IO] and the interaction of race and ethnicity and treatment in estimating mean change of BMI. The significance level of all tests was set a priori to the 0.05 level. Results: The mean age at BC dx was 61 years; pts identified were mostly white, non-Hispanic/Caucasian (55%), or Black/African American (AA) (34%). By BMI category, we did not observe any substantial difference in the mean age at BC dx and gender distribution (p = 0.81 for age and p = 0.86 for gender). However, the distributions of race and ethnicity differed among BMI categories (p &lt; .01) where the percentage of Black/AA pts was high in the BMI ≥ 30 category. Black/AA pts receiving IO were likely to have BMI change (decrease) compare to white non-Hispanic pts with similar conditions. Black/AA pts receiving no treatment or non IO-treatment were more likely to change BMI (increased, 95% CI: 0.22, 1.03) after BC dx compared to white, non-Hispanic pts. Interestingly, Black/AA pts receiving IO tended to change BMI (decreased) compared to Black/AA pts not receiving IO. Conclusion: We observed the interaction effect of race/ethnicity and treatment on BMI change in BC survivors within 2 years after a BC dx, with Black/AA pts more likely to have an increase in BMI. Table 1.Descriptive Statistics Summary, n = 630.VariableALL (n=630)BMI ≤ 24.9 (n=160, 25%)25 ≤ BMI ≤ 29.9 (n=180, 29%)BMI ≥ 30 (n=290, 46%)p-valueAge at 1st Encounter with BC dx, mean (SD)61.8 (11.8)62.1 (12.5)62.1 (12.1)61.5 (11.2)0.808Sex, n (%)Female625 (99.2)159 (99.4)178 (98.9)288 (99.3)0.857Male5 (0.8)1 (0.6)2 (1.1)2 (0.7)Race & Ethnicity, n (%)White/Caucasian348 (55.2)103 (64.4)106 (58.9)139 (47.9)&lt;.001Black/AA215 (34.1)35 (21.9)48 (26.7)132 (45.5)Hispanic/Latino20 (3.2)5 (3.1)5 (2.8)10 (3.4)Asian/Pacific Islander39 (6.2)17 (10.6)18 (10.0)4 (1.4)American Indian/Alaskan Native2 (0.3)0 (0.0)0 (0.0)2 (0.7)Unknown6 (1.0)0 (0.0)3 (1.7)3 (1.0)BMI (baseline), mean (SD)29.9 (7.1)22.2 (2.0)27.1 (1.4)35.9 (5.7)&lt;.001Treatment (Yes) , n (%)HistoricalCT2 (0.3)1 (0.6)1 (0.6)0 (0.0)0.294ET35 (5.6)7 (4.4)12 (6.7)16 (5.5)0.663IO4 (0.6)2 (1.3)1 (0.6)1 (0.3)0.487BaselineCT20 (3.2)4 (2.5)7 (3.9)9 (3.1)0.815ET54 (8.6)16 (10.0)15 (8.3)23 (7.9)0.742IO11 (1.7)5 (3.1)2 (1.1)4 (1.4)0.3111 yearCT154 (24.4)41 (25.6)42 (23.3)71 (24.5)0.886ET309 (49.0)73 (45.6)93 (51.7)143 (49.3)0.535IO29 (4.6)10 (6.3)8 (4.4)11 (3.8)0.4892 yearsCT71 (11.3)20 (12.5)15 (8.3)36 (12.4)0.337ET231 (36.7)50 (31.3)73 (40.6)108 (37.2)0.198IO32 (5.1)7 (4.4)4 (2.2)21 (7.2)0.051 Citation Format: Maysa Abu-Khalaf, Fnu Nikita, Ayako Shimada, Hannah Hackbart, Dina Alnabulsi, Scott Keith, Ana Maria Lopez, Meghan Butryn. Change in body mass index in breast cancer survivors [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 P4-11-32.

Abstract Imatinib is a tyrosine kinase that effectively inhibits the bcr-abl fusion protein in Philadelphia (Ph) chromosome positive CML and c-kit, which is overexpressed in gastrointestinal stomal tumors (GIST). We identified a group of patients treated with Imatinib at Memorial Hospital who developed low phosphate (PO4) levels and studied metabolic bone and mineral parameters associated with this finding. A total of 61 patients who received a prescription for Imatinib from the hospital pharmacy were screened to determine whether a PO4 level had ever been drawn. Of these, 26 had at least one PO4 level, and 10 of these (38%) had a low value (&lt;2.5 mg/dL).Patients samples were then studied for calcium (Ca++), parathyroid horme (PTH), 25-(OH)-vitamin D and 1,25-(OH)2-vitamin D, as well as serum markers of bone formation (bone alkaline phosphatase and osteocalcin) and resorption (N-telopeptide). Urinary calcium and PO4 were measured and fractional excretion of PO4 (FEPO4) was calculated as well. A total of 10 patients (8 men, 2 women) median age 47 (range 32–60) with CML (n=8) or GIST (n=2) were studied. The median time interval between diagnosis and starting Imatinib was 3.8 mos (range 0.4–161) and the median interval between starting Imatinib and first low PO4 was 3.9 mos (range 0.3–23). Results of Bone Metabolism UPIN PO4 Calcium PTH FePO4 N-Telopep Osteocalcin Bone Alk phos ND: Not done: NMA: No measurable amount; 25-(OH)-vitD levels were low to mid-normal, and 1,25-(OH)2 vit D levels were typically borderline high or elevated (data not shown) 2.5–4.2mg/dL 8.5–10.5mg/dL 10–65pg/mL &lt; 5% 5.5–19.5nM 3.1–12.7ng/ml 15–441U/L 1 2.0 8.7 84 25 ND ND ND 2 1.7 8.6 97 24 ND ND ND 3 2.3 9.4 68 44 ND ND ND 4 1.9 9.5 84 25 7.1 3.7 18 5 1.8 8.9 85 17 6.2 NMA 15 6 2.1 9.3 83 23 ND ND ND 7 1.7 8.7 57 16 5.6 NMA 17 8 1.3 8.1 136 38 10.1 NMA 53 9 2.3 9.2 81 10 13.4 NMA 17 10 2.1 8.9 41 17 5.8 2.6 15 Two patients who temporarily stopped Imatinib had normalization of their PO4, which again decreased upon resumption of the drug. In summary, patients who develop hypophosphatemia while on Imatinib have low-normal to mildly low serum Ca++ but elevated PTH, elevated FEPO4, low-normal levels of N-telopeptide, very low levels of osteocalcin, and low levels of bone alkaline phosphatase. These values distinctly differ from patients with either inherited or tumor induced forms of hypophosphatemia with renal phosphate wasting (X-linked hypophosphatemic rickets, adult dominant hypophosphatemic rickets, and tumor-induced osteomalacia). Our preliminary data suggest that in some patients, Imatinib results in profound suppression of bone formation and mild suppression of bone resorption, leading to a state of hypodynamic bone remodeling. Further investigation is planned comparing patients on Imatinib who become hypophosphatemic and those who do not. Better characterization of bone and mineral metabolism in this setting is important for several reasons: (1) myalgias from Imatinb, a common side effect, may be related to hyphophosphatemia and correctible with appropriate replacement; (2) while these data are premature, it is conceivable that Imatinib might be useful in situations where suppression of bone formation and turnover is desirable, such as in osteoblastic bone metastases, osteopetrosis, and other diseases of abnormally increased bone formation.

Abstract Abstract 525 Background: Role and timing of allografting in myeloma are hotly debated. Before the introduction of new drugs, we carried out a trial where the treatment assignment was based only on the presence/absence of an HLA-identical sibling (Bruno et al, N Engl J Med 2007). Methods: Overall, 162/199 (81%) of patients with at least one sibling were HLA-typed. First-line treatments included induction with VAD-based regimens and a cytoreductive autograft, followed by a nonmyeloablative allograft (Tandem auto-allo) or a second melphalan-based autograft (Double-auto). We now report an update at a median follow up of 7.1 years. Results: Response rates [complete (CR) and partial remissions (PR)] at the time and after the non-myeloablative allograft and at the time and after the second autograft did not differ between the two cohorts: 76% and 86%, and 76% and 91% respectively (p=1 and p=0,54). However, CR rate was significantly higher after the non-myeloablative allograft than after the second autograft: 55% versus 26% (p=0,0026). At a median follow up of 7.1 years (range 2.5 – 10.7+), by intention-to-treat analysis, median overall survival (OS) and event free survival (EFS) were significantly longer in patients with HLA-identical siblings (No.80) as compared with those without (No.82): not reached vs. 4.25 years (HR 0.51, CI 95% 0.34–0.76, p=0.001) and 2.8 vs. 2.4 years (HR 0.62, CI 95% 0.44–0.87, p=0.005). By multivariate analysis, independent of age, gender, myeloma protein isotype, Durie&Salmon stage, and disease status at the first autograft; the presence of an HLA-identical sibling was significantly associated with longer OS (HR 0.5, CI 95% 0.3–0.8, p=0.001) and EFS (HR 0.63, CI 95% 0.4–0.9, p=0.01). At a median follow up of 7.3 (range 5.4 – 10.7+ years), median OS was not reached in the 58 patients who received a non-myeloablative allograft and 5.3 years in the 46 who received a second high-dose melphalan autograft (HR 0.55, CI 95% 0.32–0.94, p=0.02), whereas EFS was 39 months and 33 months (HR 0.62, CI 95% 0.40–0.96, p=0.02) respectively. Cumulative incidence of transplant related mortality was 11% and 2% at 2 years respectively. At median follow-ups of 7.3 years from diagnosis (range 5.4 – 10.4+) and 6.5 years from the allograft (range 4.2 – 9.4+), and 7.4 years from diagnosis (range 5.6 – 10.7+) and 6.2 years from the second autograft (range 4.7 – 9.1+), 30/58 (52%) and 37/46 (80%) patients, respectively, were treated for disease relapse/progression. Salvage therapies included bortezomib- or thalidomide-containing regimens in most patients of both cohorts. After 1–3 lines of therapy, 22/30 (73%) had a response, including 5 CR and 17 PR, in the tandem auto-allo group, whereas 21/37 (54%) had a response, including 4 CR and 16 PR after the second autograft. Of note, at a median follow up of 3.9 years from the start of the first salvage therapy, OS was not reached and was 1.7 years in patients who had relapsed/progressed after the allograft and the second high-dose melphalan (HR 0.44, CI 95% 0.24–0.82, p=0.01) respectively. Conclusions: In this study, allografting conferred a long term survival advantage over standard autografting. Salvage therapy was associated with longer OS perhaps due to a synergistic effect between new drugs and residual graft-vs.-myeloma effects. In prospective clinical trials, the combination of graft-vs.-myeloma effects with “new drugs” should be explored and may increase the cure rate of myeloma patients. Disclosures: Bringhen: Celgene: Honoraria; Janssen-Cilag: Honoraria. Palumbo:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees. Boccadoro:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

BackgroundDuvelisib, an FDA-approved oral phosphoinositide 3-kinase (PI3K)-δ,γ inhibitor, targets tumor cells of B/T cell malignancies, but may modulate non-malignant immune cells in the tumor microenvironment (TME) of many cancers. PI3K–δ and PI3K–γ downmodulate immunosuppressive Tregs and myeloid cells in solid tumors.1, 2, 3 We used single-cell RNA analysis of PIK3CD and PIK3CG to explore resistance mechanisms to checkpoint inhibitors (CPI).MethodsSingle-cell melanoma (SKCM) RNAseq datasets: GSE120575;4 CD45+ cells from 48 CPI responders and non-responder tumors, and GSE115978;5 33 treatment-naïve and CPI-progressing (resistant) tumors. Cancer cells and CD45+ TME subpopulations, specified by gene expression signatures and tSNE plots, had PI3K gene expressions profiled. Differential gene expression (DE) was gated in MAST/Seurat. Fishers test Odds Ratio (OR) was calculated for ‘high’ expression.ResultsPIK3CD expression is higher in SKCM than most cancers (10.8 median RSEM log 2).7 By single-cell analysis, PIK3CD (> 0.3 log2 TPM) occurs in 68.2% of cancer cells, with PIK3CB, PIK3CA, and PIK3CG expressed in 32.3%, 12.0%, and 7.2% respectively. PIK3CD-high cancer cells (>4 log2 TPM) have a 711-gene DE gene signature mostly related to immune processes. A higher proportion of cancer cells in CPI resistant tumors express PIK3CD, than untreated tumors (OR 2.02, 95% CI 1.65–2.48, p=3.04 × 10–12), as do PIK3CD+PIK3CG-expressing cancer cells (OR 2.14, 95% CI 1.47–3.13, p=4.2 × 10-5). Additionally, in PI3K–δ or PI3K–γ high melanoma cell lines duvelisib inhibited proliferation, p-AKT and c-myc.7 PIK3CD and PIK3CG are prominently expressed in many SKCM CD45+ TME cells (84.5% and 31.7% CD45+ respectively). PIK3CD (>0.3 log2 TPM) occurs in a high fraction of T (85.7%), CD8+ T (86.3%), CD4+ T (86.9%), B (78.5%), macrophages (88%), and NK (85%). PIK3CG is highest in B, dendritic, cycling lymphocytes and plasma cells. Strikingly, a significantly higher proportion of PIK3CD+ cells occur in resistant tumors compared to untreated for all CD45+ cells, (OR 1.64, 95% CI 1.40–1.94, p=4.79 × 10-10), CD8+ T (OR 2.15, 95% CI 1.61–2.86, p=6.5 × 10-8), and an exhausted C8+ T subpopulation (OR 3.17, 95% CI 1.89–5.37, p=2.95 × 10-6). PIK3CD+PIK3CG-expressing CD45+ cells are significantly increased in CPI-resistant tumors (OR 1.22, 95% CI 1.07–1.39, p=0.002).ConclusionsThese findings support a mechanism where CPI therapies may contribute to modulation of PI3Kδ expression in cancer cells and the immune TME. The PI3K-δ,γ inhibitor duvelisib is being investigated in combination with CPI and evaluated in the context of CPI resistance in clinical trials: pembrolizumab (HNSC, NCT04193293), and nivolumab (Richter’s Syndrome, NCT03892044).ReferencesAli K, Soond DR, Pineiro R, Hagemann T, Pearce W, Lim EL, Bouabe H, Scudamore CL, Hancox T, Maecker H, Friedman L, Turner M, Okkenhaug K, Vanhaesebroeck B. Inactivation of PI(3)K p110δ breaks regulatory T-cell-mediated immune tolerance to cancer Nature 2014; 510(7505):407–411.Kaneda MM, Messer KS, Ralainirina N, Li H, Leem CJ, Gorjestani S, Woo G, Nguyen AV, Figueiredo CC, Foubert P, Schmid MC, Pink M, Winkler DG, Rausch M, Palombella VJ, Kutok J, McGovern K, Frazer KA, Wu X, Karin M, Sasik R, Cohen EE, Varner JA. PI3Kγ is a molecular switch that controls immune suppression. Nature 2016; 539(7629):437–442.De Henau O, Rausch M, Winkler D, Campesato LF, Liu C, Cymerman DH, Budhu S, Ghosh A, Pink M, Tchaicha J, Douglas M, Tibbitts T, Sharma S, Proctor J, Kosmider N, White K, Stern H, Soglia J, Adams J, Palombella VJ, McGovern K, Kutok JL, Wolchok JD, Merghoub T. Overcoming resistance to checkpoint blockade therapy by targeting PI3Kγ in myeloid cells. Nature 2016; 539(7629):443–447.Sade-Feldman M, Yizhak K, Bjorgaard SL, Ray JP, de Boer CG, Jenkins RW, Lieb DJ, Chen JH, Frederick DT, Barzily-Rokni M, Freeman SS, Reuben A, Hoover PJ, Villani AC, Ivanova E, Portell A, Lizotte PH, Aref AR, Eliane JP, Hammond MR, Vitzthum H, Blackmon SM, Li B, Gopalakrishnan V, Reddy SM, Cooper ZA, Paweletz CP, Barbie DA, Stemmer-Rachamimov A, Flaherty KT, Wargo JA, Boland GM, Sullivan RJ, Getz G, Hacohen N. Defining T Cell States Associated with Response to Checkpoint Immunotherapy in Melanoma. Cell 2018; 175: 998–1013.Jerby-Arnon L, Shah P, Cuoco MS, Rodman C, Su MJ, Melms JC, Leeson R, Kanodia A, Mei S, Lin JR, Wang S, Rabasha B, Liu D, Zhang G, Margolais C, Ashenberg O, Ott PA, Buchbinder EI, Haq R, Hodi FS, Boland GM, Sullivan RJ, Frederick DT, Miao B, Moll T, Flaherty KT, Herlyn M, Jenkins RW, Thummalapalli R, Kowalczyk MS, Cañadas I, Schilling B, Cartwright ANR, Luoma AM, Malu S2, Hwu P, Bernatchez C, Forget MA, Barbie DA, Shalek AK, Tirosh I, Sorger PK, Wucherpfennig K, Van Allen EM, Schadendorf D, Johnson BE, Rotem A, Rozenblatt-Rosen O, Garraway LA, Yoon CH, Izar B, Regev A. A Cancer Cell Program Promotes T Cell Exclusion and Resistance to Checkpoint Blockade. Cell 2018; 175: 984–997.Firebrowse Gene Expression Viewerhttp://firebrowse.org/viewGene.html.Coma S, Weaver DT, Pachter JA. [Poster #663] The dual PI3K-δ/PI3K-γ inhibitor duvelisib inhibits signaling and proliferation of solid tumor cells expressing PI3K-δ and/or PI3K-γ. AACR. 2020.

Abstract Introduction In acute and chronic leukemia, the changes in the basic properties of multipotent mesenchymal stromal cells (MSCs), including morphology, immunomodulatory abilities, and the expression of various genes, were described. The aim of the investigation was to study the ability of MSCs derived from the bone marrow (BM) of patients with acute lymphoblastic (ALL), myeloid (AML) leukemia and chronic myeloid leukemia (CML) to maintain normal hematopoietic progenitor cells. Methods The study included 14 patients with ALL, 25 with AML and 15 with CML. All work was conducted in accordance with the Declaration of Helsinki (1964). BM was aspirated from the patient during diagnostic punctures before the treatment and for patients with acute leukemia 37 and 100 days; for patients with CML on average at the 125th day and 220th day after the start of the treatment. The BM samples of 22 healthy donors were used as controls. MSCs were derived from 5-10 ml of BM and cultivated at the density 3 х 106 cells in T25 culture flasks in aMEM with 10% FCS. The ability of MSCs from patients to maintain normal hematopoietic precursor cells - coble stone area forming cells (CAFC) was performed by the limiting dilution method. One day prior to assay, MSCs from donors and patients were explanted with 1000 cells per well of 96-well plates. As a control, the cell line MS5 supporting growth of hematopoietic precursor cells was used. On the following day, with complete medium change, BM cells from healthy donors were implanted in four serial dilutions. The frequency of CAFC in the normal BM was performed using Poisson's equation and presented as the percent of control. The total RNA was extracted from MSCs at passage 1 using the standard method. The relative gene expression levels (REL) were determined by normalizing the expression of each target gene to the levels of beta-actin and glyceraldehyde 3-phosphate dehydrogenase and calculated using the ΔΔCt method. Results Total cell production of MSCs from ALL (5.6±1.5) x 106 and AML (5.4±1.0) x 106 patients decreased at the moment of diagnosis, whereas the production of MSCs from CML (7.9±1.9) x 106 patients did not differ from the donors (7.1±1.04) x 106. Reduced cell production is likely associated with a significant decrease in the expression level of FGF2, VEGF, BGLAP and SOX9 genes (Table). The ability of MSCs derived from the BM of AML patients at the onset of the disease to maintain normal CAFC (59.3±6.8) was significantly decreased (p = 0.02) when compared to donors (74.9±9.5). At the end of the first course of chemotherapy, the ability to maintain CAFC in patients' MSCs reached that of the donors(80.7±5.8); 2 months later, the CAFC frequency on MSCs from AML patients doubled (107.9±18.4) in comparison with the start of the disease (p = 0.04). The ability of MSCs derived from ALL patients to support CAFC was lower than that of MSCs of AML patients both before treatment (57.8±12) and 37 days after the start (57.2±7.4). Three months after the initiation of treatment of these patients, the ability of MSCs to maintain CAFC recovered (73.7±13.3) and reached that of the donors' MSCs. MSCs of CML patients (100.8±9.9) at the disease onset maintained CAFC better than donors' MSCs. This ability increased with treatment at 125th day (109.6±14.4) and at 220th day (169.6) after the start of the treatment. The expression levels of LIF, IGF1, IL6, CSF1 increased significantly in CML-derived as well as AML-derived MSCs, but changes were more pronounced in the case of CML. Table. REL of different genes in MSCs derived from patients at the onset of the disease. Gene AML ALL CML Donors FGF2 2.8±0.2* 2.0 ±0.4* 4.2±0.5 6.0±0.9 VEGF 1.5±0.1* 1.5±0.2* 1.7±0.2 2.5±0.9 LIF 9.1±1.3* 7.1±2.3* 21.8±7.5 2.2±0.4 IL6 12.7±1.8* 11.3±4.4 22.5±4.8* 6.2±1.8 CSF1 3.6±0.9* 2.1±1.2 0.96±0.1* 0.7±0.1 IGF1 1.3±0.3* 1.49±0.7 2.6±0.5* 0.6±0.1 BGLAP 0.6±0.2* 0.8±0.4* 1.7±0.4 2.7±0.1 SOX9 1.2±0.1* 0.9±0.3* 1.2±0.2 1.7±0.2 (*significantly different from donors) Conclusions Functional changes in MSCs, which are the part of BM stromal microenvironment and, in particular, a niche for the HSCs was revealed. The ability of MSCs to support CAFC is dramatically changed in patients with hematological malignancies; the nature of the functional alterations of MSCs depends on the diagnosis. In cases of acute leukemia, MSCs' ability to maintain CAFC normalized with the treatment, whereas the strengthening of this capacity was revealed in cases of CML. Disclosures Turkina: Bristol Myers Squibb: Consultancy; Pfizer: Consultancy; Novartis Pharma: Consultancy.

Abstract AIHA is characterized by a high erythrocyte destruction rate associated to autoantibodies directed against blood cell antigens and is usually treated with glucocorticoid (GC). SIRP-a (Signal Regulatory Protein-a)) is an inhibitory receptor in phagocytes and a direct substrate for the phosphatase SHP-1, an important regulator of macrophage proliferation and activation. SIRP-a activation and consequent phosphorylation of immunoreceptor tyrosine-based inhibitory motifs, occur by the binding to CD47 on the erythrocyte membrane, and allow SHP-1, SHP-2 and SHIP recruitment, which in turn dephosphorylate specific protein substrates involved in the mediation of several physiologic effects. The aim of this study was to evaluate the “in vitro” and “in vivo” effects of GC on SIRPa and SHP-1 expression. Peripheral blood monocytes (PBM) were isolated from AIHA patients with and without GC therapy. For the “in vitro” studies PBM from healthy donors and U937 cells were cultured for 48 hours with Dexamethasone (Dexa-1mM) and/or IFNg (100U/ml) and TNFa (1000U/ml). SIRPa and SHP-1 mRNA expression was determined by Real Time PCR, using b-actin expression as an internal control and PBM from healthy donor as a calibrator. AIHA patients underwent clinical and immunohematological investigation. SIRPa and SHP-1 mRNA expression was significantly increased in U937 cells and normal PBM treated with IFN/TNF alone (Mean±SD, SIRPa U937: 4.0±3.2, p=0.009; PBM: 14.9±9.0, p=0.004)(SHP- 1 U937:8.1±6.9, p=0.0002; PBM 12.3±7.1, p=0.006) or associated with Dexa (Mean SIRPa U937:2.7±1.3, p=0.02; PBM 36.1±34.5, p=0.0001)(SHP-1 U937 :5.7±4.2, p=0.002; PBM: 18.9±16.0, p=0.001) compared to basal conditions (Mean SIRPa U937 :1.8±2.1; PBM 3.8±3.9)(SHP 1 U937 :1.7±2.2; PBM 3.9±4.0). Regarding treatment with Dexa alone, SIRPa and SHP-1 were significantly increased in normal PBM but not in U937 (SIRPa 24.8±12, p=0.0004, SHP-1 19.2±6.2, p=0.0001). SIRP-a and SHP-1 expression was significantly higher in PBM from AIHA patients (SIRPa 5.6±1.9, SHP-1 6.1±1.8 n=6) compared to normal (SIRPa 1.8±1.40; p=0.008, SHP-1 2.4±2.1, n=10; p=0.01). After GC therapy, SIRP-a and SHP-1 expression was similar in PBM of AIHA patients (SIRPa 0.6±0.3, SHP-1 0.9±0.18, n=5) compared to healthy donors. AIHA patients studied before GC therapy showed positive direct antiglobulin test (DAT) with anti-IgG and C3d, low hemoglobin (7.7±3.3g/dl) and hematocrit (23.6±11.6%), and reticulocytosis (258.1±194.5). AIHA patients studied after GC therapy showed DAT with only anti-IgG, normal level of hemoglobin (12.1±1.6), hematocrit (35.1±4.8) and reticulocytes (71.8±42.3). In the present study, SIRPa and SHP1 mRNA were higher in mature monocytes compared to U937 and upregulated by dexametasone and IFN /TNF. This result could suggest that this pathway is involved in the reduction of phagocytosis by GC. However, patients with AIHA showed upregulation of these proteins in basal conditions and after GC treatment and hemolysis reduction, SIRPa and SHP1 mRNA expression decreased to normal levels. A balance between inhibition and activation signals determined the macrophage phagocytic activity. Increased SIRP-a and SHP-1 expression in AIHA patients before GC therapy could be a consequence of a homeostatic mechanism, activated by massive phagocytosis, with the purpose of inhibiting the predominant activating signals.

Category: Bunion; Midfoot/Forefoot Introduction/Purpose: The Distal Metatarsal Articular Angle (DMAA) has long been described as a valgus increase of the distal articular surface of the first metatarsal in Hallux Valgus (HV) deformity. Since then, several studies have reported a poor reliability of this measurement and some authors currently claim that DMAA is misinterpreted as just the rounded shape of the lateral part of the first metatarsal head reflecting pronation of the first ray and could also be biased by the first metatarsal plantarflexion angle. Our study aimed to compare the DMAA in HV and control populations after correcting, with a dedicated software, pronation and plantarflexion of the first metatarsal. We hypothesized that after correction, DMAA will be higher in the HV population, especially in juvenile cases. Methods: We performed a retrospective case-control study including 36 HV and 20 control feet. Patients under 15 or with surgery antecedent were excluded. DMAA1 was measured as initially described on X-rays by the angle between the distal articular surface and the longitudinal axis of the first metatarsal. DMAA2 was measured on Weight Bearing Computed Tomography (WBCT) without any corrections. DMAA3 was measured after correction of the first metatarsal plantarflexion in the sagittal plane. DMAA4 was measured after correction of the pronation of the first ray relative to the ground in the coronal plane using the alpha-angle. And DMAA5 after both corrections. Corrections in the coronal and sagittal planes were performed along the axis of the first metatarsal. Normality was assessed using Shapiro-Wilk tests. Comparisons were made using Student tests for normal variables and Mann-Whitney for non-normals. Correlations between age and angles were assessed by the Pearson correlation coefficient. Results: HV and Control groups were comparable on BMI (p=0.69), Age (p=0.58) and Gender (p=0.27). DMAA1 (25.9°+/-7.3 vs 7.6°+/-4.2; p<0.01), DMAA2 (19.1°+/-7.1 vs 3.3°+/-2.4; p<0.01), DMAA3 (16.1°+/-6.2 vs 2.9°+/-2.4; p<0.01), DMAA4 (14.4°+/-5.7 vs 2.6°+/-2.5; p<0.01) and DMAA5 (11.9°+/-4.9 vs 3.3°+/-2.9; p<0.01) were significantly higher in the HV group than in the Control group. Significant decreases in angles were present between DMAA1 and DMAA2 (Δ=-6.9; CI95[-8.6;-5.1]; p<0.01), DMAA2 and DMAA3 (Δ=-3; CI95[-4.1;-1.9]; p<0.01), DMAA2 and DMAA4 (Δ=-4.7; CI95%[-6.3;-3.1]; p<0.01), DMAA2 and DMAA5 (Δ=-7.2 ;CI95%[-8.8;-5.6]; p<0.01) and between DMAA3 and DMAA4 (Δ=-1.7 ;CI95%[-2.9;-0.5]; p<0.01) in the HV group. No significant correlation was found between the 5 different DMAA values and the age in the HV group (respectively ρ=0.1,p=0.55 ; ρ=0.31,p=0.07 ; ρ=0.19,p=0.28 ; ρ=0.1,p=0.56 ; ρ=0.04,p=0.83). Conclusion: Although overestimated with the 2-dimensional DMAA assessment, the valgus increase of the distal articular surface of the first metatarsal was present in the HV deformity, even after correction of pronation and plantarflexion of the first ray. DMAA overestimation was close to 14 degrees on X-rays and 7 degrees on WBCT without any correction and pronation of the first metatarsal seemed to play a more important role on this overestimation than plantarflexion. Age did not seem to influence this deformity. Increase of valgus of the distal articular surface of the first metatarsal should be considered in HV correction surgical planning.

BackgroundManagement of patients with recurrent endometrial cancer after failure on platinum-based therapy remains a clinical challenge. Retifanlimab (INCMGA00012) is an investigational humanized immunoglobulin G4 monoclonal antibody against programmed cell death 1 (PD-1). We previously reported encouraging results from a preplanned interim analysis in patients with microsatellite instability-high (MSI-H) recurrent endometrial cancer treated with retifanlimab in POD1UM-101 [1]. Here, we provide top-line results from the full cohort of patients in the POD1UM-101 study.MethodsEligible patients have histologically proven, unresectable recurrent MSI-H or deficient mismatch repair (dMMR) endometrial cancer (per local testing), ECOG PS ≤1, disease progression during or following 1 to ≤5 prior systemic treatments, measurable disease (per RECIST v1.1), and are naïve to prior immune checkpoint inhibitors. MSI-H and dMMR status were centrally confirmed using PCR and IHC, respectively. Patients receive retifanlimab 500 mg every 4 weeks for up to 2 years. The primary study endpoint is safety. Confirmed best overall response and duration of response (DOR) were evaluated by independent central review (ICR) using RECIST v1.1.ResultsAs of July 6, 2021, 76 patients with centrally confirmed MSI-H (65 [85.5%]) or dMMR (11 [14.5%]) endometrial cancer had received ≥1 dose of retifanlimab; median age was 67.0 (49–88) years, 70 (92.1%) had endometrioid histology, 67 (88.2%) had metastatic disease, and 61 (80.3%) had visceral metastases. Sixty-eight (89.5%) patients had prior surgery or procedure, 54 (71.1%) patients were treated with radiotherapy, and 75 (98.7%) patients had received prior systemic therapy for advanced disease (33 [43.4%] received ≥2 prior systemic therapies for advanced disease). Median retifanlimab exposure was 7.4 (0.03–23.0) months. At data cutoff, 2 (2.6%) patients completed treatment and 30 (39.5%) were on treatment. Grade ≥3 treatment emergent AEs (TEAEs) occurred in 33 (43.4%) patients, including 10 (13.2%) with anemia and 7 (9.2%) with an immune-related AE (nephritis, n=2; autoimmune hepatitis, hepatitis, myositis, rash, and pneumonitis, n=1 each). There were no treatment-related AEs with fatal outcome. Centrally confirmed objective responses were observed in 33 (43.4%) patients (95% CI, 32.1–55.3), with 11 (14.5%) complete and 22 (28.9%) partial responses. Of the 33 patients with objective response, 25 (75.8%) had DOR for ≥6 months; median DOR was not reached. Median follow-up time for response was 8.4 (range, 1.9–28.3) months.ConclusionsRetifanlimab was well tolerated and demonstrated encouraging antitumor activity in patients with pretreated recurrent MSI-H or dMMR endometrial cancer, consistent with that achieved with other PD-1 therapies.AcknowledgementsThis study is sponsored by Incyte Corporation (Wilmington, DE).Trial RegistrationClinicaltrialsgov NCT03059823, EudraCT 2017-000865-63ReferenceBerton-Rigaud D, et al. J ImmunoTher Cancer 2020;8(Suppl 3):A164–A165 [Abstract 268].Ethics ApprovalThis study was approved by institutional review boards or independent ethics committees in Belgium (Aan de Commissie Medische Ethiek University Hospitals Leuven [CEC: S62335]; Ethics Committee of Hospital-Faculty University of Liège [LEC: 2019/48]); Bulgaria (Ethics Committee for Clinical Trials, Sofia [RA: IAL-24443/08.06.2017; CEC: КИ-80/08.06.2017]); Finland (HUS Tutkimuseettiset toimikunnat Biomedicum Helsinki [RA: KLnro 124/2019]); France (CPP Île-de-France X Hôpital, Aulnay-sous-Bois cedex [RA: MED MSA NAT-2019-08-00080; CEC: CN-RIPH 19.02.17.56415/CPP 27-2019]); Germany (Ethik-Kommission der Albert-Ludwigs-Universität Freiburg, Freiburg [RA: 3102/012; EC: 506/18]; Ethics Committee at the Technical University of Dresden, Dresden [RA: 3102/012; EC: EK 4854 AB]; Ethics Committee of the State of Berlin, Berlin [RA: 3102/012; EC: 17/0411 EK 12/15]); Italy (Comitato Etico del Policlinico Gemelli Fondazione Policlinico Universitario ”Agostino Gemelli”, Roma (RM) [no approval number issued by RA or EC]; Comitato Etico IRCCS di Candiolo, Candiolo-TO [no approval number issued by RA or EC]); Latvia (Ethics Committee for Clinical Research at Development Society of Pauls Stradins Clinical University Hospital, Riga [no approval number issued by RA or EC]); Lithuania (Lithuanian Bioethics Committee, Vilnius [no approval number issued by RA or EC]); Poland (Komisja Bioetyczna przy Uniwersytecie Medycznym, Pozna&nacute; [RA: UR.DBL.474.0350.2017; CEC: 622/17]); Spain (Comité de Ética de Investigación con Medicamentos, Madrid Centro Actividades Ambulatoria [RA: 17-073 (Locator: 2VK42NE57D); CEC: 17/211]); Ukraine (Ethical Committee at Prykarpatsky Regional Clinical Oncology Center of Ivano-Frankivsk Regional Rada, Ivano-Frankivsk [no approval number issued by RA or EC]); United States (IntegReview IRB, Austin, TX [no approval number issued by IRB]; The University of Texas MD Anderson Cancer Center Institutional Review Board, Houston, TX [no approval number issued by IRB]).

Abstract Introduction: PIK3CA mutations (mut) occur in ~40% of patients (pts) with HR+, HER2- ABC, and lead to phosphatidylinositol 3-kinase (PI3K) pathway hyperactivation, endocrine resistance, and poor survival in advanced disease. Alpelisib, an α-selective PI3K inhibitor and degrader, demonstrated efficacy in combination with fulvestrant in the Phase III SOLAR-1 trial in pts with PIK3CA-mut HR+, HER2- ABC. Notably, treatment benefit was not seen in pts without PIK3CA-mut tumors. Expert guidelines now recommend testing for PIK3CA mut at advanced diagnosis; however, data on PIK3CA mut prevalence in a broader population outside of clinical trials are limited. This real-world study snapshot describes the global prevalence of PIK3CA mut across geographic areas in HR+, HER2- ABC. Methods: This noninterventional, retrospective cohort study of ~2,000 adults (≥18 years) in ~20 countries from Europe, Asia, Middle East (ME), and Latin America (LA) is assessing the frequency of PIK3CA mut in HR+, HER2- ABC. Key inclusion criteria are histologically/cytologically confirmed estrogen/progesterone receptor-positive and HER2- ABC with available fresh or archival tumor tissue. The primary endpoint is the percentage of pts with PIK3CA-mut tumors, specifying each hotspot. Key secondary endpoints include the percentage of pts with PIK3CA-mut tumors by geographic region, demographics by PIK3CA status, clinical characteristics, number of lines of treatment in the advanced setting, and time to subsequent treatment by PIK3CA status. Tumor tissue samples are assessed at a local laboratory, at a minimum, for PIK3CA mut in C420R, E542K, E545A/D/G/K, Q546E/R, and H1047L/R/Y. All statistical analyses are descriptive, and the prognostic role of PIK3CA mut will be evaluated in the final analysis. Results: As of data cut-off (03 May 2021), 1,361 pts were enrolled in the Full Analysis Set, 574 (42.2%) of whom have tumors harboring a PIK3CA mut. Table 1 summarizes demographics and baseline characteristics in the mut and non-mut cohorts. Polymerase chain reaction and next-generation sequencing were the common methods used to assess PIK3CA mut in 570 (41.9%) and 625 (45.9%) of pts, respectively. PIK3CA mut rates are generally consistent across regions (30.7-44.0%, Table 2). Table 2 shows sample types and most common biomarker muts. Conclusions: In this study, PIK3CA mut rates, 43.0% in Asia, 44.0% in Europe, 40.9% in LA, and 30.7% in ME, were consistent across regions and closely followed previous reports, supporting the prevalence of this mut outside the trial setting and in a more diverse real-world pt population. The most common PIK3CA muts found in this study were H1047R, E545K, and E542K, consistent with SOLAR-1. PIK3CA mut rates were comparable in primary vs metastatic samples, supporting the existing body of evidence that PIK3CA mut are truncal and can be tested on any available tissue. Further analysis, including treatment-related information, will be presented. Table 1.Demographics, baseline characteristics, and disease history (Full Analysis Set)Mutant PIK3CANon-mutant PIK3CAAll patientsn=574n=787N=1,361Median age (range) at early disease diagnosisa50.0 (28.0-85.0)51.0 (23.0-83.0)51.0 (23.0-85.0)Median age (range) at advanced disease diagnosis57.0 (26.0-89.0)55.5 (23.0-87.0)56.0 (23.0-89.0)Median age (range) at enrollment59.5 (27.0-89.0)59.0 (23.0-87.0)59.0 (23.0-89.0)Sex, n (%)Female566 (98.6)778 (98.9)1,344 (98.8)Male8 (1.4)8 (1.0)16 (1.2)Unknown01 (0.1)1 (0.1)Race, n (%)White294 (51.2)418 (53.1)712 (52.3)Asian183 (31.9)239 (30.4)422 (31.0)Black or African American5 (0.9)13 (1.7)18 (1.3)Multiple1 (0.2)0 (0.0)1 (0.1)Unknown91 (15.9)117 (14.9)208 (15.3)Menopausal status at advanced disease diagnosis, n (%)bMutant PIK3CANon-mutant PIK3CAAll patientsn=566n=778N=1,344Postmenopausal410 (72.4)554 (71.2)964 (71.7)Premenopausal146 (25.8)214 (27.5)360 (26.8)Stage at initial diagnosis, n (%)Mutant PIK3CANon-mutant PIK3CAAll patientsn=574n=787N=1,361Recurrent breast cancerc299 (52.1)414 (52.6)713 (52.4)De novo advanced breast cancerd265 (46.2)357 (45.4)622 (45.7)Unknown10 (1.7)16 (2.0)26 (1.9)Time from early diagnosis to advanced disease, n (%)&lt;1 year32 (5.6)33 (4.2)65 (4.8)1 to &lt;2 years25 (4.4)25 (3.2)50 (3.7)2 to &lt;3 years29 (5.1)40 (5.1)69 (5.1)≥ 3 years149 (26.0)214 (27.2)363 (26.7)Extent of metastatic disease, n (%)Bone390 (67.9)456 (57.9)846 (62.2)Liver141 (24.6)204 (25.9)345 (25.3)Lung171 (29.8)245 (31.1)416 (30.6)Other127 (22.1)155 (19.7)282 (20.7)Number of metastatic sites, n (%)013 (2.3)21 (2.7)34 (2.5)1229 (39.9)324 (41.2)553 (40.6)&gt;1332 (57.8)442 (56.2)774 (56.9)aCensored patients initially diagnosed as de novo advanced breast cancer.bMenopausal status is applicable only to female patients. Sites are provided the option to choose from 1) Able to bear children, 2) Post-menopausal, or 3) Sterile - of childbearing age.cStage 0-IIIA at initial diagnosis.dStage IIIB, IIIC, or IV at initial diagnosis. Table 2.PIK3CA mutation status by region and sample typeFrequency of mutant PIK3CA by regionMutant/Number of patients% (95% CI)All patients574/1,36142.2 (39.5-44.9)Asia193/44943.0 (38.4-47.7)Europe312/70944.0 (40.3-47.8)Latin America27/6640.9 (29.0-53.7)Middle East42/13730.7 (23.1-39.1)Mutant PIK3CANon-mutant PIK3CAAll patientsn=574n=787N=1,361Region, n (%)Asia193 (33.6)256 (32.5)449 (33.0)Europe312 (54.4)397 (50.4)709 (52.1)Latin America27 (4.7)39 (5.0)66 (4.8)Middle East42 (7.3)95 (12.1)137 (10.1)Tumor tissue type, n (%)Archival tumor536 (93.4)754 (95.8)1,290 (94.8)Newly obtained tumor sample38 (6.6)33 (4.2)71 (5.2)Source of tumor biopsy, n (%)Primary372 (64.8)496 (63.0)868 (63.8)Metastatic202 (35.2)291 (37.0)493 (36.2)Most common PIK3CA mutationsa, n (%); 95% CIbH1047R197 (34.3); 95% CI (30.4-38.4)0197 (14.5); 95% CI (12.6-16.5)E545K100 (17.4); 95% CI (14.4-20.8)0100 (7.3); 95% CI (6.0-8.9)E542K66 (11.5); 95% CI (9.0-14.4)066 (4.8); 95% CI (3.8-6.1)aIncludes patients with double or multiple mutations.b95% Confidence Interval (CI) is calculated using exact binomial method. Citation Format: Pathmanathan Rajadurai, Tatiana Semiglazova, Alinta Hegmane, Fadi El Karak, Joanne W Chiu, Sudeep Gupta, Hamdy A Azim, Josef JEM Kitzen, Antoine Arnaud, Sina Haftchenary, Jiwen Wu, Lakshmi Menon-Singh, LaTonya Smith, Lyudmila Zhukova. PIK3CA registry: A noninterventional, descriptive, retrospective cohort study of PIK3CA mutations in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) [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 P5-13-25.

Background:Routine Assessment of Patient Index Data 3 (RAPID3) is a pooled index of 3 patient-reported measures: patient global assessment, pain, and physical function. RAPID3 was shown to correlate with other composite measures of disease activity1 and is recommended by the American College of Rheumatology for use in clinical practice.2Objectives:To evaluate the impact of upadacitinib (UPA) versus comparators on RAPID3 over 60 weeks, as well as the correlation of RAPID3 scores with other disease measures in the UPA phase 3 SELECT clinical program.Methods:This post hoc analysis included placebo-controlled (SELECT-NEXT, -BEYOND, and -COMPARE) and active comparator-controlled (SELECT-EARLY, -MONOTHERAPY, and -COMPARE) trials. Patients received UPA as monotherapy or in combination with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). Mean change from baseline in RAPID3 and the proportion of patients reporting RAPID3 remission (≤3), low (LDA, >3 to ≤6), moderate (MDA, >6 to ≤12), and high disease activity (HDA, >12) were assessed. Correlations between absolute scores for RAPID3 and Clinical Disease Activity Index (CDAI), Simplified Disease Activity Index (SDAI), and 28-joint Disease Activity Score with C-reactive protein (DAS28[CRP]) were assessed using Spearman correlation coefficients. All data are as observed.Results:A total of 661, 498, 648, 1629, and 945 patients were included from SELECT-NEXT, -BEYOND, -MONOTHERAPY, -COMPARE, and -EARLY. At baseline, the majority of patients across all studies were in RAPID3 HDA (mean baseline RAPID3 [across all studies], 17.2–19.2) (Table 1 and Figure 1). Improvements from baseline in RAPID3 were observed with UPA 15 mg and 30 mg through Week 60, with numerically greater improvements observed with UPA compared with active comparators (Table 1). Across studies, mean improvements in RAPID3 exceeded the minimal clinically important difference (MCID) with UPA and adalimumab (ADA) treatment (MCID=3.83). By Week 60, approximately one-half of UPA-treated patients were in RAPID3 remission or LDA, with only 10–25% remaining in HDA, except for the more refractory population in SELECT-BEYOND, in which ~38% of patients remained in HDA (Figure 1). RAPID3 scores moderately to strongly correlated with CDAI (ρ=0.69–0.83), SDAI (ρ=0.69–0.82), and DAS28(CRP) (ρ=0.58–0.77), across all studies, at Week 60 (all p<0.001).Conclusion:UPA, as monotherapy or in combination with csDMARDs, was associated with improvements in patient-reported disease activity, pain, and physical function, as assessed by RAPID3 over 60 weeks in the phase 3 SELECT clinical program. RAPID3 continues to be an important tool in clinical practice to assess disease activity, as it was shown to correlate to other disease activity measures and allows for rapid scoring.References:[1]Pincus T, et al. Arthritis Care Res (Hoboken) 2010;62:181–9.[2]England BR, et al. Arthritis Care Res (Hoboken) 2019;71:1540–55.[3]Ward MM, et al. J Rheumatol 2019;46:27–30.Table 1.Change from BL in RAPID3 at Week 60 (as observed)Phase 3 studyGroupnaMean (SD) BL scoreMean (SD) change from BLbSELECT-EARLYc(MTX-naïve)MTX23618.5 (5.6)−9.6 (7.5)UPA 15 mg QD26918.9 (5.6)−12.0 (7.6)UPA 30 mg QD25318.2 (5.6)−13.4 (7.2)SELECT-NEXT(csDMARD-IR)UPA 15 mg QD17217.7 (5.1)−11.1 (7.3)UPA 30 mg QD17217.6 (5.3)−10.4 (6.8)SELECT-MONOTHERAPY(MTX-IR)UPA 15 mg QD17217.4 (5.8)−9.6 (7.4)UPA 30 mg QD18017.2 (5.9)−10.6 (7.2)SELECT-COMPAREc(MTX-IR)UPA 15 mg QD55218.5 (5.5)−10.2 (7.1)ADA 40 mg EOW26418.7 (5.4)−8.8 (6.7)SELECT-BEYOND(bDMARD-IR)UPA 15 mg QD13319.2 (5.1)−8.6 (6.8)UPA 30 mg QD11818.5 (5.3)−9.3 (7.3)b, biologic; BL, baseline; EOW, every other week; IR, inadequate response; MTX, methotrexate; QD, once daily; SD, standard deviationaNumber of patients with RAPID3 values at both BL and Week 60. bNegative values indicate improvement from BL. cObserved data include patients rescued to UPA and/or ADA; treatment effect may include both the randomized and switch treatments in these patientsAcknowledgements:AbbVie funded this study; contributed to its design; participated in data collection, analysis, and interpretation of the data; and participated in the writing, review, and approval of the abstract. No honoraria or payments were made for authorship. Medical writing support was provided by Grant Kirkpatrick, MSc, of 2 the Nth (Cheshire, UK), and was funded by AbbVie.Disclosure of Interests:Martin Bergman Shareholder of: Johnson & Johnson, Speakers bureau: AbbVie, Celgene, GSK, MSD, Novartis, Pfizer, and Sanofi/Regeneron, Consultant of: AbbVie, Amgen, Boehringer Ingelheim, Genentech/Roche, Gilead, Horizon, Janssen, MSD, Novartis, Pfizer, Sandoz, Sanofi/Regeneron, and Scipher, Maya H Buch Consultant of: AbbVie, Eli Lilly, Merck-Serono, Pfizer, Sandoz, and Sanofi, Grant/research support from: Pfizer, Roche, and UCB, Yoshiya Tanaka Speakers bureau: AbbVie, Asahi Kasei, Astellas, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eisai, Eli Lilly, GSK, Janssen, Mitsubishi Tanabe, Novartis, Pfizer, Sanofi, Takeda, UCB, and YL Biologics, Grant/research support from: AbbVie, Astellas, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eisai, Mitsubishi Tanabe, MSD, Ono, Taisho Toyama, and Takeda, Gustavo Citera Consultant of: AbbVie, Bristol-Myers Squibb, Eli Lilly, Genzyme, Pfizer, and Roche, Sami Bahlas: None declared, Ernest Wong Consultant of: AbbVie, Chugai, Eli Lilly, MSD, Novartis, Pfizer, Roche, and UCB, Grant/research support from: AbbVie, Chugai, Novartis, and UCB, Yanna Song Shareholder of: May own stock or options in AbbVie, Employee of: AbbVie, Namita Tundia Shareholder of: May own stock or options in AbbVie, Employee of: AbbVie, Jessica Suboticki Shareholder of: May own stock or options in AbbVie, Employee of: AbbVie, Vibeke Strand Consultant of: AbbVie, Amgen, Arena, AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Celltrion, Eli Lilly, Gilead, Ichnos, Inmedix, Janssen, Kiniksa, MSD, Myriad Genetics, Novartis, Pfizer, Regeneron, Samsung, Sandoz, Sanofi, Scipher, Setpoint, and UCB.

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Although dobutamine stress echocardiography (SE) has a high specificity, there is still a subset of patients (P) with false positive tests (FP) and their prognosis remains unclear. Purpose To identify the clinical and echocardiographic predictors of FP on SE and to evaluate the prognostic impact of FP on SE. Methods Retrospective study of 355 consecutive adult P who underwent SE for ischemia assessment over a one-year period: 134 (37,7%) women, 70,3 ± 0,57 years, body surface area (ASC) 1,85±0,01 cm2. Demographics, risk factors, clinical and laboratorial parameters and SE variables were evaluated. A FP result was defined as a positive SE for ischemia in the absence of ≥50% coronary artery (CA) lesion in a major artery of the corresponding coronary territory on subsequent angiography. P were divided into 2 groups regarding the presence (FP+) or the absence (FP0: 15,5% true positives, 79,7% true negatives, 0,3% false negatives ) of a FP result on SE and a comparative analysis was performed in order to characterize the groups and identify potencial predictors of FP results. P were followed for 2 years to assess acute myocardial infarction (AMI), hospitalization for acute heart failure (HF) and mortality (M). Results The FP rate was 4,5% (16P). Comparing to F0, P in group FP+ were younger (65,1±2,4 vs 70,5±0,6 years; p=0,045), baseline wall motion abnormalities were more frequent (75,0% vs 41,6%; p=0,009), had higher mean blood pressure values at rest (99,3±5,4 vs 82,0±1,3 mmHg; p=0,004) and at peak stage (140,3±5,6 vs 102,8±2,3 mmHg; p&lt;0,001) and more often hypertensive response (37,5% vs 7,1%; p&lt;0,001). There were no significant differences regarding previous CA disease, medication or complete left bundle branch block. By multivariate analysis, only mean blood pressure values at rest (OR 0,01; 95%CI 0,005-0,02; p=0,003) and at peak stage (OR 0,02; 95%CI 0,000-0,004; p=0,003) were independente predictors of FP. During follow-up was observed: AMI (FP+: 12,5% vs FP0: 1,8%, p=0,046), HF (FP+: 6,3% vs FP0: 11,5%, p=0,44) and M (FP+: 6,3% vs FP0: 6,2%, p=0,65). After adjustment for age, sex and comorbidities, there were no diferences between the groups regarding HF (p=0,45) and M (p=0,77), but the group FP+ mantained a higher rate of AMI (OR 0,21; 95%CI 0,065-0,354; p=0,005). Conclusion A FP result on SE is associated with higher mean blood pressure values during the test and with higher rates of AMI during follow-up. This result on SE should therefore be faced as a risk marker for ischemic events and can identify P that may benefit from aggressive risk factor control and careful clinical follow-up.

Abstract Abrupt loss of preexcitation identifies low-risk Wolff-Parkinson-White (WPW). We hypothesize that the autonomous nervous system (ANS) modulates the conduction of the accessory pathway (AP). PURPOSE To compare heart rate variability (HRV) in children with (WPWi) and without (WPWp) intermittent preexcitation. METHODS The study conforms to the Declaration of Helsinki. 18 WPW children and controls performed ECG Holter for HRV analysis. Intermittent preexcitation was defined as abrupt loss of WPW pattern. Kolmogorov-Smirnov test confirmed normal distribution of data. T-test and Fisher"s exact test were used for continuous and categorical variables. Multivariate regression excluded the effect of potential confounders (figure 1 shows correlation between HRV and HR). RESULTS WPWi (11/18, 61.1%) have higher HRV as compared with WPWp. Despite WPWp patients are younger, with higher HR, corrected multivariate analysis confirmed significant differences (table 1), also between WPW patients and controls. CONCLUSIONS WPW patients have lower HRV. WPWp may have worst autonomic control to the excitability of AP. Table 1 WPW (n = 18)A WPWi (n = 11)B WPWp (n = 7)C Controls (n = 18)D P value A vs. D P value B vs. C P value B vs. D P valueC vs. D Age 7.6 ± 4 10.1 ± 4.2 4.1 ± 2.9 7.8 ± 4.7 0.9 &lt;0.01 0.1 0.03 24 hours mean HR 92.8 ± 15.9 81.1 ± 11.2 104.9 ± 12.6 90.3 ± 16.5 0.7 &lt;0.01 0.03 0.07 pNN50 20 ± 11.4 30.5 ± 11.8 14.7 ± 9.9 24.3 ± 13.4 &lt;0.001 &lt;0.001 &lt;0.001 &lt;0.001 RMSSD 53 ± 19.1 68.8 ± 21.4 44.6 ± 14.7 59.4 ± 22.2 &lt;0.001 &lt;0.001 &lt;0.001 &lt;0.01 ASDNN 64.9 ± 21.1 78.4 ± 20.7 48.8 ± 11.8 66.9 ± 22.9 &lt;0.001 &lt;0.001 &lt;0.001 &lt;0.001 SDANN 108.2 ± 39.8 127.9 ± 36 77.5 ± 16.9 108.3 ± 38.8 &lt;0.001 &lt;0.01 &lt;0.001 &lt;0.01 VLF 7.4 ± 0.8 7.8 ± 0.4 6.9 ± 0.5 7.5 ± 0.6 &lt;0.001 &lt;0.001 &lt;0.001 &lt;0.001 LF 6.8 ± 0.8 7.3 ± 0.4 6.4 ± 0.4 6.9 ± 0.6 &lt;0.001 &lt;0.001 &lt;0.001 &lt;0.001 HF 6.6 ± 0.8 7.1 ± 0.7 6.2 ± 0.6 6.7 ± 0.8 &lt;0.001 &lt;0.01 &lt;0.001 &lt;0.01 LF/HF 1.4 ± 0.8 1.4 ± 0.7 1.4 ± 0.6 1.4 ± 0.6 0.2 0.3 0.05 0.7 VarIndex% 4.8 ± 1.4 5.8 ± 1.2 4.4 ± 1.4 5.3 ± 1.4 &lt;0.001 &lt;0.01 &lt;0.01 &lt;0.01 Total Power 8.2 ± 0.7 8.6 ± 0.4 7.8 ± 0.4 8.3 ± 0.6 &lt;0.001 &lt;0.001 &lt;0.001 &lt;0.001 Frequent SVB 2 (11%) 1 (9.1%) 1 (14%) 0 0.5 1.0 0.4 0.3 SVT 1 (5.6%) 1 (9.1%) 0 0 n.a. n.a. n.a. n.a. P values from multivariate analysis and t-test for age and HR. HR: heart rate; WPWi: intermittent preexcitation; WPWp: persistent preexcitation; VarIndex%: variability index (%); SVB: supraventricular beats; SVT: supra ventricular tachycardia. Values are expressed as mean ± SD for age, HR and time domain variables (ms). Variables in the frequency domain are expressed as ln. P &lt;0.05: significant. Abstract Figure 1