Detrimental effect of an early exposure to antibiotics on the outcomes of immunotherapy in a multi-tumor cohort of patients.

BACKGROUND: Immune checkpoint inhibitors (ICI) have changed the therapeutic landscape of many solid tumors. Modulation of the intestinal microbiota by antibiotics (Abx) has been suggested to impact on ICI outcomes. METHODS: Retrospective analysis of 475 patients with advanced solid tumors treated with ICI from 2015 to 2022. For each patient, the use of Abx was recorded from 1 month before ICI initiation until disease progression or death. The impact of Abx on objective response rates (ORR), disease control rates (DCR), progression-free survival (PFS), and overall survival (OS) was analyzed. Kaplan-Meier and log-rank tests were used to compare survival outcomes. RESULTS: In total 475 patients with advanced solid tumors were evaluated. Median age was 67.5 years and performance status (PS) was 0-1 in 84.6%. 66.5% of patients received Abx during treatment with ICI, mainly beta-lactams (53.8%) and quinolones (35.9%). The early exposure to Abx (from 60 days before to 42 days after the first cycle of ICI) was associated with a lower ORR (27.4% vs 39.4%; P < .01), a lower DCR (37.3% vs 57.4%; P < .001), lower PFS (16.8 m vs 27.8 m; HR 0.66; P < .001]) and lower OS (2.5 m vs 6.6 m; HR 0.68; P = .001]). The negative impact of Abx on OS and PFS was confirmed by a multivariable analysis. This effect was not observed among patients receiving Abx after 6 weeks from ICI initiation. CONCLUSIONS: Our results validate the hypothesis of a detrimental effect of an early exposure to Abxon the efficacy of ICI in a multi-tumor cohort of patients.

Negative association of steroids with immunotherapy efficacy in a multi-tumor cohort: time and dose-dependent.

Previous studies have suggested a negative impact of steroids on the efficacy of immune checkpoint inhibitors (ICI), but how this effect is modulated by the dosage and time of administration is yet to be clarified. We have performed a retrospective analysis of 475 patients with advanced solid tumors treated with ICI as monotherapy from 2015 to 2022. Data regarding immune-related adverse events (irAEs) and clinical outcomes were collected. For each patient, the daily steroid dose (in mg/kg of prednisone) was registered until disease progression or death. The impact of cumulative doses on response rates and survival outcomes was analyzed within different periods. The objective response rate (ORR) was significantly lower among patients exposed to steroids within 30 days before the first cycle of ICI (C1) (20.3% vs. 36.7%, p < 0.01) and within the first 90 days of treatment (25.7% vs. 37.7%, p = 0.01). This negative association was confirmed by multivariable analysis. Higher mean steroid doses were observed among non-responders, and cumulative doses were inversely correlated with the disease control rate (DCR) around ICI initiation. Remarkably, poorer outcomes were observed even in patients belonging to the lowest dose quartile compared to the steroid-naïve population. The exposure to steroids after 6 months of ICI was not associated with worse survival outcomes. Our results suggest that the potential impact of steroids on ICI efficacy may be time-dependent, prevailing around ICI initiation, and dose-dependent, with modulation of neutrophil-to-lymphocyte ratio as a possible underlying mechanism.

Exploring the Combined Action of Adding Pertuzumab to Branded Trastuzumab versus Trastuzumab Biosimilars for Treating HER2+ Breast Cancer.

The binding activity of various trastuzumab biosimilars versus the branded trastuzumab towards the glycosylated extracellular domain of the human epidermal growth factor receptor 2 (HER2) target in the presence of pertuzumab was investigated. We employed size exclusion chromatography with tetra-detection methodology to simultaneously determine absolute molecular weight, concentration, molecular size, and intrinsic viscosity. All trastuzumab molecules in solution exhibit analogous behavior in their binary action towards HER2 regardless of the order of addition of trastuzumab/pertuzumab. This analogous behavior of all trastuzumab molecules, including biosimilars, highlights the robustness and consistency of their binding activity towards HER2. Furthermore, the addition of HER2 to a mixture of trastuzumab and pertuzumab leads to increased formation of high-order HER2 complexes, up to concentrations of one order of magnitude higher than in the case of sequential addition. The observed increase suggests a potential synergistic effect between these antibodies, which could enhance their therapeutic efficacy in HER2-positive cancers. These findings underscore the importance of understanding the complex interplay between therapeutic antibodies and their target antigens, providing valuable insights for the development of more effective treatment strategies.

Top advances of the year: Breast cancer.

Although breast cancer has led the way toward precision medicine, more research is still needed to increase curation rates in patients with early disease and to prolong survival with an optimal quality of life in the metastatic setting. Last year, big advances were achieved toward these goals thanks to the significant impact of immunotherapy on survival in triple-negative breast cancer and the exciting results of antibody-drug conjugates. PLAIN LANGUAGE SUMMARY: The development of new drugs and biomarkers to select those patients who will benefit of them are crucial in improving survival in breast cancer. Last year, the emergence of antibody-drug conjugates and the reaffirmation of the potential of immunotherapy in breast cancer were the most important findings.

Onset of ulcerative colitis and complete response during the treatment of a metastatic colon cancer: case report and literature review.

Colorectal cancer is a common cancer worldwide. Several risk factors have been described, such as age, lifestyle and family history. Inflammatory bowel diseases (IBD) are a well-recognized risk factor for the development of colorectal cancer. However, the onset of an IBD de novo in the context of the treatment of a colorectal neoplasia has not been reported before, except in the context of the treatment with immunocheckpoint inhibitors. Fifty-nine-years old man diagnosed with a metastatic colorectal cancer who received conventional treatment with chemotherapy and an antiangiogenic inhibitor. The patient had a complete response with the therapy after few cycles. Nevertheless, during the treatment, the patient presented with rectal bleeding, and was diagnosed with ulcerative colitis. Although the treatment was discontinued, tumoral complete remission is maintained. The relevance of this case lies in the concurrence of the onset of an autoimmune disease and a complete response of the malignancy. The concurrence of these events has been described previously only with immunotherapy. There are not cases reported involving chemotherapy and antiangiogenic drugs. Other causes of colitis were ruled out due to the unusual presentation of the case.

Discordant Humoral and T-Cell Response to mRNA SARS-CoV-2 Vaccine and the Risk of Breakthrough Infections in Women with Breast Cancer, Receiving Cyclin-Dependent Kinase 4 and 6 Inhibitors.

Few data are available about the immune response to mRNA SARS-CoV-2 vaccines in patients with breast cancer receiving cyclin-dependent kinase 4/6 inhibitors (CDK4/6i). We conducted a prospective, single-center study of patients with breast cancer treated with CDK4/6i who received mRNA-1273 vaccination, as well as a comparative group of healthcare workers. The primary endpoint was to compare the rate and magnitude of humoral and T-cell response after full vaccination. A better neutralizing antibody and anti-S IgG level was observed after vaccination in the subgroup of women receiving CDK4/6i, but a trend toward a reduced CD4 and CD8 T-cell response in the CDK4/6i group was not statistically significant. There were no differences in the rate of COVID-19 after vaccination (19% vs. 12%), but breakthrough infections were observed in those with lower levels of anti-S IgG and neutralizing antibodies after the first dose. A lower rate of CD4 T-cell response was also found in those individuals with breakthrough infections, although a non-significant and similar level of CD8 T-cell response was also observed, regardless of breakthrough infections. The rate of adverse events was higher in patients treated with CDK4/6i, without serious adverse events. In conclusion, there was a robust humoral response, but a blunted T-cell response to mRNA vaccine in women receiving CDK4/6i, suggesting a reduced trend of the adaptative immune response.

Maintained complete response to talazoparib in a BRCA-2 mutated metastatic luminal breast cancer: case report and review of literature.

PARP inhibitors are progressively becoming a part of our therapeutic arsenal against BRCA-defective tumors, because of their capacity to induce synthetic lethality in cells with a deficiency in the homologous recombination repair system. Olaparib and talazoparib have been approved for metastatic breast cancer in carriers of germline BRCA mutations, which are found in approximately 6% of patients with breast cancer. We report the case of a patient with metastatic breast cancer, carrier of a germline mutation in BRCA2, with a complete response to first-line treatment with talazoparib, maintained after 6 years. To the best of our knowledge, this is the longest response reported with a PARP inhibitor in a BRCA-mutated tumor. We have made a review of literature, regarding the rationale for PARP inhibitors in carriers of BRCA mutations and their clinical relevance in the management of advanced breast cancer, as well as their emerging role in early stage disease, alone and in combination with other systemic therapies.

Event-related potentials elicited by face identity processing in elderly adults with cognitive impairment.

UNLABELLED: BackGROUND/STUDY CONTEXT: Patients with mild Alzheimer's disease and mild cognitive impairment show selective loss of knowledge regarding facial identification. METHODS: The authors focus on decline effects on event-related potentials (ERPs) P100, N170, N250, and N400, associated with the processing of facial identity. Different famous and unknown faces were presented in explicit and implicit familiarity tasks. RESULTS: Patients with cognitive impairment showed modulations on P100 and N170 and greater activity in prefrontal areas in the earlier component. In healthy elderly individuals, but not in patients, famous faces modulated the long-latency ERPs N250 and N400, related to the access and retrieval of stored facial-related information, respectively. CONCLUSION: ERPs have potential as markers of neurodegenerative disease such as dementia. The neural systems supporting facial identification may differ in normal and cognitively impaired older adults.

Oligometastatic Disease: When Stage IV Breast Cancer Could Be "Cured".

Although metastatic breast cancer remains an incurable disease, there are patients with a limited number of metastatic lesions that, in addition to systemic therapy, can be treated with "radical therapy" and sometimes reach the status of no long-term evidence of disease. Whether or not these patients can be considered cured is still a matter of debate. Unfortunately, the definition of the oligometastatic disease remains unclear, and it can occur with multiple different presentations. The absence of remarkable biomarkers, the difficulty in designing the appropriate clinical trials, and the failure to offer this group of patients radical approaches in advanced-stage clinical trials are just some of the current problems that we face in treating patients with oligometastatic breast cancer. Although most of the data come from retrospective studies and do not use the same definition of "oligometastatic disease," here we review the main studies exploring the role of surgery or radiotherapy in patients with the oligometastatic disease and the different results. Some, but not all, studies have shown an increase in survival when surgery and/or radiotherapy were performed for oligometastatic disease. However, better clinical trial designs are needed to confirm the role of "aggressive" approaches for patients with breast cancer and oligometastatic disease.

Neurologic Toxicity of Immune Checkpoint Inhibitors: A Review of Literature.

Immune checkpoint inhibitors have entailed a change of paradigm in the management of multiple malignant diseases and are acquiring a key role in an increasing number of clinical sceneries. However, since their mechanism of action is not limited to the tumor microenvironment, their systemic activity may lead to a wide spectrum of immune-related side effects. Although neurological adverse events are much less frequent than gastrointestinal, hepatic, or lung toxicity, with an incidence of <5%, their potential severity and consequent interruptions to cancer treatment make them of particular importance. Despite them mainly implying peripheral neuropathies, immunotherapy has also been associated with an increased risk of encephalitis and paraneoplastic disorders affecting the central nervous system, often appearing in a clinical context where the appropriate diagnosis and early management of neuropsychiatric symptoms can be challenging. Although the pathogenesis of these complications is not fully understood yet, the blockade of tumoral inhibitory signals, and therefore the elicitation of cytotoxic T-cell-mediated response, seems to play a decisive role. The aim of this review was to summarize the current knowledge about the pathogenic mechanisms, clinical manifestations, and therapeutic recommendations regarding the main forms of neurotoxicity related to checkpoint inhibitors.

Limited T cell response to SARS-CoV-2 mRNA vaccine among patients with cancer receiving different cancer treatments.

INTRODUCTION: Patients with cancer (PC) are at high risk of acquiring COVID-19 and can develop more serious complications. Deeper understanding of vaccines immunogenicity in this population is crucial for adequately planning vaccines programs. The ONCOVac study aimed to comprehensively assess the immunogenicity of mRNA-1273 vaccine in terms of humoral and cellular response. METHODS: We conducted a prospective, single-center study including patients with solid tumours treated with cyclin-dependent kinases 4 and 6 inhibitors (CDK4/6i), immunotherapy (IT) or chemotherapy (CT). Patients were enrolled previously to vaccination with mRNA-1273. We also involved health care workers (HCW) to serve as a control group. We took blood samples before first dose administration (BL), after first dose (1D), and after second dose (2D). The primary objective was to compare the rate and magnitude of T cell response after second dose whereas safety and humoral response were defined as secondary objectives. We also collected patient reported outcomes after both the first and second vaccine dose and a six-month follow-up period to diagnose incident COVID-19 cases was planned. RESULTS: The rate of specific anti-S serologic positivity (anti-S IgG cut-off point at 7,14 BAU/mL) was significantly higher in HCW compared to PC after 1D (100% versus 83.8%; p = 0.04), but similar after 2D (100% versus 95.8%; p = 0.5). This difference after 1D was driven by PC treated with CT (100% versus 64.5%; p = 0.001). Cellular response after 2D was significantly lower in PC than in HCW for both CD4+ (91.7% versus 59.7%; p = 0.001) and CD8+ (94.4% versus 55.6%; p < 0.001) T cells. We found a difference on pre-existing CD4+ T cell response in HCW comparing to PC (36% and 17%, p = 0.03); without difference in pre-existing CD8+ T cell response (31% and 23%, p = 0.5). After excluding patients with pre-existing T cell response, PC achieved even lower CD4+ (50.9% versus 95.5%, p < 0.001) and CD8+ (45.5% versus 95.5%, p < 0.001) T cell response compared with HCW. Regarding safety, PC reported notably more adverse events than HCW (96.6% versus 69.2%, p < 0.001). CONCLUSION: We demonstrated that PC showed a similar humoral response but a lower T cell response following two doses of mRNA-1273 vaccination. Further studies are needed to complement our results and determine the implication of low T cell response on clinical protection of PC against COVID-19.

Relevance of positive resection margins in ductal pancreatic adenocarcinoma and prognostic factors. / Relevancia del margen de resección positivo en adenocarcinoma ductal de páncreas y otros factores pronósticos.

INTRODUCTION: Currently, R1 resection is defined by the presence of tumor cells within <1mm of the resection margin. The main aim of this study was to analyze the impact of positive margins (R1) on survival outcomes in pancreatic cancer. METHODS: We performed a retrospective analysis with multivariate regression analysis of a prospective database from 2008-2017, which included resection margin status, expanded resection margin (R1<1mm), vascular resection, lymphatic involvement, surgical complications, tumor differentiation grade and adjuvant treatment. RESULTS: A total of 80 patients were analyzed: 42 (52%) R1; 38 (48%) R0. No differences were found in the composition of the two groups except for the vascular resection, which was more frequent in the R1 group: 12 (21%) vs 2 (3%). Overall survival in the R0 group was 19 months vs 24 months in the R1 group (p=0.13). Wide R1 (R1<1mm) had an overall survival of 21 months versus 31 months in wide R0 (p=0.55). In the multivariate analysis, only lymph node involvement (p=0.02, HR=2.88), tumor differentiation (p=0.02, HR=3.2) and adjuvant therapy (p<0.01; HR=0.21) were found to be factors related to survival. CONCLUSIONS: R1 resection is not an independent risk factor. Lymph node involvement, differentiation grade and adjuvant treatment are prognostic factors. The benefit of expanding the resection margins should be demonstrated. More studies are needed to assess the impact of the resection margin.

Resolution of necrolytic migratory erythema with somatostatin analogue in a patient diagnosed with pancreatic glucagonoma.

A 70-year-old man reported progressive weight loss, fatigue and a generalised rash. The rash was consistent with necrolytic migratory erythema, further investigations were performed and the patient was diagnosed with a mass in the tail of the pancreas, in keeping with a localised glucagonoma. Somatostatin analogue therapy was started for symptom control, leading to complete resolution of the skin rash and an improvement in constitutional symptoms. Subsequently, the pancreatic lesion was excised, and pathology assessment confirmed the diagnosis of well-differentiated neuroendocrine tumour with high expression of glucagon compatible with glucagonoma.

Spotlight on telotristat ethyl for the treatment of carcinoid syndrome diarrhea: patient selection and reported outcomes.

Neuroendocrine tumors (NETs) are rare cancers with an associated prolonged survival in some patients. A proportion of patients diagnosed with NETs will present with carcinoid syndrome symptoms, characterized by diarrhea, flushing and/or wheezing. This review summarizes the current treatment options for carcinoid syndrome, focusing on the latest novel treatment option, telotristat ethyl. In addition, information on patient-reported outcomes and impact of carcinoid syndrome on quality of life (QOL) and improvement of following treatment with telotristat ethyl are reviewed. This article also provides an overview of the current QOL questionnaires for patients with NETs and addresses unmet needs in this field of patient-reported outcomes.

Brain Signals of Face Processing as Revealed by Event-Related Potentials.

We analyze the functional significance of different event-related potentials (ERPs) as electrophysiological indices of face perception and face recognition, according to cognitive and neurofunctional models of face processing. Initially, the processing of faces seems to be supported by early extrastriate occipital cortices and revealed by modulations of the occipital P1. This early response is thought to reflect the detection of certain primary structural aspects indicating the presence grosso modo of a face within the visual field. The posterior-temporal N170 is more sensitive to the detection of faces as complex-structured stimuli and, therefore, to the presence of its distinctive organizational characteristics prior to within-category identification. In turn, the relatively late and probably more rostrally generated N250r and N400-like responses might respectively indicate processes of access and retrieval of face-related information, which is stored in long-term memory (LTM). New methods of analysis of electrophysiological and neuroanatomical data, namely, dynamic causal modeling, single-trial and time-frequency analyses, are highly recommended to advance in the knowledge of those brain mechanisms concerning face processing.

Relevancia del margen de resección positivo en adenocarcinoma ductal de páncreas y otros factores pronósticos / Relevance of positive resection margins in ductal pancreatic adenocarcinoma and prognostic factors

Introducción: Actualmente en cirugía del cáncer de páncreas se considera margen de resección afecto (R1) la presencia de células tumorales a <1mm del borde de resección. El objetivo principal del estudio es analizar el impacto del margen de resección en la supervivencia. Métodos: Análisis retrospectivo con análisis de regresión multivariante de una base de datos prospectiva (2008-2017), donde se incluye el margen de resección, el margen de resección ampliado (R1 < 1 mm), la resección vascular, la afectación linfática, las complicaciones quirúrgicas, la diferenciación tumoral y el tratamiento adyuvante. Resultados: Un total de 80 pacientes fueron analizados, 42 (52%) R1 y 38 (48%) R0. No se encontraron diferencias en la composición de ambos grupos salvo en la resección vascular, que fue mayor en el grupo R1, 12 (21%) vs. 2 (3%). La supervivencia en el grupo R0 fue de 19 meses vs. 24 meses en el grupo R1 (p = 0,13). El margen ampliado (R1 < 1 mm) tuvo una supervivencia de 21 meses vs. 31 meses en R0 ampliado (p = 0,55). En el análisis multivariante solo se encontraron la afectación ganglionar (p = 0,02; HR = 2,88), la diferenciación tumoral (p = 0,02; HR = 3,2) y la adyuvancia (p < 0,01; HR = 0,21) como factores pronósticos de supervivencia. Conclusiones: En el estudio la resección R1 no supone un factor pronóstico. La afectación ganglionar, el grado de diferenciación y el tratamiento adyuvante son factores pronósticos. Debe demostrarse el beneficio de ampliar los márgenes de resección. Son necesarios más estudios para valorar el impacto del margen de resección

Introduction: Currently, R1 resection is defined by the presence of tumor cells within < 1 mm of the resection margin. The main aim of this study was to analyze the impact of positive margins (R1) on survival outcomes in pancreatic cancer. Methods: We performed a retrospective analysis with multivariate regression analysis of a prospective database from 2008-2017, which included resection margin status, expanded resection margin (R1 < 1 mm), vascular resection, lymphatic involvement, surgical complications, tumor differentiation grade and adjuvant treatment. Results: A total of 80 patients were analyzed: 42 (52%) R1; 38 (48%) R0. No differences were found in the composition of the two groups except for the vascular resection, which was more frequent in the R1 group: 12 (21%) vs 2 (3%). Overall survival in the R0 group was 19 months vs 24 months in the R1 group (p = 0.13). Wide R1 (R1 < 1 mm) had an overall survival of 21 months versus 31 months in wide R0 (p = 0.55). In the multivariate analysis, only lymph node involvement (p = 0.02, HR = 2.88), tumor differentiation (p = 0.02, HR = 3.2) and adjuvant therapy (p < 0.01; HR = 0.21) were found to be factors related to survival. Conclusions: R1 resection is not an independent risk factor. Lymph node involvement, differentiation grade and adjuvant treatment are prognostic factors. The benefit of expanding the resection margins should be demonstrated. More studies are needed to assess the impact of the resection margin

Long-term information and distributed neural activation are relevant for the "internal features advantage" in face processing: electrophysiological and source reconstruction evidence.

In face processing tasks, prior presentation of internal facial features, when compared with external ones, facilitates the recognition of subsequently displayed familiar faces. In a previous ERP study (Olivares & Iglesias, 2010) we found a visibly larger N400-like effect when identity mismatch familiar faces were preceded by internal features, as compared to prior presentation of external ones. In the present study we contrasted the processing of familiar and unfamiliar faces in the face-feature matching task to assess whether the so-called "internal features advantage" relies mainly on the use of stored face-identity-related information or if it might operate independently from stimulus familiarity. Our participants (N = 24) achieved better performance with internal features as primes and, significantly, with familiar faces. Importantly, ERPs elicited by identity mismatch complete faces displayed a negativity around 300-600 msec which was clearly enhanced for familiar faces primed by internal features when compared with the other experimental conditions. Source reconstruction showed incremented activity elicited by familiar stimuli in both posterior (ventral occipitotemporal) and more anterior (parahippocampal (ParaHIP) and orbitofrontal) brain regions. The activity elicited by unfamiliar stimuli was, in general, located in more posterior regions. Our findings suggest that the activation of multiple neural codes is required for optimal individuation in face-feature matching and that a cortical network related to long-term information for face-identity processing seems to support the internal feature effect.

Cognitive decline effects at an early stage: evidence from N170 and VPP.

The perceptual processing of faces was studied using event-related potentials (ERPs) in 12 elderly patients with cognitive impairment, 15 elderly adults and 16 young adults in order to explore the sensitivity of N170/VPP to the cognitive decline associated to Alzheimer's disease. Famous and unknown faces were presented in a familiarity categorization task. Eight patients and 11 elderly adults repeated this task to obtain longitudinal data. Topographical effects were analyzed using PCA. The posterior N170 showed reduced amplitude in patients with cognitive impairment and elderly adults, compared to young adults, which could indicate perceptual impairment in configural face-encoding processing. The anterior VPP showed enhanced amplitude in patients with cognitive impairment, compared to young and elderly adults, which might relate to the prefrontal dysfunction associated to mild dementia. These preliminary findings suggest that N170/VPP could be modulated by the decline related to pathological cognitive aging.

Masa abdominal gigante de origen indeterminado, ¿es el carcinoma de células cromófobas un diagnóstico a tener en cuenta? / Giant abdominal mass of undetermined origin: Should the diagnosis of chromophobe carcinoma be considered?

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