•In patients with ALK-rearranged NSCLC who received lorlatinib within the compassionate use program, the objective tumor response (OR) and disease control (DC) were observed in 43% and 94% cases, ...respectively.•Lorlatinib showed particularly high efficacy against brain metastases, with OR and DC for intracranial disease reaching 81% and 100%, respectively.•Patients with V.1 and V.3 ALK translocations had similar response to the therapy.•Complete lack of adverse events tended to correlate with poor outcome of lorlatinib treatment.
Lorlatinib is a novel potent ALK inhibitor, with only a few studies reporting the results of its clinical use.
This study describes the outcomes of lorlatinib treatment for 35 non-small cell lung cancer patients with ALK rearrangements, who had 2 (n = 5), 1 (n = 26) or none (n = 4) prior tyrosine kinase inhibitors and received lorlatinib mainly within the compassionate use program.
Objective tumor response (OR) and disease control (DC) were registered in 15/35 (43%) and 33/35 (94%) patients, respectively; brain metastases were particularly responsive to the treatment (OR: 22/27 (81%); DC: 27/27 (100%)). Median progression free survival (PFS) was estimated to be 21.8 months, and median overall survival (OS) approached to 70.1 months. Only 4 out of 35 patients experienced no adverse effects; two of them were the only subjects who had no clinical benefit from lorlatinib. PFS and OS in the no-adverse-events lorlatinib users were strikingly lower as compared to the remaining patients (1.1 months vs. 23.7 months and 10.5 months vs. not reached, respectively; p < 0.0001 for both comparisons). ALK translocation variants were known for 28 patients; there was no statistical difference between patients with V.1 and V.3 rearrangements with regard to the OS or PFS.
Use of lorlatinib results in excellent disease outcomes, however caution must be taken for patients experiencing no adverse effects from this drug.
We analyzed the expression of several microRNAs (miRs) implicated in breast cancer (BC) pathogenesis (miR-21, miR-10b, miR17-5p, mir-31, miR-155, miR-200c, miR-18a, miR-205, and miR-27a) in 80 breast ...carcinomas obtained from patients with bilateral BC (biBC) and 40 cases of unilateral BC (uBC). Unexpectedly, three miRs (miR-21, miR-10b and miR-31) demonstrated significantly higher level of expression in biBC vs. uBC (
P
= 0.0001, 0.00004 and 0.0002, respectively). Increased contents of miR-21, miR-10b and miR-31 were observed in all categories of biBC tumors, i.e., in synchronous biBC as well as in first and second tumors from metachronous biBC cases. Synchronous biBC showed more similarity of miR expression profiles within pairs that the metachronous doublets (
P
= 0.004). This study suggests that bilateral breast tumors have somewhat distinct pattern of molecular events as compared to the unilateral disease.
In the present study, total and partial charge changing cross-sections of 300A MeV Fe26+ ion beam in aluminum target were measured by a new system of analysis installed with the Leica QWin Plus ...software. The CR39 nuclear track detectors were used to identify the incident charged particles and their fragments. The CR39 detectors just before and just after the target were calibrated and found to have the same charge response and the charge resolution, which were 0.19e and 0.20e, respectively. The response points were fitted with a polynomial of degree one and all the points are within the limits of experimental errors. The value of total charge changing cross-section was calculated to be stot=(1663+/-236) mb. To determine the partial charge changing cross-sections for DZ=-23,-22,...,-1, number of events corresponding to each fragment were determined from multiple Gaussian fitting of diameter distributions within 95.5% confidence levels and the numbers of incident and survived beam ions were counted within 99.7% confidence levels. Charge pick-up cross-section for DZ=+1 was calculated and is (92+/-6) mb.
Purpose
Germline mutations in CHEK2 gene represent the second most frequent cause of hereditary breast cancer (BC) after BRCA1/2 lesions. This study aimed to identify the molecular characteristics of ...CHEK2-driven BCs.
Methods
Loss of heterozygosity (LOH) for the remaining CHEK2 allele was examined in 50 CHEK2-driven BCs using allele-specific PCR assays for the germline mutations and analysis of surrounding single-nucleotide polymorphisms (SNPs). Paired tumor and normal DNA samples from 25 cases were subjected to next-generation sequencing analysis.
Results
CHEK2 LOH was detected in 28/50 (56%) BCs. LOH involved the wild-type allele in 24 BCs, mutant CHEK2 copy was deleted in 3 carcinomas, while in one case the origin of the deleted allele could not be identified. Somatic PIK3CA and TP53 mutations were present in 13/25 (52%) and 4/25 (16%) tumors, respectively. Genomic features of homologous recombination deficiency (HRD), including the HRD score ≥ 42, the predominance of BRCA-related mutational signature 3, and the high proportion of long (≥ 5 bp) indels, were observed only in 1/20 (5%) BC analyzed for chromosomal instability. Tumors with the deleted wild-type CHEK2 allele differed from LOH-negative cases by elevated HRD scores (median 23 vs. 7,
p
= 0.010) and higher numbers of chromosomal segments affected by copy number aberrations (
p
= 0.008).
Conclusion
Somatic loss of the wild-type CHEK2 allele is observed in approximately half of CHEK2-driven BCs. Tumors without CHEK2 LOH are chromosomally stable. BCs with LOH demonstrate some signs of chromosomal instability; however, its degree is significantly lower as compared to BRCA1/2-associated cancers.
Low-penetrance genetic variations appear to form the most essential component of the heritability of cancer risk. Search for relevant polymorphic candidates faces significant obstacles, due to both ...the high number of potentially promising single nucleotide polymorphisms (SNPs) and the intrinsic difficulties in identification of weak gene-disease interactions. At present, extensive case-control studies can be applied only to a limited number of gene polymorphisms. Therefore, the choice of SNPs that deserve an exhaustive populational analysis is of primary importance. Preferences are usually given to those genetic pathways, whose variability and role in cancer causation have been already shown by prior studies. The available electronic databases and software tools may allow further SNP sorting, based on functional predictions. The design for the pilot study may need to be different from the one for large-scale case-control analysis. Some investigations justify non-random patient selection for preliminary assessment of low-penetrance effects, with the emphasis on particularly susceptible individuals (familial, early onset, multiple cancer cases). Other presumably accelerating approaches suggest a decisive exclusion of SNP candidates showing only marginal effects, relaxed formats for rapid dissemination of preliminary data, use of more demonstrative controls such as elderly tumor-free subjects, etc. These short-cuts cannot be properly validated for the time being, due to the paucity of identified low-penetrance risk modifiers.. It is expected that the increasing capacities of available DNA collections, coupled with the rapid development of high-throughput genotyping technologies, will vastly accelerate the research on polygenic cancer susceptibility.
The SLIM experiment was a large array of nuclear track detectors located at the Chacaltaya high altitude Laboratory (5230 m a.s.l.). The detector was in particular sensitive to intermediate mass ...magnetic monopoles, with masses 10
5
GeV <M
M
< 10
12
GeV. From the analysis of the full detector exposed for more than 4 years a flux upper limit of 1.3×10
-15
cm
-2
s
-1
sr
-1
for downgoing fast intermediate mass monopoles was established at the 90% C.L.
In the present study, CR39 track etch detector was calibrated with a new system and the total charge changing cross-section of 300 A MeV Fe26+ ion beam in aluminum target was measured. The CR39 ...nuclear track detectors were used to identify the incident charged particles and their fragments using an optical microscope DM6000 M and automated image analyzer system installed with Leica QWin Plus software. The CR39 detectors before and after the target were calibrated and found to have the same charge response; the charge resolution in both of the detectors were 0.19e and 0.20e, respectively. The calibration points were fitted with a polynomial of degree one and all the points are within the limits of the experimental errors. The response functions were also obtained and fitted with a polynomial of degree three which are quite good throughout Z/β = 4.6 to 41.4. The value of the total charge changing cross-section is σtot = (1663 ± 236) mb. The total charge changing cross-section was compared with the experimental results of others and also fitted by the Bradt-Peters geometrical cross-section.
► A new system of optical microscope DM6000 M with Leica QWin Plus software was used in the present measurement. ► New features of Leica QWin Plus were explored to achieve a higher accuracy. ► Better charge resolution and improved threshold were achieved in the present measurements. ► The calibration curves of CR39 detectors were obtained and fitted with first degree polynomial. ► The total charge changing cross-section of 300 A MeV Fe26+ ion beam in aluminum target was measured.
Novel ALK fusion partners in lung cancer Iyevleva, Aglaya G; Raskin, Grigory A; Tiurin, Vladislav I ...
Cancer letters,
06/2015, Letnik:
362, Številka:
1
Journal Article
Recenzirano
Highlights • Combination of two distinct PCR assays is a highly reliable approach for detection of both known and new ALK translocations. • Two novel ALK fusion partners, DCTN1 and SQSTM1, have been ...identified. • Increased frequency of ALK rearrangements among female patients is attributed to the low prevalence of smoking, not to the gender per se.
The SLIM experiment at the Chacaltaya high altitude laboratory was sensitive to nuclearites and Q-balls which could be present in the cosmic radiation as possible Dark Matter components. It was ...sensitive also to strangelets, i.e. small lumps of Strange Quark Matter predicted at such altitudes by various phenomenological models. The analysis of 427 m
2
of Nuclear Track Detectors exposed for 4.22 years showed no candidate event. New upper limits on the flux of downgoing nuclearites and Q-balls at the 90% C.L. were established. The null result also restricts models for strangelets propagation through the Earth atmosphere.
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