5728 research outputs found
Sort by
Solid tumour cellular therapy - principles of toxicity management.
No full textFollowing the Food and Drug Administration (FDA) approval of lifileucel and afami-cel for patients with advanced melanoma and synovial sarcoma, respectively, there is a need for improved understanding and guidance regarding the management of toxicity associated with adoptive cellular therapies (ACTs) for solid tumours. Further approvals are expected in coming years, with toxicity management representing a significant consideration for centres looking to implement such advanced therapy medicinal products. Importantly, first-generation tumour-infiltrating lymphocyte therapies are associated with unique toxicities compared with gene-modified T-cell therapies such as chimeric antigen receptor T-cell therapy (CAR T) and T-cell receptor-modified therapy (TCR T), presenting novel challenges for treating healthcare professionals. Extrapolating from experience with CAR T in the field of haemato-oncology, coupled with the historical use of high-dose interleukin-2 in solid tumour therapeutic regimens and more recently lifileucel and afami-cel, has led to the development of core principles for managing toxicity, which is discussed here. Looking to the future, a rapidly developing field with next-generation ACT products, a basic knowledge of such core principles will be an important foundation for healthcare professionals working in this space
Chest wall perforator flaps are safe and can decrease mastectomy rates in breast cancer surgery: multicentre cohort study.
No full textBACKGROUND: Chest wall perforator flaps are emerging in oncoplastic breast conservation, mostly as an alternative to mastectomy. However, standardization and consensus on patient selection, techniques, and outcomes have not yet been reached. The aim of this international multicentre collaborative study was to explore practice patterns and outcomes in high-volume centres from different countries. METHODS: Patients with both pre-invasive and invasive breast cancer treated at the Uppsala University Hospital in Uppsala, Sweden, the Royal Marsden Hospital in London, UK, and the Westmead Breast Cancer Institute in Sydney, Australia, were included in this study. The rationale for offering chest wall perforator flaps and surgical outcomes were prospectively documented. RESULTS: In total, 603 patients were analysed median age of 54 (interquartile range (i.q.r.) 48-63) years, median BMI of 25.0 (i.q.r. 22.5-28.1) kg/m2, median tumour extent of 30 (IQR 19-45) mm, median breast volume of 280 (i.q.r. 216-430) ml, and median calculated resection ratio of 16% (i.q.r. 9%-28%). In 67.7%, the treating surgeon had offered chest wall perforator flaps to avoid mastectomy. The procedure was performed as day surgery in 69.5% of patients, with an overall complication rate of 8.6% and the majority of complications being classified as Clavien-Dindo grade I (5.3% of patients). The re-excision rate was 15.9%, with only 1.5% of patients converting to a mastectomy. There were no flap losses. At a median follow-up of 22 (range 12 to 98) months, rates of local recurrence, distant recurrence, and breast cancer-related mortality were 1.9%, 4.9%, and 1.7% respectively. CONCLUSION: Chest wall perforator flaps are a useful option to allow more women to avoid mastectomy. In experienced hands, the procedure is safe and should be offered to suitable patients
Outcomes with single-agent gilteritinib for relapsed or refractory FLT3-mutant AML after contemporary induction therapy.
No full textGilteritinib is the current standard of care for relapsed or refractory fms related receptor tyrosine kinase 3 (FLT3)-mutated acute myeloid leukemia in many countries, however outcomes for patients relapsing after contemporary first-line therapies (intensive chemotherapy with midostaurin, or nonintensive chemotherapy with venetoclax) are uncertain. Moreover, reported data on toxicity and health care resource use is limited. Here, we describe a large real-world cohort of 152 patients receiving single-agent gilteritinib in 38 UK hospitals. Median age was 61 years, and 36% had received ≥2 prior lines of therapy, including a FLT3 inhibitor in 41% and venetoclax in 24%. A median of 4 cycles of gilteritinib were administered, with 56% of patients requiring hospitalization in the first cycle (median, 10 days). Over half of patients required transfusion in each of the first 4 cycles. Complete remission (CR) was achieved in 21%, and CR with incomplete recovery (CRi) in a further 9%. Remission rates were lower for patients with FLT3-tyrosine kinase domain or adverse karyotype. Day-30 and day-60 mortality were 1% and 10.6%, respectively, and median overall survival was 9.5 months. On multivariable analysis, increasing age, KMT2A rearrangement, and complex karyotype were associated with worse survival whereas RUNX1 mutations were associated with improved survival. Twenty patients received gilteritinib as first salvage having progressed after first-line therapy with venetoclax, with CR/CRi achieved in 25% and median survival 4.5 months. Real-world results with gilteritinib mirror those seen in the clinical trials, but outcomes remain suboptimal, with more effective strategies needed
Economic, cultural, and social inequalities in potentially inappropriate medication: A nationwide survey- and register-based study in Denmark.
No full textBACKGROUND: Potentially inappropriate medication (PIM) is associated with negative health outcomes and can serve as an indicator of treatment quality. Previous studies have identified social inequality in treatment but often relied on narrow understandings of social position or failed to account for mediation by differential disease risk among social groups. Understanding how social position influences PIM exposure is crucial for improving the targeting of treatment quality and addressing health disparities. This study investigates the association between social position and PIM, considering the mediation effect of long-term conditions. METHODS AND FINDINGS: This cross-sectional study utilized data from the 2017 Danish National Health Survey, including 177,495 individuals aged 18 or older. Data were linked to national registers on individual-level. PIM was defined from the STOPP/START criteria and social position was assessed through indicators of economic, cultural, and social capital (from Bourdieu's Capital Theory). We analyzed odds ratios (ORs) and prevalence proportion differences (PPDs) for PIM using logistic regression, negative binomial regression, and generalized structural equation modeling. The models were adjusted for age and sex and analyzed separately for indicators of under- (START) and overtreatment (STOPP). The mediation analysis was conducted to separate direct and indirect effects via long-term conditions. Overall, 14.7% of participants were exposed to one or more PIMs, with START PIMs being more prevalent (12.5%) than STOPP PIMs (3.1%). All variables for social position except health education were associated with PIM in a dose-response pattern. Individuals with lower wealth (OR: 1.85 [95% CI 1.77, 1.94]), lower income (OR: 1.78 [95% CI 1.69, 1.87]), and lower education level (OR: 1.66 [95% CI 1.56, 1.76]) exhibited the strongest associations with PIM. Similar associations were observed for immigrants, people with low social support, and people with limited social networks. The association with PIM remained significant for most variables after accounting for mediation by long-term conditions. The disparities were predominantly related to overtreatment and did not relate to the number of PIMs. The study's main limitation is the risk of reverse causation due to the complex nature of social position and medical treatment. CONCLUSIONS: The findings highlight significant social inequalities in PIM exposure, driven by both economic, cultural, and social capital despite a universal healthcare system. Understanding the social determinants of PIM can inform policies to reduce inappropriate medication use and improve healthcare quality and equity
Low-grade fibromyxoid sarcoma and sclerosing epithelioid fibrosarcoma, outcome of advanced disease: retrospective study from the Ultra-Rare Sarcoma Working Group.
No full textBACKGROUND: To present findings from a retrospective study conducted by the Ultra-Rare Sarcoma Working Group on metastatic low-grade fibromyxoid sarcoma (LGFMS), sclerosing epithelioid fibrosarcoma (SEF), and hybrid (H)-LGFMS/SEF across 28 global centres. METHODS: Patients treated at participating institutions from January 2000 to September 2022 were retrospectively selected. Diagnosis was confirmed by expert pathologists. Primary endpoint was progression-free survival (PFS-1) from metastasis detection to first progression or death. PFS-2 was calculated from therapy initiation. RESULTS: A total of 101 patients were identified (32 LGFMS, 50 SEF, 19 H-LGFMS/SEF). Median (m) follow-up was 62.1 months. mPFS-1 was 28.7, 11.8, and 20.3 months for LGFMS, SEF, and H-LGFMS/SEF, respectively. mOS was 145.8, 41.9, and 113.5 months, respectively. Treatments included anthracycline-based chemotherapy, gemcitabine-based chemotherapy (G), pazopanib, trabectedin, others. mPFS-2 was: 20.1, 5.5, and 3.5 months in H-LGFMS/SEF, SEF, and LGFMS, respectively, with anthracyclines; 19.5, 7.7, and 6.9 months in LGFMS, SEF, and H-LGFMS/SEF, respectively, with pazopanib; 12.0, 9.7, and 3.1 months in H-LGFMS/SEF, LGFMS, and SEF, respectively. Occasional responses occurred with ifosfamide/oral cyclophosphamide, and prolonged stable disease with immune checkpoint inhibitors. CONCLUSIONS: In this series, the largest available, metastatic LGFMS, SEF, and H-LGFMS/SEF showed different courses. Systemic agents have modest efficacy, informing future trials of novel agents for these tumours
Preliminary Metabolomics Study Suggests Favorable Metabolic Changes in the Plasma of Breast Cancer Patients after Surgery and Adjuvant Treatment.
No full textBackground/Objectives: The management of early breast cancer (BC) includes surgery, followed by adjuvant radiotherapy, chemotherapy, hormone therapy, or immunotherapy. However, the influence of these interventions in metabolic reprogramming remains unknown. This study explored alterations in the plasma metabolome of BC patients following distinct treatments to deepen our understanding of BC pathophysiology, outcomes, and the identification of potential biomarkers. Methods: We included 52 women diagnosed with BC and candidates for surgery as primary oncological treatment. Blood samples were collected at diagnosis, two weeks post-surgery, and one month post-radiotherapy. Plasma samples from 49 healthy women served as controls. Targeted metabolomics assessed 74 metabolites spanning carbohydrates, amino acids, lipids, nucleotide pathways, energy metabolism, and xenobiotic biodegradation. Results: Before treatment, the BC patients exhibited notable changes in carbohydrate, nucleotide, lipid, and amino acid metabolism. We noticed a gradual restoration of specific metabolite levels (hypoxanthine, 3-phosphoglyceric acid, xylonic acid, and maltose) throughout different treatments, suggesting a normalization of the nucleotide and carbohydrate metabolic pathways. Moreover, we observed increased dodecanoic acid concentrations, a metabolite associated with cancer protection. These variations distinguished patients from controls with high specificity and sensitivity. Conclusions: Our preliminary study suggests that oncological treatments modify the metabolism of patients towards a favorable profile with a decrease in the pathways that favor cell proliferation and an increase in the levels of anticancer molecules. These findings emphasize the pivotal role of metabolomics in recognizing the biological pathways influenced by each cancer treatment and the resulting metabolic consequences. Furthermore, it aids in identifying potential biomarkers for disease onset and progression
Surgical Outcomes Following Neoadjuvant Treatment for Locally Advanced and Borderline Resectable Pancreatic Ductal Adenocarcinoma.
Get PDFOBJECTIVE: To assess overall survival (OS), compare the effects of neoadjuvant treatment, and describe surgical outcomes for patients undergoing pancreatic resection following chemotherapy and/or chemoradiotherapy (CRT) for borderline resectable (BR) or locally advanced (LA) pancreatic ductal adenocarcinoma (PDAC). BACKGROUND: We approach BR/LA PDAC using chemotherapy followed by selective CRT to the primary site of disease where either the surgical margin remains radiologically threatened following chemotherapy or as a further downstaging treatment. METHODS: Retrospective study of patients between December 2005 and June 2023 at the Royal Marsden Hospital, London, United Kingdom. RESULTS: A total of 54 patients were included. The OS between R1 and R0 patients was significantly different: 7.5 versus 23 versus 42 versus 51 months for R1 chemo, R1 chemo and CRT, R0 chemo and R0 chemo, and CRT groups, respectively, P < 0.001. Similarly, 9 versus 18 versus 42 versus 41 months for N1 chemo, N1 chemo and CRT, N0 chemo and N0 chemo, and CRT groups, respectively, P = 0.0026. Multivariable Cox regression model demonstrated that perineural invasion (hazard ratio: 2.88, 95% confidence interval: 1.06-7.81; P = 0.038) and perivascular invasion (PVI) (HR: 2.76, 95% CI: 1.24-6.13; P = 0.013) were associated with significantly worse OS. Chemo and CRT conferred OS benefit compared to chemo only (7 vs 23 months, P = 0.004) in PVI-positive patients. CONCLUSIONS: Neoadjuvant chemotherapy followed by CRT compared to chemotherapy alone for resected BD and LA PDAC was demonstrated to significantly improve median OS, in particular, in patients with R1 resection margins, ypN1 nodal status, and perivascular invasion
Combining Data-Driven and Structure-Based Approaches in Designing Dual PARP1-BRD4 Inhibitors for Breast Cancer Treatment.
No full textPoly(ADP-ribose) polymerase 1 (PARP1) inhibitors have revolutionized the treatment of many cancers with DNA-repairing deficiencies via synthetic lethality. Advocated by the polypharmacology concept, recent evidence discovered that a significantly synergistic effect in increasing the death of cancer cells was observed by simultaneously perturbating the enzymatic activities of bromodomain-containing protein 4 (BRD4) and PARP1. Here, we developed a novel cheminformatics approach combined with a structure-based method aiming to facilitate the design of dual PARP1-BRD4 inhibitors. Instead of linking pharmacophores, the developed approach first identified merged pharmacophores (a pool of amide-containing ring systems), from which phenanthridin-6(5H)-one was further prioritized. Based on this starting point, several small molecules were rationally designed, among which HF4 exhibited low micromolar inhibitory activity against BRD4 and PARP1, particularly exhibiting strong inhibition of BRD4 BD1 with an IC50 value of 204 nM. Furthermore, it demonstrated potent antiproliferative effects against breast cancer gene-deficient and proficient breast cancer cell lines by arresting cell cycle progression and impeding DNA damage repair. Collectively, our systematic efforts to design lead-like molecules have the potential to open doors for the exploration of dual PARP1-BRD4 inhibitors as a promising avenue for breast cancer treatment. Furthermore, the developed approach can be extended to systematically design inhibitors targeting PARP1 and other related targets
Predicting cervical cancer target motion using a multivariate regression model to enable patient selection for adaptive external beam radiotherapy.
No full textBACKGROUND AND PURPOSE: Interfraction motion during cervical cancer radiotherapy is substantial in some patients, minimal in others. Non-adaptive plans may miss the target and/or unnecessarily irradiate normal tissue. Adaptive radiotherapy leads to superior dose-volume metrics but is resource-intensive. The aim of this study was to predict target motion, enabling patient selection and efficient resource allocation. MATERIALS AND METHODS: Forty cervical cancer patients had CT with full-bladder (CT-FB) and empty-bladder (CT-EB) at planning, and daily cone-beam CTs (CBCTs). The low-risk clinical target volume (CTVLR) was contoured. Mean coverage of the daily CTVLR by the CT-FB CTVLR was calculated for each patient. Eighty-three investigated variables included measures of organ geometry, patient, tumour and treatment characteristics. Models were trained on 29 patients (171 fractions). The Two-CT multivariate model could use all available data. The Single-CT multivariate model excluded data from the CT-EB. A univariate model was trained using the distance moved by the uterine fundus tip between CTs, the only method of patient selection found in published cervix plan-of-the-day studies. Models were tested on 11 patients (68 fractions). Accuracy in predicting mean coverage was reported as mean absolute error (MAE), mean squared error (MSE) and R2. RESULTS: The Two-CT model was based upon rectal volume, dice similarity coefficient between CT-FB and CT-EB CTVLR, and uterine thickness. The Single-CT model was based upon rectal volume, uterine thickness and tumour size. Both performed better than the univariate model in predicting mean coverage (MAE 7 %, 7 % and 8 %; MSE 82 %2, 65 %2, 110 %2; R2 0.2, 0.4, -0.1). CONCLUSION: Uterocervix motion is complex and multifactorial. We present two multivariate models which predicted motion with reasonable accuracy using pre-treatment information, and outperformed the only published method
Clinicopathological Analysis of a European Cohort of MYOD1 Mutant Rhabdomyosarcomas in Children and Young Adults.
No full textBACKGROUND: Patients with PAX3/7-FOXO1 fusion-negative rhabdomyosarcomas (fnRMS) harbouring the rare L122R MYOD1 mutation have significantly poorer prognosis than other fnRMS. We undertook a detailed clinicopathological evaluation of a cohort of patients with MYOD1 mutated fnRMS in order to improve risk stratification and treatment options. PROCEDURE: Histological, mutational and clinical data from a cohort of patients with MYOD1 mutant RMS treated in Europe were analysed. RESULTS: Thirty-two cases with mutant MYOD1 RMS were identified from patients enrolled in sequential European rhabdomyosarcoma clinical trials from 1992 to 2022 (n = 22) and non-trial cohorts (n = 10). Thirty cases had the recurrent L122R missense mutation, one case harboured a K124E mutation and one case had a truncating mutation (S63X). Increased MyoD1 and reduced MYF4 immunostaining were consistent features of MYOD1L122R-mutated RMS. Applying the risk stratification of the European paediatric Soft tissue sarcoma Study Group (EpSSG) RMS2005 trial, among 20 localised RMS cases that could be assigned a risk category, one was Very High Risk, 13 were High Risk and six were Standard Risk. Eight patients had distant metastases at diagnosis. Of the 25 patients with adequate clinical follow-up data, 15/25 (60%) patients had an event at a median time of 9 months (12/15 included failure of local control) and 13/25 (52%) died of disease. CONCLUSION: This MYOD1 mutant cohort demonstrates increased MYOD and reduced MYF4 immunostaining, high risk of local failure and poor survival in agreement with other studies. Increased treatment intensity and improved local control should be considered for these patients