Query: Meningeal Metastasis Of Lung Cancer

title: Intravenous analgesia with ultra high dose morphine for the treatment of headache and successful withdrawal of morphine
abstract: Pain is the fifth vital sign of human beings. Morphine is the first choice for relieving moderate to severe cancer pain. Most of the previous studies merely focused on the analgesic effect of high dose or ultra high dose morphine in patients with advanced cancers but did not report any cases related to successful morphine withdrawal.  A 42 year old woman was admitted to our hospital in March 2019.  She was diagnosed with progressive aggravation of headache for 1 month, which was meningeal metastasis of lung cancer.  Symptomatic treatments like dehydration, hormone, intrathecal injection chemotherapy and an increased dose of osimertinib to 160 mg/day were applied but showed poor curative effects. The patient refused whole brain radiotherapy. Pain intensity level was re evaluated and the patient scored 9 based on numerical rating scale, which suggested that the patient suffered from severer cancerous pain. Thus, the patient started to receive morphine for treating headache.  The patient's headache was alleviated after receiving high dose morphine treatment, and she continued to undergo anti cancer treatment. After tumor remission, the patient's morphine dose gradually decreased and eventually stopped, without any withdrawal symptoms. In addition, the quality of life of the patient was greatly improved with performance status scored 2 and limb muscle strength increased from Grade 2 to Grade 5.  For patients with advanced cancers, the application of ultra high dose morphine may significantly relieve cancerous pain, improve survival and quality of life, and overcome their fear for death and desperation, which contributes to the establishment of a basis for subsequent anticancer treatments. Thus, timely effective pain management and routine anticancer treatments are the key to addressing the cancer pain problem.

title: Nintedanib and a bi specific anti VEGF/Ang2 nanobody selectively prevent brain metastases of lung adenocarcinoma cells
abstract: Brain metastases (BM) are an ever increasing challenge in oncology, threatening quality of life and survival of many cancer patients. The majority of BM originate from lung adenocarcinoma, and stage III patients have a risk of 40 50% to develop BM in the first years of disease onset. As therapeutic options are limited, prevention of their occurrence is an attractive concept. Here we investigated whether Nintedanib (BIBF 1120) a tyrosine kinase inhibitor (TKI) targeting the VEGF pathway approved for lung adenocarcinoma, and the dual anti VEGF A/Ang2 nanobody BI836880 have the potential to prevent BM formation. A mouse model of brain metastasis from lung adenocarcinoma was used in which tumor cells were injected intracardially. Metastases formation occurred inside and outside of the brain and was followed by MRI, IVIS, and immunohistochemistry. BM were reduced in volume and number by both Nintedanib and the dual anti VEGF A/Ang2 nanobody, which translated into improved survival. Both compounds were able to normalize cerebral blood vessels at the site of brain metastatic lesions. Extracranial metastases, however, were not reduced, and meningeal metastases only partially. Interestingly, unspecific control IgG also lead to brain vessel normalization and reduction of brain and meningeal metastases. This data indicates a brain specific group effect of antiangiogenic compounds with respect to metastasis prevention, most likely by preventing an early angiogenic switch. Thus, Nintedanib and BI836880 are promising candidates for future BM preventive study concepts in lung adenocarcinoma patients.

title: Leptomeningeal metastasis as a presenting manifestation of adenocarcinoma of the lung: a case report
abstract: Leptomeningeal metastasis (LM) also known as meningeal carcinomatosis is a rare but grave complication seen in the terminal stage of a known primary cancer. We report an uncommon case of LM in a 62 year old male patient, presenting with neurologic signs and symptoms of increased intracranial pressure at least two months before any evidence of involvement of the primary focus in lung. The prognosis of the disease was poor due to the involvement of central nervous system and bones. It is important to have a high index of suspicion and to consider systemic diseases in differential diagnosis of the syndrome of intracranial hypertension.

title: Afatinib/dexamethasone/methotrexate
abstract: Myelosuppression and skin rash on face and trunk: case report A 34 year old man developed myelosuppression during treatment with methotrexate and dexamethasone, and skin rash on face and trunk during treatment with afatinib for metastatic lung adenocarcinoma [not all routes stated;duration of treatments to reaction onsets and outcomes not stated] The man, who had refractory headache for 6 months and blindness in both eyes for 3 weeks, was admitted to hospital on 18 April 2018. Two years prior, in May 2016, he was diagnosed with lung adenocarcinoma. He was treated with 6 cycles of docetaxel and cisplatin chemotherapy. However, these chemotherapy regimen showed a partial response to lung adenocarcinoma. In April 2017, due to progression of disease, he was treated with second line chemotherapy with 10 cycles of pemetrexed and carboplatin till December 2017. Thereafter, he developed meningeal metastasis of lung cancer, and was treated with mannitol for dehydration and to reduced the intracranial pressure. In September 2017, he underwent blood sample gene test which did not show any EGFR gene sensitive mutation. Then, he received whole brain radiation therapy for 15 times. In October 2017, his dizziness deteriorated with intense headache. Hence, the dose of mannitol was gradually increased, but the symptoms of headache and nausea were still aggravated. Around 3 weeks before the current presentation, in March 2018, he became blind in both eyes. Later, he was admitted to the hospital (current presentation) for further evaluation. He was diagnosed with stage IV peripheral lung cancer in the left lung with meningeal and lymph node metastasis. Additionally, he developed intermittent limb convulsion accompanied by unconsciousness. Therefore, after the consultation with neurosurgery department, he underwent right ventriculo peritoneal shunt placement on 21 April 2018. Subsequently, he started receiving intrathecal injection of methotrexate 8mg and dexamethasone 1mL mixed with 9mL of sodium chloride [saline] On 11 May 2018, he was again administered the same intrathecal chemotherapy. Subsequently, he developed grade III myelosuppression due to chemotherapy. The man's methotrexate and dexamethasone treatments were discontinued. He received symptomatic treatment. However, his disease deteriorated further. On 22 May 2018, his CSF pressure was 160 mmH2O. Subsequent gene testing revealed EGFRG719A mutation. Later, due to poor general condition, he started receiving afatinib 30 mg/day for molecule targeted chemotherapy. After 7 days of afatinib treatment, his headache improved, but he still had no light perception in both eyes. After consultation with the ophthalmology department, it was concluded that the optic nerve injury caused blindness in both eyes, which was irreversible. Thereafter, he was discharged on afatinib 30 mg/day for molecule targeted chemotherapy. A partial remission was noted. However, he developed skin rash on the face and trunk secondary to afatinib. His headache resolved; however, due to the Eastern Cooperative Oncology Group Performance Status Ranking (ECOG PSR) score of 2, the dose of afatinib was increased to 40 mg/day. Thereafter, an improvement in his disease was noted. He was maintained on afatinib 40 mg/day, and was continuously followed up.

title: Meningeal metastasis patients with EGFR G724S who develop resistance to osimertinib benefit from the addition of afatinib.
abstract: Transl Lung Cancer Res 2020;9(5):2188 2190 http:/dx.doi.org/10.21037/tlcr 20 847 A case study of a patient with EGFR G724S who responded to afatinib monotherapy after disease progression on osimertinib was reported before (1) Incidentally, we encountered a patient who also had EGFR G724S who developed meningeal metastases. After treatment with a regimen of osimertinib combined with afatinib, our patient achieved significant clinical benefits. A 49 year old Chinese male smoker was found to have a pulmonary mass in the right middle lobe by chest computed tomography (CT) scan during a health checkup on October 25, 2016. The patient underwent positron emission tomography computed tomography (PET CT) on November 01, 2016  which showed irregular soft tissue nodules in the right middle lobe (measuring approximately 2.1 cm x 2.4 cm) lymph node metastasis in the right hilar and mediastinum (3A, 4R, 10R, and 7 areas) and multiple bone metastases. On November 07, 2016, the patient underwent thoracoscopy lung wedge resection and pleural biopsy. During the operation, extensive pleural cavity implantation and metastases were observed. Postoperative pathology and next generation sequencing (NGS) led to the diagnosis of lung adenocarcinoma with an EGFR exon 19 deletion mutation (EGFR 19del) Subsequently, the patient started gefitinib 250 mg daily as first line therapy on November 25, 2016, and achieved partial response (PR) On December 14, 2017, craniocerebral magnetic resonance imaging (MRI) showed multiple progressive small metastases in the brain (Figure 1B) Consequently, the patient's regimen was changed to osimertinib 80 mg daily from December 15, 2017. On November 19, 2018, the patient experienced an increase in pleural effusion as disease progression. An NGS test of the patient's pleural effusion revealed the emergence of EGFR G724S with pre existing EGFR 19del. Thereafter, while maintaining the use of osimertinib, the patient received chemotherapy including carboplatin and pemetrexed, with bevacizumab as an antiangiogenic therapy. After experiencing dizziness and headache, the patient was reexamined by craniocerebral MRI on August 05, 2019, which revealed extensive abnormal thickening and enhancement of the meninges; meningeal metastases were considered. CT at the same time showed multiple liver metastases and peritoneal metastases. Another NGS examination of the patient's pleural effusion and blood was performed, which showed EGFR G724S and 19del mutation were still present in both samples. Considering both in vitro and in vivo studies have indicated that EGFR G724S/19del can induce resistance to osimertinib in patients while maintaining sensitivity to afatinib (2,3) the patient began afatinib 40 mg daily while continuing osimertinib 80 mg daily on August 06, 2019. After 1 month, the patient's neurological symptoms were significantly relieved, and after 2 months, follow up CT and MRI showed that the patient's meningeal metastases, liver metastases and peritoneal metastases were significantly reduced (Figure 1C,D) To date (March 26, 2020, the cutoff day) the patient has continued to receive afatinib in combination with osimertinib, and no obvious adverse reactions have been observed  All procedures performed in studies involving human participants were in Letter to the Editor

title: Detection of Meningeal Metastasis in the Cerebrospinal Fluid in Lung Adenocarcinoma: Case Report.
abstract: The standard method of detection of epidermal growth factor receptor (EGFR) mutations is the amplification of the refractory mutation system (ARMS) in tissue, blood, and cerebrospinal fluid (CSF) samples. Circulating tumor cells (CTCs) harvested from the CSF, using CellSearch(r) technology, are used for ARMS analysis. This may further enhance the sensitivity and effectiveness of the diagnosis of meningeal metastases and may be a preferred detection method protocol for liquid biopsy of non small cell lung cancer with meningeal metastasis. In this case report, we have studied a rare case of EGFR mutated lung adenocarcinoma with a point mutation in exon 21 (L858R) in a 54 year woman with meningeal metastasis after gefitinib treatment for approximately 1 year. The patient was receiving treatment with osimertinib at the time of this study. This study shows that the detection of circulating tumor DNA or CTC in CSF, via next generation sequencing or digital PCR, is a promising diagnostic method for the identification of meningeal metastasis.

title: [Cerebrospinal fluid TP53 gene mutation in patients with lung cancer associated meningitis and its clinical implications]
abstract: To observe the role of cerebrospinal fluid (CSF) TP53 gene mutation in lung cancer associated meningitis.  A retrospective analysis was performed on 35 patients diagnosed with lung cancer associated meningitis at the Second Hospital of Hebei Medical University from December 2015 to December 2018.All patients underwent the next generation sequencing of CSF, and TP53 gene was found to be mutant or wild type, including 23 patients with TP53 mutant type and 12 patients with TP53 wild type. The clinical characteristics, CSF leukocyte, protein, glucose, chloride, Karnofsky performance (KPS) and overall survival were observed.  Headache, nausea and vomiting were the main clinical manifestations in both groups.There were no significant differences in CSF pressure, leukocyte, biochemical indicators and KPS between the two groups. The average time from diagnosis of lung cancer to diagnosis of lung cancer associated meningitis in the TP53 mutant group was significantly shorter than that in the TP53 wild type group (5.79 months vs 25.5 months).The median survival time of patients in the TP53 mutant group from lung cancer diagnosis to the observation endpoint was 19.77 months, while it was 88.73 months in the TP53 wild type group, and the difference was statistically significant (P=0.043)  Mutation in the tumor suppressor gene TP53 can be detected in the CSF of patients with lung cancer associated meningitis. Patients with such mutation have earlier meningeal metastasis and shorter median survival time.

title: Nivolumab efficacy in leptomeningeal metastasis of renal cell carcinoma: a case report
abstract: Meningeal carcinomatosis is rare in patients with kidney cancer and treatment options are limited. Few patients treated with systemic approaches have been reported. We describe a case of complete remission of leptomeningeal metastasis in a patient with renal cell carcinoma treated with nivolumab. To our knowledge, this is the first report of nivolumab safety and efficacy in this particular site of metastasis.  Our patient was a 60 year old Caucasian man with bone and lung metastases from renal cell carcinoma. He developed leptomeningeal metastasis and progression of bone and lung lesions after only 2 months of his first line treatment. He was then treated with nivolumab in second line setting and experienced a rapid improvement of cancer related symptoms, complete remission of leptomeningeal and lung lesions, and increased bone mineral density in bone metastasis. The patient did not experience any drug related toxicity.  Meningeal carcinomatosis metastasis from renal cancer is a rare condition. Diagnosis is often challenging: the onset of nonspecific presenting symptoms could be initially attributed to bone involvement, side effects of oncologic therapy, or paraneoplastic syndromes. Our case suggests that nivolumab could be an effective and safe treatment option in patients with pretreated renal cancer with leptomeningeal metastasis.

title: Application of cerebrospinal fluid circulating cell free DNA in the diagnosis and treatment of leptomeningeal metastases from non small cell lung cancer
abstract: To investigate the application value of cerebrospinal fluid circulating cell free DNA (cfDNA) in the diagnosis and treatment of leptomeningeal metastases in non small cell lung cancer (NSCLC)  Twenty five patients with leptomeningeal metastases of NCSLC from Fudan University Huashan Hospital North during the period from September 2017 to November 2018 were enrolled. All 25 patients were confirmed leptomeningeal metastases by cerebrospinal fluid cytology and immunocytochemical staining of cytokeratin(CK7) carcinoembryonic antigen(CEA) thyroid transcription factor 1(TTF 1) and Ki67. The cerebrospinal fluid cfDNA was extracted and genetic variation of 12 genes including epidermal growth factor receptor(EGFR) TP53 and anaplastic lymphoma kinase(ALK) was detected by next generation sequencing [PlasAim TM gene non invasive detection of lung cancer (12 gene) kit, Singlera Genomics].The application value of cerebrospinal fluid cfDNA in the diagnosis and treatment of leptomeningeal metastases of NSCLC was analyzed with the cfDNA mutation data and the clinical follow ups.  Morphologically typical lung cancer tumor cells with tumor immunochemistry markerCK, CK7 and CEA were found in the cerebrospinal fluid of all 25 patients. Next generation sequencing of cerebrospinal fluid showed that 96% (24/25) patients had at least one single nucleotide variation (SNV) or copy number variation (CNV) The EGFR and TP53 mutations were identified in 80% (20/25) and 48%(12/25) of the patients, respectively. In addition, patients with bone metastases had a higher rate of EGFR mutations than those without bone metastases (100% vs 64% P<0.05) Changes in the mutant allele frequency of EGFR and TP53 in cerebrospinal fluid were consistent with patients' disease progression parameters including neurological symptoms, imaging, and tumor biomarkers. The results indicate that genetic alteration of EGFR in cerebrospinal fluid cfDNA is an actionable biomarker for targeted therapy of leptomeningeal metastases of lung cancer.  Cerebrospinal fluid cfDNA accurately reveals the unique genetic background of leptomeningeal metastasis in NSCLC, showing great application value in the diagnosis and treatment of the leptomeningeal metastasis of NSCLC.  Carcinoma, non small cell lung; Neoplasm metastasis; Meningeal neoplasms; Cell free nucleic acids; Cerebrospinal fluid; High throughput nucleotide sequencing

title: Evaluating the cerebrospinal fluid ctDNA detection by next generation sequencing in the diagnosis of meningeal Carcinomatosis
abstract: BackgroundMeningeal carcinomatosis (MC) is the most severe form of brain metastasis and causes significant morbidity and mortality. Currently, the diagnosis of MC is routinely confirmed on the basis of clinical manifestation, positive cerebrospinal fluid (CSF) cytology, and/or neuroimaging features. However, negative rate of CSF cytology and neuroimaging findings often result in a failure to diagnose MC from the patients who actually have the disease. Here we evaluate the CSF circulating tumor DNA (ctDNA) in the diagnosis of MC.MethodsA total of 35 CSF samples were collected from 35 patients with MC for CSF cytology examination, CSF ctDNA extraction and cancer associated gene mutations detection by next generation sequencing (NGS) at the same time.ResultsThe most frequent primary tumor in this study was lung cancer (26/35, 74% followed by gastric cancer (2/35, 6% breast cancer (2/35, 6% prostatic cancer (1/35, 3% parotid gland carcinoma (1/35, 3% and lymphoma (1/35, 3% while no primary tumor could be found in the remaining 2 patients in spite of using various inspection methods. Twenty five CSF samples (25/35; 71% were found neoplastic cells in CSF cytology examination while all of the 35 CSF samples (35/35; 100% were revealed having detectable ctDNA in which cancer associated gene mutations were detected. All of 35 patients with MC in the study underwent contrast enhanced brain MRI and/or CT and 22 neuroimaging features (22/35; 63% were consistent with MC. The sensitivity of the neuroimaging was 88% (95% confidence intervals [95% CI] 75 to 100) (p 22/25) and 63% (95% CI, 47 to 79) (p 22/35) compared to those of CSF cytology and CSF ctDNA, respectively. The sensitivity of the CSF cytology was 71% (95% CI, 56 to 86) (n 25/35) compared to that of CSF ctDNA.ConclusionsThis study suggests a higher sensitivity of CSF ctDNA than those of CSF cytology and neuroimaging findings. We find cancer associated gene mutations in ctDNA from CSF of patients with MC at 100% of our cohort, and utilizing CSF ctDNA as liquid biopsy technology based on the detection of cancer associated gene mutations may give additional information to diagnose MC with negative CSF cytology and/or negative neuroimaging findings.