Programmed cell death protein-1 (PD-1) and programmed cell death ligand-1 (PD-L1) checkpoint blockade immunotherapy elicits durable antitumor effects in multiple cancers, yet not all patients ...respond. We report the evaluation of >300 patient samples across 22 tumor types from four KEYNOTE clinical trials. Tumor mutational burden (TMB) and a T cell-inflamed gene expression profile (GEP) exhibited joint predictive utility in identifying responders and nonresponders to the PD-1 antibody pembrolizumab. TMB and GEP were independently predictive of response and demonstrated low correlation, suggesting that they capture distinct features of neoantigenicity and T cell activation. Analysis of The Cancer Genome Atlas database showed TMB and GEP to have a low correlation, and analysis by joint stratification revealed biomarker-defined patterns of targetable-resistance biology. These biomarkers may have utility in clinical trial design by guiding rational selection of anti-PD-1 monotherapy and combination immunotherapy regimens.
Pediatric and adult congenital heart disease (ACHD) patients encounter physical and emotional barriers. Cardiac implantable electronic devices (CIEDs), including pacemakers and implantable cardiac ...defibrillators (ICD) often compound these issues. Patient fear associated with damaging the CIED system can lead to avoidance of physical activity and reduced quality of life (QOL). CIED personal protective equipment (PPE) is a potential treatment for decreasing this fear. We sought to determine the effects of CIED PPE use in the pediatric and ACHD population. Patients 5 years or older with a CIED at a single pediatric and ACHD heart rhythm center received a CIED protector and customized athletic shirt. QOL was assessed using the PedsQL TM 4.0 SF15 prior to and after 6–12 months. Of the 77 patients enrolled, 26 completed repeat assessment. The mean age at enrollment was 15.6 years (range 5–36) with a mean device age of 2.2 years (< 1–10 years). Pacemakers were present in 77% and 23% had ICDs. The PPE was used in 92% with no PPE malfunction. Fear associated with physical activity was reduced,
z
= − 4,
p
< 0.001, with a large effect size (
r
= 0.55). There was a trend toward increased physical activity. Total QOL scores improved,
z
= − 2.771,
P
< 0.05, with a medium effect size (
r
= 0.4). This first study of CIED PPE in children shows that providing CIED PPE to pediatric and ACHD patients may decrease their fear of damaging their device system, increasing physical activity levels, and improving quality of life.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Abstract
Aims
Calmodulinopathy due to mutations in any of the three CALM genes (CALM1–3) causes life-threatening arrhythmia syndromes, especially in young individuals. The International ...Calmodulinopathy Registry (ICalmR) aims to define and link the increasing complexity of the clinical presentation to the underlying molecular mechanisms.
Methods and results
The ICalmR is an international, collaborative, observational study, assembling and analysing clinical and genetic data on CALM-positive patients. The ICalmR has enrolled 140 subjects (median age 10.8 years interquartile range 5–19), 97 index cases and 43 family members. CALM-LQTS and CALM-CPVT are the prevalent phenotypes. Primary neurological manifestations, unrelated to post-anoxic sequelae, manifested in 20 patients. Calmodulinopathy remains associated with a high arrhythmic event rate (symptomatic patients, n = 103, 74%). However, compared with the original 2019 cohort, there was a reduced frequency and severity of all cardiac events (61% vs. 85%; P = .001) and sudden death (9% vs. 27%; P = .008). Data on therapy do not allow definitive recommendations. Cardiac structural abnormalities, either cardiomyopathy or congenital heart defects, are present in 30% of patients, mainly CALM-LQTS, and lethal cases of heart failure have occurred. The number of familial cases and of families with strikingly different phenotypes is increasing.
Conclusion
Calmodulinopathy has pleiotropic presentations, from channelopathy to syndromic forms. Clinical severity ranges from the early onset of life-threatening arrhythmias to the absence of symptoms, and the percentage of milder and familial forms is increasing. There are no hard data to guide therapy, and current management includes pharmacological and surgical antiadrenergic interventions with sodium channel blockers often accompanied by an implantable cardioverter–defibrillator.
Structured Graphical Abstract
Structured Graphical Abstract
Number and percentages of patients with CALM variants and LQTS, CPVT, LQTS/CPVT overlap, IVF, UD, and SCD are reported in the upper left part of the graphical abstract together with two examples of LQTS and CPVT electrocardiograms. In the upper right part, it is shown a graphical representation of the reduction of all cardiac events and SCD between the original cohort (up to 2019) and the cases enrolled between 2019 and 2023. In the lower part, it is reported the number or percentage of CALM patients with cardiomyopathies, congenital heart defects, and neurological features. CALM, calmodulin; LQTS, long QT syndrome; CPVT, catecholaminergic polymorphic ventricular tachycardia; ICD, implantable cardioverter–defibrillator; IVF, idiopathic ventricular fibrillation; UD, uncertain diagnosis; SCD, sudden cardiac death.
The NKX2.5 gene is an important cardiac developmental transcription factor, and variants in this gene are most commonly associated with CHD. However, there is an increased need to recognise ...associations with conduction disease and potentially dangerous ventricular arrhythmias. There is an increased risk of arrhythmia and sudden cardiac death in patients with NKX2.5 variants, an association with relatively less attention in the literature.
We created a family pedigree and reconstructed familial relationships involving numerous relatives with CHD, conduction disease, and ventricular non-compaction following the sudden death of one family member. Two informative but distantly related family members had genetic testing to determine the cause of arrhythmias via arrhythmia/cardiomyopathy gene testing, and we identified obligate genetic-positive relatives based on family relationships and Mendelian inheritance pattern.
We identified a novel pathogenic variant in the NKX2.5 gene (c.437C > A; p. Ser146*), and segregation analysis allowed us to link family cardiac phenotypes including CHD, conduction disease, left ventricular non-compaction, and ventricular arrhythmias/sudden cardiac death.
We report a novel NKX2.5 gene variant linking a spectrum of familial heart disease, and we also encourage recognition of the association between NKX2.5 gene and potentially dangerous ventricular arrhythmias, which will inform clinical risk stratification, screening, and management.
Purpose: Molecular classification of breast cancer has been proposed based on gene expression profiles of human tumors. Luminal, basal-like,
normal-like, and erbB2+ subgroups were identified and were ...shown to have different prognoses. The goal of this research was
to determine if these different molecular subtypes of breast cancer also respond differently to preoperative chemotherapy.
Experimental Design: Fine needle aspirations of 82 breast cancers were obtained before starting preoperative paclitaxel followed by 5-fluorouracil,
doxorubicin, and cyclophosphamide chemotherapy. Gene expression profiling was done with Affymetrix U133A microarrays and the
previously reported “breast intrinsic” gene set was used for hierarchical clustering and multidimensional scaling to assign
molecular class.
Results: The basal-like and erbB2+ subgroups were associated with the highest rates of pathologic complete response (CR), 45% 95%
confidence interval (95% CI), 24-68 and 45% (95% CI, 23-68), respectively, whereas the luminal tumors had a pathologic CR
rate of 6% (95% CI, 1-21). No pathologic CR was observed among the normal-like cancers (95% CI, 0-31). Molecular class was
not independent of conventional cliniocopathologic predictors of response such as estrogen receptor status and nuclear grade.
None of the 61 genes associated with pathologic CR in the basal-like group were associated with pathologic CR in the erbB2+
group, suggesting that the molecular mechanisms of chemotherapy sensitivity may vary between these two estrogen receptor–negative
subtypes.
Conclusions: The basal-like and erbB2+ subtypes of breast cancer are more sensitive to paclitaxel- and doxorubicin-containing preoperative
chemotherapy than the luminal and normal-like cancers.
Prevalence of tumor PD-L1 expression in extensive-stage small-cell lung cancer (ES-SCLC) is variable, and data on PD-L2 expression are limited. The prognostic values of these biomarkers are not well ...understood. The current study was conducted to address these data gaps.
A retrospective cohort study of Danish patients with histologically confirmed ES-SCLC and evaluable tumor samples who were receiving usual care before the introduction of immunotherapy was conducted. Protein expression of PD-L1 and PD-L2 was determined by immunohistochemistry (IHC) using the PD-L1 IHC 22C3 pharmDx assay and a PD-L2 IHC assay using a propriety mouse monoclonal antibody. A combined positive score (CPS) of ≥1 was used to define biomarker positivity. Kaplan-Meier plots and Cox proportional hazard models were employed to assess the relationship between PD-L1 and PD-L2 protein expression and OS.
Among 80 patients, 31% (n=25) and 36% (n=29) had disease positive for PD-L1 and PD-L2, respectively. Overall, 85% (n=68) of patients had concordant PD-L1/PD-L2 status; 26% (n=21) had double positive disease (both PD-L1 and PD-L2 CPS ≥1) and 59% (n=47) had double negative disease (both PD-L1 and PD-L2 CPS <1). PD-L1 and PD-L2 positivity were each associated with longer OS (unadjusted hazard ratios HRs, 0.35 95% CI, 0.21-0.61 and 0.50 95% CI, 0.31-0.82); the associations persisted after adjustment for several known prognostic factors (HRs, 0.41 95% CI, 0.22-0.75 and 0.44 95% CI, 0.25-0.79 for PD-L1 and PD-L2 positivity, respectively). When evaluating OS in patients with double positive disease, unadjusted and adjusted HRs for double positive compared with double negative were similar to those with only PD-L1 or PD-L2 positivity (unadjusted HR, 0.36 95% CI, 0.20-0.64; adjusted HR, 0.36 0.18-0.73).
PD-L1 and PD-L2 positivity were observed in approximately one-third of assessed ES-SCLC tumor samples and were highly congruent. Patients with PD-L1 and PD-L2 positivity, alone or combined, were associated with longer OS, independent of other prognostic factors.
Purpose: Hepatocellular carcinoma (HCC) is the fifth most common primary neoplasm; surgery is the only curative option but 5-year
survival rates are only 25% to 50%. Vascular endothelial growth ...factor (VEGF) and fibroblast growth factor (FGF) are known
to be involved in growth and neovascularization of HCC. Therefore, agents that target these pathways may be effective in the
treatment of HCC. The aim of this study was to determine the antineoplastic activity of brivanib alaninate, a dual inhibitor
of VEGF receptor (VEGFR) and FGF receptor (FGFR) signaling pathways.
Experimental Design: Six different s.c. patient-derived HCC xenografts were implanted into mice. Tumor growth was evaluated in mice treated with
brivanib compared with control. The effects of brivanib on apoptosis and cell proliferation were evaluated by immunohistochemistry.
The SK-HEP1 and HepG2 cells were used to investigate the effects of brivanib on the VEGFR-2 and FGFR-1 signaling pathways
in vitro . Western blotting was used to determine changes in proteins in these xenografts and cell lines.
Results: Brivanib significantly suppressed tumor growth in five of six xenograft lines. Furthermore, brivanib–induced growth inhibition
was associated with a decrease in phosphorylated VEGFR-2 at Tyr 1054/1059 , increased apoptosis, reduced microvessel density, inhibition of cell proliferation, and down-regulation of cell cycle regulators.
The levels of FGFR-1 and FGFR-2 expression in these xenograft lines were positively correlated with its sensitivity to brivanib-induced
growth inhibition. In VEGF-stimulated and basic FGF stimulated SK-HEP1 cells, brivanib significantly inhibited VEGFR-2, FGFR-1,
extracellular signal-regulated kinase 1/2, and Akt phosphorylation.
Conclusion: This study provides a strong rationale for clinical investigation of brivanib in patients with HCC.
BackgroundTo characterize genomic determinants of response to pembrolizumab in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) in the KEYNOTE-012 study.MethodsAssociations ...between biomarkers (tumor mutational burden (TMB), neoantigen load (NL), 18-gene T-cell-inflamed gene expression profile (TcellinfGEP), and PD-L1 combined positive score (CPS)) and clinical outcomes with pembrolizumab were assessed in patients with R/M HNSCC (n=192). Tumor human papillomavirus (HPV) status was also evaluated with the use of p16 immunohistochemistry and whole exome sequencing (WES; HPV+, mapping >20 HPV reads) in pretreatment tumor samples (n=106).ResultsTMB, clonality-weighted TMB, and TcellinfGEP were significantly associated with objective response (p=0.0276, p=0.0201, and p=0.006, respectively), and a positive trend was observed between NL and PD-L1 CPS and clinical response (p=0.0550 and p=0.0682, respectively). No correlation was observed between TMB and TcellinfGEP (Spearman ρ=–0.026) or TMB and PD-L1 (Spearman ρ=0.009); a correlation was observed between TcellinfGEP and PD-L1 (Spearman ρ=0.511). HPV status by WES and p16 immunohistochemistry showed concordance (84% ҡ=0.573) among patients whose HPV results were available using both methods.ConclusionsTMB and inflammatory biomarkers (TcellinfGEP and PD-L1) may represent distinct and complementary biomarkers predicting response to anti-programmed death 1 therapies in HNSCC; further study of these relationships in randomized clinical trials is needed.Trial registration numberNCT01848834.
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