Anti-Zic4 paraneoplastic cerebellar degeneration in a patient with EGFR-mutated NSCLC: a case report.

Paraneoplastic cerebellar degeneration (PCD) is one of the most prevalent neurological paraneoplastic syndromes, typically associated with small cell lung cancer (SCLC). PCD is thought to be caused by proteins expressed by tumor cells which trigger an antibody-mediated immune response. Despite PCD being commonly associated with anti-Yo, anti-Hu and anti-Tr/DNER antibodies, PCD is the most prevalent paraneoplastic syndrome in patients harboring anti-Zic4 antibodies. We report what, to our knowledge, is the first known case of anti-Zic4 mediated PCD in a patient with EGFR-mutated metastatic non-small cell lung cancer (NSCLC). Our patient was in complete response (CR) to targeted therapy and presented to the emergency room with drowsiness, unsteady gait and memory lapses. The diagnostic work-up revealed a diffuse cerebellar atrophy in the MRI, ruling out brain metastasis and leptomeningeal carcinomatosis. A body-CT scan showed no signs of recurrent disease. The cerebrospinal fluid (CSF) was within normal parameters. An onconeural antibody panel was conducted in a peripheral blood sample, detecting high levels of anti-Zic4 antibody by indirect immunofluorescence (IFI), results later confirmed by immunoblot testing. With the suspected diagnosis of an anti-Zic4 PCD, the case was discussed with the neurology department and treatment with high dose methylprednisolone was initiated. Considering the lack of substantial clinical benefit, the patient was then treated with intravenous immunoglobulins (IVIG) for 5 days, showing modest improvement. At this time, the patient presented minor disease relapse in the form of a sub-centimetric pulmonary nodule. Despite one cycle of chemotherapy, the patient's neurological condition deteriorated leading to fatal pneumonia secondary to progressive dysphagia. There is scarce evidence of paraneoplastic syndromes in EGFR-mutated NSCLC. Further research is warranted to stablish a possible association between anti-Zic4 and the EGFR molecular pathway.

Targeting KRAS in Non-Small Cell Lung Cancer.

Kirsten Rat Sarcoma viral oncogene homolog (KRAS) is the most frequently altered oncogene in Non-Small Cell Lung Cancer (NSCLC). KRAS mutant tumors constitute a heterogeneous group of diseases, different from other oncogene-derived tumors in terms of biology and response to treatment, which hinders the development of effective drugs against KRAS. Therefore, for decades, despite enormous efforts invested in the development of drugs aimed at inhibiting KRAS or its signaling pathways, KRAS was considered to be undruggable. Recently, the discovery of a new pocket under the effector binding switch II region of KRAS G12C has allowed the development of direct KRAS inhibitors such as sotorasib, the first FDA-approved drug targeting KRAS G12C, or adagrasib, initiating a new exciting era. However, treatment with targeted KRAS G12C inhibitors also leads to resistance, and understanding the possible mechanisms of resistance and which drugs could be useful to overcome it is key. Among others, KRAS G12C (ON) tricomplex inhibitors and different combination therapy strategies are being analyzed in clinical trials. Another area of interest is the potential role of co-mutations in treatment selection, particularly immunotherapy. The best first-line strategy remains to be determined and, due to the heterogeneity of KRAS, is likely to be based on combination therapies.

Development of Thyroid Carcinoma During Treatment With Pembrolizumab in a Lung Cancer Patient.

Pembrolizumab, a programmed death 1 inhibitor, has been shown to have clinically significant efficacy in different types of cancer, providing long-term survival benefit for patients with lung cancer. Herein, we report the development of a primary thyroid cancer in a lung cancer patient that was being treated with pembrolizumab. Primary thyroid malignancy (and not only metastatic disease or immunotherapy-induced thyroiditis) should be considered in patients with lung cancer being treated with immune checkpoint inhibitors who develop new incidental thyroid lesions on imaging studies.

Executive summary of the SEPAR recommendations for the diagnosis and treatment of non-small cell lung cancer. / Sumario ejecutivo de las recomendaciones SEPAR de diagnóstico y tratamiento del cáncer de pulmón de células no pequeñas.

The Thoracic Surgery and Thoracic Oncology groups of the Spanish Society of Pulmonology and Thoracic Surgery (SEPAR) have backed the publication of a handbook on recommendations for the diagnosis and treatment of non-small cell lung cancer. Due to the high incidence and mortality of this disease, the best scientific evidence must be constantly updated and made available for consultation by healthcare professionals. To draw up these recommendations, we called on a wide-ranging group of experts from the different specialties, who have prepared a comprehensive review, divided into 4 main sections. The first addresses disease prevention and screening, including risk factors, the role of smoking cessation, and screening programs for early diagnosis. The second section analyzes clinical presentation, imaging studies, and surgical risk, including cardiological risk and the evaluation of respiratory function. The third section addresses cytohistological confirmation and staging studies, and scrutinizes the TNM and histological classifications, non-invasive and minimally invasive sampling methods, and surgical techniques for diagnosis and staging. The fourth and final section looks at different therapeutic aspects, such as the role of surgery, chemotherapy, radiation therapy, a multidisciplinary approach according to disease stage, and other specifically targeted treatments, concluding with recommendations on the follow-up of lung cancer patients and surgical and endoscopic palliative interventions in advanced stages.