Clinical activity of brigatinib in ROS1-rearranged non-small cell lung cancer.

BACKGROUND: Brigatinib is a potent ROS1 inhibitor. The existing data on its clinical activity in ROS1-rearranged non-small cell lung cancer (NSCLC) are limited to four cases. METHODS: Six patients with ROS1-rearranged advanced NSCLC treated with brigatinib were identified through search of the internal databases of four participating cancer centers. Four additional patients were selected by PubMed and Google Scholar search. The objective response rate (ORR), progression-free survival (PFS) (RECIST v.1.1), duration of treatment (DOT), and safety were assessed. RESULTS: Of eight patients evaluable for response assessment (crizotinib naive-1, crizotinib resistant -7), three patients demonstrated a partial response (ORR-37%). One crizotinib-naive patient had an ongoing response at 21.6 months. Of seven crizotinib-resistant patients, two patients demonstrated a partial response (ORR-29%), and one patient (14%) had stable disease. PFS, available in four crizotinib-resistant patients, was 7.6 + , 2.9, 2.0, and 0.4 months. In crizotinib-resistant patients, DOT was 9.7 + , 7.7 + , 7.6 + , 4.0, 2.0, 1.1, 0.4 months, and was not reported in two patients. Genomic profiling in one responder revealed no ROS1 alteration, suggesting that the response was attributable to "off-target" brigatinib activity. In two patients with progressive disease, genomic profiling demonstrated a cMET exon 14 mutation + KRAS G12A mutation in one case, and a persisting ROS1-CD74 fusion + TP53 K139N, FGFR2 E250G, ATM G2695D, and NF1 R2258Q mutations in the other. No grade 3-5 toxicity was observed. CONCLUSION: Brigatinib demonstrated modest activity in crizotinib-resistant ROS1-rearranged NSCLC. Its intracranial and systemic activity should be assessed in correlation with the underlying molecular mechanism of crizotinib resistance.

Our series is the first to describe brigatinib activity in ROS1-altered NSCLC. In crizotinib-resistant patients, ORR with brigatinib was 29%. PFS with brigatinib was 7.6+, 2.9, 2.0, and 0.4 months. DOT with brigatinib was 9.7+, 7.7+, 7.6+, 4.0, 2.0, 1.1, 0.4 months. The correlation between response and molecular resistance needs further exploration.

Liver metastases from colorectal cancer: regional intra-arterial treatment following failure of systemic chemotherapy.

This study was designed to determine response rate, survival and toxicity associated with combination chemotherapy delivered intra-arterially to liver in patients with hepatic metastases of colorectal origin refractory to standard systemic treatment. A total of 28 patients who failed prior systemic treatment with fluoropyrimidines received a median of 5 cycles of intra-arterial treatment consisting of 5-fluorouracil 700 mg/m(2)/d, leucovorin 120 mg/m(2)/d, and cisplatin 20 mg/m(2)/d for 5 consecutive days. Cycles were repeated at intervals of 5-6 weeks. A major response was achieved in 48% of patients: complete response in 8% and partial response in 40%. The median duration of response was 11.5 months. Median survival was 12 months at a median follow up of 12 months. On multivariate analysis, the only variables with a significant impact on survival were response to treatment and performance status. Toxicity was moderate: grades III-IV neutropenia occurred in 29% of patients. Most of the patients complained of fatigue lasting for a few days following each cycle. There were no cases of hepatobiliary toxicity. These findings indicate that regional intra-arterial treatment should be considered in selected patients with predominantly liver disease following failure of standard treatment.

Guanosine potentiates the antiproliferative effect of cytosine-beta-D-arabinofuranoside in melanoma cell lines.

Guanosine is shown to potentiate markedly the antiproliferative effect of cytosine-beta-D-arabinoside (ara-C) on B16 F10 mouse and SKMEL-28 human melanoma cell lines. Several metabolic consequences of the synergistic interaction between ara-C and guanosine on cell growth were determined in B16 F10 mouse melanoma cells. Treatment of the cells with guanosine for 24 hr resulted in an increase in the percentage of cells in the S phase of the cell cycle, a threefold increase in intracellular GTP concentration, and an increase in the incorporation of ara-C into acid-insoluble material and phosphorylated metabolites. These findings suggest that guanosine potentiates the growth-inhibitory effect of ara-C in B16 F10 melanoma cells by increasing the intracellular concentration of its active metabolites.

Aircrew selection: a prospective study.

The medical reasons for rejection among 3,000 consecutive applicants for flight training were evaluated, and the effectiveness of the screening process determined by reviewing subsequent medical wastage occurring during flight training. Of the 46 cadets who left the course because of medical reasons, 8 withheld information which would have led to their rejection on the original screening examination (epilepsy 1, recurrent syncope 1, migraine headache 2, Crohn's disease 1, asthma 1, chronic knee pain 1, and chronic recurrent headaches 1). There were also two errors in medical processing. The other 36 cases could not have been predicted by current screening procedures. We conclude that the major deficiency in our screening process is the concealment or withholding of information by candidates for flight training.

Isolated tricuspid valve prolapse.

Tricuspid valve prolapse is commonly associated with mitral valve prolapse or other heart abnormalities and is rarely found as an isolated finding. A patient with isolated tricuspid valve prolapse is described which was discovered on routine examination of an asymptomatic pilot.

Spondylolithesis in pilots: a follow-up study.

There were 21 pilots followed for 12-131 months in order to determine the natural history of spondylolithesis (SLL). Of these 21, 16 had follow-up X-ray examinations, and only 1 was found with significant progression of the posterior vertebral displacement. Of the 12 pilots with SLL and low back pain (LBP), 4 had recurrent single episodes of acute LBP, but all remained active and continued to fly over the follow-up period. None of the 9 pilots who had SLL discovered on routine X-ray examination developed LBP over the follow-up period. We conclude that pilots with SLL can continue to fly with minimal risk of morbidity and loss of flight time.

Technetium-99m macroaggregates for the study of the distribution of arterial infusion chemotherapy in the liver.

One case of primary hepatic tumor and four cases of metastatic liver disease which were treated by intra-arterial infusion are reported herein to demonstrate the importance of monitoring the perfused parenchyma by imaging in at least two views (anterior and lateral) after the injection of radiolabeled macroaggregates into the infusion system.

Asymptomatic microscopic hematuria in pilots.

Pilots were examined in order to determine whether the cumulative incidence or point prevalence of asymptomatic microscopic hematuria is associated with air duty. The cumulative incidence of recurrent microscopic hematuria over a 12-15-year period was 11.3%(17/151) in fighter pilots, 10.0%(8/80) in helicopter pilots, and 13.8% (11/80) in transport pilots. Similarly, the point prevalence of microscopic hematuria in those who had flown the day prior to the urinalysis was no higher than found in the control group. We conclude that air duty does not cause microscopic hematuria either chronically or during the day after the stress of air flight.

Primary liposarcoma of the heart.

A rare form of primary heart tumour, a liposarcoma, is reported. A discussion of diagnosis and modalities of treatment of primary heart sarcomas is presented.