Differential expression of miRNAs in acute myeloid leukemia quantified by Nextgen sequencing of whole blood samples.

New approaches are needed for understanding and treating acute myeloid leukemia (AML). MicroRNAs (miRs) are important regulators of gene expression in all cells and disruption of their normal expression can lead to changes in phenotype of a cell, in particular the emergence of a leukemic clone. We collected peripheral blood samples from 10 adult patients with newly diagnosed AML, prior to induction chemotherapy, and 9 controls. Two and a half ml of whole blood was collected in Paxgene RNA tubes. MiRNA was purified using RNeasy mini column (Qiagen). We sequenced approximately 1000 miRs from each of 10 AML patients and 9 controls. In subset analysis, patients with NPM1 and FLT3 mutations showed the greatest number of miRNAs (63) with expression levels that differed from control with adjusted p-value of 0.05 or less. Some of these miRs have been described previously in association with leukemia, but many are new. Our approach of global sequencing of miRs as opposed to microarray analysis removes the bias regarding which miRs to assay and has demonstrated discovery of new associations of miRs with AML. Another strength of our approach is that sequencing miRs is specific for the 5p or 3p strand of the gene, greatly narrowing the proposed target genes to study further. Our study provides new information about the molecular changes that lead to evolution of the leukemic clone and offers new possibilities for monitoring relapse and developing new treatment strategies.

Epidermal growth factor receptor T790M mutation-positive metastatic non-small-cell lung cancer: focus on osimertinib (AZD9291).

Adenocarcinoma is the most common type of non-small-cell lung cancer (NSCLC). Adenocarcinoma with epidermal growth factor receptor (EGFR) mutations accounts for 8%-30% of all cases of NSCLC depending on the geography and ethnicity. EGFR-mutated NSCLC usually responds to first-line therapy with EGFR tyrosine kinase inhibitors (TKIs). However, there is eventual loss of efficacy to TKIs due to development of resistance. The most frequent cause for resistance is a second EGFR mutation in exon 20 (T790M), which is encountered in up to 62% of patients. Osimertinib is one of the third-generation EGFR TKIs with a high selective potency against T790M mutants. In Phase I trial of osimertinib in advanced lung cancer after progression on EGFR TKIs, the response rate and disease control rate were 61% and 95%, respectively. A subsequent Phase II (AURA2) trial demonstrated a disease control rate of 92%, a response rate of 71%, a median duration of response of 7.8 months, and a median progression-free survival of 8.6 months. Osimertinib was approved by the US Food & Drug Administration in November 2015 for patients whose tumors exhibited T790M mutation and for those with progressive disease on other EGFR TKIs. In this review, we address the role of EGFR TKIs in the management of EGFR mutation lung cancer and the mechanisms of resistance to TKIs with a focus on the role of osimertinib. Data from completed trials of osimertinib, ongoing trials, as well as novel diagnostic methods to detect EGFR T790M mutation are reviewed.

A Case of Vanishing Brain Metastasis in a Melanoma Patient on Nivolumab.

BACKGROUND: Melanoma is among the top three cancers to present with brain metastasis. The risk of brain metastases in advanced melanoma increases with disease duration. Cytotoxic chemotherapy does not have a significant role in the management of melanoma patients with brain metastases, neither alone nor in conjunction with radiation therapy. PATIENTS AND METHODS: We herein discuss a case of a 66-year-old male diagnosed initially with stage III-B melanoma and underwent a wide local excision with a split thickness graft and sentinel lymph node biopsy, followed by adjuvant treatment with high-dose interferon. RESULTS: On subsequent follow up he was found to have a brain lesion, which later on resolved after starting ipilumumab. Five to twenty percent of patients with melanoma of any stage develop cerebral metastases. CONCLUSION: Immunotherapy modalities, ipilimumab has been shown to have activity against brain metastases.

Carcinomatous meningitis due to gastric adenocarcinoma: A rare presentation of relapse.

While solid tumors are less commonly associated with meningeal involvement; lung, breast and melanoma are the ones most often reported. A few case reports have included gastric carcinoma but these are rare and most often associated with systemic disease at the time of diagnosis. Here we report a unique presentation of gastric carcinoma relapse with leptomeningeal carcinomatosis. An 81-year-old female was diagnosed with gastric cancer approximately one year before presentation. Following neoadjuvant chemotherapy, she had gastrectomy. Her periodic surveillance was stable. Thereafter she presented with a one week history of progressive fatigue lightheadedness, syncope. During hospitalization her mental status deteriorated. A repeat computed axial tomography scan of the head showed no changes to suggest an etiology. A lumbar puncture was performed and cerebral spinal fluid (CSF) cytopathology confirmed gastric signet cell adenocarcinoma. Encephalopathy was likely caused by increased intracranial pressure from communicating hydrocephalus. Leptomeningeal carcinomatosis is associated with short life expectancy. Therapeutic lumbar punctures and best supportive care or systemic therapy can be applied with guarded prognosis. Survival, however, may improve with cytologic negative conversion of the CSF if patient performance status allows treatment.