bluuebunny/crossref_metadata_2025_split huggingface dataset:
Real-time customized precision combination therapies based on potential actionability and coalterations to provide therapeutic opportunities for hyperprogressive disease after immune checkpoint inhibitor therapy.
Authors: Wang Lili , Wang Haitao , Li Hong Zheng 
Published: June 2023

e14688 Background: Patients with hyperprogressive disease (HPD) after immune checkpoint inhibitor therapies have few treatment options and short survival times. Genomic-based precision medicine within the frame of molecular tumor board might theoretically enable effective treatment identification for HPD. Detailed data on MTB guided treatments and outcome with a focus on HPD have not been reported yet. Methods: This is a single-institution retrospective, open-label, histology-agnostic analysis of the consecutively identified HPD patients that have received a real-time precision combination treatment approach which would rapidly integrate clinical grade targeted next-generation sequencing, NGS interpretation and with or without patient-derived xenografting to identify and prioritize effective customized targeted combination treatments within the frame of molecular tumor board at the Tianjin Medical University Second Hospital, a single large academic medical center, refractory cancer-foucused, between January 2018 and January 2022. Treatment was selected using on-label, off-label or investigational agents either in monotherapy or in combination. Clinicopathologic data, next-generation sequencing results, MTB recommendations, therapy received, outcomes, response assessment based on radiologic imaging and follow-up data were assessed through database searching. Results: A total of 41 HPD suspected patients were referred to the MTB, and 38 conformed HPD with one of the criteria of Russo or Kato. 27 patients were treated with MTB recommended targeted mono or combinational therapy, 4 in accordance with guidelines (on label) in clinical practice, and 23 off label within two ongoing real-time precision medicine programme for patients with exhausted standard care. Of 25 evaluable patients, 20 (80%) achieved either partial response (n = 13, 52%) or stable disease (n = 7, 28%) and with a median overall survival of 12.2 months (95% CI, 8.4 months to not reached). Furthermore, 14 (56%) of those patients showed improvement in progression-free survival of at least 30% while on MTB-recommended treatment compared with the progression-free survival of the previous treatment line. Conclusions: It represents a proof of-concept case series as it demonstrates the feasibility of real time precision approach in the clinical setting and guide individual patient treatment in the rare and high aggressive disease. Patients with MTB-recommended treatments seemed to benefit with respect to PFS ratio and OS.
Do corticosteroids affect immunotherapy efficacy in malignancy? A systematic review.
Authors: Byron Yoni , Yegorova-Lee Sonya , Tio Martin 
Published: June 2023

e14692 Background: Early studies indicate that corticosteroids may limit survival benefits from immunotherapy, although this finding is potentially confounded by the poor prognosis of patients who require corticosteroids due to cancer-related symptoms. We conducted this systematic review to evaluate the effect corticosteroids have on immunotherapy, when adjusted for potentially confounding effects of corticosteroids given for palliative indications. Methods: 3 databases (PubMed, Embase, and Medline) were searched on 1st of February 2023. Studies that measured response or survival in patients receiving immunotherapy, while receiving corticosteroids for non-cancer indications, compared to either no corticosteroids or corticosteroids for cancer-related indications were included. Studies exclusively evaluating the effect of corticosteroids administered for immune-related adverse events were excluded to avoid immortal time bias. Pooled odds and hazard ratios with 95% confidence intervals (CI) were calculated using a random effects model. Study heterogeneity was assessed using the I2 statistic, and publication bias was evaluated by funnel plot and Egger's regression model. Results: 8,426 studies were identified, of which 8 studies met our inclusion criteria for meta-analysis. Administration of steroids has no statistically significant effect on survival and response to immunotherapy when administered for non-cancer related indications, with a pooled odds ratio for overall response rate 0.92 (95% CI 0.58-1.44); pooled hazard ratio (HR) for progression free survival 0.87 (95% CI 0.68-1.12); and pooled HR for overall survival 0.79 (95% CI 0.59-1.05). Conclusions: This systematic review indicates that administration of corticosteroids does not affect response to immunotherapy nor survival outcomes, when removing confounding palliative corticosteroid indications. Limiting or minimising corticosteroid treatment in this patient population due to concern of potential lowered efficacy of immunotherapy can therefore be reconsidered. These results are limited by the retrospective nature of the studies, small sample sizes, and the lack of information about corticosteroid dosing or length of treatment.
Immune-mediated adverse event management at a tertiary care cancer center.
Authors: Shatila Malek , Eshaghi Farzin , Thomas Austin , Kuang Andrew , Abudayyeh Ala , Sheshadri Ajay , Palaskas Nicolas , Thomas Anusha , Zhang Hao Chi , Wang Yinghong 
Published: June 2023

e14697 Background: Our understanding of immune-related adverse events (irAEs) has evolved rapidly with management guidelines constantly being updated. We aim to explore temporal changes in irAE management at a tertiary cancer care center to identify areas for potential improvement. Methods: This was a single-center, retrospective study including patients who developed a GI, pulmonary, renal, or cardiac irAE between 07/01/2019-10/01/2019 compared to a contemporary cohort from 2021. The follow-up window was for up to a year after diagnosis. Data collected included patient demographics and irAE management and outcomes. Results: Endoscopic evaluation and GI follow-up after discharge for patients with GI irAEs fell over the years. Despite this, there was a decline in symptom duration and steroid taper attempts. The pulmonary service showed improvements in consultation, hospital admission and re-admission, and ICU admission. However, follow up post-hospital discharge were consistently low ( < 50%). Rate of cardiology consultation was consistently high across the years with an equally fast time to consultation, and myocarditis cohort in 2021 had a higher clinical response rate than the 2019 cohort. There were no major differences across the years for renal irAEs. We found that outpatient treatment and earlier GI consult improved outcomes in GI irAEs. For pulmonary irAEs, hospitalization, symptom recurrence, multiple steroid tapering courses, and hospital readmission were associated with less pneumonitis remission. Conclusions: This is one of the few qualitative studies exploring current practice in managing irAEs. We identified areas to improve the management on across all specialties, and found specific factors associated with better outcomes in GI and pulmonary irAEs. Together, these findings can help improve the quality of irAE management algorithms at our institution. [Table: see text]
Plasma proteomics approach to distinguishing PD-1 inhibitor-associated myocarditis from acute myocardial infarction in patients receiving PD-1 inhibitors treatment: A clinical and preclinical study.
Authors: Luo Yuxi , Yi Yali , Lu Zhiqin , Liu Anwen , Zeng Zhimin 
Published: June 2023

e14698 Background: Immune checkpoint inhibitor (ICI)-related myocarditis is a rare but severe side effect that requires attention to distinguish it from other cardiovascular emergencies. Therefore, new biomarkers are needed for the early diagnosis of ICI-related myocarditis, especially to distinguish it from other cardiovascular emergencies. Our study aims to explore plasma biomarkers with high specificity and sensitivity using proteomic analysis for the early diagnosis of ICI-related myocarditis and to distinguish it from acute myocardial infarction (AMI). Methods: Patients with ICI-related myocarditis and AMI were selected and matched for potential confounding effects such as age, gender, smoking history, and chronic heart diseases. A label-free liquid chromatography-mass spectrometry (LC-MS) proteomics approach was used to analyze plasma samples and screen sensitive and specific myocarditis protein biomarkers. Further validation will be performed at the level of patients and animal models of ICI-related myocarditis and AMI. Results: We performed plasma proteomics on 15 plasma samples from 5 pairs of samples with PD-1 inhibitor-associated myocarditis at baseline (control group) and diagnosis (myocarditis group) and 5 cases of acute myocardial infarction (MI group) confirmed by coronary angiography in the Second Affiliated Hospital of Nanchang University. In total, we identified a total of 1521 plasma proteins and 1325 quantifiable plasma proteins across all 15 plasma samples. Further analysis of the differential proteins showed that 34 proteins with significantly differentially expressed in myocarditis group samples compared with other groups. Among them, several proteins were significantly up-regulated (MYOM3, TNNC1, MYL1, MYOM2, CA3, MYLPF, ECI1, LGALS1, PSMA7, PSMB3, PSMA4, PSMB6, CKM, ABCB6, UGP2, ALDOA, TPM2) or down-regulated (MAN1A1, SPTB, YTHDC2, CLEC11A, GSN, APOA4) in myocarditis samples. Compared with the other groups, the ICI-related myocarditis group showed molecular changes in myocardial contraction, proteasome, immunoregulation, NF-κB signaling pathway, arginine and proline metabolism, and cysteine and methionine metabolism. We then performed ELISA on additional ICI-related myocarditis and AMI patients and corresponding animal models. The Troponin C, Myom 3, UGP2, and Galectin-1 proteins related to immune or inflammation were significantly increased. Conclusions: Our study has revealed that proteins related to the immune system or inflammation may be sensitive and specific plasma biomarkers for identifying ICI-related myocarditis. However, further large sample cohorts are needed to confirm these findings.
Replacement of anti-PD-1 drugs with prolgolimab during treatment, safety and efficacy.
Authors: Andabekov Timur , Napolskaia Elena , Rodina Maria , Khlobystina Alina , Gulo Elizaveta 
Published: June 2023

e14701 Background: The anti-PD-1 treatment has been shown good response in patients with cancer. There is little information in open sources on the possibility of changing anti-PD-1 drugs during treatment for non-medical indications. Prolgolimab (formerly BCD-100) is an IgG1 anti–PD-1 mAb that contains the Fc-silencing mutation LALA, which provides an immunopotential advantage by eliminating the interaction between the Fc region of the antibody and FcyR expressed on various immune cells, thus blocking possible effector functions of the antibody. We report the replacement of anti-PD-1 drugs during treatment on safety and anti-PD-1 response in patients with melanoma and lung cancer. Methods: 5 patients with advanced melanoma and 2 non small cell lung cancer (NSCLC) with RECIST-evaluable disease, with prior anti-PD-1 treatment by nivolumab and pembrolizumab. 5 Patients were with prior anti-PD-1 treatment by nivolumab (median duration of treatment was 4 months) and 2 patients pembrolizumab (median duration of treatment was 7 months). Patients were treated (replaced) with prolgolimab (anti-PD-1) 1 mg/kg every 2 week. The primary objective was safety of replacement anti-PD-1 therapy and objective response rate (ORR) by RECIST 1.1. Replacement of anti-PD-1 drugs during treatment were associated for non-medical indications. Patients were with ECOG 0-1. Results: Median age was 57 years, 5 were male, 1 patients with NSCLC had a KRAS mutation and patients with melanoma had a BRAF mutation. Median follow-up was 10 months. Adverse events continued after prescription of prolgolimab. New adverse events have not experienced. Anti-PD-1 therapy was not discontinued. ORR was 85%, of which 3 were CR. Median PFS was not reached. 1 patient with NSCLC prior anti-PD-1 treatment by nivolumab (2 cycles 480 mg) had PD, but PR was prolgolimab. Conclusions: Anti-PD-1 treatment followed by prolgolimab (anti-PD-1) in our patients undergoing therapy is safe and does not worsen anti-tumor responses. We assume that in certain situations it is possible to make (for example, individual intolerance) substitutions of drugs in the same group anti-PD-1 Replacement anti-PD-1 may reduce financial toxicity.
Ustekinumab for the treatment of immune related cutaneous adverse events (ircAEs).
Authors: Maier Tara , Gu Stephanie , Shah Neil J. , Faleck David M. , Lacouture Mario E. 
Published: June 2023

e14702 Background: IrcAEs are one of the most common immune related adverse events (irAEs) associated with immune checkpoint inhibitors (ICI). Ustekinumab, a monoclonal antibody that targets IL12/IL23, is FDA approved for the treatment of autoimmune diseases including psoriasis and inflammatory bowel disease. The IL12/23 pathway may mediate a subset of ircAEs, and ustekinumab may be effective for the treatment of these events. Methods: Patients at Memorial Sloan Kettering Cancer Center who received ustekinumab for treatment of ircAEs were identified from 8/18/2017 to 2/17/2022. Common Terminology Criteria for Adverse Events (CTCAE) v 5.0 was used to grade ircAEs. Patient response to ustekinumab was subcategorized into complete resolution (CR, improvement of symptoms to baseline or grade 0), partial resolution (PR, improvement in CTCAE grade but not CR), or no response/worsening (NR, no clinical improvement or worsening of ircAEs). Results: A total of 11 patients were included in the study. The median age was 72 years (IQR 69.5-77) and 45% of patients were female. The most common ICIs were pembrolizumab (64%, n=7), nivolumab (18%, n=2), atezolizumab (9%, n=1), and avelumab (9%, n=1). Melanoma (27%, n=3) and bladder (27%, n=3) cancer were the two most common neoplasms. All patients had psoriasiform ircAEs (n=10), except one who had a pyoderma gangrenosum (PG) ircAE; most were either grade 2 (46%) or grade 3 (36%) at the time of ustekinumab initiation. The majority of patients (73%, n=8), including the one with PG, noted some improvement with ustekinumab, with 55% (n=6) and 18% (n=2) achieving CR and PR, respectively. The median duration of ustekinumab treatment was 169 days (0 – 1774), and among those with PR or CR, the median time to initial response was 27 days (21 – 39). In addition, the proportion of patients on topical and systemic steroids before and after ustekinumab decreased from 91% (n=10) to 56% (n=6) and from 64% (n=7) to 36% (n=3), respectively. Four patients (36.4%) discontinued ICIs because of severe ircAEs, with 1 (25%) successfully recontinuing their ICI following control of ircAE symptoms with ustekinumab. We noted progression of disease among 55% (n=6) of patients at any point after ustekinumab treatment. Among them, median time to next treatment was 345.5 days (70-925), with a median of 347.5 days (70-576) and 601 days (277-925 days) for patients with non-metastatic (33.3%) and metastatic tumors (66.7%), respectively. Conclusions: Ustekinumab has shown encouraging clinical activity especially for psoriasiform ircAEs and can be an effective steroid-sparing treatment for specific ircAEs. Despite the occurrence of cancer progression in some of our cohort, it was difficult to interpret the ICI anti-tumor activity post ustekinumab given the small numbers and multiple tumor types. Further prospective studies are needed to validate our findings given the significant potential of ustekinumab for the management of ircAEs.
A prospective non-randomized phase I trial of dendritic cell–based cryoimmunotherapy combined with checkpoint inhibitors in mCRPC.
Authors: Thomsen Liv Cecilie Vestrheim , Honoré Alfred , Gjertsen Bjorn T. , Børretzen Astrid , Reisæter Lars Anders , Almås Bjarte , Helle Svein Inge , Førde Kristina , Biermann Martin , Azeem Waqas , Gabriel Benjamin , Knappskog Stian , Halvorsen Ole Johan , Akslen Lars , Pantel Klaus , Riethdorf Sabine , Øyan Anne Margrete , Kalland Karl-Henning , Beisland Christian 
Published: June 2023

e14708 Background: Despite improvements, metastatic castration-resistant prostate cancer (mCRPC) still has dismal overall survival (OS). We treated 18 mCRPC patients with dendritic cell (DC)-based cryoimmunotherapy (CryoIT) as monotherapy or combined with checkpoint inhibitors to determine safety and immune response. Methods: mCRPC patients were biopsied before cryoablation, and subsequently injected intratumorally with autologous immature DCs. DC doses were escalated in a 3+3 design (n=9) followed by dose expansion combined with either ipilimumab (n=6) or pembrolizumab (n=3). The disease burden was assessed by PSA values, iRECISTv1.1 (PET/CT, MRI and bone scintigraphy at baseline, 14, 22 and 46 weeks) and circulating tumor cells (CTC; CellSearch). Immune response was monitored by ultradeep T-cell receptor sequencing. Results: The patients had aggressive cancer, with ISUP grade group 4 and 5 in 72% (13/18) at diagnosis and in 100% at inclusion. At baseline, higher ALP correlated with higher regulatory T cells (p=0.047), FoxP3+/CD3+ratios (p=0.014) and FoxP3+/CD8+ratios (p=0.004) in tissues. Median OS and progression-free survival (PFS) were 40.7 and 10.5 months, respectively. Of the 8 patients alive 43 to 85 months post-CryoIT, 7 had progressed and received other treatment. Early decreases in PSA (p=0.002) and LDH (p=0.01) levels 6 weeks after CryoIT indicated better outcomes at 22 weeks. Longer OS correlated with lower tissue ratios of CD4+/CD3+cells (p=0.002) and CD4+/CD8+cells (p=0.007). All patients with increased numbers of new T-cell clonotypes after CryoIT and CTC at the pretreatment level of 1-4 cells/ 7.5 mL blood changed to negative during follow-up up to 72 weeks. Conclusions: CryoIT demonstrates non-inferior OS and PFS compared to other mCRPC trials, and therapy response was suggested by decreased CTCs and induction of new T-cell clonotypes post-CryoIT. Lower CD4+cell fractions of lymphocytes in the TME indicate better OS after CryoIT. CryoIT appears not to decrease effects of post-treatment recurrence therapies. Clinical trial information: NCT02423928 . [Table: see text]
Importance of patient related outcomes in diagnosing fatigue related to immunotherapy treatment in patients with lung cancer: A real life study.
Authors: Almodovar Maria-Teresa , Picado Mariana , Gaspar Carina 
Published: June 2023

e14709 Background: Lung cancer is a common cancer with a dismal prognosis that was improved with treatment with check-point inhibitors (CPI). Fatigue is the most frequent adverse event of CPI, often undervalued by physicians. Patient report outcomes may be a key to overcome underdiagnose of fatigue. Methods: The aim of this study is to identify whether the assessment Non-Small Cell Lung Cancer (NSCLC) patients report when answering the BFI questionnaire of fatigue is consistent with the one recorded by the clinical team at the pneumology consultation the during treatment with immunotherapy in monotherapy or in combination with chemotherapy. A prospective observational study was carried out during 8 months. The research was conducted through the collection of medical records from the patients clinical files and the application of the Brief Fatigue Inventory questionnaire before each one of the 4 treatment cycles. This questionnaire was validated and linguistically translated into Portuguese and assesses the severity and functional impact of fatigue in cancer patients. A 95% confidence interval was considered. Results: The 31 patients, 26 male (84%) and 5 female (16%) with a mean age of 68.5 years. The mean value of the BFI score before the first treatment, as well as in the following 3 evaluations, was higher for the participants who presented symptoms of asthenia/tiredness/fatigue recorded in the clinical files at the consultation and lower for those who did not. However, the differences were not statistically significant (pre 1st treatment - p=0.299, pre 2nd treatment - p=0.125, pre 3rd treatment - p=0.103 and pre 4th treatment - p=0.954). By comparing the BFI score with medical records, we found that fatigue remained underreported at the consultation in different assessment times (71% of sample participants were not identified as having fatigue at the 1st assessment time; 60% at the pre 2nd treatment visit; 54% at the pre 3rd treatment visit and 40% at the pre 4th treatment visit). Conclusions: In the present study, the BFI questionnaire allowed us to identify and stratify fatigue, showing greater sensitivity when compared to the medical records of the consultation alone.
Management of immune related adverse events through electronic multidisciplinary consultation: Five years of experience from Peking Union Medical College Hospital.
Authors: Liu Xiaoyan , Shi Yuequan , Zhang Dongming , Chen Minjiang , Xu Yan , Zhao Jing , Zhong Wei , Wang Mengzhao 
Published: June 2023

e14712 Background: The increasing occurrence of immune-related adverse events (irAEs) pose a growing challenge for patients receiving immunotherapy. We sought to evaluate the utility of telemedicine in improving access to the multidisciplinary service and to provide a comprehensive overview of practical issues in the diagnosis and management of irAEs. Methods: A virtual multidisciplinary service dedicated to the diagnosis and management of irAEs was launched in July 2018. Data were collected using a digital referral system. Results: Data were collected from 1 July 2018 to 30 June 2022. After excluding 11 consultations that were lost to follow-up or had incomplete medical records, 278 consultations were included in this study. 187 consultations related to the diagnosis and management of irAEs; 68 related to the management of irAEs; 23 related to the suitability of immunotherapy. The diagnosis of irAE was ruled out in 23% (43/187) of cases. The differential diagnosis included overlapping toxicity attributed to concurrent use of targeted therapy or chemotherapy (n = 16), comorbidities (n = 11), infection (n = 10), and cancer progression (n = 6). A diagnosis of irAE was confirmed in 206 cases. Of these, 131 cases were single organ/system irAEs and 75 cases were multiple organ/system irAEs. 83% of these were grade 3-4. The most common confirmed irAEs were interstitial lung disease (n = 45), diarrhoea/colitis (n = 41), liver dysfunction (n = 38) and myocarditis (n = 33). Initiation of corticosteroids was recommended in 100% (138/138) of treatment-naïve patients. The most commonly recommended corticosteroid dose was 1-4 mg/kg/d (n = 83, 45%). Corticosteroid dose adjustment was recommended in 90% (61/68) of treated patients, including dose escalation (n = 19), dose re-escalation or prolonged tapering (n = 30), and rapid tapering (n = 12). Cardiovascular, pulmonary, rheumatic and hepatic irAEs were the top four irAEs requiring immunosuppression in addition to corticosteroids. Intravenous immunoglobulin (n = 108), tocilizumab (n = 51), mycophenolate mofetil (n = 41), and infliximab (n = 21) were the four most commonly recommended immunosuppressants. Consultation recommendations were followed in 87% (166/191) of cases. Clinical improvement was observed in 83% (137/166) of cases. Conclusions: This study demonstrated the feasibility of the electronic multidisciplinary consultation in the diagnosis and management of irAEs. Common challenges in the diagnosis of irAEs were identified, mainly the differential diagnosis of non-immune toxicity, infection, cancer progression, or comorbidities. Awareness of differential diagnosis should also be raised in patients suspected of irAE flare. The use of corticosteroids and additional immunosuppressants needs to be further investigated.