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A 57-year-old woman presented to the emergency department with progressive fatigue, oliguria, and dyspnea. Three weeks before presentation, she experienced worsening fatigue and shortness of breath. Her symptoms were associated with watery diarrhea and poor dietary intake. She also reported weight loss and decreased urinary output with no gross hematuria. Her medical history was notable for systolic heart failure of unclear etiology and unknown duration with an ejection fraction of 37% and essential hypertension. Medications included lisinopril and furosemide. She was a former smoker. Her family history was unremarkable.

Purpose The aim of this study is to better characterize the clinical characteristics and outcomes of patients diagnosed with Immune checkpoint Inhibitor (ICI) pneumonitis and propose predictive models. Patients and methods Patients diagnosed with ICI pneumonitis at Mayo Clinic from 2014 to 2022 were studied. All cases were independently reviewed by our pulmonology specialist (A.E.) to confirm the appropriate diagnosis. The grading of pneumonitis was defined in accordance with ASCO guidelines (Schneider et al. in J Clin Oncol 39(36):4073–4126, 2021. https://doi.org/10.1200/JCO.21.01440 ). Predictive modeling was performed using gradient boosting machine learning technology, XGBoost (Chen in 1(4):1, 2015), to conduct binary classification and model reverse engineering using Shapley statistics (Lundberg and Lee in Adv Neural Inf Process Syst 30, 2017). Results One hundred and seventy patients with ICI pneumonitis were included (median age 67; IQR 59, 75). Median overall survival was 2.3 years (95% CI: 1.8, NR). A higher grade of ICI pneumonitis was associated with inferior survival (HR 5.85, 95% CI: 2.27, 15.09; p  < 0.001). Patients who were rechallenged with immunotherapy had significantly improved hazard of survival compared to patients not rechallenged (HR 0.37, 95% CI: 0.21, 0.68; p  = 0.001). Risk of death from ICI pneumonitis prior to starting immunotherapy was modeled with an area under the curve of the receiver operator characteristic (AUC-ROC) of 0.79 with the most contributory features including peripheral blood lymphocyte count, oxygen dependence, pulmonary function testing, and PD-L1 expression. Conclusion The presentation of ICI pneumonitis is highly variable, and outcomes are dependent on severity, but favor grade 2 disease when patients are rechallenged with immunotherapy. However, using commonly available clinical data, we can accurately identify patients at high risk of death from ICI pneumonitis. Further effort is needed to produce clinical models able to provide clinician decision support when evaluating patients with ICI toxicities and considering ICI rechallenge.

The objectives of this article are to present a case of type II cryoglobulinemic vasculitis, explain why mucosa-associated lymphoid tissue (MALT) lymphoma is an unusual cause of type II cryoglobulins and to discuss the aetiology, epidemiology, pathophysiology and treatment of cryoglobulinemic vasculitis. A 67-year-old woman presented with 4 months of weight loss, intermittent epistaxis and a purpuric skin rash. Prior to presentation, she was found to have an elevated rheumatoid factor. Further investigation revealed an acute kidney injury and elevated type II cryoglobulins suspicious for cryoglobulinemic vasculitis, which was confirmed by kidney biopsy. Additional workup for the weight loss included biopsy of newly found splenomegaly. Pathology revealed MALT lymphoma, a rare cause of type II cryoglobulinemic vasculitis. Successful medical therapy required treating the underlying malignancy with rituximab and high-dose steroids. After initial resolution of symptoms with this regimen, the patient’s vasculitis worsened, which was thought to be secondary to undertreatment of the lymphoma. Bendamustine was added to further treat the lymphoma, after which the patient recovered and was able to discharge without recurrence of symptoms at 6 months.

Nocardiosis is caused by various species of Nocardia and typically occurs as an opportunistic infection. It frequently disseminates, most often involving the lungs, subcutaneous tissues and central nervous system. It has rarely been reported to affect native heart valves. We report the case of a 64-year-old man with disseminated nocardiosis involving the brain, lungs, muscle and tricuspid valve of a transplanted heart. Following antimicrobial therapy, the patient improved clinically and there was no evidence of residual infection on follow-up imaging. This case highlights the presentation of nocardiosis, current therapeutic guidelines and the question of prophylaxis against Nocardia in immunocompromised patients.

BackgroundImmune checkpoint inhibitor therapy-related (ICI) pneumonitis poses a significant challenge in patients with cancer. There is paucity of data on patient characteristics and outcomes in this population.MethodsThis is a retrospective study of patients diagnosed with ICI pneumonitis at the Mayo Clinic from 2014 to 2022. A list of patients was compiled using Mayo Clinic’s informatics tool, Advanced Text Explorer, with keywords ‘pneumonitis’ and ‘immunotherapy’ (n=848). All cases were independently reviewed by our pulmonology specialist (A.E.) to confirm the appropriate diagnosis which yielded 170 patients. Excluded patients were those with alternative diagnoses. The grading of pneumonitis was defined in accordance with ASCO guidelines.1 Results170 patients with ICI pneumonitis were included (median age 67; range 25–87) and 48% were male (table 1). The severity of ICI pneumonitis was as follows: grade 1 (n=17, 10%), grade 2 (n=85, 50%), grade 3 (n=53, 31%), and grade 4 (n=15, 9%). The median time from initiation of immunotherapy to development of ICI pneumonitis was 4 months (interquartile range 2 - 9.5). 47 (28%) had another ICI toxicity. Median overall survival (OS) was 2.5 years (95%, CI: 1.8-NR). A higher grade of ICI pneumonitis was associated with inferior outcomes (HR 2.0, 95% CI 1.5–2.8, p<0.001), while PD-L1 expression, age at diagnosis of ICI pneumonitis, and smoking status were not associated with inferior outcomes (p > 0.05). 51 (30%) were rechallenged with immunotherapy after an initial episode of ICI pneumonitis. Among those rechallenged, 23 (45%) developed recurrent pneumonitis (78% grade 2, 22% grade 3–4). Patients rechallenged, had significantly improved outcomes compared to patients who were not rechallenged (HR 0.37, 95% CI 0.2 – 0.7, p=0.001). On subset analysis, we identified the majority of the benefit was from patients with grade 2 severity (figure 1). The median OS based on grade of ICI pneumonitis was 28 months (95% CI: 28-NR) for grade 1, 52 months (95% CI: 38-NR) for grade 2, 13 months (95% CI: 7.6-NR) for grade 3, and 4 months (95% CI: 2.2-NR) for grade 4.ConclusionsPatients with grade 1–2 ICI pneumonitis do significantly better than patients with grade 3–4 ICI pneumonitis. Rechallenge may result in a high frequency of recurrent pneumonitis (45%); however, patients who were rechallenged had significantly improved outcomes compared to patients who were not rechallenged. Further studies should be done to validate whether all patients with ≤ grade 2 pneumonitis should undergo a rechallenge.Ethics ApprovalThis study was approved by the Mayo Clinic IRB.ReferenceSchneider BJ, et. al. Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update. J Clin Oncol. 2021 Dec 20;39(36):4073–4126. doi: 10.1200/JCO.21.01440. Epub 2021 Nov 1. Erratum in: J Clin Oncol. 2022 Jan 20;40(3):315. PMID: 34724392.Abstract 1265 Table 1Patient CharacteristicsAbstract 1265 Figure 1Swimmers plot comparing grade 1–4 immune checkpoint inhibitor therapy-related pneumonitis with and without rechallenge of immunotherapy

The optimal treatment sequence in non-small cell lung cancer harboring class I BRAF mutations and atypical BRAF variants remains unclear. To better characterize therapeutic strategy, we retrospectively evaluated a multi-institutional cohort of BRAF -mutant NSCLC patients ( n  = 97) and an independent clinico-genomic database ( n  = 342), performed structural modeling, and conducted chemical screens of BRAF -mutant cell lines. Patients with class I BRAF mutation treated with BRAF–MEK inhibitors at any line of therapy had significantly greater median overall survival compared to those who did not receive BRAF–MEK inhibitors (40 vs 10 months, Log-rank p  = 0.043). There, however, was no significant survival difference between patients treated with immune checkpoint inhibitors versus those not treated. Tumors with class II or III BRAF variants were significantly more likely to harbor concurrent MAPK pathway alterations relative to class I (Chi-Square p  < 10 −4 ). Cell line studies identified genetic dependency on BRAF in class II cell lines without sensitivity to BRAF inhibitors, and dependency on EGFR in class III cell lines.

Abstract Aims The objective of this study was to assess the effect of HER2-directed therapy (HER2-Tx) on peripheral vasoreactivity and its correlation with cardiac function changes and the additive effects of anthracycline/cyclophosphamide (AC) therapy and baseline cardiovascular risk. Methods and results Single-centre, prospective cohort study of women with newly diagnosed stage 1–3 HER2-positive breast cancer undergoing HER2-Tx +/− AC. All participants underwent baseline and 3-monthly evaluations with Endo-Peripheral Arterial Tonometry (Endo-PAT), vascular biomarkers [C-type natriuretic peptide (CNP) and neuregulin-1 beta (NRG-1β)], and echocardiography. Cardiotoxicity was defined as a decrease in the left ventricular ejection fraction (LVEF) of >10% to a value <53%. Of the 47 patients enrolled, 20 (43%) received AC in addition to HER2-Tx. Deterioration of reactive hyperaemia index (RHI) on Endo-PAT by ≥20% was more common in patients receiving HER-Tx plus AC than HER2-Tx alone (65% vs. 22%; P = 0.003). A decrease in CNP and log NRG-1β levels by 1 standard deviation did not differ significantly between the AC and non-AC groups (CNP: 20.0% vs. 7.4%; P = 0.20 and NRG-1β: 15% vs. 11%; P = 0.69) nor did GLS (35% vs. 37%; P = 0.89). Patients treated with AC had a significantly lower 3D LVEF than non-AC recipients as early as 3 months after exposure (mean 59.3% (SD 3) vs. 63.8% (SD 4); P = 0.02). Reactive hyperaemia index and GLS were the only parameters correlating with LVEF change. Conclusion Combination therapy with AC, but not HER2-Tx alone, leads to a decline in peripheral vascular and cardiac function. Larger studies will need to define more precisely the causal correlation between vascular and cardiac function changes in cancer patients. Graphical Abstract Graphical abstract

BackgroundImmune checkpoint inhibitor therapy-related (ICI) pneumonitis is a potential serious complication for patients with cancer. We have previously shown that modeling can be used to predict the risk of death from ICI pneumonitis.1 Further predictive modeling to risk stratify patients with ICI pneumonitis is needed.MethodsA database of cancer patients diagnosed with ICI pneumonitis seen at Mayo Clinic from 2014–2022 was utilized for exploratory data analysis. Within this cohort, we isolated clinical variables from before ICI pneumonitis diagnoses to determine if we could model the propensity for developing low grade (1–2) versus high grade (3–4) pneumonitis at the time of immunotherapy initiation. Those clinical variables included age, sex, weight, common laboratory values, immunotherapy treatment, cancer type, and baseline pulmonary function tests (PFTs). We used a gradient boosting machine learning technology, Xgboost2 to conduct binary classification. Given the relatively small cohort size for AI analysis (n = 170), modeling was conducted with 1,000-fold bootstrapping to minimize dependence on data arrangement and k-fold cross validation to minimize model overfitting. Model reverse engineering was done with Shapley statistics3 to determine which features had the largest contribution. Once identified, only those highly weighted features were used for logistic regression analysis providing more reproducible predictions by decreasing model variance.Results170 patients with ICI pneumonitis were included (median age 67; range 25–87). The severity of ICI pneumonitis was as follows: grade 1 (n=16, 9%), grade 2 (n=86, 51%), grade 3 (n=57, 34%), and grade 4 (n=11, 6%). 47 patients (28%) had another ICI toxicity. Median overall survival was 2.5 years (95%, CI: 1.8-NR). A higher grade of ICI pneumonitis was associated with inferior survival (HR 2.0, 95% CI 1.5–2.8, p<0.001). Our approach resulted in a low versus high grade pneumonitis binary classification model with an area under the curve of the receiver operator characteristic of 0.74 (figure 1). The features most predictive of whether a patient would develop high grade pneumonitis were baseline DLCO obtained from PFTs, hemoglobin concentration, monocyte count, total white blood cell count, and immunotherapy choice.ConclusionsWe demonstrate that commonly available clinical data can be used to risk stratify patients to low versus high grade ICI pneumonitis. Further effort is needed to produce clinical models able to provide clinician decision support when evaluating patients with ICI toxicities. Investigation is underway which uses a large cancer data set to independently validate this model and to predict who will develop immunotherapy toxicities.ReferencesHazim A, et al. Utilizing predictive modeling to identify patients at high risk of death from immune checkpoint inhibitor therapy-related pneumonitis. Journal of Clinical Oncology. 2023;41(16_suppl):1552–1552.Chen T, He T, Benesty M, Khotilovich V, Tang Y, Cho H, Chen K, Mitchell R, Cano I, Zhou T. Xgboost: extreme gradient boosting. R package version 0.4–2 , 2015;1(4):1–4.Lundberg SM, Lee SI. A unified approach to interpreting model predictions. Advances in neural information processing systems , 2017; 30 .Ethics ApprovalThis study was approved by the Mayo Clinic IRB.Abstract 1266 Figure 1Area under the curve of the receiver operator characteristic (AUC-ROC) from modeling propensity of low grade versus high grade immune checkpoint inhibitor therapy-related pneumonitis

NT-proBNP, soluble ST2 (sST2), and galectin-3 are biomarkers of cardiac dysfunction that have been proposed as identifiers of patients experiencing asymptomatic cardiac dysfunction after anthracycline-based chemotherapy. This study aimed to compare the proportion of breast cancer (BC) survivors with elevated serum levels of these three putative biomarkers by prior receipt of anthracycline (yes vs. no). Five-hundred-eighty survivors of BC who had received anthracycline-based chemotherapy were matched by age and time between diagnosis and serum storage to 580 who had not. Cardiac biomarker levels were analyzed using immunoassays. Analyses were carried out using linear and logistic regression models. Anthracycline recipients had higher values of NT-proBNP than non-recipients (mean 116.0 ng/L vs. 97.0 ng/L, respectively; p < 0.001). Values for ST2 and galectin-3 did not significantly differ by receipt of anthracycline. After further adjustment for age at breast cancer diagnosis, ethnicity, and receipt of trastuzumab, associations between receipt of anthracycline and higher NT-proBNP persisted (p < 0.001), showing that NT-proBNP may be a biomarker of cardiovascular toxicity after receipt of anthracycline-based chemotherapy. Further research to assess the clinical utility of NT-proBNP testing after receipt of anthracycline is recommended. sST2 and galectin-3 do not appear to differentiate between anthracycline recipients and non-recipients amongst breast cancer survivors.

The dynamics of PD-L1 expression are poorly understood over the development of lung adenocarcinomas from pre-invasive lesions to fully invasive carcinomas. Given the importance of PD-L1 expression for the selection of patients to receive immunotherapy in the metastatic setting and possibly in the neoadjuvant setting, we sought to evaluate the agreement of PD-L1 expression in invasive and lepidic components of resected tumor specimens. We stained 86 adenocarcinomas for PD-L1 using the SP263 clone. We assessed the agreement of PD-L1 expression by tumor cells and immune cells between lepidic and invasive components. When both lepidic and invasive components were considered, PD-L1 positive immune cells and tumor cells were observed in 50 (58.1%) and 18 (20.9%) samples, respectively, using a ≥ 1% PD-L1 expression cutoff. Using a ≥ 1% cutoff for PD-L1 expression, positively stained tumor cells were observed in 11 (13%) lepidic and 15 (17%) invasive patterns, with agreement in 76 (88%) specimens and disagreement in 10 (12%) specimens (ĸ = 0.549). At ≥ 1% PD-L1 expression cutoff, PD-L1 positive immune cells were observed in 31 (35%) lepidic and 32 (37%) invasive patterns with an agreement of PD-L1 expression in 49 (57%) specimens and disagreement in 37 (43%) specimens (ĸ = 0.073). In our study of early stage adenocarcinomas of the lung, there was poor agreement in PD-L1 expression between paired invasive and lepidic components of tumors. Our data suggest that the non-invasive tumor components may not be as immunostimulatory as the invasive components, resulting in less adaptive expression of PD-L1.