Immune Checkpoint Inhibitors Related Cystoureteritis: A Case Report and Literature Review / 中国肺癌杂志

A patient with advanced lung adenocarcinoma developed symptoms of frequent urination and urgent urination after 14 cycles of Pembrolizumab combined with chemotherapy. After making comprehensive analysis of the results of urine routine test, renal function, cystoscope and computed tomography (CT) examination, immune checkpoint inhibitors related cystoureteritis and acute kidney injury were considered. The patient's symptoms were relieved after discontinuation of Pembrolizumab combined with chemotherapy. However, the symptoms of urinary irritation worsened significantly after rechallenging Pembrolizumab combined with chemotherapy, and the symptoms was relieved after corticosteroids treatment. If patients develop urinary symptoms during immune checkpoint inhibitors treatment, immune checkpoint inhibitors related cystoureteritis should be considered for early differential diagnosis in order to implement appropriate treatment.
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Pituitary immune-related adverse events induced by programmed cell death protein 1 inhibitors in advanced lung cancer patients: A report of 3 cases / 北京大学学报(医学版)

Pituitary immune-related adverse events induced by programmed cell death protein 1 inhibitors in advanced lung cancer patients: A report of 3 cases SUMMARY Programmed cell death protein 1 (PD-1) and its ligand 1 (PD-L1) have been widely used in lung cancer treatment, but their immune-related adverse events (irAEs) require intensive attention. Pituitary irAEs, including hypophysitis and hypopituitarism, are commonly induced by cytotoxic T lymphocyte antigen 4 inhibitors, but rarely by PD-1/PD-L1 inhibitors. Isolated adrenocorticotropic hormone(ACTH) deficiency (IAD) is a special subtype of pituitary irAEs, without any other pituitary hormone dysfunction, and with no enlargement of pituitary gland, either. Here, we described three patients with advanced lung cancer who developed IAD and other irAEs, after PD-1 inhibitor treatment. Case 1 was a 68-year-old male diagnosed with metastatic lung adenocarcinoma with high expression of PD-L1. He was treated with pembrolizumab monotherapy, and developed immune-related hepatitis, which was cured by high-dose methylprednisolone [0.5-1.0 mg/(kg·d)]. Eleven months later, the patient was diagnosed with primary gastric adenocarcinoma, and was treated with apatinib, in addition to pembrolizumab. After 17 doses of pembrolizumab, he developed severe nausea and asthenia, when methylprednisolone had been stopped for 10 months. His blood tests showed severe hyponatremia (121 mmol/L, reference 137-147 mmol/L, the same below), low levels of 8:00 a.m. cortisol (< 1 μg/dL, reference 5-25 μg/dL, the same below) and ACTH (2.2 ng/L, reference 7.2-63.3 ng/L, the same below), and normal thyroid function, sex hormone and prolactin. Meanwhile, both his lung cancer and gastric cancer remained under good control. Case 2 was a 66-year-old male with metastatic lung adenocarcinoma, who was treated with a new PD-1 inhibitor, HX008, combined with chemotherapy (clinical trial number: CTR20202387). After 5 months of treatment (7 doses in total), his cancer exhibited partial response, but his nausea and vomiting suddenly exacerbated, with mild dyspnea and weakness in his lower limbs. His blood tests showed mild hyponatremia (135 mmol/L), low levels of 8:00 a.m. cortisol (4.3 μg/dL) and ACTH (1.5 ng/L), and normal thyroid function. His thoracic computed tomography revealed moderate immune-related pneumonitis simultaneously. Case 3 was a 63-year-old male with locally advanced squamous cell carcinoma. He was treated with first-line sintilimab combined with chemotherapy, which resulted in partial response, with mild immune-related rash. His cancer progressed after 5 cycles of treatment, and sintilimab was discontinued. Six months later, he developed asymptomatic hypoadrenocorticism, with low level of cortisol (1.5 μg/dL) at 8:00 a.m. and unresponsive ACTH (8.0 ng/L). After being rechallenged with another PD-1 inhibitor, teslelizumab, combined with chemotherapy, he had pulmonary infection, persistent low-grade fever, moderate asthenia, and severe hyponatremia (116 mmol/L). Meanwhile, his blood levels of 8:00 a.m. cortisol and ACTH were 3.1 μg/dL and 7.2 ng/L, respectively, with normal thyroid function, sex hormone and prolactin. All of the three patients had no headache or visual disturbance. Their pituitary magnetic resonance image showed no pituitary enlargement or stalk thickening, and no dynamic changes. They were all on hormone replacement therapy (HRT) with prednisone (2.5-5.0 mg/d), and resumed the PD-1 inhibitor treatment when symptoms relieved. In particular, Case 2 started with high-dose prednisone [1 mg/(kg·d)] because of simultaneous immune-related pneumonitis, and then tapered it to the HRT dose. His cortisol and ACTH levels returned to and stayed normal. However, the other two patients' hypopituitarism did not recover. In summary, these cases demonstrated that the pituitary irAEs induced by PD-1 inhibitors could present as IAD, with a large time span of onset, non-specific clinical presentation, and different recovery patterns. Clinicians should monitor patients' pituitary hormone regularly, during and at least 6 months after PD-1 inhibitor treatment, especially in patients with good oncological response to the treatment.

Tratamientos de primera línea para pacientes estadio IV con adenocarcinoma pulmonar de mutación EGFR / First-line treatments for stage IV patients with EGFR-mutated lung adenocarcinoma

Lung cancer is one of the leading causes of death in the world. Current treatments act directly on the signal transduction pathways in cancer cells, mainly. One of the main pathways is associated with the Epidermal Growth Factor (EGFR), whose mutations leads to uncontrolled cell proliferation and a higher rate of cell invasion. Activating mutations in the EGFR gene, which includes deletions in exon 19 and the L858R mutation in exon 21, were detected in most patients with non-small cell lung cancer (NSCLC). Studies of EGFR tyrosine kinase inhibitors (EGFR-TKIs) such as Gefitinib, Erlotinib and Afatinib, compared with platinum-based treatments, showed that EGFR-TKIs produce increased disease-free survival, although only in patients whose cancers harbor activating mutations in the EGFR gene. Clinical trials also demonstrated that EGFR-TKIs are effective as first-line therapies in stage IV pulmonary adenocarcinoma. Here, the main aspects of the activation of the EGFR pathway in NSCLC will be reviewed, highlighting the importance for health professionals of correctly identifying activating mutations in the EGFR gene and acting quickly at the molecular level based on aforementioned treatments. (AU)

Neoplasia sólida pseudopapilar pancreática: comunicación de cuatro casos clínicos y revisión de la literatura / Solid pseudopapillary tumor of the pancreas: four case reports and a review of the lilerature / Neoplasia sólida pseudopapilar pancreática: comunicação de quatro casos clínicos e revisão da literatura

Los tumores pseudopapilares del páncreas son tumores de origen pancreático poco frecuentes y de etiología desconocida. Comprenden entre el 0.2 y 2.7% de los carcinomas de páncreas. Hasta 2015 hay 900 casos reportados en la literatura, siendo una minoría en etapa diseminada. Son tumores voluminosos, de bajo potencial maligno, que se presentan con mayor frecuencia en mujeres jóvenes entre 18 y 35 años. Generalmente son asintomáticos o manifiestan clínicamente síntomas inespecíficos como dolor abdominal o presencia de masa abdominal. Anatómicamente se localizan con mayor frecuencia en la cola del páncreas, seguidos por la cabeza y el cuerpo. El tratamiento de elección es la resección quirúrgica. El rol de la quimioterapia en la enfermedad irresecable o avanzada no está claramente definido. Son tumores de excelente pronóstico, con sobrevida a 5 años de casi 100%.Se presentan cuatro casos clínicos y se hace una revisión de la literatura.

Pseudopapillary tumors of the pancreas are tumors of pancreatic origin with a low frequency and an unknown etiology. They account for 0.2 - 2.7 % of all pancreatic carcinomas. Up to 2015 there were approximately 900 well documented cases with only a small minority of them in a metastatic stage. This tumors could reach large proportions and they occur predominantly in young women between 18 and 35 years of age. Most of patients are asymptomatic or have non specific symptoms including abdominal pain or palpable abdominal mass. The most common localization is the tail of the pancreas, followed by the head and the body. Complete resection is the treatment of choice. It is not clearly stablished the rol of chemotherapy in metastatic disease. There are tumors with a favorable prognosis, with an overall 5 year survival rate about 95%. Herein, we report four clinical cases and a literatura review.

Os tumores pseudopapilares do pâncreas são tumores de origem pancreática pouco frequentes e de etiologia desconhecida. Compreendem entre 0.2 e 2.7% dos carcinomas de pâncreas. Até 2015 há 900 casos relatados na literatura, sendo uma minoria em etapa disseminada. São tumores volumosos, de baixo potencial maligno, que se apresentam com maior frequência em mulheres jovens entre 18 e 35 anos. Geralmente são assintomáticos ou apresentam clinicamente sintomas inespecíficos como dor abdominal ou presença de massa abdominal. Anatomicamente, localizam-se mais frequentemente na cauda do pâncreas, seguidos por cabeça e corpo. O tratamento de escolha é a ressecção cirúrgica. O papel da quimioterapia na doença irressecável ou avançada não está claramente definido. São tumores de excelente prognóstico, com sobrevida a 5 anos de quase 100%. Apresentam-se quatro casos clínicos e faz-se uma revisão da literatura.

Eficacia y seguridad de pembrolizumab asociado a quimioterapia en doblete basada en platino en el tratamiento de primera línea de pacientes adultos con adenocarcinoma de pulmón metastásico, con las mutaciones EGFR y ALK negativos / Efficacy and safety of pembrolizumab associated with platinum-based doublet chemotherapy in the first-line treatment of adult patients with metastatic lung adenocarcinoma, with negative EGFR and ALK mutations

INTRODUCCIÓN: El cáncer de pulmón (CP) es uno de los tumores más frecuentes en el mundo. Se clasifica en dos grupos, siendo el subgrupo de CP de células no pequeñas (CPCNP) el más frecuente (80 %). A su vez, el CPCNP se subdivide en el subtipo escamoso y el no escamoso. El adenocarcinoma de pulmón es el subtipo histológico de CPCNP no escamoso más frecuente (40 % de todos los casos de CP) y tiene como tratamiento sistémico de elección a la quimioterapia en doblete basado en platino (QT-P), cuando las células tumorales no cuentan con las mutaciones EGFR y ALK (EGFR- y ALK-). El Petitorio Farmacológico de EsSalud cuenta con diferentes esquemas de QT-P (combinación de un agente quimioterapéutico, tales como docetaxel, gemcitabina, paclitaxel o pemetrexed, con un platino [cisplatino o carboplatino]) como tratamiento de primera línea de los pacientes con adenocarcinoma de pulmón metastásico, EGFR- y ALK-. Como alternativa terapéutica, los especialistas han sugerido la evaluación del uso combinado de pembrolizumab y QT-P, sustentado que dicha combinación podría ofrecer un beneficio adicional al uso de la QT-P sola. OBJETIVO: Evaluar la mejor evidencia científica disponible a la fecha sobre la eficacia y seguridad del uso combinado de pembrolizumab + QT-P, en comparación con el placebo + QT-P, para los pacientes adultos con adenocarcinoma de pulmón metastásico, EGFR- y ALK-. TECNOLOGÍA SANITARIA DE INTERÉS: Pembrolizumab: Pembrolizumab ha sido descrito ampliamente en dos dictámenes previos (Dictamen Preliminar de Evaluación de Tecnología Sanitaria Nº 025-SDEPFyOTS-DETS-IETSI-2017 y N° 059-SDEPFyOTS-DETS-IETSI-2017). En breve, pembrolizumab es un anticuerpo monoclonal tipo IgG que se une al receptor de muerte programada PD-1, lo cual bloquea la interacción de dicho receptor con sus ligandos PD-L1 y PD-L2, y, así, promueve la actividad antitumoral de los linfocitos T. METODOLOGÍA: Se llevó a cabo una búsqueda bibliográfica exhaustiva y jerárquica de la literatura con respecto a la eficacia y seguridad del pembrolizumab asociado a la QT-P, comparado con QT-P asociado a placebo, en pacientes con adenocarcinoma de pulmón metastásico, con EGFR negativo y ALK negativo. La búsqueda se inició revisando la información sobre el uso del medicamento de acuerdo con entidades reguladoras como FDA, EMA, y DIGEMID en el Perú. RESULTADOS: Se llevó a cabo una búsqueda de evidencia científica relacionada al uso de pembrolizumab + QT-P, comparado con placebo + QT-P, como tratamiento de primera línea de pacientes con adenocarcinoma de pulmón metastásico, EGFR- y ALK-. En la presente sinopsis se describe la evidencia disponible según el tipo de publicación, siguiendo lo indicado en los criterios de elegibilidad (GPC, ETS, RS, MA y ECA fase III). CONCLUSIONES: La evidencia principal que responde a la pregunta PICO establecida en el presente dictamen proviene del ECA de fase III KEYNOTE-189, el cual es un estudio doble ciego, multicéntrico, y financiado por el fabricante de pembrolizumab, Merck & Co., Inc., que evaluó la eficacia y seguridad de pembrolizumab + pemetrexed/platino (QT-P) comparado con placebo + pemetrexed/platino, en pacientes con CPCNP no escamoso, EGFR- y ALK-, que no hayan recibido ninguna terapia sistémica para la enfermedad metastásica. Con la evidencia disponible a la fecha procedente del ECA KEYNOTE-189, la cual corresponde a un análisis preliminar, luego de una mediana de 10.5 meses de seguimiento, con una madurez de la data de mortalidad al 55 %, no es posible determinar un beneficio neto con pembrolizumab + QT-P, en comparación con placebo + QT-P, con respecto a desenlaces clínicamente relevantes como la calidad de vida o la SG. Esto debido a que, luego de la corrección por sobrestimación, no se detectaron diferencias estadísticamente significativas en la SG ni en la SLP entre los grupos de tratamiento. Asimismo, hubo confusores fuertes en el análisis de SG, como consecuencia de desbalances en la aleatorización que se tradujo en diferencias en las características basales entre los grupos de tratamiento. También hubo un alto cruzamiento entre los grupos de tratamiento, con diferencias considerables en la elección de los esquemas de terapia subsecuente luego de progresión tumoral. Los resultados de seguridad del ECA KEYNOTE-189 no mostraron diferencias estadísticamente significativas entre los grupos de tratamiento en las tasas de EA totales, EA serios, EA fatales y EA severos. Sin embargo, se encontraron diferencias estadísticamente significativas en la tasa de descontinuación del tratamiento por EA y en la proporción de pacientes que presentaron el EA serio neutropenia febril, con resultados desfavorables para el grupo pembrolizumab + QT-P. Por lo tanto, la evidencia disponible a la fecha indicaría que el uso de pembrolizumab + QT-P tendría un perfil de seguridad desfavorable en comparación con el uso de placebo + QT-P en la población de la pregunta PICO. Con todo ello, existe incertidumbre respecto al balance riesgo beneficio entre el uso combinado de pembrolizumab + QT-P, en comparación con placebo + QT-P, en el tratamiento de pacientes de la población PICO de interés para el presente dictamen. A ello se le suma el alto costo del medicamento (aproximadamente, S/ 378,436.80 anuales por paciente), por lo que su aprobación no sería una decisión costooportuna para un sistema público de salud como es EsSalud. Asimismo, actualmente se encuentra disponible en la institución la QT-P como alternativa de tratamiento, la cual también es recomendada en las GPC internacionales. Por lo expuesto, el Instituto de Evaluaciones de Tecnologías en Salud e Investigación ­ IETSI no aprueba el uso de pembrolizumab + QT-P para el tratamiento de primera línea de los pacientes adultos con adenocarcinoma de pulmón metastásico, EGFR- y ALK-.

Identification of the targets of hematoporphyrin derivative in lung adenocarcinoma using integrated network analysis

BACKGROUND: Hematoporphyrin derivative (HPD) has a sensibilization effect in lung adenocarcinoma. This study was conducted to identify the target genes of HPD in lung adenocarcinoma. METHODS: RNA sequencing was performed using the lung adenocarcinoma cell line A549 after no treatment or treatment with X-ray or X-ray + HPD. The differentially expressed genes (DEGs) were screened using Mfuzz package by noise-robust soft clustering analysis. Enrichment analysis was carried out using "BioCloud" online tool. Protein-protein interaction (PPI) network and module analyses were performed using Cytoscape software. Using WebGestalt tool and integrated transcription factor platform (ITFP), microRNA target and transcription factor (TF) target pairs were separately predicted. An integrated regulatory network was visualized with Cytoscape software. RESULTS: A total of 815 DEGs in the gene set G1 (continuously dysregulated genes along with changes in processing conditions [untreated-treated with X-ray-X-ray + treated with HPD]) and 464 DEGs in the gene set G2 (significantly dysregulated between X-ray + HPD-treated group and untreated/X-ray-treated group) were screened. The significant module identified from the PPI network for gene set G1 showed that ribosomal protein L3 (RPL3) gene could interact with heat shock protein 90 kDa alpha, class A member 1 (HSP90AA1). TFs AAA domain containing 2 (ATAD2) and protein inhibitor of activated STAT 1 (PIAS1) were separately predicted for the genes in gene set G1 and G2, respectively. In the integrated network for gene set G2, ubiquitin-specific peptidase 25 (USP25) was targeted by miR-200b, miR-200c, and miR-429. CONCLUSION: RPL3, HSP90AA1, ATAD2, and PIAS1 as well as USP25, which is targeted by miR-200b, miR-200c, and miR-429, may be the potential targets of HPD in lung adenocarcinoma.