tbuckley/cabot-search huggingface dataset:
Imaging neuroinflammation in individuals with substance use disorders
Authors: Xinyi Li, Astrid P Ramos-Rolón, Gabriel Kass, Lais S Pereira-Rufino, Naomi Shifman, Zhenhao Shi, Nora D Volkow, Corinde E Wiers
Journal: Journal of Clinical Investigation (2024)

Increasing evidence suggests a role of neuroinflammation in substance use disorders (SUDs). This Review presents findings from neuroimaging studies assessing brain markers of inflammation in vivo in individuals with SUDs. Most studies investigated the translocator protein 18 kDa (TSPO) using PET; neuroimmune markers myo-inositol, choline-containing compounds, and N-acetyl aspartate using magnetic resonance spectroscopy; and fractional anisotropy using MRI. Study findings have contributed to a greater understanding of neuroimmune function in the pathophysiology of SUDs, including its temporal dynamics (i.e., acute versus chronic substance use) and new targets for SUD treatment.
Trastuzumab deruxtecan versus trastuzumab emtansine in HER2-positive metastatic breast cancer: long-term survival analysis of the DESTINY-Breast03 trial
Authors: Javier Cortés, Sara A. Hurvitz, Seock-Ah Im, Hiroji Iwata, Giuseppe Curigliano, Sung-Bae Kim, Joanne W. Y. Chiu, Jose L. Pedrini, Wei Li, Kan Yonemori, Giampaolo Bianchini, Sherene Loi, Giuliano S. Borges, Xian Wang, Thomas Bachelot, Shunsuke Nakatani, Shahid Ashfaque, Zhengkang Liang, Anton Egorov, Erika Hamilton
Journal: Nature Medicine (2024)

Trastuzumab deruxtecan (T-DXd) demonstrated significantly improved efficacy over trastuzumab emtansine (T-DM1) in DESTINY-Breast03 (median follow-up, 28 months). We report updated efficacy and safety analyses, including secondary and exploratory efficacy endpoints (median follow-up, 41 months) of DESTINY-Breast03. Patients with advanced HER2-positive metastatic breast cancer previously treated with taxane and trastuzumab were randomized to T-DXd (5.4 mg per kg (261 patients)) or T-DM1 (3.6 mg per kg (263 patients)). The primary endpoint was progression-free survival (PFS) by blinded independent central review and was previously reported. The key secondary endpoint was overall survival (OS). Other secondary endpoints included objective response rate, duration of response and PFS (all by investigator assessment) and safety. At data cutoff, 20 November 2023, median PFS by investigator assessment was 29.0 versus 7.2 months (hazard ratio (HR), 0.30; 95% confidence interval (CI), 0.24-0.38), the 36-month PFS rate was 45.7% versus 12.4% and median OS was 52.6 versus 42.7 months (HR, 0.73; 95% CI, 0.56-0.94) with T-DXd versus T-DM1, respectively. Treatment-emergent adverse events were consistent with the previous analyses. No new instances of grade ≥3 interstitial lung disease or pneumonitis occurred (all grade rate, 16.7% (T-DXd) versus 3.4% (T-DM1)). With longer follow-up, T-DXd continued to demonstrate superior efficacy over T-DM1 with a manageable safety profile. ClinicalTrials.gov registration: NCT03529110 .
Cell-free DNA for the detection of kidney allograft rejection
Authors: Olivier Aubert, Cindy Ursule-Dufait, Romain Brousse, Juliette Gueguen, Maud Racapé, Marc Raynaud, Elisabet Van Loon, Angelica Pagliazzi, Edmund Huang, Stanley C. Jordan, Kenneth D. Chavin, Gaurav Gupta, Dhiren Kumar, Tarek Alhamad, Sanjiv Anand, Jorge Sanchez-Garcia, Basmah A. Abdalla, Julien Hogan, Rouba Garro, Darshana M. Dadhania, Pranjal Jain, Didier A. Mandelbrot, Maarten Naesens, Raja Dandamudi, Vikas R. Dharnidharka, Dany Anglicheau, Carmen Lefaucheur, Alexandre Loupy
Journal: Nature Medicine (2024)

Donor-derived cell-free DNA (dd-cfDNA) is an emerging noninvasive biomarker that has the potential to detect allograft injury. The capacity of dd-cfDNA to detect kidney allograft rejection and its added clinical value beyond standard of care patient monitoring is unclear. We enrolled 2,882 kidney allograft recipients from 14 transplantation centers in Europe and the United States in an observational population-based study. The primary analysis included 1,134 patients. Donor-derived cell-free DNA levels strongly correlated with allograft rejection, including antibody-mediated rejection (P < 0.0001), T cell-mediated rejection (P < 0.0001) and mixed rejection (P < 0.0001). In multivariable analysis, circulating dd-cfDNA was significantly associated with allograft rejection (odds ratio 2.275; 95% confidence interval (CI) 1.902-2.739; P < 0.0001) independently of standard of care patient monitoring parameters. The inclusion of dd-cfDNA to a standard of care prediction model showed improved discrimination (area under the curve 0.777 (95% CI 0.741-0.811) to 0.821 (95% CI 0.784-0.852); P = 0.0011) and calibration. These results were confirmed in the external validation cohorts (n = 1,748) including a cohort of African American patients (n = 439). Finally, dd-cfDNA showed high predictive value to detect subclinical rejection in stable patients. Our study provides insights on the potential value of assessing dd-cfDNA, in addition to standard of care monitoring, to improve the detection of allograft rejection. ClinicalTrials.gov registration: NCT05995379 .
Predicting gene expression state and prioritizing putative enhancers using 5hmC signal
Authors: Edahi Gonzalez-Avalos, Atsushi Onodera, Daniela Samaniego-Castruita, Anjana Rao, Ferhat Ay
Journal: Genome biology (2024)

Like its parent base 5-methylcytosine (5mC), 5-hydroxymethylcytosine (5hmC) is a direct epigenetic modification of cytosines in the context of CpG dinucleotides. 5hmC is the most abundant oxidized form of 5mC, generated through the action of TET dioxygenases at gene bodies of actively-transcribed genes and at active or lineage-specific enhancers. Although such enrichments are reported for 5hmC, to date, predictive models of gene expression state or putative regulatory regions for genes using 5hmC have not been developed.
Combining SiRPα decoy–coengineered T cells and antibodies augments macrophage-mediated phagocytosis of tumor cells
Authors: Evangelos Stefanidis, Aikaterini Semilietof, Julien Pujol, Bili Seijo, Kirsten Scholten, Vincent Zoete, Olivier Michielin, Raphael Sandaltzopoulos, George Coukos, Melita Irving
Journal: Journal of Clinical Investigation (2024)

The adoptive transfer of T cell receptor-engineered (TCR-engineered) T cells (ACT) targeting the HLA-A2-restricted cancer-testis epitope NY-ESO-1157-165 (A2/NY) has yielded favorable clinical responses against several cancers. Two approaches to improve ACT are TCR affinity optimization and T cell coengineering to express immunomodulatory molecules that can exploit endogenous immunity. By computational design we previously developed a panel of binding-enhanced A2/NY-TCRs including A97L, which augmented the in vitro function of gene-modified T cells as compared with WT. Here, we demonstrated higher persistence and improved tumor control by A97L-T cells. In order to harness macrophages in tumors, we further coengineered A97L-T cells to secrete a high-affinity signal regulatory protein α (SiRPα) decoy (CV1) that blocks CD47. While CV1-Fc-coengineered A97L-T cells mediated significantly better control of tumor outgrowth and survival in Winn assays, in subcutaneous xenograft models the T cells, coated by CV1-Fc, were depleted. Importantly, there was no phagocytosis of CV1 monomer-coengineered T cells by human macrophages. Moreover, avelumab and cetuximab enhanced macrophage-mediated phagocytosis of tumor cells in vitro in the presence of CV1 and improved tumor control upon coadministration with A97L-T cells. Taken together, our study indicates important clinical promise for harnessing macrophages by combining CV1-coengineered TCR-T cells with targeted antibodies to direct phagocytosis against tumor cells.
Response-adapted ultra-low-dose 4 Gy radiation as definitive therapy of gastric MALT lymphoma: a single-centre, pilot trial
Authors: Jillian R Gunther, Jie Xu, Manoop S Bhutani, Paolo Strati, Penny Q Fang, Susan Y Wu, Bouthaina S Dabaja, Wenli Dong, Priya R Bhosale, Christopher R Flowers, Ranjit Nair, Luis Malpica Castillo, Luis Fayad, Swaminathan P Iyer, Simrit Parmer, Michael Wang, Hun Ju Lee, Felipe Samaniego, Jason Westin, Sairah Ahmed, Chijioke C Nze, Preetesh Jain, Sattva S Neelapu, Maria A Rodriguez, Dai Chihara, Loretta J Nastoupil, Chelsea C Pinnix
Journal: The Lancet Haematology (2024)
Outcomes after anti-tumour necrosis factor originator to biosimilar switching in children and young people with juvenile idiopathic arthritis in the UK: a national cohort study
Authors: Lianne Kearsley-Fleet, Eileen Baildam, Michael W Beresford, Sharon Douglas, Helen E Foster, Taunton R Southwood, Kimme L Hyrich
Journal: The Lancet Rheumatology (2024)
The utility of procalcitonin in febrile neutropenia.
Authors: Jonathan Nilles, Nicole A. Shonka
Journal: Journal of Clinical Oncology (2024)

12040 Background: The utility of procalcitonin (PCT) in febrile neutropenia (FN) in oncology patients on active therapy has not been well validated. FN constitutes a critical oncologic emergency, often characterized by subtle manifestations of infection, and timely diagnosis and treatment is vital. Although a potential harbinger of dangerous infection, FN can also occur without an identifiable infection, in which case hospitalization and antibiotics may be unnecessary. PCT, an amino acid, is elevated specifically during bacterial infections in the non-cancer population and correlates with infection severity. Clinicians employ PCT levels as a diagnostic adjunct, discerning bacterial from viral infections and analyzing PCT changes to guide treatment decisions. We examined oncology patients presenting with FN to correlate PCT levels and trends with confirmed infections. Methods: We identified patients with neutropenic fever, cancer, and a PCT result seen at our institution from 12/1/2017-12/1/2022. Patients were determined to have a confirmed infection if they had a positive bacterial blood culture. Demographics and clinical characteristics were compared between infection status and induction chemotherapy or transplant status using a Wilcoxon Rank Sum test for continuous variables and a Chi-Square or Fisher’s Exact test for categorical variables. Baseline (at time of initial FN) and highest PCT levels were compared by patient and disease characteristics and proven infection using Wilcoxon Rank Sum test. Logistic regression was used to determine the association of log-transformed PCT (baseline and highest) with proven infection (yes/no) while adjusting for covariates. All tests were two-tailed with p&lt; 0.05 considered statistically significant. Results: Of 365 patients, 61 (16.7%) had an identified infection. Median baseline and peak PCT of 1.26 and 1.51 ng/mL, respectively, were significantly greater for these patients as compared to those with negative cultures at 0.54 and 0.65 ng/mL, respectively (P= 0.01 and &lt;0.01). For every unit increase in the log transformed baseline PCT, the odds of having a proven infection increased by 23%. There were no significant differences in patient or clinical characteristics between those with and without infection. Of those admitted for induction chemotherapy and transplant who developed FN, PCT at time of initial fever was higher at 0.97 vs 0.56 ng/mL (p=0.02). Interestingly, median baseline and median peak PCT differed between gender with females 0.51 and males 0.72 ng/mL (p=0.02) at baseline, and 0.63 vs 0.83 ng/mL (p=0.04), respectively, at peak. Conclusions: PCT levels in cancer patients with FN are significantly associated with culture positive infection. This data can help guide treatment and de-escalation of antibiotics in cancer patients admitted with FN. Further evaluation should be taken to determine how to best use PCT to determine the need for admission and antibiotic prescription.
Localized GIST in Hispanic population in North and South America.
Authors: Catherine Sarre-Lazcano, Berenice Carbajal, Sara Rothschild, Denisse Evans, Tomás Soulé, Jerry Call, Rodrigo Salas, German Calderillo Ruiz, Alondra Hernández, Samuel Christopher Luevano Castro, Alejandro Alfaro Goldaracena, Jason K. Sicklick
Journal: Journal of Clinical Oncology (2024)

e23513 Background: Most studies of gastrointestinal stromal tumors (GIST) focus upon patients in a single country. However, differences in patient presentation, treatment, and outcomes may differ between nations. We sought to compare Hispanic patients with localized GIST treated in North and South America. Methods: We performed a retrospective analysis including all Hispanic GIST patients treated at 3 tertiary referral centers in the United States (US), Mexico (MX) and Argentina (AR), as well as those enrolled by 2 patient advocacy groups in US and MX from 2000-2022. Demographic, clinicopathologic and survival data were collected and compared using Pearson’s chi-square or one-way ANOVA test. Disease-specific survival (DSS) was calculated using the Kaplan-Meier method and compared using the log-rank test. Results: Overall, 1,504 Hispanic patients (54.5% female) were analyzed. Median age at diagnosis was significantly lower in US (48 y) than MX/AR (55/57 y, p = 0.001). Presentation stage varied by country. Localized presentation was more frequent in US/MX (77%/88%) than AR (60%, p = 0.001). In 1,208 patients (80.4%) with localized disease, 97.9% underwent surgical resection. Rates of adjuvant imatinib treatment varied from 82.4%/77.0% in US/MX to 35.6% in AR (p &lt; 0.001). Median duration of adjuvant therapy was longer in US (29 mos; range: 16-48) than MX (12 mos; range: 4-36, p &lt; 0.001). With a median follow up of 44 mos (range: 24-78) for patients presenting with localized GIST, the estimated median DSS was 136 mos (95% CI 104-167), being significantly longer in US (267 mos, 95% CI 95-439, p = 0.02). Conclusions: While most studies of disparities focus on differences between races/ethnicities in a single country, we found that disparities also exist within similar ethnic groups across nations. Underappreciated sociopolitical determinants of health likely lead to differences in presentation, management, and long-term outcomes of Hispanic GIST patients in the Americas. Prospective cooperative studies are needed to better define barriers to care in order to improve patient outcomes in Hispanic GIST patients. [Table: see text]
A meta-analysis GWAS of taxane-induced peripheral neuropathy in patients with breast cancer.
Authors: Yuanchu James Yang, Kerry Roe Schaffer, Guanglong Jiang, Tam C Tran, Peter J Sauer, Chenjie Zeng, Bryan P. Schneider, Ben Ho Park, Joshua C Denny
Journal: Journal of Clinical Oncology (2024)

12089 Background: Taxane-induced peripheral neuropathy (TIPN) is a common dose-limiting toxicity in the medical management of breast cancer patients. Despite the clinical efficacy of taxane treatment, there is significant heterogeneity in the development of neuropathy and its severity, and no clear genetic etiologies have yet been identified. We sought to discover genetic risk variants in two large electronic health record linked DNA biobanks. Methods: A meta-analysis genome wide association study (GWAS) was performed with participants in the All of Us Research Program and BioVU biobanks. All participants of the study population were of female sex at birth and had a breast cancer diagnosis. Cases were defined as taxane-exposed participants who received their first neuropathy diagnosis code within one year after first taxane exposure. Controls were defined as taxane-exposed participants without a neuropathy diagnosis code and without gabapentin initiation after taxane exposure. GWAS was performed with PLINK version 2.0 using age at taxane initiation, number of taxane cycles received, and the first 10 principal components as covariates. Expression quantitative trait loci (eQTL) analysis was performed with the GTEx 8.0 and EyeGEx databases. Results: The All of Us cohort had 196 cases and 254 controls. The BioVU cohort had 244 cases and 528 controls. In our meta-analysis GWAS, rs3065465 (chr11:69138693; closest gene by distance is LOC338694) was associated with TIPN (OR=2.14, P= 8.27E-09) and was similar across different genetic ancestries (Table). The eQTL analysis of rs3065465 shows significant association with mRNA expression of TPCN2(P= 6.44E-06), a cation channel involved in neuronal differentiation and intracellular calcium homeostasis. Conclusions: rs3065465 represents a potential novel genetic marker for TIPN risk in breast cancer patients.[Table: see text]
Place of rank ligand inhibitor in giant cell tumour of bone.
Authors: Esma Kerboua
Journal: Journal of Clinical Oncology (2024)

e23511 Background: Giant cell tumour of bone (GCTB) is a locally aggressive and osteolytic tumour.The peak incidence is during the third and fourth decades of life. The majority of tumours occur in the metaepiphyseal (end) region of the long bones. Surgical resection is the preferred treatment option, if possible but it is a tumor which always poses progressive problems. Denosumab is indicated in recurrent or unresectable GCTB. Methods: We report a series of 70 patients treated for GCT at the medical oncology department of the CPMC (Algiers) in collaboration with the orthopedics department of Mustapha University Hospital from January 2020 to December 2023. Results: 70 patients ( 50 women and 20 men). The sex ratio is 0.54 The average age is 22 years (11-54 years). Reason for consultation : - Pathological fracture: n = 10 - Pain: n = 30 - Functional impotence: n = 20 - Tumor mass: n = 5 - Concept of trauma: n = 5 Stage of the disease: -Localized: n = 29 -Recurrence: n = 30, -Recurrence + pulmonary metastases: n = 10, -Sarcomatous transformation: n = 1 Type of treatment: -Radiotherapy, n = 1 -Exercised biopsy: n = 10, -Curettage + cementoplasty: n = 50 -Exeresis with osteosynthesis material: n = 8, -Amputation : n = 1 Medical treatment: Denosumab: n = 45 The number of courses with denosumab was between 6 and 55 cycles. Denosumab was administered neoadjuvantly in 10 patients, in 20 patients with reccurence disease, 15 patients in the metastatic phase - In terms of toxicity, we noted moderate hypocalcemia in 3 patients. -Objective responses: 95% ORR, 5 complete radiological responses and 10 partial responses, 20 stable patients and 9 out of 10 patients who received neoadjuvant denosumab were able to operate.Progression Free Survival was 28 months. Conclusions: GCTs are aggressive tumors with intermediate malignancy that should not be underestimated. The treatment is essentially surgical. Denosumab is indicated for both neoadjuvant and adjuvant use, it allows obtaining a clear clinical and radiological improvement.
The efficacy of immune checkpoint inhibitors as a part of multimodality treatment in soft tissue and bone sarcoma in an academic community setting.
Authors: Abdulrazzak Zarifa, Michele Britto, Bruce Brockstein
Journal: Journal of Clinical Oncology (2024)

e23564 Background: Prior studies have shown response to immune checkpoint inhibitors (ICI) in a variety of sarcoma subtypes, however, much is still unknown about ICI use in specific sarcoma subtypes due to disease rarity. Patients (pts) are often treated with these agents as part of clinical trials, and real world data in the community setting is lacking. The aim of this study is to report real world efficacy and safety of ICI in sarcoma either alone or with radiation (RT) and/or surgery. Methods: A retrospective cohort review was conducted to identify pts with soft tissue and bone sarcoma who were administered ICI at Kellogg Cancer Center at NorthShore University HealthSystem/Endeavor Health. Pts who received ICI as part of a clinical trial were excluded. Results: A total of 29 pts receiving ICI were identified. Pts had a median of 1 prior systemic therapy. ICI included pembrolizumab (n = 23), nivolumab (n = 5), and ipilimumab/nivolumab (n = 1). Treatment was discontinued in 28 pts due to disease progression (n = 18), toxicities (n = 3), death (n = 2), and maximal response (n = 5). One patient is still undergoing treatment. Median progression-free survival (PFS) was 4.9 months. Median overall survival (OS) was 14 months. Overall response rate (ORR) is 31%. Median duration of response was not reached (44+ months). Complete response (CR) (n = 5) reported in 3 pts with undifferentiated pleomorphic sarcoma (UPS), 1 pt with SMARCA4 deficient undifferentiated sarcoma, and 1 pt with dedifferentiated chondrosarcoma. Partial response (PR) (n = 4) reported in 1 pt with UPS, 1 pt with dedifferentiated liposarcoma, 1 pt with high grade spindle sarcoma of bone, and 1 pt with malignant peripheral nerve sheath tumor. Of those pts with a CR, 2 patients received only pembrolizumab, 1 pt was administered concomitant RT, and 2 pts had administered concomitant surgery. Of the pts who had PR, 3 were also treated with concomitant RT. Grade 3 immune related adverse effects were reported in 5 of the 29 patients. Of these patients, 2 had documented CR and 3 documented PR. Conclusions: This study expands on the real world efficacy of ICI in a variety of sarcoma subtypes. CR and PR rates in this setting were high, and responses were durable, although selection bias for treatment may have played a role. This data supports the treatment of metastatic sarcoma with ICI, especially with concomitant RT and surgery, in a variety of subtypes.
Chalazion associated with proteasome inhibitors approved for multiple myeloma: Analysis of FAERS database.
Authors: Harkarandeep Singh, Uttamjot Kaur, Niraj Neupane, Hassan Saeed, Himal Kharel, Prabhsimrat Gill, Asis Shrestha
Journal: Journal of Clinical Oncology (2024)

e23325 Background: Proteasome inhibitors (PI) are a class of drugs used in the treatment of Multiple Myeloma. The FDA has approved three PIs for this indication (Bortezomib, Carfilzomib, and Ixazomib). Various studies, and case reports have described the occurrence of chalazion with Bortezomib use and subsequent discontinuation of therapy but it’s association with other PIs from the class remains poorly understood. Methods: We conducted a retrospective pharmacovigilance study using the FDA Adverse Event Reporting System database to analyze the strength of association of chalazion with Bortezomib, and with other Proteasome Inhibitors in patients above 18 years of age. We employed disproportionality signal analysis and calculated the reporting odds ratio with a 95% confidence interval. Results: Within the FAERS database, a total of 78,596 adverse events were reported with the use of the three FDA approved PIs in adults, out of which chalazion accounted for 56 cases. Most of the cases were reported with Bortezomib use (54 cases), followed by Carfilzomib (2 cases), and Ixazomib (1 case). In cases with mention of sex, and age, 64.7% were in females, and 35.3% in male patients, whereas 47% patients were within the age group of 18-64, and 53% being above 64 years of age. While most of the cases had non-serious outcomes, death was reported in 2 cases, and hospitalization was needed for 5 cases. Only Bortezomib was associated with a significantly positive signal strength (ROR 32.9, 95% CI 25.1-43.1, Chi-squared Yates 1596.27). Conclusions: The study offers the largest retrospective review of association of chalazion with proteasome inhibitors. It is most strongly associated with Bortezomib use, and females are twice as likely to develop it as compared to males. Elderly patients also seem to be at a slightly higher risk. Overall, chalazion seems to account for only a small number of side effects reported with proteasome inhibitors, and a majority of cases have non-serious outcomes.