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Background: Human epidermal growth factor receptor 2 (HER2)-low has emerged as a potential new entity in breast cancer (BC). Data on this subset are limited, and prognostic results are controversial, evidencing the need of further data in a BC real-world cohort. Methods: Patients with HER2-negative stage I–III BC diagnosed between 2006 and 2016 were retrospectively reviewed in a single cohort from the Catalan Institute of Oncology Badalona. Demographics and clinicopathological characteristics were examined via medical charts/electronic health records. We aim to describe and compare HER2-0/HER2-low populations through Chi-square or Fisher test, and explore its prognostic impact using Kaplan–Meier curves and Cox regression models. Results: From a cohort of 1755 BC patients, 1401 invasive HER2-negative, stage I–III cases were evaluated. 87% were hormone receptor (HR)-positive versus 13% triple negative (TNBC). Overall, 43% were HER2-0 and 57% HER2-low (61% immunohistochemistry (IHC) 1+ and 39% IHC 2+). Comparing HER2-low versus HER2-0, HER2-low showed higher proportion of estrogen receptor (ER)-positive (91.6% vs 79.9%, p ⩽ 0.001) and progesterone receptor (PR)-positive (79.8% vs 68.9%, p ⩽ 0.001) cases. HER2-0 exhibited higher proportion of TNBC (20.1% vs 8.4%, p = 0.001), grade III tumors (28.8% vs 23.5%, p = 0.039), and higher Ki67 median value (26.47% vs 23.88%, p = 0.041). HER2-low was associated with longer time to distant recurrence (TTDR) compared to HER2-0 (67.8 vs 54.1 months; p = 0.015) and better BC-related survival (19.2 vs 16.3 years; p = 0.033). In the multivariable analysis, HER2-low was not an independent prognostic factor for TTDR and BC-related survival. ER expression showed a strong association with longer TTDR (Hazard Ratio: 0.425, p ⩽ 0.001) and improved BC-related survival (Hazard Ratio: 0.380, p ⩽ 0.001). PR expression was also associated with longer TTDR (Hazard Ratio: 0.496, p ⩽ 0.001), and improved BC-related survival (Hazard Ratio: 0.488, p ⩽ 0.001). Histological grade III was significantly associated with shorter TTDR (Hazard Ratio: 1.737, p = 0.002). Positive nodal status was the strongest factor correlated with worse BC-related survival (Hazard Ratio: 2.747, p ⩽ 0.001). Conclusion: HER2-low was significantly associated with HR-positive disease, whereas HER2-0 group had higher incidence of TNBC, histological grade III and higher Ki67%. Although HER2-low group was associated with longer TTDR and improved BC-related survival, these findings could be explained by the greater proportion of favorable prognostic features in this subgroup compared to HER2-0.

Gastric cancer is an aggressive disease with increasing global incidence in recent years. Human epidermal growth receptor 2 (HER2) is overexpressed in approximately 10–20% of gastric cancers. The implementation of targeted therapy against HER2 as part of the standard of care treatment in metastatic disease has improved the prognosis of this subset of patients. However, gastric cancer still has high mortality rates and urgently requires new treatment strategies. The combination of immunotherapy with HER2-targeted therapies has shown synergistic effects in preclinical models, this being the rationale behind exploring this combination in clinical trials in locally advanced and metastatic settings. Additionally, the irruption of antibody–drug conjugates and other novel HER2-targeted agents has led to the development of numerous clinical trials showing promising results. This review presents the molecular mechanisms supporting the use of HER2-targeted drugs in combination with immunotherapy and provides an overview of the therapeutic scenario of HER2-positive disease. We focus on the role of immunotherapy but also summarize emerging therapies and combinations under clinical research that may change the standard treatment in HER-2 positive disease in the future.

Despite the improvement achieved by the introduction of HER2-targeted therapy, up to 25% of early human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC) patients will relapse. Beyond trastuzumab, other agents approved for early HER2+ BC include the monoclonal antibody pertuzumab, the antibody-drug conjugate (ADC) trastuzumab-emtansine (T-DM1) and the reversible HER2 inhibitor lapatinib. New agents, such as trastuzumab-deruxtecan or tucatinib in combination with capecitabine and trastuzumab, have also shown a significant improvement in the metastatic setting. Other therapeutic strategies to overcome treatment resistance have been explored in HER2+ BC, mainly in HER2+ that also overexpress estrogen receptors (ER+). In ER+ HER2+ patients, target therapies such as phosphoinositide-3-kinase (PI3K) pathway inhibition or cyclin-dependent kinases 4/6 blocking may be effective in controlling downstream of HER2 and many of the cellular pathways associated with resistance to HER2-targeted therapies. Multiple trials have explored these strategies with some promising results, and probably, in the next years conclusive results will succeed. In addition, HER2+ BC is known to be more immunogenic than other BC subgroups, with high variability between tumors. Different immunotherapeutic agents such as HER-2 therapy plus checkpoint inhibitors, or new vaccines approaches have been investigated in this setting, with promising but controversial results obtained to date.

Triple-negative breast cancer (TNBC) is a highly aggressive subtype with limited therapeutic options, leading to higher relapse rates and mortality. Identifying prognostic biomarkers like caveolin-1 (CAV1) is crucial for personalized treatment. CAV1 influences tumor progression and chemotherapy response, particularly through its interaction with the tumor microenvironment (TME) and cancer metabolism. Understanding the prognostic value of CAV1 in different cellular compartments is essential for its clinical application in TNBC. In the methods section CAV1 gene expression in TNBC was evaluated using in silico analysis, followed by the immunohistochemical staining of tumor cytoplasm (cCAV1) and stromal cells (sCAV1) in 58 early-stage TNBC patients. Statistical analyses were performed to correlate CAV1 expression with clinicopathological features and survival. In the results section, in silico analysis revealed higher CAV1 expression in TNBC, correlating with shorter overall survival. In the patient samples, cCAV1 was observed in 10.3% of cases, and was associated with larger tumors, higher grades, and poorer prognoses. sCAV1 was detected in 42% of cases, associated with less proliferative and less aggressive tumors, but did not significantly impact prognoses. In conclusion, cCAV1 expression is a significant prognostic marker in early-stage TNBC, highlighting the importance of assessing CAV1 in different cellular compartments. Further research is needed to explore the mechanisms and clinical implications of cCAV1.

Lung cancer patients represent a subgroup of special vulnerability in whom the SARS-CoV-2 infection could attain higher rates of morbidity and mortality. Therefore, those patients were recommended to receive SARS-CoV-2 vaccines once they were approved. However, little was known at that time regarding the degree of immunity developed after vaccination or vaccine-related adverse events, and more uncertainty involved the real need for a third dose. We sought to evaluate the immune response developed after vaccination, as well as the safety and efficacy of SARS-CoV-2 vaccines in a cohort of patients with lung cancer. Patients were identified through the Oncology/Hematology Outpatient Vaccination Program. Anti-Spike IgG was measured before any vaccine and at 3–6-, 6–9- and 12–15-month time points after the 2nd dose. Detailed clinical data were also collected. In total, 126 patients with lung cancer participated and received at least one dose of the SARS-CoV-2 vaccine. At 3–6 months after 2nd dose, 99.1% of baseline seronegative patients seroconverted and anti-Spike IgG titers went from a median value of 9.45 to 720 UI/mL. At the 6–9-month time point, titers raised to a median value of 924 UI/mL, and at 12–15 months, after the boost dose, they reached a median value of 3064 UI/mL. Adverse events to the vaccine were mild, and no SARS- CoV-2 infection-related deaths were recorded. In this lung cancer cohort, COVID-19 vaccines were safe and effective irrespective of the systemic anticancer therapy. Most of the patients developed anti-Spike IgG after the second dose, and these titers were maintained over time with low infection and reinfection rates with a mild clinical course.

Negative symptoms in schizophrenia, which are related to poor functioning, are thought to be grounded on aberrant functioning in the reward system. We aimed to disentangle how negative symptoms and two cognitive aspects of goal-directed behavior, mental representation of reward and reward value, affect willingness to invest effort to attain a reward in schizophrenia. To this purpose, 43 schizophrenia patients and 35 healthy controls were assessed for negative symptoms and general functioning, and completed an effort-based reward task. Patients were split in high and low negative symptoms scorers. A series of ANOVA tests were conducted in order to test the effects of group controlling for representation of reward (Task 1) and balance between reward value and effort (Task 2) on will to invest effort to attain a reward. Schizophrenia patients with high negative symptoms chose to invest lower amounts of effort for a reward compared both to low negative symptoms patients and to controls in both tasks. Neither mental representation of reward (Task 1) nor reward value (Task 2) did differentially affect will to invest effort between-groups. These findings suggest that the lower willingness to invest effort observed in schizophrenia patients with high negative symptoms may not be related to cognitive aspects of goal-oriented behavior. •Negative symptoms in schizophrenia are associated to lower willingness to reward-based effort.•Schizophrenia subjects without negative symptoms are not impaired in willingness to reward-based effort.•Impairment in willingness to exert effort in schizophrenia is not related to reward value.

Background/Objectives: Few large cohorts with relatively uniform treatment approaches and long-term follow-up are available for assessing clinical outcomes for breast cancer (BC) patients. The Institut Català d’Oncologia (ICO) Breast Cancer Cohort was designed to well characterize treatment patterns and overall survival outcomes at 5 and 10 years, with a particular focus on patients < 40 and ≥70 years old, age groups often underrepresented in clinical trials. Methods: In this retrospective, observational study, we included all pathologically confirmed invasive BC patients diagnosed and treated between 2010 and 2014 at ICO, a Spanish reference cancer center, with a follow-up until November 2023. We collected comprehensive real-world data on clinicopathologic characteristics and treatment modalities. Overall survival (OS) was estimated using the Kaplan–Meier technique and was reported stratified by prognostic factors for the age groups of ≤40, 41–69 and ≥70. The Multivariate Cox model was used to estimate the risk of death for subgroups of age, adjusting for subtype, stage and grade. Results: Overall, 3451 patients with stage I to IV BC were diagnosed and treated, with a mean age of 58 years (range 19–98); 371 (10.8%) were diagnosed ≤40 years, and 756 (21.9%) were ≥70 years. With a mean follow-up of 9.9 years (SD = 3.5), the 5- and 10-year OS were 89% (95% CI: 86–92%) and 85% (95% CI: 81–88%) for patients ≤ 40, respectively; for those aged 41–69 years, 91% (95% CI: 90–92%) and 85% (95% CI: 83–86%), respectively; and 70% (95% CI: 66–73%) and 50% (95% CI: 47–54%) for those ≥70 years, respectively. The 5- and 10-year relative survival (RS) were 92% and 88% for patients < 70 years, respectively, and 82% and 77% for those ≥70 years, respectively. The Multivariate Cox model identified a HR of 4.90 (95% CI: 3.44–6.97, p < 0.001) for patients ≥ 70 years compared to those between 41 and 69 years. Conclusions: The ICO Breast Cancer Cohort, as far as we know, the largest in Spain with long-term follow-up, underscores the critical role of age and subtype in determining overall survival outcomes in patients with breast cancer.

p38α is a versatile protein kinase that can control numerous processes and plays important roles in the cellular responses to stress. Dysregulation of p38α signaling has been linked to several diseases including inflammation, immune disorders and cancer, suggesting that targeting p38α could be therapeutically beneficial. Over the last two decades, numerous p38α inhibitors have been developed, which showed promising effects in pre-clinical studies but results from clinical trials have been disappointing, fueling the interest in the generation of alternative mechanisms of p38α modulation. Here, we report the in silico identification of compounds that we refer to as non-canonical p38α inhibitors (NC-p38i). By combining biochemical and structural analyses, we show that NC-p38i efficiently inhibit p38α autophosphorylation but weakly affect the activity of the canonical pathway. Our results demonstrate how the structural plasticity of p38α can be leveraged to develop therapeutic opportunities targeting a subset of the functions regulated by this pathway. The p38α protein kinase is an attractive druggable target for many human diseases. Here, the authors show how the structural plasticity of p38α can be leveraged to selectively inhibit a subset of the functions regulated by this kinase and aid in the development of therapeutic compounds.

Purpose: The purpose of this study is to assess the correlation between metabolic response with fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) and pathological response in patients with locally advanced esophageal cancer treated with neoadjuvant chemoradiotherapy and to study FDG-PET parameters for the prediction of pathological response and outcome. Methods: Twenty-five patients with locally advanced esophageal cancer underwent two FDG-PET/CT scans for initial staging and after neoadjuvant chemoradiotherapy. FDG uptake in the primary tumor was calculated in both scans (SUVmax, SULpeak, and TLG). Metabolic response was assessed according to the reduction of PET parameters: complete response (mCR = 100%), partial response (mPR ≥50%), and no response (mNR ≤50%). Pathological response was also classified as complete (pCR), partial (pPR), or no response (pNR). Patients were followed up (range, 8-99 months) determining free-disease interval (FDI) and overall survival (OS). Results: Two patients were excluded due to exitus for nonesophageal-related causes. The metabolic response was observed in 18/23 remaining patients (3mCR, 15 mPR), of which 12/18 patients showed a pathological response (3 pCR, 9 pPR). A major discrepancy was observed in 2 mNR patients who achieved pPR. FDI and OS were longer in patients with metabolic response than nonresponders, but no statistical difference was found. No significant correlation was found between PET parameters and pathological response, FDI, and OS. Conclusions: FDG-PET/CT is a useful technique to assess response to neoadjuvant chemoradiotherapy in esophageal cancer. Although in this preliminary study, no correlation between metabolic and pathologic response was found and no statistical differences between responders and nonresponders were observed, a tendency of longer FDI and OS was apparently found in responders patients.