The aim of this study was to detect the epidermal growth factor receptor (EGFR)-activating mutations and other oncogene alterations in patients with non-small-cell lung cancers (NSCLC) who ...experienced a treatment failure in response to EGFR-tyrosine kinase inhibitors (TKIs) with a next generation sequencer.
Fifteen patients with advanced NSCLC previously treated with EGFR-TKIs were examined between August 2005 and October 2014. For each case, new biopsies were performed, followed by DNA sequencing on an Ion Torrent Personal Genome Machine (PGM) system using the Ion AmpliSeq Cancer Hotspot Panel version 2.
All 15 patients were diagnosed with NSCLC harboring EGFR-activating mutations (seven cases of exon 19 deletion, seven cases of L858R in exon 21, and one case of L861Q in exon 21). Of the 15 cases, acquired T790M resistance mutations were detected in 9 (60.0%) patients. In addition, other mutations were identified outside of EGFR, including 13 cases (86.7%) exhibiting TP53 P72R mutations, 5 cases (33.3%) of KDR Q472H, and 2 cases (13.3%) of KIT M541L.
Here, we showed that next-generation sequencing (NGS) is able to detect EGFR T790M mutations in cases not readily diagnosed by other conventional methods. Significant differences in the degree of EGFR T790M and other EGFR-activating mutations may be indicative of the heterogeneity of disease phenotype evident within these patients. The co-existence of known oncogenic mutations within each of these patients may play a role in acquired EGFR-TKIs resistance, suggesting the need for alternative treatment strategies, with PCR-based NGS playing an important role in disease diagnosis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We report the new finding of barroisite (Brs)–bearing metabasites within a metabasite layer from the Kebara Formation, a unit exposed between the Sanbagawa and the Chichibu belts in NW Kii Peninsula. ...The dominant lithotype of the metabasite layer shows pale–green colors and is mainly composed of sodium amphibole, actinolite, pumpellyite and epidote. It is in agreement with reported mineral assemblages in the Kebara Formation which document pumpellyite–actinolite (PA) or pumpellyite–blueschist (PBS) facies conditions (<340 °C and 0.8 GPa), and with geothermometry based on the Raman analysis of carbonaceous material from metapelite samples which give peak metamorphic temperatures of 300–340 °C. Brs grains are identified from metabasites with dark–green color in the layer, and are closely associated with epidote, chlorite, white mica, albite and quartz, but not with pumpellyite. Brs grains are replaced by sodium amphibole and/or winchite at the rim with a distinct compositional gap. Thermodynamic calculation suggests that the Brs + epidote + chlorite + albite + quartz assemblage is stable at P–T conditions higher than 450 °C and 0.4 GPa. The abovementioned data suggest that the Brs–bearing metabasites suffered an early higher temperature (>450 °C) metamorphism and then overprinted by PA or PBS facies metamorphism along with the main constituents of the Kebara Formation. In the Besshi area of the Sanbagawa belt, the earlier subducted higher grade rocks are considered to juxtapose to the newly subducted rocks and overprinted retrograde metamorphism during their exhumation stage. Our new finding suggests that the similar phenomenon was took place in the lower grade part of the Sanbagawa belt.
We previously reported the synergistic effect of S-1 and eribulin in preclinical models. In addition, our phase I study revealed the recommended dose for the phase II study of the combination therapy ...in advanced breast cancer (ABC) patients pre-treated with anthracycline and taxane. Our current study reports on the efficacy and safety of the combined use of eribulin and S-1 in patients with ABC and poor prognosis.
Patients with breast cancer who received prior anthracycline- and/or taxane-based therapy were assigned to receive a combination therapy of eribulin (1.4 mg/m
on days 1 and 8, every 21 days) and S-1 (65 mg/m
, on days 1 to 14, every 21 days) for advanced/metastatic disease. All patients had at least one clinicopathological factor such as being oestrogen receptor negative, Human Epidermal Growth Factor Receptor 2 (HER2) receptor negative, presence of visceral involvement, presence of three or more metastatic sites, or having a disease-free interval shorter than 2 years. The primary endpoint was the independent-reviewer assessed objective response rate (ORR). Secondary endpoints were clinical benefit rate, disease control rate, progression-free survival (PFS), and overall survival (OS).
This study enrolled 33 patients. Confirmed ORR was 33.3% (95% CI: 17.3 to 52.8). Median PFS was 7.5 months (95% CI: 4.0 to 14.3). Median OS time was not reached during the current experimental periods. The most common grade 3/4 adverse event was neutropenia (68.8%).
The combination of eribulin and S-1 is safe and effective for treatment in patients with ABC and poor prognosis.
Current Controlled Trials UMIN000015049 , date of registration: September 5th 2014.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Background
Despite the widespread use of opioids for the treatment of cancer pain, results from several surveys consistently show that pain is still prevalent in some patients with malignant ...diseases. The purinergic P2Y12 receptor is a primary site leading to microglial activation and hyperalgesic pain behaviors and is considered a key regulator in the prevention of the aggravation of clinical pain conditions. Genetic variability in the P2RY12 gene may contribute to individual differences in pain and opioid sensitivity.
Methods
We genotyped 31 single nucleotide polymorphisms (SNPs) throughout the P2RY12 gene and compared genotypes against pain measurements and opioid requirements in Japanese cancer pain patients (N = 90). The most promising SNP association with pain severity was validated by genotyping an additional postoperative pain patient cohort (N = 355).
Results
Five SNPs (rs3732765, rs9859538, rs17283010, rs11713504, and rs10935840) of the P2RY12 gene were significantly associated with cancer pain severity, although opioid requirements were comparable in each genotype of the five SNPs. The alleles of these SNPs represented one absolute linkage disequilibrium block of the P2RY12 gene. In the second association study of postoperative pain, subjects carrying the minor T allele of the rs3732765 SNP demonstrated more intense 24-hour postoperative pain compared with subjects not carrying this allele although total 24-hour postoperative opioid consumptions based on weight were comparable.
Conclusions
Polymorphisms of the P2RY12 gene may predict individual differences in both cancer and postoperative pain severity; this might be caused by functional alteration of nociceptive neurons through neuron-glia interaction.
Abstract
Observation of the evolution process of laser-induced periodic surface structure (LIPSS) will provide clues to its formation mechanism. We constructed a pulse-by-pulse image capture setup ...using oil-immersion optical microscopy with which we observed the evolution process on a coverslip of borosilicate glass, finding three LIPSS patterns: stripe patterns parallel and perpendicular to the electric field of the laser pulse, and a dot pattern. Furthermore, “reversing” motion was observed, that is, bright and dark interchange from pulse to pulse. The reversing motion had remarkable anisotropy, moving only perpendicular to the electric field of the laser pulse.
Thermal structure of the Kebara Formation and its proximal areas in the western Kii Peninsula was examined by Raman spectra of carbonaceous material (RSCM) geothermometer for pelitic rocks. A mean ...temperature of 313 ± 5 °C is obtained for the Kebara Formation, which is comparable with that of the neighboring unit of the Mikabu belt (319 ± 5 °C). The Sanbagawa belt of the relevant area, within a few kilometers to the north of the Kebara Formation, shows a mean temperature of 285 ± 7 °C, which is slightly but evidently lower value than those of the above two units. Peak temperatures estimated from the Chichibu belt and Shimanto belt located to the south of the Kebara Formation are 289 ± 13 °C and 216 ± 24 °C, respectively. Published geochronological data of the Kebara Formation are slightly older than those of the Sanbagawa belt in the Kii Peninsula and are similar to those of the Mikabu belt in the relevant area. These two data sets (geothermometry and geochronology) suggest that the Kebara Formation is possibly correlated with the Mikabu belt, but is not coherent to the southern margin of the Sanbagawa belt in the western Kii Peninsula, in tectonic contact with each other.
Data on prognosis and predictors of overall survival in advanced lung cancer patients diagnosed following emergency admission (DFEA) are currently lacking. We retrospectively analysed data from 771 ...patients with advanced nonsmall cell lung cancer between April 2004 and April 2012. Of the 771 patients, 103 (13%) were DFEA. DFEA was not an independent predictor of overall survival by multivariate Cox proportional hazard models, whereas good performance status (PS), epidermal growth factor receptor gene mutation, stage IIIB, adenocarcinoma and chemotherapy were independent predictors of overall survival (hazard ratio (95% CI) 0.36 (0.29-0.44), p<0.001; 0.49 (0.38-0.63), p<0.001; 0.64 (0.51-0.80), p<0.001; 0.81 (0.67-0.99), p=0.044; and 0.40 (0.31-0.52), p<0.001, respectively). Good PS just prior to opting for chemotherapy, but not at emergency admission, was a good independent predictor of overall survival in DFEA patients (hazard ratio (95% CI) 0.26 (0.12-0.55); p<0.001). DFEA is relatively common. DFEA and PS at emergency admission were not independent predictors of overall survival, but good PS just prior to opting for chemotherapy was an independent predictor of longer overall survival. Efforts to improve patient PS after admission should be considered vital in such circumstances.
Aim
Cancer pain impairs not only physical functions but also social functions and roles. Consequently, the overall health‐related quality of life of patients with cancer pain deteriorates. Opioid ...analgesics are recommended for treating moderate to strong cancer pain. Advances in human genome research have fueled a growing interest to understand individual differences in responsiveness to opioid analgesics. This study aimed to explore and identify novel loci for genes predisposing an individual to opioid analgesic responsiveness.
Methods
A total of 71 cancer patients rated their pain on an 11‐point numerical rating scale twice before and after increasing opioid analgesics. A genomewide association study focusing on single nucleotide polymorphisms (SNPs) was conducted to associate pain decrease with increased dosage of opioid analgesics based on weight (ie, responsiveness to opioid analgesics). A genomewide significance (P < 5E‐8) was set for multiplicity of analyses to control for false positives.
Results
Two SNPs passed the genomewide threshold for significance. One exonic SNP (rs1641025) was located in the ABAT 4‐aminobutyrate aminotransaminase (GABA transaminase) gene on chromosome 16. The other SNP (rs12494691) was located on chromosome 3, which was not associated with any known genes. These SNPs were not associated with opioid‐related adverse effects.
Conclusions
Our results preliminarily suggest that both SNPs might be potential candidate loci for responsiveness to opioid analgesics, and GABA transaminase might be a possible target for developing adjuvant pharmacotherapy with opioid analgesics in adjuvant pharmacotherapy. Our results should be validated in a large‐scale study with a larger sample size.
A genome‐wide association study revealed two candidate single nucleotide polymorphisms for responsiveness to opioid analgesics in patients with cancer pain, one of which locates on the GABA transaminase gene.
Recent gene profiling studies have identified at least 5 major subtypes of breast cancer, including normal type, luminal A type, luminal B type, human epidermal growth factor receptor (HER)-2 ...positive type, and basal-like type. Triple-negative breast cancer (TNBC), showing no or low expressions of estrogen receptor (ER), progesterone receptor (PgR), and HER2, considered important clinical biomarkers, accounts for 10% to 20% of all breast cancers. Hormonal therapy and molecular targeted therapy are not indicated for the management of TNBC, resulting in poor outcomes. Because TNBC lacks clear-cut therapeutic targets, effective treatment strategies remain to be established. However, TNBC is known to share similar biologic characteristics with basal-like type breast cancer and is often accompanied by loss of functional BRCA, a gene-modifying enzyme. Breast cancer with BRCA1 or BRCA2 mutations is accompanied by activation of the enzyme poly(ADP-ribose) polymerase (PARP). PARP, a DNA base-excision repair enzyme, is known to play a central role in gene repair, along with BRCA. Because some breast cancers with BRCA1 or BRCA2 mutations are TNBC, the suppression of PARP has attracted attention as a new treatment strategy for TNBC. In this article, we review the clinical characteristics of TNBC, discuss problems in treatment, and briefly summarize the international development status of PARP inhibitors.
Immune-related adverse events (irAEs) have been associated with the efficacy of PD-1 (programmed cell death protein 1) inhibitors in patients with melanoma, but whether such an association exists for ...non-small-cell lung cancer (NSCLC) has remained unknown.
To evaluate the relation of irAEs to nivolumab efficacy in NSCLC.
In this study based on landmark and multivariable analyses, a total of 134 patients with advanced or recurrent NSCLC who were treated with nivolumab in the second-line setting or later between December 2015 and August 2016 were identified from a review of medical records from multiple institutions, including a university hospital and community hospitals. Data were updated as of December 31, 2016.
The absence or presence of any irAE before the landmark date.
Kaplan-Meier curves of progression-free survival (PFS) according to the development of irAEs in 6-week landmark analysis were evaluated with the log-rank test as a preplanned primary objective. Overall survival (OS) was similarly evaluated. Multivariable analysis of both PFS and OS was performed with Cox proportional hazard regression models.
In a cohort of 134 patients (median range age, 68 33-85 years; 90 men 67%, 44 women 33%), irAEs were observed in 69 of the 134 study patients (51%), including 12 patients (9%) with such events of grade 3 or 4, and 24 patients (18%) requiring systemic corticosteroid therapy. In 6-week landmark analysis, median PFS was 9.2 months (95% CI, 4.4 to not reached NR) and 4.8 months (95% CI, 3.0 to 7.5) (P = .04) whereas median OS was NR (95% CI, 12.3 to NR) and 11.1 months (95% CI, 9.6 to NR) (P = .01) for patients with or without irAEs, respectively. Multivariable analysis also revealed that irAEs were positively associated with survival outcome, with hazard ratios of 0.525 (95% CI, 0.287 to 0.937; P = .03) for PFS and 0.282 (95% CI, 0.101 to 0.667; P = .003) for OS.
Development of irAEs was associated with survival outcome of nivolumab treatment in patients with advanced or recurrent NSCLC. Further studies are needed to confirm our findings.
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