HER2 expression and genOmic characterization of rESected brain metastases from colorectal cancer: the HEROES study.

BACKGROUND: Little is known about prognostic factors of brain metastases (BM) from colorectal cancer (CRC). HER2 amplification/overexpression (HER2+) was previously described; its impact on prognosis remains uncertain. METHODS: In the translational study HEROES, extensive molecular analysis was performed on primary CRC (prCRC) and their matched resected BM by means of NGS comprehensive genomic profiling and HER2 status as assessed by immunohistochemical/ in situ hybridization. Count of tumour-infiltrating lymphocytes (TILs) was also performed. PRIMARY OBJECTIVE: to describe the molecular landscape of paired BM/prCRC. SECONDARY OBJECTIVES: to search for new prognostic biomarkers of outcome after BM resection: intracranial-only Progression-Free Survival (BM-iPFS), Progression-Free Survival (BM-PFS), and Overall Survival (BM-OS). RESULTS: Out of 22 patients having paired samples of prCRC and BM, HER2+ was found on 4 (18%) BM, 3 (75%) of which also HER2+ in matched prCRC. Lower tumour mutation burden (HR 3.08; 95%CI 1.06-8.93; p = 0.0386) and HER2-negative BM (HER2neg) (HR 7.75;95%CI 1.97-30.40; p = 0.0033) were associated with longer BM-iPFS; HER2neg BM (HR 3.44; 95%CI 1.03-11.53; p = 0.0449) and KRASmut BM (HR 0.31; 95%CI 0.12-0.80; p = 0.0153) conferred longer BM-PFS. Longer BM-OS was found in pts with TILs-enriched (≥1.6/HPF) BM (HR 0.11; 95%CI0.01-0.91; p = 0.0403). CONCLUSIONS: This study shows HER2+ enrichment in both BM and their prCRC. TILs-enriched BM conferred better BM-OS.

Activated phosphoinositde 3-kinase (PI3Kδ) syndrome: an Italian point of view on diagnosis and new advances in treatment.

Activated phosphoinositide 3-kinase (PI3Kδ) Syndrome (APDS) is an inborn error of immunity (IEI) with a variable clinical presentation, characterized by infection susceptibility and immune dysregulation that may overlaps with other Primary Immune Regulatory Disorders (PIRDs). The rarity of the disease, its recent discovery, and the multiform /multifaced clinical presentation make it difficult to establish a correct diagnosis, especially at an early stage. As a result, the true prevalence of the pathology remains unknown. There is no treatment protocol for APDS, and drug therapy is primarily focused on treating symptoms. The most common therapies include immunoglobulin replacement therapy, antimicrobial prophylaxis, and immunosuppressive drugs. Hematopoietic stem cell transplantation (HSCT) has been used in some cases, but the risk-benefit balance remains unclear. With the upcoming introduction of specific medications, such as selective inhibitors for PI3Kδ, clinicians are shifting their attention towards target therapy.This review provides a comprehensive overview of APDS with a focus on diagnostic and treatments procedures available. This review may be useful in implementing strategies for a more efficient patients' management and therapeutic interventions.Main Text.

Understanding the Variability of 22q11.2 Deletion Syndrome: The Role of Epigenetic Factors.

Initially described as a triad of immunodeficiency, congenital heart defects and hypoparathyroidism, 22q11.2 deletion syndrome (22q11.2DS) now encompasses a great amount of abnormalities involving different systems. Approximately 85% of patients share a 3 Mb 22q11.2 region of hemizygous deletion in which 46 protein-coding genes are included. However, the hemizygosity of the genes of this region cannot fully explain the clinical phenotype and the phenotypic variability observed among patients. Additional mutations in genes located outside the deleted region, leading to "dual diagnosis", have been described in 1% of patients. In some cases, the hemizygosity of the 22q11.2 region unmasks autosomal recessive conditions due to additional mutations on the non-deleted allele. Some of the deleted genes play a crucial role in gene expression regulation pathways, involving the whole genome. Typical miRNA expression patterns have been identified in 22q11.2DS, due to an alteration in miRNA biogenesis, affecting the expression of several target genes. Also, a methylation epi-signature in CpG islands differentiating patients from controls has been defined. Herein, we summarize the evidence on the genetic and epigenetic mechanisms implicated in the pathogenesis of the clinical manifestations of 22q11.2 DS. The review of the literature confirms the hypothesis that the 22q11.2DS phenotype results from a network of interactions between deleted protein-coding genes and altered epigenetic regulation.

Durvalumab Plus Gemcitabine and Cisplatin Versus Gemcitabine and Cisplatin in Biliary Tract Cancer: a Real-World Retrospective, Multicenter Study.

BACKGROUND: The TOPAZ-1 phase III trial reported a survival benefit with the anti-programmed cell death ligand 1 (anti-PD-L1) durvalumab in combination with gemcitabine and cisplatin in patients with advanced biliary tract cancer (BTC). OBJECTIVE: The present study investigated for the first time the impact on survival of adding durvalumab to cisplatin/gemcitabine compared with cisplatin/gemcitabine in a real-world setting. PATIENTS AND METHODS: The analyzed population included patients with unresectable, locally advanced, or metastatic BTC treated with durvalumab in combination with cisplatin/gemcitabine or with cisplatin/gemcitabine alone. The impact of adding durvalumab to chemotherapy in terms of overall survival (OS) and progression free survival (PFS) was investigated with univariate and multivariate analysis. RESULTS: Overall, 563 patients were included in the analysis: 213 received cisplatin/gemcitabine alone, 350 received cisplatin/gemcitabine plus durvalumab. At the univariate analysis, the addition of durvalumab was found to have an impact on survival, with a median OS of 14.8 months versus 11.2 months [hazard ratio (HR) 0.63, 95% confidence interval (CI) 0.50-0.80, p = 0.0002] in patients who received cisplatin/gemcitabine plus durvalumab compared to those who received cisplatin/gemcitabine alone. At the univariate analysis for PFS, the addition of durvalumab to cisplatin/gemcitabine demonstrated a survival impact, with a median PFS of 8.3 months and 6.0 months (HR 0.57, 95% CI 0.47-0.70, p < 0.0001) in patients who received cisplatin/gemcitabine plus durvalumab and cisplatin/gemcitabine alone, respectively. The multivariate analysis confirmed that adding durvalumab to cisplatin/gemcitabine is an independent prognostic factor for OS and PFS, with patients > 70 years old and those affected by locally advanced disease experiencing the highest survival benefit. Finally, an exploratory analysis of prognostic factors was performed in the cohort of patients who received durvalumab: neutrophil-lymphocyte ratio (NLR) and disease stage were to be independent prognostic factors in terms of OS. The interaction test highlighted NLR ≤ 3, Eastern Cooperative Oncology Group Performance Status (ECOG PS) = 0, and locally advanced disease as positive predictive factors for OS on cisplatin/gemcitabine plus durvalumab. CONCLUSION: In line with the results of the TOPAZ-1 trial, adding durvalumab to cisplatin/gemcitabine has been confirmed to confer a survival benefit in terms of OS and PFS in a real-world setting of patients with advanced BTC.

Durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer: A large real-life worldwide population.

BACKGROUND: The TOPAZ-1 phase III trial showed a survival benefit with durvalumab plus gemcitabine and cisplatin in patients with advanced biliary tract cancer (BTC). To understand this combination's real-world efficacy and tolerability, we conducted a global multicenter retrospective analysis of its first-line treatment outcomes. METHODS: We included patients with unresectable, locally advanced, or metastatic BTC treated with durvalumab, gemcitabine, and cisplatin at 39 sites in 11 countries (Europe, the United States, and Asia). The primary endpoint was overall survival (OS). RESULTS: 666 patients were enrolled. Median OS was 15.1 months and median PFS was 8.2 months. The investigator-assessed overall response rate was 32.7 %, with stable disease in 45.2 % of patients. High baseline CEA levels, ECOG PS > 0, metastatic disease, and NLR > 3 were associated with poor survival. Any grade adverse events (AEs) occurred in 92.9 % of patients (grade >2: 46.6 %). Immune-related AEs (irAEs) occurred in 20.0 % (grade >2: 2.5 %). Three deaths (0.5 %) were deemed treatment-related, none linked to immunotherapy. Common irAEs were rash (8.2 % all grades; 0.3 % grade >2), itching (10.3 % all grades; 0.2 % grade >2), and hypothyroidism (5.1 % all grades; 0.3 % grade >2). Durvalumab discontinuation rate due to AEs was 1.5 %. ESMO-recommended genes were analyzed and no outcome differences were found. A comparative analysis with a historical cohort of patients treated with chemotherapy alone confirmed the positive survival impact of durvalumab in combination with cisplatin/gemcitabine. CONCLUSION: This first global real-world analysis largely confirmed the TOPAZ-1 findings, supporting gemcitabine, cisplatin, and durvalumab as a first-line standard of care for patients with advanced BTC.

Endocarditis infecciosa producida por Bartonella quintana / Infective endocarditis due to Bartonella quintana

Presentamos el caso de un hombre de 68 años que ingresó por mareos y sensación de pérdida de la conciencia. El examen clínico reveló una temperatura de 37.5 °C y un soplo de regurgitación mitral. El ecocardiograma mostró una insuficiencia mitral grave con dilatación de las cavidades izquierdas, y el ecocardiograma transesofágico una vegetación en la valva anterior de la mitral. Los hemocultivos demostraron una bacteria Gram-negativa que luego se identificó como Bartonella spp. La PCR demostró que se trataba de una Bartonella quintana. Se trató con gentamicina, doxiciclina y ceftriaxona, evolucionando satisfactoriamente. La insuficiencia mitral remanente espera el tratamiento quirúrgico.

We present the clinical case of a man of 68 years who was admitted for dizziness and sensation of loss of conscience. The clinical examination revealed a body temperature of 37.5 °C and a murmur of mitral regurgitation. The echocardiogram showed a severe mitral regurgitation and left cavitie's dilatation; transesophageal echocardiogram showed a vegetation in the anterior leaflet of the mitral valve. In blood cultures grew a Gram-negative bacteria identified as Bartonella spp. A PCR demonstrated that it was a Bartonella quintana. The patient was treated with gentamicin, doxiciclin and ceftriaxone with satisfactory evolution. The remaining mitral insufficiency awaits surgical treatment.

Discinesia apical transitoria / Apical ballooning

La discinesia apical transitoria es una entidad infrecuente, de descripción reciente, que se presenta como un síndrome coronario agudo, generalmente ST pero sin lesiones coronarias significativas que lo justifiquen. Se presenta un caso clínico con revisión bibliográfica actualizada.

Endocarditis infecciosa asociada con marcapasos y cardiodesfibriladores: formas de presentación, tratamiento y comparación con el resto de las endocarditis / Infective endocarditis associated to pacemekers and defibrillators: presentation, treatment and comparison with other endocarditis

Introducción: Debido al implante de marcapasos (MP) y cardiodesfibriladores (CDI) se ha registrado un número creciente de endocarditis infecciosa (EI) asociada con estos tipos de dispositivos. El presente estudio se realizó con el objetivo de analizar las características de esta enfermedad y compararlas con las del resto de las EI tratadas por nuestro grupo. Material y métodos: Se incorporaron pacientes de ambos sexos y cualquier edad con EI tratados en nuestro servicio en forma consecutiva desde octubre de 1994 hasta octubre de 2003. El diagnóstico de EI se efectuó con los criterios de la Duke University y su modificación para los pacientes con MP o CDI. La población se dividió en dos grupos: el grupo I estuvo constituído por los que tenían colocado un MP o CDI y el grupo II estuvo conformado por el resto de pacientes. Se estudiaron las características clínicas y bacteriológicas del grupo I y luego se compararon con el grupo II. Se utilizaron las pruebas de Student y de chi cuadrado, se calcularon los OR y el IC 95 y se aceptó como significativa una p < 0,05. Resultados: De los 85 pacientes con EI, 22 (26 por ciento) pertenecían al grupo I, 21 tenían colocado MP y 1 CDI, habiéndose efectuado el implante en nuestra institución solamente en 3 pacientes. Los pacientes del grupo I tenían una media de 62,4 años (± 17,1) y 13 (59 por ciento) eran hombres. No hubo diferencias de edad entre ambos sexos. Los pacientes del grupo II tenían una edad media de 45 años (± 19), significativamente menor que la del grupo I (p = 0,000014) y 46 (73 por ciento) eran hombres. En el grupo I la EI fue causada por S. epidermidis en el 45 por ciento de los casos y por S. aureus en el 23 por ciento. La fiebre estuvo presente en el 86,3 por ciento, los síntomas respiratorios (tos, expectoración, hemoptisis, opacidad pulmonar en la radiografía, etc., sugestivos de embolias pulmonares sépticas) en el 50 por ciento, la flogosis del bolsillo en el 36 por ciento y en el 32 por ciento se observó supuración de éste. El tiempo transcurrido desde el implante y el diagnóstico de la enfermedad fue de 1310 días de media con un rango de 7 a 3540 y solamente en 3 pacientes el diagnóstico se hizo dentro de las 6 semanas del implante (forma aguda) y el resto luego de este período (forma crónica). La sensibilidad del ecocardiograma transtorácico (ETT) y del ecocardiograma transesofágico (ETE) fue del 23 por ciento y 59 por ciento, respectivamente, y en el 67 por ciento de los casos las ...

Disección aórtica aguda asociada con inhalación de cocaína / Acute aortic dissection associated with cocaine abuse

Se presenta el caso de un paciente de sexo masculino de 21 años de edad, con disección aórtica aguda, del tipo A de la clasificación de Daily, complicada con taponamiento cardíaco por hemopericardio, seguida de muerte. Adicto a la cocaína, había inhalado la misma hasta la internación. No presentaba hipertensión arterial y la necropsia no mostró necrosis quísticade la media aórtica. Se compara con otros casos similares hallados en la literatura