20146086 Visualization

A 54 Age - year Age - old Age woman Sex with stage Detailed_description IV Detailed_description NSCLC Disease_disorder was treated with carboplatin Medication and paclitaxel Medication without Detailed_description disease Detailed_description response Detailed_description .
Molecular Diagnostic_procedure analysis Diagnostic_procedure of tumor Diagnostic_procedure tissue Diagnostic_procedure was unavailable Detailed_description at that time.
However, her demographic profile ( Asian Personal_background , minimal Severity smoking History history History , non Detailed_description - small Detailed_description cell Detailed_description histology Diagnostic_procedure ) predicted her Coreference disease Coreference would harbor EGFR Diagnostic_procedure TKI Diagnostic_procedure sensitive Diagnostic_procedure cells Diagnostic_procedure [2].
Therefore, she then initiated standard Detailed_description daily Dosage dosing Dosage of erlotinib Medication ( 150 Lab_value mg Lab_value ) and her Coreference disease Coreference responded Detailed_description .
Twenty Date - eight Date months Date later Date , she acquired resistance Other_event to erlotinib Medication with progression Detailed_description of disease Coreference systemically Detailed_description .
Following further progression through an experimental Detailed_description angiogenesis Medication inhibitor Medication , she initiated pemetrexed Medication and resumed standard Coreference dose Coreference erlotinib Coreference .
After initial response, 11 Date months Date later Date , her Coreference disease Coreference again progressed Detailed_description .
DNA Biological_structure was extracted from biopsy Diagnostic_procedure of a progressing Detailed_description lung Biological_structure lesion Disease_disorder and examined using established techniques for analysis of EGFR Diagnostic_procedure mutations Diagnostic_procedure [5].
Direct Diagnostic_procedure sequencing Diagnostic_procedure of exons Detailed_description 18–21 encoding the kinase Detailed_description domain Detailed_description of EGFR Diagnostic_procedure revealed the L858R Diagnostic_procedure mutation Diagnostic_procedure associated with EGFR Detailed_description TKI Detailed_description sensitivity Detailed_description (Fig.1) [2].
It Coreference also demonstrated the T790M Diagnostic_procedure mutation Diagnostic_procedure associated with acquired Detailed_description EGFR Detailed_description TKI Detailed_description resistance Detailed_description (Fig.1) [2].
She also developed headaches Sign_symptom and there was a high clinical suspicion of CNS Biological_structure metastases Disease_disorder despite negative Lab_value imaging Diagnostic_procedure (not shown).
She refused a lumbar Therapeutic_procedure puncture Therapeutic_procedure .
She initiated empiric Detailed_description temozolomide Medication plus standard Detailed_description dose Detailed_description erlotinib Medication ( 150 Dosage mg Dosage daily Dosage ) for presumed CNS Disease_disorder disease Disease_disorder , but after Time one Time cycle Time her headaches Sign_symptom worsened Lab_value , and she developed nausea Sign_symptom and vomiting Sign_symptom concerning for CNS Disease_disorder metastases Disease_disorder with associated raised Lab_value intracranial Diagnostic_procedure pressure Diagnostic_procedure .
Magnetic Diagnostic_procedure resonance Diagnostic_procedure imaging Diagnostic_procedure (MRI) Diagnostic_procedure of the brain Biological_structure now demonstrated LM Disease_disorder (Fig.2) confirmed by CSF Diagnostic_procedure cytology Diagnostic_procedure (not shown).
By direct Detailed_description sequencing Diagnostic_procedure , DNA Biological_structure from CSF Diagnostic_procedure cells Diagnostic_procedure harbored L858R Diagnostic_procedure predicting EGFR Diagnostic_procedure TKI Diagnostic_procedure sensitivity Diagnostic_procedure (Fig.3, left panel) but not the T790M Diagnostic_procedure resistance Diagnostic_procedure mutation Diagnostic_procedure (data not shown).
Because the result for T790M Diagnostic_procedure was negative Lab_value in this Coreference sample Coreference , we performed a more Lab_value sensitive Lab_value fluorescence Detailed_description detection Detailed_description PCR Detailed_description - based Detailed_description assay Diagnostic_procedure that takes advantage of a PCR Diagnostic_procedure restriction Diagnostic_procedure fragment Diagnostic_procedure length Diagnostic_procedure polymorphism Diagnostic_procedure generated by the Coreference specific Coreference missense Coreference mutation Coreference (Fig.3, right panel, arrow, positive control) [6].
That Coreference result Coreference was also negative Lab_value , as only the wild Diagnostic_procedure type Diagnostic_procedure peak Diagnostic_procedure was detected (Fig.3, right panel, bottom).
Therefore, we hypothesized that the LM remained sensitive to an EGFR TKI if sufficiently high concentrations of drug could be achieved in the CSF.
The erlotinib concentration required to inhibit growth of cell lines harboring L858R by 50% (IC50) is 100 nM (nM) [2].
Standard dose erlotinib (150 mg daily) achieves 3000 nM in plasma [7], but CSF concentrations of EGFR TKIs are as low as 1% plasma levels below the IC50 [3, 8].
Increasing the daily dose of gefitinib to enhance CSF penetration has been an effective strategy [3], but gefitinib is no longer available in the United States following failure in phase III NSCLC trials.
An analogous increase of the daily erlotinib dose above 150–200 mg daily induces unacceptable toxicity.
However, weekly high-dose erlotinib up to 2000 mg is tolerable [4].
Pharmacokinetic Diagnostic_procedure analysis Diagnostic_procedure of CSF Biological_structure from another Subject patient Subject with NSCLC Disease_disorder LM Disease_disorder (not shown) treated with 1500 Dosage mg Dosage erlotinib Medication weekly Dosage demonstrated a peak Diagnostic_procedure plasma Diagnostic_procedure concentration Diagnostic_procedure of 11,300 Lab_value nM Lab_value with a concurrent CSF Diagnostic_procedure concentration Diagnostic_procedure of 130 Lab_value nM.
Therefore, such high dose weekly administration of erlotinib achieved a CSF concentration exceeding Detailed_description the Detailed_description IC50 Detailed_description .
Therefore, to increase CSF penetrance over standard daily erlotinib dosing in this patient, we initiated high Dosage - dose Dosage weekly Dosage erlotinib Medication at 1000 Lab_value mg Lab_value then 1200 Lab_value mg Lab_value ; persistent Detailed_description nausea Sign_symptom precluded higher doses.
Pharmacokinetic Diagnostic_procedure analysis Diagnostic_procedure was not undertaken in this patient.
After Date 1 Date month Date there was a partial Diagnostic_procedure radiographic Diagnostic_procedure response Diagnostic_procedure of LM Disease_disorder on brain Biological_structure MRI Diagnostic_procedure (Fig.2b) and after Date 2 Date months Date in the cauda Biological_structure equina Biological_structure (not shown).
However, hydrocephalus Disease_disorder and persistent Detailed_description symptoms Sign_symptom referable to increased Lab_value intracranial Diagnostic_procedure pressure Diagnostic_procedure led to a VP Therapeutic_procedure shunt Therapeutic_procedure and whole Biological_structure - brain Biological_structure radiation Therapeutic_procedure therapy Therapeutic_procedure , after which she resumed treatment with 1500 Dosage mg Dosage weekly Dosage erlotinib Medication .
One Date month Date later Date , progressive Detailed_description intra Disease_disorder - thoracic Disease_disorder disease Disease_disorder led to initiation of cetixumab Medication and erlotinib Medication was continued but changed to low Dosage dose Dosage ( 100 Lab_value mg Lab_value ) daily Dosage .
She survived Sign_symptom 14 Date months Date following Date the Date diagnosis Date of Date CNS Date disease Date .