Median Cumulative Dose Research Articles

QOL-27. EARLY CHEMOTHERAPY-INDUCED HEARING LOSS IN CHILDREN WITH MEDULLBLASTOMA AND EMBRYONAL BRAIN TUMOURS

Abstract BACKGROUND The purpose of this study was to examine the prevalence, severity and time to develop Chemotherapy-induced hearing loss (HL) in a cohort of embryonal brain tumors(ET) treated with cisplatin and cranial radiation(RT). METHODS Our cohort included children 3-15years treated between January2022 and June2023 for medulloblastoma and other ETs with surgery, craniospinal RT and 6 cycles of CET chemotherapy (cyclophosphamide,vincristine,cisplatin). Cisplatin 75mg/m2 was given in alternate cycles with a cumulative dose of 225 mg/m2. Children underwent clinical evaluation and age-appropriate audiological assessment at diagnosis,every 1-2cycles of cisplatin and end-of-treatment. Grading of ototoxicity was done per SIOP-Boston grading. Children with grade2 and above HL did not receive further cisplatin.Children with grade1HL underwent frequent monitoring.For this study, pure-tone-audiometry from start of treatment to end of treatment were analyzed and ≥Grade2HL was considered significant. RESULTS A total of 63 children were included in the study, 28(44.%)female, median age 7years (range 3-15years). Twenty (31.7%) children developed >grade2HL; the worse ear had grade 4 HL in 1(1.6%),grade 3 in 13(20.6%) and grade 2 in 6(9.5%).One had grade 2HL and 4 had grade 1HL even prior to start of cisplatin.The median cumulative cisplatin dose at developing >grade2HL was 0mg/m2(n=1), 75mg/m2(n=8), 150mg/m2(n=3) and 225mg/m2(n=9; 5 at end-of-treatment and 4 at follow-up). Age, gender and diagnosis were not associated with development of HL. CONCLUSION The high prevalence of early-onset ototoxicity in children with embryonal brain tumours is concerning.We recommend close monitoring of hearing function,at least every 2 cycles of cisplatin chemotherapy, if not more frequently. Incorporation of pharmacogenomics to identify highly susceptible individuals and therapeutic interventions such as cessation of cisplatin or replacement with alternatives in early ototoxicity would help reduce a potentially life-altering and long-term health concern.

Malignancy in systemic lupus erythematosus: relation to disease characteristics in 92 patients – a single center retrospective study

ObjectiveSystemic lupus erythematosus (SLE) is a chronic autoimmune disease with a variable clinical manifestation, potentially leading to death. Importantly, patients with SLE have an increased risk of neoplastic disorders. Thus, this study aimed to comprehensively evaluate the clinical and laboratory characteristics of patients with SLE and with or without malignancy.MethodsWe conducted a retrospective analysis of medical records of 932 adult Caucasian patients with SLE treated at the University Hospital in Kraków, Poland, from 2012 to 2022. We collected demographic, clinical, and laboratory characteristics, but also treatment modalities with disease outcomes.ResultsAmong 932 patients with SLE, malignancy was documented in 92 (9.87%), with 7 (7.61%) patients experiencing more than one such complication. Non-hematologic malignancies were more prevalent (n = 77, 83.7%) than hematologic malignancies (n = 15, 16.3%). Patients with SLE and malignancy had a higher mean age of SLE onset and a longer mean disease duration than patients without malignancy (p < 0.001 and p = 0.027, respectively). The former group also presented more frequently with weight loss (odds ratio [OR] = 2.62, 95% confidence interval [CI] 1.61–4.23, p < 0.001), fatigue/weakness (OR = 2.10, 95% CI 1.22–3.77, p = 0.005), and fever (OR = 1.68, 95% CI 1.06–2.69, p = 0.024). In the malignancy-associated group, we noticed a higher prevalence of some clinical manifestations, such as pulmonary hypertension (OR = 3.47, 95% CI 1.30–8.42, p = 0.007), lung involvement (OR = 2.64, 95% CI 1.35–4.92, p = 0.003) with pleural effusion (OR = 2.39, 95% CI 1.43–3.94, p < 0.001), and anemia (OR = 2.24, 95% CI 1.29–4.38, p = 0.006). Moreover, the patients with SLE and malignancy more frequently had internal comorbidities, including peripheral arterial obliterans disease (OR = 3.89, 95% CI 1.86–7.75, p < 0.001), myocardial infarction (OR = 3.08, 95% CI 1.41–6.30, p = 0.003), heart failure (OR = 2.94, 95% CI 1.30–6.17, p = 0.005), diabetes mellitus (OR = 2.15, 95% CI 1.14–3.91, p = 0.011), hypothyroidism (OR = 2.08, 95% CI 1.29–3.34, p = 0.002), arterial hypertension (OR = 1.97, 95% CI 1.23–3.23, p = 0.003), and hypercholesterolemia (OR = 1.87, 95% CI 1.18-3.00, p = 0.006). Patients with SLE and malignancy were treated more often with aggressive immunosuppressive therapies, including cyclophosphamide (OR = 2.07, 95% CI 1.30–3.28, p = 0.002), however median cumulative cyclophosphamide dose in malignancy-associated SLE subgroup was 0 g (0–2 g). Interestingly, over a median follow-up period of 14 years (ranges: 8–22 years) a total of 47 patients with SLE died, with 16 cases (5.28%) in the malignancy-associated SLE group and 31 cases (5.73%) in the non-malignancy SLE group (p = 0.76). The most common causes of death were infections (21.28%) and SLE exacerbation (8.51%).ConclusionThe study highlights the relatively frequent presence of malignancies in patients with SLE, a phenomenon that demands oncological vigilance, especially in patients with a severe clinical course and comorbidities, to improve long-term outcomes in these patients.

Treatment for paraganglioma with stereotactic radiotherapy.

Paragangliomas (PG) are rare neoplasms of neuroendocrine origin that tend to be highly vascularized, slow-growing, and usually sporadic. To date, common treatment options are surgical resection (SR), with or without radiation therapy (RT), and a watch-and-wait approach. To evaluate the local control and effectiveness of exclusive fractionated stereotactic RT (FSRT) treatment in unresectable PG (uPG). We retrospectively evaluated patients with uPG (medically inoperable or refused SR) treated with FSRT with a Cyberknife System (Accuray Incorporated, Sunnyvale, California). Toxicity and initial efficacy were evaluated. From May 2009 to January 2023, 6 patients with a median age of 68 (range 20-84) were treated with FSRT. The median delivered dose was 21 Gy (range 20-30 Gy) at a median isodose line of 75.5% (range 70%-76%) in 4 fractions (range 3-5 fractions). The median volume was 13.6 mL (range 12.4-65.24 mL). The median cumulative biological effective dose and equivalent dose in 2-Gy fractions were 70 Gy and 37.10 Gy respectively. Site of origin involved were the timpa-nojugular glomus (4/6), temporal bone, and cervical spine. In 1 of the 6 patients, the follow-up was insufficient; 5 of 6 patients showed a 5-year overall survival and 5-year progression-free survival of 100%. We observed negligible toxicities during and after RT. The majority of patients showed stable symptoms during follow-up. Only 1 patient developed spine metastases. Our preliminary results on this small cohort of patients suggest that FSRT could be an effective and safe alternative to SR.

The efficacy of cumulative cisplatin dose on survival in patients with locally advanced cervical cancer treated with definitive chemoradiotherapy: A multicenter study by the Turkish Oncology Group (TOG).

e17534 Background: This multicentric study aimed to investigate the impact of cumulative cisplatin dose on clinical outcomes in locally advanced cervical cancer patients undergoing definitive chemoradiotherapy (CRT). Methods: A retrospective analysis was conducted on 654 patients with stage IB3-IVA disease treated with definitive CRT. Radiotherapy (RT) was applied as external beam pelvic with or without para-aortic RT and brachytherapy. Concomitant chemotherapy was in the form of weekly or 3-weekly cisplatin. Data on demographics, treatment protocols, cumulative cisplatin dose, adverse effects, and survival outcomes were collected. Statistical analyses, including univariate and multivariate Cox regression models, were employed to assess factors influencing progression-free survival (PFS) and overall survival (OS). Results: The median cumulative cisplatin dose was 210 mg (range, 40-320 mg), and it was ≥200 mg in 503 (76.9%) patients. Median follow-up was 35 months. The 5-year PFS and OS rates were 66.9% and 77.1%, respectively. Multivariate analysis (MVA) identified poor performance status, non-squamous cell histology, presence of lymph node metastasis and hemoglobin &lt;10 g/dl before CRT were poor prognostic factors for both PFS and OS in the whole group. When stage III cases were evaluated separately, the cumulative cisplatin dose below 200 mg was also found to be a significant poor prognostic factor in OS (HR 1.79, 95% CI, 1.1 to 3.0, p=0.031). Conclusions: The study revealed that a cumulative cisplatin dose exceeding 200 mg, particularly in patients with lymph node metastasis, significantly improved OS. Factors such as anemia, toxicity-related challenges, and comorbidities were identified as critical considerations in treatment planning. These findings emphasize the delicate balance between maximizing therapeutic efficacy and managing toxicity, guiding personalized treatment approaches for locally advanced cervical cancer. [Table: see text]

#2315 Impact of iron and erythropoiesis-stimulating agent dose on mortality of hemodialysis patients with cancer

Abstract Background and Aims Anemia and iron deficiencies are frequent in hemodialysis (HD) patients and in patients with cancer. If specific guidelines on the management of erythropoiesis-stimulating agent (ESA) in HD patients with cancer have been published, the association between the iron status and the risk of morbidity and mortality in this population remains elusive. Method This retrospective, observational study include HD patients who had been diagnosed with cancer after the start of HD, between September 2009 and March 2021. Demographics, lab test, iron status and cumulative dose of iron and ESA were collected quarterly, from one year before cancer diagnosis to one year after. Univariate analyses were performed to assess the impact of iron or ESA exposure on mortality, after modelling exposure before and after diagnosis of cancer. Then, each model was adjusted, using the baseline variables that were found to be independently associated with mortality. Cox proportional-hazards modelling was used for all regression analyses. P-value &amp;lt; .05 is considered significant. Results Seventy-nine patients were included, with a median follow-up of 2.2 years (IQR: 0.9–5.3). At baseline, the median age was 72 years (IQR 63–79), 30.4% were women. The median dialysis vintage before the diagnosis of cancer was 3 years (IQR 2-7). The main cancers found were prostate (14%), colorectal (13%), bronchopulmonary (11%), urothelial (10%) and skin (10%). Lymph node involvement were observed in 18% and metastasis in 16% patients. The median hemoglobin level was 10.4 g/dL (IQR 9.9–11.7), the median ferritin level was 412 ng/mL (IQR 213–626). The median cumulative quarterly dose of iron was 600 (215–900) mg and the cumulative dose of ESA was 71 (IQR 40–148) UI/kg/week of darbopoetin alfa or equivalent. The year following the cancer diagnosis, the median dose of iron administered remained stable, but with significant variations between patients. There was an increase in the median dose of ESA, particularly after the 6th month, up to 134 (35–314) UI/kg/week. The median hemoglobin remained between 10 and 12 g/dL. The median ferritin level rises moderately during the first 6 months, then returns to values equivalent to those preceding the diagnosis of cancer. Mortality after 12 months of follow-up was high (mortality rate of 47.4%). Age, the presence of a atrial fibrillation, lymphatic invasion, metastatic invasion, or the need for more than one antitumor treatment were independently associated with mortality. In adjusted analysis (using baseline characteristics associated with death), an association with all-cause mortality was only observed with the cumulative dose of ESA in the year preceding the diagnosis of cancer (HR 1.41 [1.06–1.88], P = .017). In multivariate analysis, an association was observed between all-cause mortality and the cumulative dose of ESA in the year preceding the diagnosis of cancer, with an HR of 1.37 (1.03-1.83, P = .031). This association between all-cause mortality and cumulative dose of ESA was also found in the year following cancer diagnosis, but without reaching significance (HR 1.37 [0.95-1.98], P = .092). However, there was no association between mortality and the cumulative dose of iron administered before or after the diagnosis of cancer in multivariate analyses. Conclusion In HD patients diagnosed with cancer, the amount of iron administered was not associated with an increased risk of mortality, probably making it possible to increase the doses administered, if necessary, without any additional risk. However, it was not possible to guarantee the safety of increasing the dose of ESA in these patients. These findings should be confirmed in a larger population in order to define guideline for iron and ESA supplementation in this population.

Prevalence and risk factors of cytomegalovirus reactivation in critically Ill patients with COVID-19 pneumonia.

In critically ill patients with COVID-19, secondary infections are potentially life-threatening complications. This study aimed to determine the prevalence, clinical characteristics, and risk factors of CMV reactivation among critically ill immunocompetent patients with COVID-19 pneumonia. A retrospective cohort study was conducted among adult patients who were admitted to ICU and screened for quantitative real-time PCR for CMV viral load in a tertiary-care hospital during the third wave of the COVID-19 outbreak in Thailand. Cox regression models were used to identify significant risk factors for developing CMV reactivation. A total of 185 patients were studied; 133 patients (71.9%) in the non-CMV group and 52 patients (28.1%) in the CMV group. Of all, the mean age was 64.7±13.3 years and 101 patients (54.6%) were males. The CMV group had received a significantly higher median cumulative dose of corticosteroids than the non-CMV group (301 vs 177 mg of dexamethasone, p<0.001). Other modalities of treatments for COVID-19 including anti-viral drugs, anti-cytokine drugs and hemoperfusion were not different between the two groups (p>0.05). The 90-day mortality rate for all patients was 29.1%, with a significant difference between the CMV group and the non-CMV group (42.3% vs. 24.1%, p = 0.014). Median length of stay was longer in the CMV group than non-CMV group (43 vs 24 days, p<0.001). The CMV group has detectable CMV DNA load with a median [IQR] of 4,977 [1,365-14,742] IU/mL and 24,570 [3,703-106,642] in plasma and bronchoalveolar fluid, respectively. In multivariate analysis, only a cumulative corticosteroids dose of dexamethasone ≥250 mg (HR = 2.042; 95%CI, 1.130-3.688; p = 0.018) was associated with developing CMV reactivation. In critically ill COVID-19 patients, CMV reactivation is frequent and a high cumulative corticosteroids dose is a significant risk factor for CMV reactivation, which is associated with poor outcomes. Further prospective studies are warranted to determine optimal management.

High prevalence of severe pain is associated with low opioid availability in patients with advanced cancer: Combined database study and nationwide questionnaire survey in Japan.

Opioid availability for the palliative care of patients with advanced cancer is increasing globally. However, opioid availability remains extremely low in Japan. We investigated whether pain is appropriately controlled by low-dose opioid prescriptions in patients with advanced cancer in Japan. A web-based nationwide survey for caregivers from 2000 community comprehensive support care centers was performed in Japan to assess details about pain in the 30 days before patients died of end-stage cancer. Separately, the data for opioid prescription doses and medical services in the 90 days before the death of patients with cancer were extracted from a health insurance claim database. Responses from 1034 responders were retrieved and 665 patients were included. In total, 254 patients (38.2%) complained of severe-to-intolerable cancer-related pain. The median cumulative prescription dose of opioids in the 90 days before patient death was 311.0 mg by oral morphine equivalent doses. Multiple regression analyses across prefectures revealed that the proportion of patients with severe-to-intolerable cancer-related pain was negatively associated with the cumulative opioid consumption expressed as morphine-equivalent doses within 90 days before death. The very low availability of opioids for patients with end-stage cancer could result in high rate of severe-to-intolerable cancer-related pain patients. There were several limitations in this study, and the interpretations of the findings should be carefully. However, the increase in the absolute dose of opioids could improve the palliative care framework to the pain control levels of the global standard.

Abstract PO2-22-03: Reirradiation for locally recurrent breast cancer: a long-term single centre experience

Abstract Background: About 10–15% of patients with breast cancer will eventually develop an ipsilateral breast recurrence. The management of cancer relapse in previously irradiated tissues is a challenging therapeutic issue, and data on breast re-irradiation are currently lacking. Hence, the aim of this work was to report our experience with breast re-irradiation for non-metastatic recurrent breast cancer. Material and Methods: All patients who underwent a breast or chest wall re-irradiation in the Institut Curie, Paris, France between 2003 and 2019 were identified. Those who underwent re-irradiation only in other volumes than the ipsilateral breast were excluded. Local recurrence-free (LRFS), overall survival (OS), disease-specific survival (DSS), progression-free survival (PFS), and metastasis-free survival (MFS) were evaluated. Physician-reported acute and late toxicities were assessed using the Common Terminology Criteria for Adverse Events (CTCAE) 5.0. Results: Between 2003 and 2019, 21.372 patients underwent a breast irradiation in our institution. Of these, 453 received a new irradiation to the controlateral breast and/or lymph nodes, 105 to the homolateral lymph nodes without breast/chest wall re-irradiation and 28 received a second course of radiotherapy (RT) to the homolateral breast. These 28 patients were included in this study. Median follow up after re-irradiation was 45.5 months (IQR 33.5-79.75 months). The median age at the time of second breast RT was 63 years (IQR, 49-78). The median RT dose to the breast/chest wall was 60 Gy (interquartile range (IQR) 50-66 Gy) for the first irradiation and 48 Gy (IQR 30-50 Gy) for the second. The median cumulative dose was 100 Gy (IQR 92-114 Gy). The median time between the two courses of RT was 47 months (IQR 22.75-109.5 months). Eighteen (64%) patients were treated with a curative intent and 10 (36%) for palliative purposes. Ten (36%) had a macroscopic breast residue at re-irradiation. The second RT course was performed with electrons, photons and a combination of both in 13 (46%), 8 (29%) and 6 (21%) patients, respectively. At 2 years, LRFS, OS, DSS, PFS and MFS were respectively 59%, 79%, 82%, 50% and 75% in the whole cohort. 2-year-LRFS (72% vs 31%, p=0.02), OS (94% vs 50%, p&amp;lt; 0.01), DSS (94% vs 56%, p&amp;lt; 0.01) and PFS (61% vs 20%, p=0.02) differed significantly between patients treated in a curative or in a palliative intent, but not MFS (78% vs 69%, p=0.77). Among patients, 8 (29%) remained relapse-free 5 years after the second course of RT. Only one patient experienced an acute grade 3 adverse event (dermatitis), and 1 presented a late grade 3 one (skin fibrosis). One patient with major cardiovascular risk factors died of myocardial infarction 13 months after the second left breast irradiation. Conclusion: Breast or chest wall re-irradiation appears to be feasible with good disease control in patients treated with a curative intent, and acceptable toxicity rates. In addition, a significant number of patients were disease-free 5 years after the second course of RT. Prospective larger data with longer follow-up are needed to confirm these findings. Citation Format: Jérémy Baude, Rémi Dendale, Alain Fourquet, Youlia Kirova. Reirradiation for locally recurrent breast cancer: a long-term single centre experience [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-22-03.

Safety and Efficacy of Extended Therapy with [177Lu]Lu-PSMA: A German Multicenter Study.

Prospective results have demonstrated favorable safety and efficacy of [177Lu]Lu-PSMA radiopharmaceutical therapy for up to 6 cycles in men with metastatic castration-resistant prostate cancer. However, no systematic data are available outlining the feasibility of extended therapy beyond 6 cycles. We aim to evaluate the safety and efficacy of extended [177Lu]Lu-PSMA radiopharmaceutical therapy in patients who have received more than 6 cycles. Methods: In total, 111 patients were included in this multicenter retrospective analysis. Based on individual decisions, patients underwent uninterrupted continuation of therapy (continuous treatment) or reexposure after a therapy break (rechallenge treatment) between 2014 and 2023. Overall survival, 50% prostate-specific antigen (PSA) decline (measured 8-12 wk after treatment initiation or rechallenge), PSMA PET response, and grades per Common Terminology Criteria for Adverse Events were assessed. χ2 tests, multivariable Cox regression analysis, and log-rank tests were applied for statistical analyses. Results: Patients received extended treatment with [177Lu]Lu-PSMA, either as a continuous treatment (43/111, 38.7%) or as a rechallenge (68/111, 61.3%) treatment, with median cumulative doses of 57.4 or 60.8 GBq, respectively. Overall survival from the initiation of [177Lu]Lu-PSMA was 31.3, 23.2, and 40.2 mo for the entire cohort, the continuous treatment group, and the rechallenge treatment group, respectively. The initial 50% PSA decline was significantly higher in the retreated group than in the continuous group (57/63 [90.4%] vs. 26/42 [61.9%]; P = 0.006). A 50% PSA decline was observed in 23 of 62 patients (37.1%) after the first rechallenge. The rate of grades 3-4 toxicity was comparable between continuous and rechallenge treatments (anemia, 7/43 [16.3%] vs. 13/68 [19.1%)], P = 0.6; leukocytopenia, 1/43 [2.3%] vs. 2/67 [3.0%], P = 0.3; thrombocytopenia, 3/43 [7.0%] vs. 3/68 [4.4%], P = 0.3; renal, 2/43 [4.7%] vs. 5/68 [7.4%], P = 0.2). Conclusion: Extended therapy with [177Lu]Lu-PSMA is safe and has not been associated with increased grades 3-4 toxicity. Patient candidates for extended treatment experienced a favorable median survival of 31.3 mo from the first administration. Response under [177Lu]Lu-PSMA rechallenge demonstrated preserved efficacy of [177Lu]Lu-PSMA after a treatment break.

Intermittent intravenous paracetamol versus continuous morphine in infants undergoing cardiothoracic surgery: a multi-center randomized controlled trial

BackgroundTo determine whether intermittent intravenous (IV) paracetamol as primary analgesic would significantly reduce morphine consumption in children aged 0–3 years after cardiac surgery with cardiopulmonary bypass.MethodsMulti-center, randomized, double-blinded, controlled trial in four level-3 Pediatric Intensive Care Units (PICU) in the Netherlands and Belgium. Inclusion period; March 2016–July 2020. Children aged 0–3 years, undergoing cardiac surgery with cardiopulmonary bypass were eligible. Patients were randomized to continuous morphine or intermittent IV paracetamol as primary analgesic after a loading dose of 100 mcg/kg morphine was administered at the end of surgery. Rescue morphine was given if numeric rating scale (NRS) pain scores exceeded predetermined cutoff values. Primary outcome was median weight-adjusted cumulative morphine dose in mcg/kg in the first 48 h postoperative. For the comparison of the primary outcome between groups, the nonparametric Van Elteren test with stratification by center was used. For comparison of the proportion of patients with one or more NRS pain scores of 4 and higher between the two groups, a non-inferiority analysis was performed using a non-inferiority margin of 20%.ResultsIn total, 828 were screened and finally 208 patients were included; parents of 315 patients did not give consent and 305 were excluded for various reasons. Fourteen of the enrolled 208 children were withdrawn from the study before start of study medication leaving 194 patients for final analysis. One hundred and two patients received intermittent IV paracetamol, 106 received continuous morphine. The median weight-adjusted cumulative morphine consumption in the first 48 h postoperative in the IV paracetamol group was 5 times lower (79%) than that in the morphine group (median, 145.0 (IQR, 115.0–432.5) mcg/kg vs 692.6 (IQR, 532.7–856.1) mcg/kg; P < 0.001). The rescue morphine consumption was similar between the groups (p = 0.38). Non-inferiority of IV paracetamol administration in terms of NRS pain scores was proven; difference in proportion − 3.1% (95% CI − 16.6–10.3%).ConclusionsIn children aged 0–3 years undergoing cardiac surgery, use of intermittent IV paracetamol reduces the median weight-adjusted cumulative morphine consumption in the first 48 h after surgery by 79% with equal pain relief showing equipoise for IV paracetamol as primary analgesic.Trial Registration Clinicaltrials.gov, Identifier: NCT05853263; EudraCT Number: 2015-001835-20.

Hydroxychloroquine-induced pigmentation in rheumatic diseases: prevalence, clinical features and influencing factors.

To describe the clinical features of Chinese patients with hydroxychloroquine (HCQ)-induced pigmentation and analyze the potential risk factors associated with HCQ-induced pigmentation. A cross-sectional study was conducted over a duration of 7 months, during which patients who had received HCQ treatment for >6 months were included. Data was collected through a structured questionnaire that encompassed demographic and geographic characteristics, information on HCQ and concomitant medication usage, sun exposure characteristics, and hyperpigmentation-related characteristics. Univariate and multivariate analyses were employed to calculate the statistical association between HCQ-induced pigmentation and multiple variables. Out of 316 patients, 83 (26.3%) patients presented hyperpigmentation during HCQ treatment. Hyperpigmentation presented after a median duration of HCQ treatment of 12 months (interquartile range, 6.0 months-30.0 months) with a median cumulative dose of 108 g of HCQ (interquartile range, 36-288 g). The most frequently affected sites of pigmentation were the face (60.2%), lower limbs (36.1%), and hands (20.5%). There was a linear decrease in the incidence of pigmentation with increasing daily sun exposure time (p= 0.030). In the multivariate analysis, variables (cumulative HCQ dose and daily sun exposure time) were included in the final models. The results revealed an independent correlation between HCQ-induced pigmentation and daily sun exposure exceeding 1 h (OR: 0.431; 95%CI: 0.208-0.892; p= 0.023). The occurrence of HCQ-induced pigmentation is not uncommon, with an incidence rate of 26.3%. Daily sun exposure time exhibited a protective effect against HCQ-induced pigmentation.

Postnatal Steroids Use for Bronchopulmonary Dysplasia in a Quaternary Care NICU.

Intercenter variation and trends in postnatal steroids (PNS) use among preterm infants for prevention or treatment of bronchopulmonary dysplasia (BPD) is known. Understanding intracenter PNS use patterns facilitate implementation of center-specific change interventions to optimize outcomes.This study aimed to (i) quantify the proportion of infants who received PNS, and describe the timing, type, trends over time, regimen used, and deviations, and (2) describe the clinical characteristics and unadjusted outcomes of infants who received PNS. This was a cohort study in a quaternary neonatal intensive care unit including infants born at less than 33 weeks, and who received PNS for prevention or treatment of BPD between 2011 and 2021. Following data were included: proportion of babies who received PNS; type of PNS; age at initiation and duration; trends over time; deviation from published regimen; morbidity, mortality, and cointerventions. One hundred and eighty four infants (8% of <33 week' infants) received PNS. The median (interquartile range [IQR]) gestational age and birth weight were 25 (24-26) weeks and 720 (625-841) grams, respectively. The median (IQR) day of initiation and duration of PNS use were 29 (19-38) and 10 (10-22) days, respectively. One hundred and fifty-seven (85%) infants received dexamethasone (DX) and 22 (12%) received hydrocortisone as the first PNS course, and 71 (39%) infants received multiple courses. The proportion of infants receiving PNS remained unchanged, but the cumulative median dose received for BPD per patient increased by 56%. Nearly one-third of cumulative PNS dose came from PNS used for non-BPD indications. Forty-six percent infants had a deviation from published regimen (±20% deviation in duration or ±10% deviation in dose). Survival, survival without major morbidity, moderate-to-severe BPD, and technology dependence at discharge were 87, 2, 91, and 67%, respectively. Increased variation in PNS use, deviation from published regimen, and concurrent PNS exposure from non-BPD indication offer insights into implementing interventions to improve processes. · In this quaternary NICU, 8% of infants born before 33 weeks were administered postnatal steroids (PNS).. · The percentage of infants given PNS remained stable; however, the cumulative dose per patient for BPD rose.. · The study identified targeted interventions to minimize clinical practice variations at the center..

High-dose individualized antithymocyte globulin with therapeutic drug monitoring in high-risk cord blood transplant

BackgroundGraft-versus-host disease (GvHD) and rejection are main limitations of cord blood transplantation (CBT), more so in patients with severe inflammation or previous rejections. While rigorous T-cell depletion with antithymocyte globulin (ATG) is needed to prevent GvHD and rejection, overexposure to ATG leads to slow T-cell recovery after transplantation, especially in CBT. ObjectiveTo evaluate high-dose, upfront ATG with individualized dosing and therapeutic drug monitoring (TDM) in pediatric CBT for patients at high risk for GvHD and rejection. Study designHeavily inflamed patients and patients with a recent history of rejection were eligible for individualized high-dose ATG with real-time TDM. The ATG dosing scheme was adjusted to target a post-CBT exposure of <10 AU*day/mL, while achieving a pre-CBT exposure of 60–120 AU*day/mL; exposure levels previously defined for optimal efficacy and safety in terms of reduced GvHD and rejection, respectively. Main outcomes of interest included efficacy (target exposure attainment) and safety (incidence of GvHD and rejection). Other outcomes of interest included T-cell recovery and survival. ResultsTwenty-one patients were included ranging from 2 months to 18 years old, receiving an actual median cumulative dose of ATG of 13.3 mg/kg (range 6–30 mg/kg) starting at a median 15 days (range 12–17) prior to CBT. Dosing was adjusted in 14 patients (increased in 3 and decreased in 11 patients). Eighteen (86%) and 19 (91%) patients reached the target pre-CBT and post-CBT exposure, respectively. Cumulative incidence for acute GvHD was 34% (95% CI 23–45) and 5% (95% CI 0–10%) for grade 2–4 and grade 3–4, respectively; cumulative incidence of rejection was 9% (95% CI 2–16%). Overall survival was 75% (95% CI 65–85%). ConclusionIndividualized high-dose ATG with TDM is feasible and safe for patients with hyperinflammation in a CBT setting. We observe high target ATG exposure attainment, good immune reconstitution (despite very high doses of ATG) and acceptable rates of GvHD and rejection.

Ocular complications in pediatric nephrotic syndrome treated with corticosteroids

Background Posterior subcapsular cataracts (PSC) and raised intraocular pressure (IOP) are the most common ocular complications of oral steroid administration, particularly following long-term use or treatment with high doses.&#x0D; Objective To evaluate the association between cumulative steroid dose and duration of treatment with the occurrence of PSC and raised IOP, as well as its associated factors in children with idiopatic nephrotic syndrome (INS).&#x0D; Methods This cross-sectional study included children aged 4–18 years with INS who received oral steroid therapy for at least six consecutive months. Patients underwent complete eye examinations by an ophthalmologist to evaluate their visual acuity as well as the occurrence of PSC and/or raised IOP. Results Of 92 subjects, 19.6% had PSC, 12% had raised IOP, and one had a best corrected visual acuity (BCVA) of &lt;6/20. The median cumulative steroid dose was 12,161 (range 1,795–81,398) mg and median treatment duration was 23 (range 6–84) months. There were significant positive associations between cumulative steroid dose as well as treatment duration and the occurrence of PSC, with cut-off points of 11,475 mg and 24 months, respectively, as determined by receiver operator characteristic (ROC) curves. Females were four times more likely to have PSC compared to males (PR 4; 95%CI 1.57 to 13.38; P=0.001). Cumulative steroid dose and duration of treatment were not associated with raised IOP.&#x0D; Conclusion Cumulative steroid dose of 11,475 mg or higher and/or duration of steroid therapy of 24 months of more were significantly associated with the occurrence of PSC, but not with raised IOP.

Prospective study of complications and sequelae of glucocorticoid therapy in ANCA-associated vasculitis

ObjectiveGlucocorticoids (GC) are a cornerstone in treating antineutrophil cytoplasmic antibodies-associated vasculitides (AAV), however, they add to morbidity and mortality. To date, GC toxicity in AAV has rarely been systematically investigated.MethodsPatients...

Brain and Brain Stem Necrosis After Reirradiation for Recurrent Childhood Primary Central Nervous System Tumors: A PENTEC Comprehensive Review

Reirradiation is increasingly used in children and adolescents/young adults (AYA) with recurrent primary central nervous system tumors. The Pediatric Normal Tissue Effects in the Clinic (PENTEC) reirradiation task force aimed to quantify risks of brain and brain stem necrosis after reirradiation. A systematic literature search using the PubMed and Cochrane databases for peer-reviewed articles from 1975 to 2021 identified 92 studies on reirradiation for recurrent tumors in children/AYA. Seventeen studies representing 449 patients who reported brain and brain stem necrosis after reirradiation contained sufficient data for analysis. While all 17 studies described techniques and doses used for reirradiation, they lacked essential details on clinically significant dose-volume metrics necessary for dose-response modeling on late effects. We, therefore, estimated incidences of necrosis with an exact 95% CI and qualitatively described data. Results from multiple studies were pooled by taking the weighted average of the reported crude rates from individual studies. Treated cancers included ependymoma (n = 279 patients; 7 studies), medulloblastoma (n = 98 patients; 6 studies), any CNS tumors (n = 62 patients; 3 studies), and supratentorial high-grade gliomas (n = 10 patients; 1 study). The median interval between initial and reirradiation was 2.3 years (range, 1.2-4.75 years). The median cumulative prescription dose in equivalent dose in 2-Gy fractions (EQD22; assuming α/β value = 2 Gy) was 103.8 Gy (range, 55.8-141.3 Gy). Among 449 reirradiated children/AYA, 22 (4.9%; 95% CI, 3.1%-7.3%) developed brain necrosis and 14 (3.1%; 95% CI, 1.7%-5.2%) developed brain stem necrosis with a weighted median follow-up of 1.6 years (range, 0.5-7.4 years). The median cumulative prescription EQD22 was 111.4 Gy (range, 55.8-141.3 Gy) for development of any necrosis, 107.7 Gy (range, 55.8-141.3 Gy) for brain necrosis, and 112.1 Gy (range, 100.2-117 Gy) for brain stem necrosis. The median latent period between reirradiation and the development of necrosis was 5.7 months (range, 4.3-24 months). Though there were more events among children/AYA undergoing hypofractionated versus conventionally fractionated reirradiation, the differences were not statistically significant (P = .46). Existing reports suggest that in children/AYA with recurrent brain tumors, reirradiation with a total EQD22 of about 112 Gy is associated with an approximate 5% to 7% incidence of brain/brain stem necrosis after a median follow-up of 1.6 years (with the initial course of radiation therapy being given with conventional prescription doses of ≤2 Gy per fraction and the second course with variable fractionations). We recommend a uniform approach for reporting dosimetric endpoints to derive robust predictive models of late toxicities following reirradiation.

177Lu]Lu-DOTA-TATE in newly diagnosed patients with advanced grade 2 and grade 3, well-differentiated gastroenteropancreatic neuroendocrine tumors: Primary analysis of the phase 3 randomized NETTER-2 study.

LBA588 Background: Currently, there is no universally accepted first line (1L) therapy for higher grade, well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and an unmet medical need remains in these patients (pts). Radioligand therapy (RLT) is an innovative cancer treatment that crosses the traditional domains of systemic, radiation or surgical therapies. The Phase 3 NETTER-2 study (NCT03972488) evaluated [177Lu]Lu-DOTA-TATE (hereafter 177Lu-DOTATATE) as 1L treatment in pts with Grade (G) 2 and G3 advanced GEP-NETs. This is the first trial to assess 1L RLT in any solid tumor. Methods: Eligible pts were newly diagnosed with somatostatin receptor-positive high G2 or G3 (Ki-67 ≥10% and ≤55%) advanced GEP-NETs within the last 6 months prior to enrollment. Pts were randomized (2:1) to receive 4 cycles of 177Lu-DOTATATE (4 × 7.4 GBq) plus 30 mg octreotide long-acting release (LAR) at 8-weekly intervals during 177Lu-DOTATATE treatment then every 4 weeks (177Lu-DOTATATE arm), or 60 mg octreotide LAR every 4 weeks (control arm), stratified by grade (G2 vs G3) and tumor origin (pancreas vs other). The primary endpoint was progression-free survival (PFS), centrally assessed using RECIST 1.1. Objective response rate (ORR), a key secondary endpoint, was tested hierarchically after PFS. Results: Overall, 226 pts were randomized to the 177Lu-DOTATATE (n = 151) or control (n = 75) arms. Most tumors originated in the pancreas (54.4%) or small intestine (29.2%); G3 tumors were reported in 35.0% of pts. Median cumulative dose of 177Lu-DOTATATE was 29.2 GBq, with 87.8% of pts receiving all 4 doses. Median PFS (95% confidence interval [CI]) was significantly prolonged by ~14.3 months from 8.5 months (7.7, 13.8) in the control arm to 22.8 months (19.4, not estimable) in the 177Lu-DOTATATE arm; stratified hazard ratio 0.276 (95% CI: 0.182, 0.418; p &lt; 0.0001). The ORR was significantly higher in the 177Lu-DOTATATE arm (43.0%) vs the control arm (9.3%); stratified odds ratio 7.81 (95% CI: 3.32, 18.4; p &lt; 0.0001). PFS and ORR results were consistent across all pre-specified demographic and prognostic subgroups. Among adverse events of special interest to RLT, G3/4 leukopenia, anemia and thrombocytopenia occurred in ≤3 pts each in the 177Lu-DOTATATE arm. One case of myelodysplastic syndrome was reported (177Lu-DOTATATE arm). Conclusion: 177Lu-DOTATATE significantly prolonged PFS and demonstrated a clinically meaningful ORR, compared with high-dose octreotide LAR, in pts with newly diagnosed advanced G2 and G3 GEP-NETs. Safety was in line with the established profile of 177Lu-DOTATATE. This is the first randomized study to demonstrate efficacy of RLT as 1L treatment in any malignancy and will change clinical practice. Further investigations of RLT as a therapeutic option in other settings is warranted. Clinical trial information: NCT03972488 .

Long-term effects of high-dose systemic corticosteroids on growth and bone mineral density in patients treated for childhood interstitial lung disease (chILD).

Children's interstitial lung disease (chILD) is a rare and potentially life-threatening condition. For many chILD conditions, systemic corticosteroids (sCCS) are considered the primary treatment despite a broad spectrum of potential side effects. We aimed to determine the long-term effects of sCCS treatment on growth, bone mineral density (BMD), and body composition after chILD. This descriptive cross-sectional single-center study included patients diagnosed with chILD before the age of 18 years treated with sCCS in the period 1998-2020. Dual-energy X-ray absorptiometry, anthropometric measurements, bone age determination, and blood tests were performed in 53 (55% males) of 89 eligible patients. Median (range) age was 19.3 (6.4;30.7 years). Participants received a median (range) cumulative sCCS dose of 1144 (135; 6178) mg over a 2.0 (0.1; 13.8) years period and latest dose was administered 11.7 (1.2; 19.6) years before follow-up. Mean delta height (height standard deviation scores[SDS] - target height SDS) was reduced at sCCS treatment initiation (mean: -0.55, 95% confidence interval [CI]: -0.91; -0.20, p < .005) and at sCCS treatment cessation (mean: -0.86, 95%CI:-1.22; -0.51, p < .001), but normalized in the majority at follow-up (mean: -0.29, 95%CI:-0.61; 0.03, p = .07). Mean (SD) BMD z-score for the spine and whole body was -0.34 (1.06) and 0.52 (1.13), with no significant correlation to sCCS dose. Excess body fat (>30% in females, >25% in males) was found in 58% of patients. Long-term treatment with sCCS did not cause significant long-term reduction of height but showed subtle effects on fat mass percentage and BMD. Given the severity of chILD, the observed long-term effects of sCCS on growth and BMD appear acceptable.

Platelet versus fresh frozen plasma transfusion for coagulopathy in cardiac surgery patients.

Platelets (PLTS) and fresh frozen plasma (FFP) are often transfused in cardiac surgery patients for perioperative bleeding. Their relative effectiveness is unknown. We conducted an entropy-weighted retrospective cohort study using the Australian and New Zealand Society of Cardiac and Thoracic Surgeons National Cardiac Surgery Database. All adults undergoing cardiac surgery between 2005-2021 across 58 sites were included. The primary outcome was operative mortality. Of 174,796 eligible patients, 15,360 (8.79%) received PLTS in the absence of FFP and 6,189 (3.54%) patients received FFP in the absence of PLTS. The median cumulative dose was 1 unit of pooled platelets (IQR 1 to 3) and 2 units of FFP (IQR 0 to 4) respectively. After entropy weighting to achieve balanced cohorts, FFP was associated with increased perioperative (Risk Ratio [RR], 1.63; 95% Confidence Interval [CI], 1.40 to 1.91; P<0.001) and 1-year (RR, 1.50; 95% CI, 1.32 to 1.71; P<0.001) mortality. FFP was associated with increased rates of 4-hour chest drain tube output (Adjusted mean difference in ml, 28.37; 95% CI, 19.35 to 37.38; P<0.001), AKI (RR, 1.13; 95% CI, 1.01 to 1.27; P = 0.033) and readmission to ICU (RR, 1.24; 95% CI, 1.09 to 1.42; P = 0.001). In perioperative bleeding in cardiac surgery patient, platelets are associated with a relative mortality benefit over FFP. This information can be used by clinicians in their choice of procoagulant therapy in this setting.

Real‐World Accuracy of a Continuous Glucose Monitoring System after Radiologic Exposure

Background. The increasing use of continuous glucose monitor (CGM) necessitates a review of variables that impact accuracy and interrupt use. Manufacturer recommendations include removing CGMs before diagnostic imaging, such as X‐ray and computed tomography (CT). Early removal and replacement of CGM components present financial, clinical, and psychosocial burdens to the wearer and interrupt optimal management of diabetes for pediatric patients who receive a total pancreatectomy with islet autotransplantation (TPIAT). The study’s aim was to evaluate the effect of scatter dose exposure during X‐ray or CT if the CGM remained intact but outside the field of view (FoV). Materials and Methods. Participants were followed through the first 3 months after TPIAT surgery, managed diabetes with an insulin pump and CGM, and were routinely exposed to diagnostic imaging. Participants’ CGMs were unshielded by a protective apron during any X‐ray or CT procedures for the duration of the study period, and the transmitter was collected after expiration or removal. Glucometer data was collected from hospital records and home glucometer downloads. Mixed models were used to analyze absolute differences between matched CGM and glucometer values, and Clarke error grid analyses (EGA) were performed. Scatter dose exposure was derived using anthropomorphic phantoms and calculated retrospectively. Results. A total of 14 patients (median 12.2 years, 64% female) received a median of five diagnostic imaging procedures with a median cumulative scatter dose of 559 µGy. The absolute difference between the CGM and glucometer values was not significantly associated with the cumulative scatter dose (p = 0.17) or time from TPIAT (p = 0.24) when analyzed in a mixed model. Regardless of scatter dose exposure, time from TPIAT, or glucometer, ≥98% of glucose values fell within zones A and B on EGA. Conclusion. Scatter dose exposure from diagnostic imaging did not affect the clinical accuracy of CGM values for the duration of transmitter use. Leaving CGM components in place when not in the FoV during diagnostic imaging successfully mitigated interruptions to use and undue burden or cost to participants.