Cell-cycle inhibition and immune microenvironment in breast cancer treated with ribociclib and letrozole or chemotherapy.

In this study, we performed genomic analyses of cell cycle and tumor microenvironment changes during and after ribociclib and letrozole or chemotherapy in the CORALLEEN trial. 106 women with untreated PAM50-defined Luminal B early breast cancers were randomly assigned to receive neoadjuvant ribociclib and letrozole or standard-of-care chemotherapy. Ki67 immunohistochemistry, tumor-infiltrating lymphocytes quantification, and RNA sequencing were obtained from tissue biopsies pre-treatment, on day 14 of treatment, and tumor specimens from surgical resection. Results showed that at surgery, Ki67 and the PAM50 proliferation scores were lower after ribociclib compared to chemotherapy. However, consistent reactivation of tumor cell proliferation from day 14 to surgery was only observed in the ribociclib arm. In tumors with complete cell cycle arrest (CCCA) at surgery, PAM50 proliferation scores were lower in the ribociclib arm compared to chemotherapy (p < 0.001), whereas the opposite was observed with tumor cellularity (p = 0.002). Gene expression signatures (GES) associated with antigen-presenting cells (APCs) and innate immune system activity showed increased expression post-chemotherapy but decreased expression post-ribociclib. Interferon-associated GES had decreased expression with CCCA and increased expression with non-CCCA. Our findings suggest that while both treatment strategies decreased proliferation, the depth and the patterns over time differed by treatment arm. Immunologically, ribociclib was associated with downregulated GES associated with APCs and the innate immune system in Luminal B tumors, contrary to existing preclinical data. Further studies are needed to understand the effect of CDK4/6 inhibition on the tumor cells and microenvironment, an effect which may vary according to tumor subtypes.

Tumor Intrinsic Subtypes and Gene Expression Signatures in Early-Stage ERBB2/HER2-Positive Breast Cancer: A Pooled Analysis of CALGB 40601, NeoALTTO, and NSABP B-41 Trials.

Importance: Biologic features may affect pathologic complete response (pCR) and event-free survival (EFS) after neoadjuvant chemotherapy plus ERBB2/HER2 blockade in ERBB2/HER2-positive early breast cancer (EBC). Objective: To define the quantitative association between pCR and EFS by intrinsic subtype and by other gene expression signatures in a pooled analysis of 3 phase 3 trials: CALGB 40601, NeoALTTO, and NSABP B-41. Design, Setting, and Participants: In this retrospective pooled analysis, 1289 patients with EBC received chemotherapy plus either trastuzumab, lapatinib, or the combination, with a combined median follow-up of 5.5 years. Gene expression profiling by RNA sequencing was obtained from 758 samples, and intrinsic subtypes and 618 gene expression signatures were calculated. Data analyses were performed from June 1, 2020, to January 1, 2023. Main Outcomes and Measures: The association of clinical variables and gene expression biomarkers with pCR and EFS were studied by logistic regression and Cox analyses. Results: In the pooled analysis, of 758 women, median age was 49 years, 12% were Asian, 6% Black, and 75% were White. Overall, pCR results were associated with EFS in the ERBB2-enriched (hazard ratio [HR], 0.45; 95% CI, 0.29-0.70; P < .001) and basal-like (HR, 0.19; 95% CI, 0.04-0.86; P = .03) subtypes but not in luminal A or B tumors. Dual trastuzumab plus lapatinib blockade over trastuzumab alone had a trend toward EFS benefit in the intention-to-treat population; however, in the ERBB2-enriched subtype there was a significant and independent EFS benefit of trastuzumab plus lapatinib vs trastuzumab alone (HR, 0.47; 95% CI, 0.27-0.83; P = .009). Overall, 275 of 618 gene expression signatures (44.5%) were significantly associated with pCR and 9 of 618 (1.5%) with EFS. The ERBB2/HER2 amplicon and multiple immune signatures were significantly associated with pCR. Luminal-related signatures were associated with lower pCR rates but better EFS, especially among patients with residual disease and independent of hormone receptor status. There was significant adjusted HR for pCR ranging from 0.45 to 0.81 (higher pCR) and 1.21-1.94 (lower pCR rate); significant adjusted HR for EFS ranged from 0.71 to 0.94. Conclusions and relevance: In patients with ERBB2/HER2-positive EBC, the association between pCR and EFS differed by tumor intrinsic subtype, and the benefit of dual ERBB2/HER2 blockade was limited to ERBB2-enriched tumors. Immune-activated signatures were concordantly associated with higher pCR rates and better EFS, whereas luminal signatures were associated with lower pCR rates.

Is there a preferred platinum and fluoropyrimidine regimen for advanced HER2-negative esophagogastric adenocarcinoma? Insights from 1293 patients in AGAMENON-SEOM registry.

BACKGROUND: The optimal chemotherapy backbone for HER2-negative advanced esophagogastric cancer, either in combination with targeted therapies or as a comparator in clinical trials, is uncertain. The subtle yet crucial differences in platinum-based regimens' safety and synergy with combination treatments need consideration. METHODS: We analyzed cases from the AGAMENON-SEOM Spanish registry of HER2-negative advanced esophagogastric adenocarcinoma treated with platinum and fluoropyrimidine from 2008 to 2021. This study focused exclusively on patients receiving one of the four regimens: FOLFOX (5-FU and oxaliplatin), CAPOX (capecitabine and oxaliplatin), CP (capecitabine and cisplatin) and FP (5-FU and cisplatin). The aim was to determine the most effective and tolerable platinum and fluoropyrimidine-based chemotherapy regimen and to identify any prognostic factors. RESULTS: Among 1293 patients, 36% received either FOLFOX (n = 468) or CAPOX (n = 466), 20% CP (n = 252), and 8% FP (n = 107). FOLFOX significantly increased PFS (progression free survival) compared to CP, with a hazard ratio of 0.73 (95% CI 0.58-0.92, p = 0.009). The duration of treatment was similar across all groups. Survival outcomes among regimens were similar, but analysis revealed worse ECOG-PS (Eastern Cooperative Oncology Group-Performance Status), > 2 metastatic sites, bone metastases, hypoalbuminemia, higher NLR (neutrophil-to-lymphocyte ratio), and CP regimen as predictors of poor PFS. Fatigue was common in all treatments, with the highest incidence in FOLFOX (77%), followed by FP (72%), CAPOX (68%), and CP (60%). Other notable toxicities included neuropathy (FOLFOX 69%, CAPOX 62%), neutropenia (FOLFOX 52%, FP 55%), hand-foot syndrome in CP (46%), and thromboembolic events (FP 12%, CP 11%). CONCLUSIONS: FOLFOX shown better PFS than CP. Adverse effects varied: neuropathy was more common with oxaliplatin, while thromboembolism was more frequent with cisplatin.

Endocrine-Sensitive Disease Rate in Postmenopausal Patients With Estrogen Receptor-Rich/ERBB2-Negative Breast Cancer Receiving Neoadjuvant Anastrozole, Fulvestrant, or Their Combination: A Phase 3 Randomized Clinical Trial.

Importance: Adding fulvestrant to anastrozole (A+F) improved survival in postmenopausal women with advanced estrogen receptor (ER)-positive/ERBB2 (formerly HER2)-negative breast cancer. However, the combination has not been tested in early-stage disease. Objective: To determine whether neoadjuvant fulvestrant or A+F increases the rate of pathologic complete response or ypT1-2N0/N1mic/Ki67 2.7% or less residual disease (referred to as endocrine-sensitive disease) over anastrozole alone. Design, Setting, and Participants: A phase 3 randomized clinical trial assessing differences in clinical and correlative outcomes between each of the fulvestrant-containing arms and the anastrozole arm. Postmenopausal women with clinical stage II to III, ER-rich (Allred score 6-8 or >66%)/ERBB2-negative breast cancer were included. All analyses were based on data frozen on March 2, 2023. Interventions: Patients received anastrozole, fulvestrant, or a combination for 6 months preoperatively. Tumor Ki67 was assessed at week 4 and optionally at week 12, and if greater than 10% at either time point, the patient switched to neoadjuvant chemotherapy or immediate surgery. Main Outcomes and Measures: The primary outcome was the endocrine-sensitive disease rate (ESDR). A secondary outcome was the percentage change in Ki67 after 4 weeks of neoadjuvant endocrine therapy (NET) (week 4 Ki67 suppression). Results: Between February 2014 and November 2018, 1362 female patients (mean [SD] age, 65.0 [8.2] years) were enrolled. Among the 1298 evaluable patients, ESDRs were 18.7% (95% CI, 15.1%-22.7%), 22.8% (95% CI, 18.9%-27.1%), and 20.5% (95% CI, 16.8%-24.6%) with anastrozole, fulvestrant, and A+F, respectively. Compared to anastrozole, neither fulvestrant-containing regimen significantly improved ESDR or week 4 Ki67 suppression. The rate of week 4 or week 12 Ki67 greater than 10% was 25.1%, 24.2%, and 15.7% with anastrozole, fulvestrant, and A+F, respectively. Pathologic complete response/residual cancer burden class I occurred in 8 of 167 patients and 17 of 167 patients, respectively (15.0%; 95% CI, 9.9%-21.3%), after switching to neoadjuvant chemotherapy due to week 4 or week 12 Ki67 greater than 10%. PAM50 subtyping derived from RNA sequencing of baseline biopsies available for 753 patients (58%) identified 394 luminal A, 304 luminal B, and 55 nonluminal tumors. A+F led to a greater week 4 Ki67 suppression than anastrozole alone in luminal B tumors (median [IQR], -90.4% [-95.2 to -81.9%] vs -76.7% [-89.0 to -55.6%]; P < .001), but not luminal A tumors. Thirty-six nonluminal tumors (65.5%) had a week 4 or week 12 Ki67 greater than 10%. Conclusions and Relevance: In this randomized clinical trial, neither fulvestrant nor A+F significantly improved the 6-month ESDR over anastrozole in ER-rich/ERBB2-negative breast cancer. Aromatase inhibition remains the standard-of-care NET. Differential NET response by PAM50 subtype in exploratory analyses warrants further investigation. Trial Registration: ClinicalTrials.gov Identifier: NCT01953588.

Gene-Expression Profiling to Decipher Breast Cancer Inter- and Intratumor Heterogeneity.

Breast cancer is heterogeneous and differs substantially across different tumors (intertumor heterogeneity) and even within an individual tumor (intratumor heterogeneity). Gene-expression profiling has considerably impacted our understanding of breast cancer biology. Four main "intrinsic subtypes" of breast cancer (i.e., luminal A, luminal B, HER2-enriched, and basal-like) have been consistently identified by gene expression, showing significant prognostic and predictive value in multiple clinical scenarios. Thanks to the molecular profiling of breast tumors, breast cancer is a paradigm of treatment personalization. Several standardized prognostic gene-expression assays are presently being used in the clinic to guide treatment decisions. Moreover, the development of single-cell-level resolution molecular profiling has allowed us to appreciate that breast cancer is also heterogeneous within a single tumor. There is an evident functional heterogeneity within the neoplastic and tumor microenvironment cells. Finally, emerging insights from these studies suggest a substantial cellular organization of neoplastic and tumor microenvironment cells, thus defining breast cancer ecosystems and highlighting the importance of spatial localizations.

Association of PIK3CA Mutation With Pathologic Complete Response and Outcome by Hormone Receptor Status and Intrinsic Subtype in Early-Stage ERBB2/HER2-Positive Breast Cancer.

Importance: PIK3CA mutations may be associated with outcomes of patients with ERBB2/HER2-positive early breast cancer (EBC). Objectives: To assess if PIK3CA mutations among patients with ERBB2/HER2-positive EBC are associated with treatment response and outcome, and if these associations vary by hormone receptor (HR) status or intrinsic molecular subtype (IMS). Design, Setting, and Participants: This cohort study derived data on 184 patients from the phase 3 neoadjuvant Cancer and Leukemia Group B (CALGB) 40601 trial that enrolled patients with ERBB2/HER2-positive EBC in North America between January 1, 2008, and December 31, 2012. Participants received neoadjuvant paclitaxel with trastuzumab, lapatinib, or both. Statistical analysis was performed from March 23, 2022, to March 9, 2023. Exposures: Gene expression profiling by RNA sequencing with Prediction Analysis of Microarray 50-determined IMS and PIK3CA mutations from whole-exome sequencing were obtained from pretreatment biopsies from 184 of 305 trial participants. Main Outcomes and Measures: The primary end point was pathologic complete response (pCR) and the secondary end point of event-free survival (EFS). The association of PIK3CA mutations with pCR and EFS by HR status and IMS was estimated using logistic and Cox proportional hazards regression models. Results: All 184 participants were women, with a median age of 49 years (range 24-75 years). A total of 121 participants (66%) had clinical stage II tumors; 32 (17%) had PIK3CA mutations, most frequently H1047R (38% [12 of 32]) and E545K (22% [7 of 32]). PIK3CA mutations were present in 20 of 102 cases of HR-positive EBC (20%) and 12 of 82 cases HR-negative EBC (15%) and varied by IMS (luminal B, 9 of 25 [36%]; luminal A, 2 of 21 [10%]; and ERBB2/HER2-enriched tumors, 19 of 102 [19%]). Pathologic complete response rates were lower in PIK3CA mutated than PIK3CA wild type in the overall population (34% [11 of 32] vs 49% [74 of 152]; P = .14) and were significantly different among those receiving trastuzumab (30% [7 of 23] vs 54% [63 of 117]; P = .045). At a median follow-up of 9 years, PIK3CA mutations were significantly associated with worse EFS in the overall cohort (hazard ratio, 2.58 [95% CI, 1.24-5.35]; P = .01), which persisted in a multivariable model including pCR, HR status, stage, and IMS (hazard ratio, 2.52 [95% CI, 1.16-5.47]; P = .02). The negative association of PIK3CA mutation was significant in HR-positive (hazard ratio, 3.60 [95% CI, 1.45-8.96]; P = .006) and luminal subtypes (hazard ratio, 4.84 [95% CI, 1.08-21.70]; P = .04), but not in nonluminal and HR-negative tumors. Conclusions and Relevance: In ERBB2/HER2-positive EBC, PIK3CA mutations were associated with lower pCR rates and independently associated with worse long-term EFS. These findings appear to be associated with PIK3CA mutations in HR-positive and luminal EBC.

Immunological and clinicopathological features predict HER2-positive breast cancer prognosis in the neoadjuvant NeoALTTO and CALGB 40601 randomized trials.

The identification of prognostic markers in patients receiving neoadjuvant therapy is crucial for treatment optimization in HER2-positive breast cancer, with the immune microenvironment being a key factor. Here, we investigate the complexity of B and T cell receptor (BCR and TCR) repertoires in the context of two phase III trials, NeoALTTO and CALGB 40601, evaluating neoadjuvant paclitaxel with trastuzumab and/or lapatinib in women with HER2-positive breast cancer. BCR features, particularly the number of reads and clones, evenness and Gini index, are heterogeneous according to hormone receptor status and PAM50 subtypes. Moreover, BCR measures describing clonal expansion, namely evenness and Gini index, are independent prognostic factors. We present a model developed in NeoALTTO and validated in CALGB 40601 that can predict event-free survival (EFS) by integrating hormone receptor and clinical nodal status, breast pathological complete response (pCR), stromal tumor-infiltrating lymphocyte levels (%) and BCR repertoire evenness. A prognostic score derived from the model and including those variables, HER2-EveNT, allows the identification of patients with 5-year EFS > 90%, and, in those not achieving pCR, of a subgroup of immune-enriched tumors with an excellent outcome despite residual disease.

Prognostic and Predictive Value of Immune-Related Gene Expression Signatures vs Tumor-Infiltrating Lymphocytes in Early-Stage ERBB2/HER2-Positive Breast Cancer: A Correlative Analysis of the CALGB 40601 and PAMELA Trials.

Importance: Both tumor-infiltrating lymphocytes (TILs) assessment and immune-related gene expression signatures by RNA profiling predict higher pathologic complete response (pCR) and improved event-free survival (EFS) in patients with early-stage ERBB2/HER2-positive breast cancer. However, whether these 2 measures of immune activation provide similar or additive prognostic value is not known. Objective: To examine the prognostic ability of TILs and immune-related gene expression signatures, alone and in combination, to predict pCR and EFS in patients with early-stage ERBB2/HER2-positive breast cancer treated in 2 clinical trials. Design, Setting, and Participants: In this prognostic study, a correlative analysis was performed on the Cancer and Leukemia Group B (CALGB) 40601 trial and the PAMELA trial. In the CALGB 40601 trial, 305 patients were randomly assigned to weekly paclitaxel with trastuzumab, lapatinib, or both for 16 weeks. The primary end point was pCR, with a secondary end point of EFS. In the PAMELA trial, 151 patients received neoadjuvant treatment with trastuzumab and lapatinib for 18 weeks. The primary end point was the ability of the HER2-enriched subtype to predict pCR. The studies were conducted from October 2013 to November 2015 (PAMELA) and from December 2008 to February 2012 (CALGB 40601). Data analyses were performed from June 1, 2020, to January 1, 2022. Main Outcomes and Measures: Immune-related gene expression profiling by RNA sequencing and TILs were assessed on 230 CALGB 40601 trial pretreatment tumors and 138 PAMELA trial pretreatment tumors. The association of these biomarkers with pCR (CALGB 40601 and PAMELA) and EFS (CALGB 40601) was studied by logistic regression and Cox analyses. Results: The median age of the patients was 50 years (IQR, 42-50 years), and 305 (100%) were women. Of 202 immune signatures tested, 166 (82.2%) were significantly correlated with TILs. In both trials combined, TILs were significantly associated with pCR (odds ratio, 1.01; 95% CI, 1.01-1.02; P = .02). In addition to TILs, 36 immune signatures were significantly associated with higher pCR rates. Seven of these signatures outperformed TILs for predicting pCR, 6 of which were B-cell related. In a multivariable Cox model adjusted for clinicopathologic factors, including PAM50 intrinsic tumor subtype, the immunoglobulin G signature, but not TILs, was independently associated with EFS (immunoglobulin G signature-adjusted hazard ratio, 0.63; 95% CI, 0.42-0.93; P = .02; TIL-adjusted hazard ratio, 1.00; 95% CI, 0.98-1.02; P = .99). Conclusions and Relevance: Results of this study suggest that multiple B-cell-related signatures were more strongly associated with pCR and EFS than TILs, which largely represent T cells. When both TILs and gene expression are available, the prognostic value of immune-related signatures appears to be superior.

[Cardiovascular risk and insulin resistance in childhood leukemia survivors]. / Riesgo cardiovascular y resistencia insulínica en supervivientes de leucemia infantil.

Introduction: Material and methods: a retrospective study of childhood acute leukemia survivors. Survivors with a diagnosis of leukemia before 16 years of age in a tertiary hospital, during the period of 1998-2018, were selected, who had completed their treatment at least two years earlier. We examined: blood adipokine levels and carbohydrate metabolism, body composition by bioimpedance, and carotid status by ultrasound. Somatometric measures were also taken. Results: the registry showed 82 children diagnosed with acute leukemia, aged between 6 and 16 years. Only 22 met the criteria to be included in the study. Results reveled that 32 % of the sample met the criteria for overweight-obesity, and 36 % had high insulin resistance indexes (IR). Leptin levels were higher in women (15.45 vs. 3.25; p = 0.044) and in obese and overweight subjects, as was the leptin/adiponectin ratio, which rises in the presence of IR (2.52 vs. 0.45; p = 0.037). We observed an increase in carotid intima-media thickness in relation to BMI (0.008; CI, -0.002 to 0.013; p = 0.007) without any association with an increase in fat mass in these patients (0.204; CI, -0.043 to 0.451; p = 0.101). Conclusions: childhood leukemia survivors have a high cardiovascular risk, characterized by an increase in IR, not associated with an increase in fat mass. This risk could justify the implementation of preventive actions in these long-lived patients.

Introducción: Material y métodos: estudio retrospectivo de supervivientes de leucemia aguda en edad infantil. Se seleccionaron aquellos supervivientes con diagnóstico de leucemia antes de los 16 años de edad, en un hospital de tercer nivel y durante el período 1998-2018, que hubieran finalizado su tratamiento como mínimo dos años antes. Se analizaron: niveles de adipokinas y metabolismo hidrocarbonado en sangre, composición corporal mediante bioimpedancia y evaluación ecográfica carotídea. Se tomaron además datos somatométricos. Resultados: de 82 niños con diagnóstico de leucemia aguda, con edades comprendidas entre 6 y 16 años, incluidos en el registro, solamente 22 cumplieron los criterios para ser incluídos en el estudio. Entre los resultados destaca que el 32 % de la muestra cumplían los criterios de sobrepeso-obesidad y el 36 % presentaban índices de resistencia insulínica (RI) elevados. Los niveles de leptina fueron más elevados en las mujeres (15,45 vs. 3,25; p = 0,044) y en los individuos con obesidad o sobrepeso, así como la ratio leptina/adiponectina, que se eleva en presencia de RI (2,52 vs. 0,45; p = 0,037). Se observó un incremento del grosor mediointimal carotídeo en relación con el IMC (0,008; IC: -0,002 a 0,013; p = 0,007) sin asociarse a un aumento de masa grasa en estos pacientes (0,204; IC: -0,043 a 0,451; p = 0,101). Conclusiones: los pacientes supervivientes de leucemia en la edad infantil tienen un riesgo cardiovascular elevado, caracterizado por un aumento de la RI no asociado a aumento de la masa grasa. Este riesgo podría justificar la implementación de medidas preventivas en estos pacientes, cada vez más longevos.

Riesgo cardiovascular y resistencia insulínica en supervivientes de leucemia infantil / Cardiovascular risk and insulin resistance in childhood leukemia survivors

Material y métodos: estudio retrospectivo de supervivientes de leucemia aguda en edad infantil. Se seleccionaron aquellos supervivientes con diagnóstico de leucemia antes de los 16 años de edad, en un hospital de tercer nivel y durante el período 1998-2018, que hubieran finalizado su tratamiento como mínimo dos años antes. Se analizaron: niveles de adipokinas y metabolismo hidrocarbonado en sangre, composición corporal mediante bioimpedancia y evaluación ecográfica carotídea. Se tomaron además datos somatométricos. Resultados: de 82 niños con diagnóstico de leucemia aguda, con edades comprendidas entre 6 y 16 años, incluidos en el registro, solamente 22 cumplieron los criterios para ser incluídos en el estudio. Entre los resultados destaca que el 32 % de la muestra cumplían los criterios de sobrepeso-obesidad y el 36 % presentaban índices de resistencia insulínica (RI) elevados. Los niveles de leptina fueron más elevados en las mujeres (15,45 vs. 3,25; p = 0,044) y en los individuos con obesidad o sobrepeso, así como la ratio leptina/adiponectina, que se eleva en presencia de RI (2,52 vs. 0,45; p = 0,037). Se observó un incremento del grosor mediointimal carotídeo en relación con el IMC (0,008; IC: -0,002 a 0,013; p = 0,007) sin asociarse a un aumento de masa grasa en estos pacientes (0,204; IC: -0,043 a 0,451; p = 0,101). Conclusiones: los pacientes supervivientes de leucemia en la edad infantil tienen un riesgo cardiovascular elevado, caracterizado por un aumento de la RI no asociado a aumento de la masa grasa. Este riesgo podría justificar la implementación de medidas preventivas en estos pacientes, cada vez más longevos. (AU)

Material and methods: a retrospective study of childhood acute leukemia survivors. Survivors with a diagnosis of leukemia before 16 years of age in a tertiary hospital, during the period of 1998-2018, were selected, who had completed their treatment at least two years earlier. We examined: blood adipokine levels and carbohydrate metabolism, body composition by bioimpedance, and carotid status by ultrasound. Somatometric measures were also taken. Results: the registry showed 82 children diagnosed with acute leukemia, aged between 6 and 16 years. Only 22 met the criteria to be included in the study. Results reveled that 32 % of the sample met the criteria for overweight-obesity, and 36 % had high insulin resistance indexes (IR). Leptin levels were higher in women (15.45 vs. 3.25; p = 0.044) and in obese and overweight subjects, as was the leptin/adiponectin ratio, which rises in the presence of IR (2.52 vs. 0.45; p = 0.037). We observed an increase in carotid intima-media thickness in relation to BMI (0.008; CI, -0.002 to 0.013; p = 0.007) without any association with an increase in fat mass in these patients (0.204; CI, -0.043 to 0.451; p = 0.101). Conclusions: childhood leukemia survivors have a high cardiovascular risk, characterized by an increase in IR, not associated with an increase in fat mass. This risk could justify the implementation of preventive actions in these long-lived patients. (AU)

Predicción del desarrollo de tromboembolia pulmonar en pacientes con infección por SARS-CoV-2 / Prediction of pulmonary embolism in patients with SARS-CoV-2 infection

Objetivo:Pretendemos determinar los factores predictores de enfermedad tromboembólica pulmonar (ETEP) en pacientes con infección por SARS-CoV-2 (COVID-19) atendidos en el servicio de urgencias de un hospital terciario durante la primera ola pandémica.Métodos:Estudio observacional unicéntrico realizado en una cohorte retrospectiva de pacientes con infección confirmada por SARS-CoV-2 (o alta sospecha clínico-radiológica de COVID-19) sometidos a despistaje de ETEP mediante tomografía computarizada de arterias pulmonares (TCAP). Se exploraron los factores predictores de ETEP mediante regresión logística, creándose dos modelos predictivos (sin o con los valores de dímeros-D).Resultados:De un total de 274 TCAP realizados, 70 procedimientos presentaron hallazgos diagnósticos de ETEP, representando una incidencia acumulada del 25,54% (intervalo de confianza [IC] 95%: 20,49-31,14). En el modelo no ajustado por el nivel de dímeros-D, la frecuencia respiratoria >22rpm (odds ratio [OR]: 3,162; IC 95%: 1,627-6,148; p=0,001) y la ausencia de hallazgos sugerentes de COVID-19 en la radiología simple de tórax (OR: 3,869; IC 95%: 0,869-17,225; p=0,076) fueron predictores de ETEP. En el segundo modelo se mantuvo la presencia de taquipnea (OR: 4,967; IC 95%: 2,053-12,018; p<0,001), identificándose además un nivel de dímeros-D>3.000ng/mL (OR: 7,494; IC 95%: 3,038-18,485; p<0,001).Conclusiones:La presencia de taquipnea (>22rpm) y la ausencia de hallazgos radiológicos sugestivos de infección por SARS-CoV-2 en la radiografía simple de tórax, además de los valores de dímero-D>3.000ng/mL, fueron identificados como factores predictores de ETEP en pacientes con COVID-19.

Objective:To determine the predictive factors of pulmonary thromboembolic (PTE) in patients with SARS-CoV-2 infection (COVID-19) assessed in the emergency department at a tertiary hospital during the first pandemic wave.Methods:Observational single-center study conducted in a retrospective cohort of patients with confirmed SARS-CoV-2 infection (or high clinical-radiological suspicion) who underwent PTE screening by computed tomography pulmonary angiography (CTPA). Predictive factors of PTE were explored using logistic regression, creating two predictive models (without or with D-dimer values).Results:Out of a total of 274 CTPA performed, 70 procedures presented diagnostic findings of PTE, representing a cumulative incidence of 25.54% (95% confidence interval [CI]: 20.49-31.14). In the non–D-dimer based model, respiratory rate>22bpm (odds ratio [OR]: 3.162; 95% CI: 1.627-6.148; p=0.001) and the absence of findings suggestive of COVID-19 in plain chest X-ray (OR: 3.869; 95% CI: 0.869-17.225; p=0.076) were predictors of PTE. In the D-dimer-based model, tachypnea remained as a predictive factor (OR: 4.967; 95% CI: 2.053-12.018; p<0.001), as well as D-dimers>3,000ng/ml (OR: 7.494; 95% CI: 3.038-18.485; p<0.001).Conclusions:The presence of tachypnea (>22bpm) and the absence of radiological findings suggestive of SARS-CoV-2 infection in the chest X-ray, in addition to D-dimer values>3,000 ng/mL, were identified as predictive factors of PTE in patients with COVID-19. (AU)

Prediction of pulmonary embolism in patients with SARS-CoV-2 infection.

OBJECTIVE: To determine the predictive factors of pulmonary thromboembolic (PTE) in patients with SARS-CoV-2 infection (COVID-19) assessed in the emergency department at a tertiary hospital during the first pandemic wave. METHODS: Observational single-center study conducted in a retrospective cohort of patients with confirmed SARS-CoV-2 infection (or high clinical-radiological suspicion) who underwent PTE screening by computed tomography pulmonary angiography (CTPA). Predictive factors of PTE were explored using logistic regression, creating two predictive models (without or with D-dimer values). RESULTS: Out of a total of 274 CTPA performed, 70 procedures presented diagnostic findings of PTE, representing a cumulative incidence of 25.54% (95% confidence interval [CI]: 20.49-31.14). In the non-D-dimer based model, respiratory rate >22 bpm (odds ratio [OR]: 3.162; 95% CI: 1.627-6.148; p = 0.001) and the absence of findings suggestive of COVID-19 in plain chest X-ray (OR: 3.869; 95% CI: 0.869-17.225; p = 0.076) were predictors of PTE. In the D-dimer-based model, tachypnea remained as a predictive factor (OR: 4.967; 95% CI: 2.053-12.018; p < 0.001), as well as D-dimers > 3000 ng/mL (OR: 7.494; 95% CI: 3.038-18.485; p < 0.001). CONCLUSIONS: The presence of tachypnea (>22 bpm) and the absence of radiological findings suggestive of SARS-CoV-2 infection in the chest X-ray, in addition to D-dimer values >3000 ng/mL, were identified as predictive factors of PTE in patients with COVID-19.

OBJETIVO: Pretendemos determinar los factores predictores de enfermedad tromboembólica pulmonar (ETEP) en pacientes con infección por SARS-CoV-2 (COVID-19) atendidos en el servicio de urgencias de un hospital terciario durante la primera ola pandémica. MÉTODOS: Estudio observacional unicéntrico realizado en una cohorte retrospectiva de pacientes con infección confirmada por SARS-CoV-2 (o alta sospecha clínico-radiológica de COVID-19) sometidos a despistaje de ETEP mediante tomografía computarizada de arterias pulmonares (TCAP). Se exploraron los factores predictores de ETEP mediante regresión logística, creándose dos modelos predictivos (sin o con los valores de dímeros-D). RESULTADOS: De un total de 274 TCAP realizados, 70 procedimientos presentaron hallazgos diagnósticos de ETEP, representando una incidencia acumulada de 25,54% (intervalo de confianza [IC] 95%: 20,49­31,14). En el modelo no ajustado por el nivel de dímeros-D, la frecuencia respiratoria >22 rpm (odds ratio [OR]: 3,162; IC 95%: 1,627­6,148; p = 0,001) y la ausencia de hallazgos sugerentes de COVID-19 en la radiología simple de tórax (OR: 3,869; IC 95%: 0,869­17,225; p = 0,076) fueron predictores de ETEP. En el segundo modelo se mantuvo la presencia de taquipnea (OR: 4,967; IC 95%: 2,053­12,018; p < 0,001), identificándose además un nivel de dímeros-D > 3.000 ng/mL (OR: 7,494; IC 95%: 3,038­18,485; p < 0,001). CONCLUSIONES: La presencia de taquipnea (>22 rpm) y la ausencia de hallazgos radiológicos sugestivos de infección por SARS-CoV-2 en la radiografía simple de tórax, además de los valores de dímero-D > 3.000 ng/mL, fueron identificados como factores predictores de ETEP en pacientes con COVID-19.

CALGB 40603 (Alliance): Long-Term Outcomes and Genomic Correlates of Response and Survival After Neoadjuvant Chemotherapy With or Without Carboplatin and Bevacizumab in Triple-Negative Breast Cancer.

PURPOSE: CALGB 40603 (NCT00861705), a 2 × 2 randomized phase II trial, demonstrated that adding carboplatin or bevacizumab to weekly paclitaxel (wP) followed by doxorubicin and cyclophosphamide significantly increased the pathologic complete response (pCR) rate in stage II-III triple-negative breast cancer. We now report long-term outcomes (LTOs) and correlative science end points. PATIENTS AND METHODS: The Kaplan-Meier method was used to estimate LTOs in 443 patients who initiated study treatment. Log-rank tests and Cox proportional hazards models evaluated the impact of clinical characteristics, pathologic response, calculated residual cancer burden (RCB) in patients with residual disease (RD), treatment assignment, and dose delivery during wP on LTOs, including event-free survival (EFS). Genomic predictors of treatment response and outcomes were assessed on pretreatment tumor samples by mRNA sequencing. RESULTS: Among baseline characteristics, only the clinical stage was associated with LTOs. At a median follow-up of 7.9 years, LTOs were not significantly improved with either carboplatin or bevacizumab, overall or in patients with basal-like subtype cancers by genomic analysis. Patients with pCR (n = 205, 46.3%) had significantly higher 5-year EFS (85.5% v 56.6%, log-rank P < .0001) and overall survival (87.9% v 63.4%, P < .0001) rates compared with patients with RD, even those with RCB class I. Among clinical and genomic features, evidence of immune activation, including tumor-infiltrating lymphocytes and low B-cell receptor evenness, was associated with pCR and improved EFS. CONCLUSION: Despite higher pCR rates, neither carboplatin nor bevacizumab appeared to improve LTOs although the study was not powered to assess these secondary end points. pCR was associated with superior LTOs even when compared with minimal RD. Markers of immune activation in pretreatment tumor biopsies were independently associated with higher pCR rates and improved survival.

[Prediction of pulmonary embolism in patients with SARS-CoV-2 infection]. / Predicción del desarrollo de tromboembolia pulmonar en pacientes con infección por SARS-CoV-2.

OBJECTIVE: To determine the predictive factors of pulmonary thromboembolic (PTE) in patients with SARS-CoV-2 infection (COVID-19) assessed in the emergency department at a tertiary hospital during the first pandemic wave. METHODS: Observational single-center study conducted in a retrospective cohort of patients with confirmed SARS-CoV-2 infection (or high clinical-radiological suspicion) who underwent PTE screening by computed tomography pulmonary angiography (CTPA). Predictive factors of PTE were explored using logistic regression, creating two predictive models (without or with D-dimer values). RESULTS: Out of a total of 274 CTPA performed, 70 procedures presented diagnostic findings of PTE, representing a cumulative incidence of 25.54% (95% confidence interval [CI]: 20.49-31.14). In the non-D-dimer based model, respiratory rate>22bpm (odds ratio [OR]: 3.162; 95% CI: 1.627-6.148; p=0.001) and the absence of findings suggestive of COVID-19 in plain chest X-ray (OR: 3.869; 95% CI: 0.869-17.225; p=0.076) were predictors of PTE. In the D-dimer-based model, tachypnea remained as a predictive factor (OR: 4.967; 95% CI: 2.053-12.018; p<0.001), as well as D-dimers>3,000ng/ml (OR: 7.494; 95% CI: 3.038-18.485; p<0.001). CONCLUSIONS: The presence of tachypnea (>22bpm) and the absence of radiological findings suggestive of SARS-CoV-2 infection in the chest X-ray, in addition to D-dimer values>3,000 ng/mL, were identified as predictive factors of PTE in patients with COVID-19.

Erratum: Bosch-Sierra, N., et al. Effect of Fibre-Enriched Orange Juice on Postprandial Glycaemic Response and Satiety in Healthy Individuals: An Acute, Randomised, Placebo-Controlled, Double-Blind, Crossover Study. Nutrients 2019, 11, 3014.

The authors have requested that the following changes be made to their paper [...].

Is advanced esophageal adenocarcinoma a distinct entity from intestinal subtype gastric cancer? Data from the AGAMENON-SEOM Registry.

BACKGROUND: Advanced esophageal adenocarcinoma (EAC) is generally treated similarly to advanced gastroesophageal junction (GEJ-AC) and gastric (GAC) adenocarcinomas, although GAC clinical trials rarely include EAC. This work sought to compare clinical characteristics and treatment outcomes of advanced EAC with those of GEJ-AC and GAC and examine prognostic factors. PATIENTS AND METHODS: Participants comprised patients with advanced EAC, intestinal GEJ-AC, and GAC treated with platin and fluoropyrimidine (plus trastuzumab when HER2 status was positive). Overall and progression-free survival were estimated using the Kaplan-Meier method. Cox proportional hazards regression gauged the prognostic value of the AGAMENON model. RESULTS: Between 2008 and 2019, 971 participants from the AGAMENON-SEOM registry were recruited at 35 centers. The sample included 67.3% GAC, 13.3% GEJ-AC, and 19.4% EAC. Pulmonary metastases were most common in EAC and peritoneal metastases in GAC. Median PFS and OS were 7.7 (95% CI 7.3-8.0) and 13.9 months (12.9-14.7). There was no difference in PFS or OS between HER2- and HER2+ tumors from the three locations (p > 0.05). Five covariates were found to be prognostic for the entire sample: ECOG-PS, histological grade, number of metastatic sites, NLR, and HER2+ tumors treated with trastuzumab. In EAC, the same variables were prognostic except for grade. The favorable prognosis for HER2+ cancers treated with trastuzumab was homogenous for all three subgroups (p = 0.351) and, after adjusting for the remaining covariates, no evidence supported primary tumor localization as a prognostic factor (p = 0.331). CONCLUSION: Our study supports the hypothesis that EAC exhibits clinicopathological characteristics, prognostic factors, and treatment outcomes comparable to intestinal GEJ-AC and GAC.

Independent Validation of the PAM50-Based Chemo-Endocrine Score (CES) in Hormone Receptor-Positive HER2-Positive Breast Cancer Treated with Neoadjuvant Anti-HER2-Based Therapy.

PURPOSE: We do not yet have validated biomarkers to predict response and outcome within hormone receptor-positive/HER2-positive (HR+/HER2+) breast cancer. The PAM50-based chemo-endocrine score (CES) predicts chemo-endocrine sensitivity in hormone receptor-positive/HER2-negative (HR+/HER2-) breast cancer. Here, we evaluate the relationship of CES with response and survival in HR+/HER2+ breast cancer. EXPERIMENTAL DESIGN: Intrinsic subtype and clinicopathologic data were obtained from seven studies in which patients were treated with HER2-targeted therapy either with endocrine therapy (ET) or with chemotherapy (CTX). CES was evaluated as a continuous variable and categorically from low to high scores [CES-C (chemo-sensitive), CES-U (uncertain), and CES-E (endocrine-sensitive)]. We first analyzed each dataset individually, and then all combined. Multivariable analyses were used to test CES association with pathologic complete response (pCR) and disease-free survival (DFS). RESULTS: A total of 457 patients were included (112 with ET and 345 with CTX). In the combined cohort, CES-C, CES-U, and CES-E were identified in 60%, 23%, and 17% of the patients, respectively. High CES (i.e., CES-E) was associated with a lower probability of achieving pCR independently of clinical characteristics, therapy, intrinsic subtype, and study (adjusted OR = 0.42; P = 0.016). A total of 295 patients were analyzed for DFS with a median follow-up of 66 months. High CES was also associated with better DFS (adjusted HR, 0.174; P = 0.003) independently of pCR, clinical characteristics and intrinsic subtype. In patients with residual disease, the adjusted DFS HR of CES was 0.160 (P = 0.012). CONCLUSIONS: In HER2+/HR+ breast cancer, CES is useful for predicting chemo-endocrine sensitivity and provides additional prognostication beyond intrinsic subtype and clinicopathologic characteristics.

Clinical, pathological, and PAM50 gene expression features of HER2-low breast cancer.

Novel antibody-drug conjugates against HER2 are showing high activity in HER2-negative breast cancer (BC) with low HER2 expression (i.e., 1+ or 2+ and lack of ERBB2 amplification). However, the clinical and molecular features of HER2-low BC are yet to be elucidated. Here, we collected retrospective clinicopathological and PAM50 data from 3,689 patients with HER2-negative disease and made the following observations. First, the proportion of HER2-low was higher in HR-positive disease (65.4%) than triple-negative BC (TNBC, 36.6%). Second, within HR-positive disease, ERBB2 and luminal-related genes were more expressed in HER2-low than HER2 0. In contrast, no gene was found differentially expressed in TNBC according to HER2 expression. Third, within HER2-low, ERBB2 levels were higher in HR-positive disease than TNBC. Fourth, HER2-low was not associated with overall survival in HR-positive disease and TNBC. Finally, the reproducibility of HER2-low among pathologists was suboptimal. This study emphasizes the large biological heterogeneity of HER2-low BC, and the need to implement reproducible and sensitive assays to measure low HER2 expression.

Fit for purpose? Footwear for patients with and without diabetic peripheral neuropathy: A cross-sectional study.

AIM: This paper determines whether patients with and without Diabetic Peripheral Neuropathy use suitable footwear, taking into account that these persons are subject to a significant loss of sensitivity in the feet. METHODS: Cross-sectional observational study was conducted of 108 participants with diabetes mellitus. Inclusion criteria were at least five years' progression of diabetes, the ability to walk unaided and no distal amputation of the foot. The presence of DPN was evaluated according to the criteria of the International Working Group on the Diabetic Foot. Foot length was measured using a Brannock® device and internal shoe length was determined using a CEGI® pedometer. RESULTS: In relation to adjustment, 21.6% of the shoes examined had no type of closure. The most common form of closure was laces, which were used in 32.4% of the shoes. 92.5% of footwear had internal seams. No significant relationship was found between the presence or otherwise of DPN and the use of appropriate shoe closure (p = 0.304), recommended heel height (p = 0.18), leather material (p = 0.77) and absence of internal seams (p = 0.759). CONCLUSIONS: The majority of our participants living with DPN do not wear fitting shoes. Therefore, it is advisable to evaluate their use of footwear, both in primary health care and in podiatry clinics, to forestall potential complications.