ARID1A genomic alterations driving microsatellite instability through somatic MLH1 methylation with response to immunotherapy in metastatic lung adenocarcinoma: a case report.

BACKGROUND: Tumor molecular screening allows categorization of molecular alterations to select the best therapeutic strategy. AT-rich interactive domain-containing 1A (ARID1A) gene mutations are present in gastric, endometrial, and clear cell ovarian tumors. Inactivation of this gene impairs mismatch repair (MMR) machinery leading to an increased mutation burden that correlates with microsatellite instability (MSI), associated with tumor-infiltrating lymphocytes and programmed death ligand 1 (PD-L1) expression. This is the first case report in lung adenocarcinoma of ARID1A gene alterations leading to sporadic MSI, through somatic mutL homolog 1 (MLH1) promoter methylation, with an MLH1 gene mutation as the second somatic hit. CASE PRESENTATION: A 50-year-old never-smoker Bulgarian woman, with no comorbidities and no family history of cancer, was diagnosed with metastatic lung adenocarcinoma. PD-L1 immunohistochemistry (IHC) of tissue biopsies on right groin adenopathies resulted in 30% positivity. Liquid biopsy test reported actionable alterations in ARID1A gene, rearranged during transfection (RET) gene fusions, epidermal growth factor receptor (EGFR) gene R776H mutation, breast cancer (BRCA) genes 1/2, and cyclin-dependent kinase inhibitor 2A (CDKN2A) gene mutations. The patient was treated with immunotherapy, and showed a treatment response lasting for 19 months until a new metastasis appeared at the right deltoid muscle. Genomic analysis of a sample of this metastasis confirmed PD-L1 positivity of greater than 50% with CD8+ T cells expression and showed MSI with a deleterious c.298C>T (p.R100*) MLH1 gene mutation. Multiplex ligation-dependent probe amplification (MLPA) of this sample unveiled MLH1 gene promoter methylation. The MLH1 gene mutation and the MLH1 gene methylation were not present at the germline setting. CONCLUSIONS: In this particular case, we show that ARID1A gene mutations with sporadic MSI due to somatic MLH1 gene promoter methylation and MLH1 gene mutation could change the prognosis and define the response to immunotherapy in a patient with lung adenocarcinoma. Comprehensive solid and liquid biopsy tests are useful to find out resistance mechanisms to immune checkpoint inhibitors. Our data encourages the development of new therapies against ARID1A mutations and epigenomic methylation when involved in MSI neoplasms.

Impact on clinical practice of the implementation of guidelines for the toxicity management of targeted therapies in kidney cancer. The protect-2 study.

BACKGROUND: The impact of such recommendations after their implementation of guidelines has not usually been evaluated. Herein, we assessed the impact and compliance with the Spanish Oncology Genitourinary Group (SOGUG) Guidelines for toxicity management of targeted therapies in metastatic renal cell carcinoma (mRCC) in daily clinical practice. METHODS: Data on 407 mRCC patients who initiated first-line targeted therapy during the year before and the year after publication and implementation of the SOGUG guideline program were available from 34 Spanish Hospitals. Adherence to SOGUG Guidelines was assessed in every cycle. RESULTS: Adverse event (AE) management was consistent with the Guidelines as a whole for 28.7% out of 966 post-implementation cycles compared with 23.1% out of 892 pre-implementation cycles (p = 0.006). Analysis of adherence by AE in non-compliant cycles showed significant changes in appropriate management of hypertension (33% pre-implementation vs. 44.5% post-implementation cycles; p < 0.0001), diarrhea (74.0% vs. 80.5%; p = 0.011) and dyslipemia (25.0% vs. 44.6%; p < 0.001). CONCLUSIONS: Slight but significant improvements in AE management were detected following the implementation of SOGUG recommendations. However, room for improvement in the management of AEs due to targeted agents still remains and could be the focus for further programs in this direction.

Cisplatino intrapericárdico en el taponamiento neoplásico / Intrapericardial cisplatin for malignant tamponade

EEl tratamiento de elección de la efusión pericárdica maligna es controvertido. La pericardiocentesis suele ser eficaz para resolver el taponamiento pero, desafortunadamente, es frecuente que haya recurrencias, y los pacientes se exponen de nuevo a una situación crítica y necesitan hospitalización. Se han sugerido distintos protocolos para evitar la reacumulación de líquido pericárdico, la mayoría de ellos bastante molestos. Presentamos nuestra experiencia con la administración intrapericárdica de cisplatino. Fueron 6 pacientes, y los tumores primarios eran carcinoma de mama en 2, pulmón en 1, ovario en 1, fibrosarcoma mediastínico en 1 y desconocido en 1. La administración de cisplatino se desarrolló prácticamente sin incidencias, fue no dolorosa, y no hubo ninguna recurrencia, con una supervivencia de 2 a 18 meses (media, 5,6).Concluimos que el cisplatino es seguro y eficaz en el tratamiento del taponamiento pericárdico maligno y en la prevención de su recurrencia (AU)