Neoadjuvant Immunotherapy: A Promising New Standard of Care.

Neoadjuvant immunotherapy has emerged as a promising approach in the treatment of various malignancies, with preclinical studies showing improved immune responses in the preoperative setting. FDA-approved neoadjuvant-immunotherapy-based approaches include triple-negative breast cancer and early non-small cell lung cancer on the basis of improvement in pathological response and event free survival. Nevertheless, current trials have only shown benefits in a fraction of patients. It is therefore crucial to identify predictive biomarkers to improve patient selection for such approaches. This review aims to provide an overview of potential biomarkers of neoadjuvant immunotherapy in early triple-negative breast cancer, bladder cancer, melanoma, non-small cell lung cancer, colorectal cancer and gastric cancer. By the extrapolation of the metastatic setting, we explore known predictive biomarkers, i.e., PD-L1, mismatch repair deficiency and tumour mutational burden, as well as potential early-disease-specific biomarkers. We also discuss the challenges of identifying reliable biomarkers and the need for standardized protocols and guidelines for their validation and clinical implementation.

Chemotherapy-related agranulocytosis as a predictive factor for germline BRCA1 pathogenic variants in breast cancer patients: a retrospective cohort study.

BACKGROUND: Carriers of germline pathogenic variants of the BRCA1 gene (gBRCA1) tend to have a higher incidence of haematological toxicity upon exposure to chemotherapy. We hypothesised that the occurrence of agranulocytosis during the first cycle of (neo-)adjuvant chemotherapy (C1) in breast cancer (BC) patients could predict gBRCA1 pathogenic variants. PATIENTS AND METHODS: The study population included non-metastatic BC patients selected for genetic counselling at Hôpitaux Universitaires de Genève (Jan. 1998 to Dec. 2017) with available mid-cycle blood counts performed during C1. The BOADICEA and Manchester scoring system risk-prediction models were applied. The primary outcome was the predicted likelihood of harbouring gBRCA1 pathogenic variants among patients presenting agranulocytosis during C1. RESULTS: Three hundred seven BC patients were included: 32 (10.4%) gBRCA1, 27 (8.8%) gBRCA2, and 248 (81.1%) non-heterozygotes. Mean age at diagnosis was 40 years. Compared with non-heterozygotes, gBRCA1 heterozygotes more frequently had grade 3 BC (78.1%; p = 0.014), triple-negative subtype (68.8%; p <0.001), bilateral BC (25%; p = 0.004), and agranulocytosis following the first cycle of (neo-)adjuvant chemotherapy (45.8%; p = 0.002). Agranulocytosis and febrile neutropenia that developed following the first cycle of chemotherapy were independently predictive for gBRCA1 pathogenic variants (odds ratio: 6.1; p = 0.002). The sensitivity, specificity, positive predictive value, and negative predictive value for agranulocytosis predicting gBRCA1 were 45.8% (25.6-67.2%), 82.8% (77.5-87.3%), 22.9% (6.1-37.3%), and 93.4% (88.9-96.4%), respectively. Agranulocytosis substantially improved the positive predictive value of the risk-prediction models used for gBRCA1 evaluation. CONCLUSION: Agranulocytosis following the first cycle of (neo-)adjuvant chemotherapy is an independent predictive factor for gBRCA1 detection in non-metastatic BC patients.

Hematologic toxicities of chemotherapy in breast and ovarian cancer patients carrying BRCA1/BRCA2 germline pathogenic variants. A single center experience and review of the literature.

BRCA1 and BRCA2 play a central role in DNA repair and their germline pathogenic variants (gBRCA) confer a high risk for developing breast and ovarian cancer. Standard chemotherapy regimens for these cancers include DNA-damaging agents. We hypothesized that gBRCA carriers might be at higher risk of developing chemotherapy-related hematologic toxicity and therapy-related myeloid neoplasms (t-MN). We conducted a retrospective study of women newly diagnosed with invasive breast or ovarian cancer who were screened for gBRCA1/gBRCA2 at Geneva University Hospitals. All patients were treated with (neo-)adjuvant chemotherapy. We evaluated acute hematologic toxicities by analyzing the occurrence of febrile neutropenia and severe neutropenia (grade 4) at day 7-14 of the first cycle of chemotherapy and G-CSF use during the entire chemotherapy regimen. Characteristics of t-MN were collected. We reviewed medical records from 447 patients: 58 gBRCA1 and 40 gBRCA2 carriers and 349 non-carriers. gBRCA1 carriers were at higher risk of developing severe neutropenia (32% vs. 14.5%, p = 0.007; OR = 3.3, 95% CI [1.6-7], p = 0.001) and of requiring G-CSF for secondary prophylaxis (58.3% vs. 38.2%, p = 0.011; OR = 2.5, 95% CI [1.4-4.8], p = 0.004). gBRCA2 carriers did not show increased acute hematologic toxicities. t-MN were observed in 2 patients (1 gBRCA1 and one non-carrier). Our results suggested an increased acute hematologic toxicity upon exposure to chemotherapy for breast and ovarian cancer among gBRCA1 but not gBRCA2 carriers. A deeper characterization of t-MN is warranted with the recent development of PARP inhibitors in frontline therapy in gBRCA breast and ovarian cancer.

Primary spontaneous intracerebral hemorrhage in COVID-19 patients: differences among presentation patterns - A systematic review.

OBJECTIVE: The objective of this study was to determine if there are differences between the presentation patterns of hemorrhagic stroke (HS) associated to COVID-19. METHODS: It was performed a systematic search based on PRISMA guidelines of the cases reported in PUBMED of HS associated to SARS-CoV-2 infection and we added to this sample cases from our own hospital cohort. Patients in the database were separated by groups according to presentation symptoms: if they debuted with neurological symptoms or debuted with pulmonary symptoms. RESULTS: Seventy cases were included in the study. Patients that debuted with pulmonary symptoms accounted for 68.6% of the cases with an interval between the development of symptoms and the presentation of HS of 15.6 days. We found that the use of anticoagulants during hospitalization, multifocal image pattern, and the elevation of D-dimer, Ferritin, and lactate dehydrogenase levels were significantly associated with the group of pulmonary presentation, whereas the presence of hypertension during hospitalization, and a lower hemoglobin level was associated with the group of neurologic symptoms. CONCLUSION: Although HS associated with COVID-19 is a clinical entity with increasing evidence, it is necessary to establish that there are two forms of presentation with their own characteristics.

OBJETIVO: determinar si existen diferencias entre los patrones de presentación de hemorragia intracraneal asociada a COVID-19. PACIENTES Y MÉTODOS: Se realizó una búsqueda sistemática basada en la guía PRISMA de los casos reportados en PUBMED de hemorragia intracraneal asociados a infección por SARS-CoV-2 y se agregaron a esta muestra casos de nuestra propia cohorte hospitalaria. RESULTADOS: se incluyeron 70 casos. Los pacientes que debutaron con síntomas pulmonares representaron el 68.6% de los casos con un intervalo entre el desarrollo de los síntomas y la presentación de la hemorragia intracraneal de 15.6 días. Encontramos que el uso de anticoagulantes durante la hospitalización, el patrón de imagen multifocal y la elevación de los niveles de dímero D, ferritina y deshidrogenasa láctica se asociaron significativamente con el grupo de presentación pulmonar, mientras que la presencia de hipertensión durante la hospitalización, y un nivel de hemoglobina más bajo se asoció con el grupo que debutó con síntomas neurológicos. CONCLUSIÓN: si bien la hemorragia intracraneal asociada a COVID-19 es una entidad clínica con evidencia creciente, es necesario establecer que existen dos formas de presentación con características propias.

Hospital Arrival and Functional Outcome after Intracerebral Hemorrhage.

BACKGROUND: Intracerebral hemorrhage (ICH) is associated with an ominous outcome influenced by the time to hospital presentation. OBJECTIVE: This study aims to identify the factors that influence an early hospital arrival after ICH and the relationship with outcome. METHODS: In this multicenter registry, patients with confirmed ICH on CT scan and well-known time of symptoms onset were studied. Clinical data, arrival conditions, and prognostic scores were analyzed. Multivariate models were built to find independent predictors of < 6 h arrival (logistic regression) and in-hospital death (Cox proportional-hazards model). RESULTS: Among the 473 patients analyzed (51% women, median age 63 years), the median delay since onset to admission was 6.25 h (interquartile range: 2.5-24 h); 7.8% arrived in < 1 h, 26.3% in < 3 h, 45.3% in < 6 h, and 62.3% in < 12 h. The in-hospital, 30-day and 90-day case fatality rates were 28.8%, 30.0%, and 32.6%, respectively. Predictors of arrival in < 6 h were hypertension treatment (odds ratios [OR]: 1.675, 95% confidence intervals [CI]: 1.030-2.724), ≥ 3 years of schooling (OR: 1.804, 95% CI: 1.055-3.084), and seizures at ICH onset (OR: 2.416, 95% CI: 1.068-5.465). Predictors of death (56.9% neurological) were systolic blood pressure > 180 mmHg (hazards ratios [HR]: 1.839, 95% CI: 1.031-3.281), ICH score ≥ 3 (HR: 2.302, 95% CI: 1.300-4.074), and admission Glasgow Coma Scale < 8 (HR: 4.497, 95% CI: 2.466-8.199). Early arrival was not associated with outcome at discharge, 30 or 90 days. CONCLUSIONS: In this study, less than half of patients with ICH arrived to the hospital in < 6 h. However, early arrival was not associated with the short-term outcome in this data set.

Reliability of Bystander Recognition of Clinical Features in Pre-Hospital Classification of Acute Cerebrovascular Syndromes: Preliminary Findings

ABSTRACT Background: The recognition of stroke symptoms by patients or bystanders directly affects the outcomes of patients with acute cerebrovascular disease. Objective: The objective of the study was to assess the predictive value of the medical history and clinical features recognized by the patients’ bystanders to classify neurovascular syndromes in pre-hospital settings. Methods: We included 150 stroke patients of two Mexican referral centers: 50 with acute ischemic stroke (AIS), 50 with intracerebral hemorrhage (ICH), and 50 with subarachnoid hemorrhage (SAH). The performance of clinical prediction rules (CPR) to identify the stroke types was evaluated with features recognized by the patients’ bystanders before hospital arrival. The impact of CPRs on early arrival and in-hospital mortality was also analyzed. Results: Overall, 72% of the patients had previous medical evaluations in other centers before final referral to our hospitals, and therefore, only 45% had a final onset-to-door time <6 h, even when the first medical assessment had occurred in ≤1 h in 75% of cases. Clinical features noticed by the patients’ bystanders had low positive predictive values (PPV) for any stroke type. The CPR “language or speech disorder + focal motor deficit” had 93% sensitivity and a negative predictive value (NPV) of 84% to distinguish AIS. In SAH, headache alone showed a sensitivity of 84% and NPV of 97%. No CPR had an adequate performance on ICH. CPRs were not associated with final onset-to-door time. Altered consciousness, age ≥65 years, indirect arrival with stops before final referral, and atrial fibrillation increased in-hospital mortality. Conclusion: Clinical features referred by the witness of a neurovascular emergency have limited PPV, but adequate NPV in ruling-out AIS and SAH among stroke types. The use of CPRs had no impact on onset-to-door time or in-hospital mortality when the final arrival to a third-level center occurs with previous medical referrals.

Reliability of Bystander Recognition of Clinical Features in Pre-Hospital Classification of Acute Cerebrovascular Syndromes: Preliminary Findings.

BACKGROUND: The recognition of stroke symptoms by patients or bystanders directly affects the outcomes of patients with acute cerebrovascular disease. OBJECTIVE: The objective of the study was to assess the predictive value of the medical his- tory and clinical features recognized by the patients' bystanders to classify neurovascular syndromes in pre-hospital settings. METHODS: We included 150 stroke patients of two Mexican referral centers: 50 with acute ischemic stroke (AIS), 50 with intracerebral hemorrhage (ICH), and 50 with subarachnoid hemorrhage (SAH). The performance of clinical prediction rules (CPR) to identify the stroke types was evaluated with features recognized by the patients' bystanders before hospital arrival. The impact of CPRs on early arrival and in-hospital mortality was also analyzed. RESULTS: Overall, 72% of the patients had previous medical evaluations in other centers before final referral to our hospitals, and therefore, only 45% had a final onset- to-door time <6 h, even when the first medical assessment had occurred in ≤1 h in 75% of cases. Clinical features noticed by the patients' bystanders had low positive predictive values (PPV) for any stroke type. The CPR "language or speech disor- der + focal motor deficit" had 93% sensitivity and a negative predictive value (NPV) of 84% to distinguish AIS. In SAH, head- ache alone showed a sensitivity of 84% and NPV of 97%. No CPR had an adequate performance on ICH. CPRs were not as- sociated with final onset-to-door time. Altered consciousness, age ≥65 years, indirect arrival with stops before final referral, and atrial fibrillation increased in-hospital mortality. CONCLUSION: Clinical features referred by the witness of a neurovascular emergency have limited PPV, but adequate NPV in ruling-out AIS and SAH among stroke types. The use of CPRs had no impact on onset-to-door time or in-hospital mortality when the final arrival to a third-level center occurs with previous medical refer- rals.

Acute Disseminated Encephalomyelitis with Baló-like Lesion by Scorpion Sting: Case Report.

Acute disseminated encephalomyelitis (ADEM) has been linked to immunizations, viral infections, and occasionally to arthropods stings. Its association with scorpion stings has not been described. A 29-year-old man, who after being stung by a scorpion presented right hemiparesis and language impairment. Brain MRI showed subcortical bihemispheric lesion characteristics of ADEM and a bigger one compatible with Baló concentric sclerosis (BCS). Patient was managed with steroids, showing complete clinical improvement. Magnetic resonance imaging (MRI) after 6 months showed cavitation of the bigger lesion with no new findings. In 2 years of follow-up, there is no clinical relapse or new lesions in MRI. Although cases of ADEM have been reported due to venom of chilopoda and hymenoptera, the scorpion sting can be considered as another new cause; this case being even more relevant due to present a Baló-like lesion in MRI.

Vinpocetina de liberación prolongada: un posible tratamiento adyuvante en crisis epiléptica de inicio focal / Extended-release vinpocetine: a possible adjuvant treatment for focal onset epileptic seizures

Resumen Introducción: La vinpocetina de liberación prolongada ha demostrado ser efectiva en el control de crisis de inicio focal en pacientes epilépticos con una baja frecuencia de eventos adversos. Se realizó un estudio clínico para evaluar la eficacia y tolerabilidad de la vinpocetina como tratamiento adyuvante en pacientes con este padecimiento. Métodos: Se realizó un estudio clínico, doble ciego, de grupos paralelos. Se reclutaron 87 pacientes con diagnóstico de epilepsia focal tratados con uno a tres fármacos antiepilépticos. Los pacientes se aleatorizaron para ser tratados con vinpocetina (n = 41) o placebo (n = 46) de manera adyuvante a su tratamiento, e ingresaron a la fase basal (4 semanas), a la fase de titulación (4 semanas) y a la fase de evaluación (8 semanas) conservando estables las dosis de la vinpocetina y de los fármacos antiepilépticos. Resultados: La vinpocetina fue más efectiva que el placebo en la reducción de las crisis al finalizar la fase de evaluación (p < 0.0001). El 69% de los pacientes tratados con vinpocetina presentaron una reducción mayor al 50% en las crisis en comparación con el 13% de los pacientes tratados con placebo. No se presentaron diferencias significativas en cuanto a la presencia de efectos adversos en los pacientes tratados con vinpocetina comparados con los tratados con placebo. Los eventos adversos más frecuentes observados con vinpocetina fueron cefalea (7.9%) y diplopía (5.2%). Conclusiones: Como tratamiento adyuvante, la vinpocetina (2 mg/kg/día) redujo eficazmente la frecuencia de crisis epilépticas y demostró ser bien tolerada. Presenta un amplio perfil de seguridad y eventos adversos conocidos, que son transitorios y sin secuelas.

Abstract Background: Extended-release vinpocetine is effective to control focal onset epileptic seizures with a low rate of adverse events. A clinical study was performed to evaluate the efficacy and tolerability of vinpocetine as an adjuvant treatment in patients with this condition. Methods: A double-blind clinical study of parallel groups was conducted, in which 87 patients with a diagnosis of focal epilepsy treated with one to three antiepileptic drugs were recruited. Patients were randomized to receive vinpocetine (n = 41) or placebo (n = 46) adjuvant to their treatment. Patients entered the baseline phase (4 weeks), the titration phase (4 weeks) and the evaluation phase (8 weeks), maintaining stable doses of vinpocetine and their respective antiepileptic drug treatment. Results: Vinpocetine was more effective than placebo in reducing seizures at the end of the evaluation phase (p < 0.0001). Sixty-nine percent of the vinpocetine-treated patients had a 50% reduction in seizures compared to 13% of placebo-treated patients. No significant differences in the presence of adverse effects in patients treated with vinpocetine compared to those treated with placebo were observed. The most frequent adverse events observed with vinpocetine were headache (7.9%) and diplopia (5.2%). Conclusions: As an adjuvant treatment, vinpocetine (2 mg/kg/day) effectively reduced the frequency of epileptic seizures and proved to be well tolerated. Vinpocetine has a wide safety profile and well-known adverse events, which are transient and with no sequelae.

Extended-release vinpocetine: a possible adjuvant treatment for focal onset epileptic seizures.

Background: Extended-release vinpocetine is effective to control focal onset epileptic seizures with a low rate of adverse events. A clinical study was performed to evaluate the efficacy and tolerability of vinpocetine as an adjuvant treatment in patients with this condition. Methods: A double-blind clinical study of parallel groups was conducted, in which 87 patients with a diagnosis of focal epilepsy treated with one to three antiepileptic drugs were recruited. Patients were randomized to receive vinpocetine (n = 41) or placebo (n = 46) adjuvant to their treatment. Patients entered the baseline phase (4 weeks), the titration phase (4 weeks) and the evaluation phase (8 weeks), maintaining stable doses of vinpocetine and their respective antiepileptic drug treatment. Results: Vinpocetine was more effective than placebo in reducing seizures at the end of the evaluation phase (p < 0.0001). Sixty-nine percent of the vinpocetine-treated patients had a 50% reduction in seizures compared to 13% of placebo-treated patients. No significant differences in the presence of adverse effects in patients treated with vinpocetine compared to those treated with placebo were observed. The most frequent adverse events observed with vinpocetine were headache (7.9%) and diplopia (5.2%). Conclusions: As an adjuvant treatment, vinpocetine (2 mg/kg/day) effectively reduced the frequency of epileptic seizures and proved to be well tolerated. Vinpocetine has a wide safety profile and well-known adverse events, which are transient and with no sequelae.

Introducción: La vinpocetina de liberación prolongada ha demostrado ser efectiva en el control de crisis de inicio focal en pacientes epilépticos con una baja frecuencia de eventos adversos. Se realizó un estudio clínico para evaluar la eficacia y tolerabilidad de la vinpocetina como tratamiento adyuvante en pacientes con este padecimiento. Métodos: Se realizó un estudio clínico, doble ciego, de grupos paralelos. Se reclutaron 87 pacientes con diagnóstico de epilepsia focal tratados con uno a tres fármacos antiepilépticos. Los pacientes se aleatorizaron para ser tratados con vinpocetina (n = 41) o placebo (n = 46) de manera adyuvante a su tratamiento, e ingresaron a la fase basal (4 semanas), a la fase de titulación (4 semanas) y a la fase de evaluación (8 semanas) conservando estables las dosis de la vinpocetina y de los fármacos antiepilépticos. Resultados: La vinpocetina fue más efectiva que el placebo en la reducción de las crisis al finalizar la fase de evaluación (p < 0.0001). El 69% de los pacientes tratados con vinpocetina presentaron una reducción mayor al 50% en las crisis en comparación con el 13% de los pacientes tratados con placebo. No se presentaron diferencias significativas en cuanto a la presencia de efectos adversos en los pacientes tratados con vinpocetina comparados con los tratados con placebo. Los eventos adversos más frecuentes observados con vinpocetina fueron cefalea (7.9%) y diplopía (5.2%). Conclusiones: Como tratamiento adyuvante, la vinpocetina (2 mg/kg/día) redujo eficazmente la frecuencia de crisis epilépticas y demostró ser bien tolerada. Presenta un amplio perfil de seguridad y eventos adversos conocidos, que son transitorios y sin secuelas.

Hypertensive thalamic hemorrhage: analysis of short-term outcome.

BACKGROUND: Hypertension is the main cause of intracerebral hemorrhage with a thalamic location frequency that varies from 6% to 26.5%. OBJECTIVE: We aimed to identify clinical and radiological features that could impact the short-term prognosis in patients with hypertensive thalamic hemorrhage (HTH). METHODS: Consecutive patients presenting to a tertiary referral hospital with HTH were analyzed from 2010 to 2014. Clinical features at emergency department and a 30-day outcome using the modified Rankin Scale (mRS) were obtained. RESULTS: A total of 104 patients were studied (53 women, mean age 68.2 years, range 27-91 years), 91 (87.5%) of them with hypertension history. Mean hemorrhage volume was 12.2 mL (range 2-45 mL), without significant differences according to gender or age group. Irruption into the ventricular system occurred in 79 (76%) cases. Thirty-day mortality was 38.5% and occurred with a higher frequency in men, in patients with GCS <8, intraventricular irruption, ventriculostomy, and intracerebral hemorrhage volumes >15 mL. CONCLUSIONS: Although HTH is associated with relatively small hemorrhage volume, it had a higher frequency of ventricular irruption and bad prognosis at short-term.

Global transcriptional analysis identifies a novel role for SOX4 in tumor-induced angiogenesis.

The expression of the transcription factor SOX4 is increased in many human cancers, however, the pro-oncogenic capacity of SOX4 can vary greatly depending on the type of tumor. Both the contextual nature and the mechanisms underlying the pro-oncogenic SOX4 response remain unexplored. Here, we demonstrate that in mammary tumorigenesis, the SOX4 transcriptional network is dictated by the epigenome and is enriched for pro-angiogenic processes. We show that SOX4 directly regulates endothelin-1 (ET-1) expression and can thereby promote tumor-induced angiogenesis both in vitro and in vivo. Furthermore, in breast tumors, SOX4 expression correlates with blood vessel density and size, and predicts poor-prognosis in patients with breast cancer. Our data provide novel mechanistic insights into context-dependent SOX4 target gene selection, and uncover a novel pro-oncogenic role for this transcription factor in promoting tumor-induced angiogenesis. These findings establish a key role for SOX4 in promoting metastasis through exploiting diverse pro-tumorigenic pathways.

SOX4 can redirect TGF-ß-mediated SMAD3-transcriptional output in a context-dependent manner to promote tumorigenesis.

Expression of the transcription factor SOX4 is often elevated in human cancers, where it generally correlates with tumor-progression and poor-disease outcome. Reduction of SOX4 expression results in both diminished tumor-incidence and metastasis. In breast cancer, TGF-ß-mediated induction of SOX4 has been shown to contribute to epithelial-to-mesenchymal transition (EMT), which controls pro-metastatic events. Here, we identify SMAD3 as a novel, functionally relevant SOX4 interaction partner. Genome-wide analysis showed that SOX4 and SMAD3 co-occupy a large number of genomic loci in a cell-type specific manner. Moreover, SOX4 expression was required for TGF-ß-mediated induction of a subset of SMAD3/SOX4-co-bound genes regulating migration and extracellular matrix-associated processes, and correlating with poor-prognosis. These findings identify SOX4 as an important SMAD3 co-factor controlling transcription of pro-metastatic genes and context-dependent shaping of the cellular response to TGF-ß. Targeted disruption of the interaction between these factors may have the potential to disrupt pro-oncogenic TGF-ß signaling, thereby impairing tumorigenesis.