To evaluate whether the epidermal growth factor receptor (EGFR), K-Ras and PTEN, all members of the EGFR signalling pathway, may affect the clinical response in cetuximab-treated metastatic ...colorectal cancer (mCRC) patients. Twenty-seven cetuximab-treated mCRC patients were evaluated for drug response and investigated for EGFR protein expression and gene status, K-Ras mutational status and PTEN protein expression. Ten patients achieved a partial response (PR) to cetuximab-based therapy. All 27 patients showed EGFR protein overexpression. Epidermal growth factor receptor gene amplification was observed in eight out of 27 (30%) and chromosome 7 marked polysomy in 16 (59%) patients. Partial response was observed in six out of eight patients with EGFR gene amplification, four out of 16 with marked polysomy and none out of three with eusomy (P<0.05). The K-Ras wild-type sequence was observed in 17 patients, and nine of them experienced a PR. Conversely, K-Ras was mutated in 10 cases, of which one patient experienced a PR (P<0.05). The PTEN protein was normally expressed in 16 patients, and 10 of them achieved a PR. In contrast, no benefit was documented in 11 patients with loss of PTEN activity (P<0.001). Patients with EGFR gene amplification or chromosome 7 marked polysomy respond to cetuximab. In addition to K-Ras mutations, we demonstrate for the first time that the loss of PTEN protein expression is associated with nonresponsiveness to cetuximab.
Background: Breast cancer may be classified into distinct molecular subtypes based on gene expression profiling and/or immunophenotypic characteristics. Aim of the study was to investigate ...prevalence, clinicopathologic features and overall survival (OS) of molecular subtypes, in a large European population-based study. Patients and methods: All invasive breast cancers from 2003 to 2007 were selected from the files of Ticino Cancer Registry. Molecular subtypes were defined by immunohistochemical markers. Clinicopathological characteristics and short-term OS were analyzed. Results: Of 1214 invasive breast cancers, 73.2% were luminal A subtype, 13.8% luminal B, 7.4% basal like and 5.6% Her2/neu. Basal like presented largely in premenopausal women and displayed aggressive features, such as large tumor size, poorly differentiated cancers, high Ki-67 proliferation index and the worst 24-month OS. Luminal A included the highest percentage of patients >70, the highest proportion of stage I tumors and well/moderately differentiated lesions. Her2/neu was more frequent in postmenopausal women and showed the highest percentage of positive lymph nodes and stage IV cases. Conclusion: This is a comprehensive European population-based study on breast cancer molecular subtypes. We provide strong evidence that the molecular classification is useful for clinical management and superior to World Health Organization classification in terms of short-term prognostic value.
Minerals trapped as inclusions within other host minerals will develop non‐lithostatic pressures during both prograde and retrograde metamorphism because of the differences between the thermoelastic ...properties of the host and inclusion phases. There is only a single possible path in P–T space, the entrapment isomeke, along which no residual pressure would be developed in a host–inclusion system; non‐lithostatic pressures are developed in inclusions as a result of the external pressure and temperature deviating from the isomeke that passes through the entrapment conditions. With modern equation of state and elasticity data for minerals now available, it is possible to perform precise calculations of the isomekes for mineral pairs. These show that isomeke lines are not straight lines in P–T space at metamorphic conditions. We show that silicate inclusions in silicate hosts tend to have flat isomekes, with small values of ∂P∂Tisomeke, because of the small range of thermal expansion coefficients of silicate minerals. As a consequence, the general behaviour under decompression is for soft silicate inclusions in stiffer hosts to develop excess pressures, whereas a stiff silicate inclusion in a softer matrix will experience lower pressures than lithostatic pressure. The opposite effects occur for compression after entrapment on the prograde path. The excess pressures in inclusions, including allowance for mutual elastic relaxation of the host and inclusion, are most easily calculated by using the isomeke as a basis. Analysis of the simplest possible model of a host–inclusion system indicates that deviations from lithostatic pressure in excess of 1 GPa can be readily produced in quartz inclusions within garnet in metamorphic rocks. For softer host minerals such as feldspar, the pressure deviations are smaller, because of greater elastic relaxation of the host. The maximum pressure deviation from lithostatic pressure in the host phase around the inclusion is one‐third of the pressure deviation in the inclusion. Routines for performing these calculations have been added to the EosFit7c software package.
Histologic transformation in marginal zone lymphomas Conconi, A.; Franceschetti, S.; Aprile von Hohenstaufen, K. ...
Annals of oncology,
November 2015, 2015-Nov, 2015-11-00, 20151101, Letnik:
26, Številka:
11
Journal Article
Recenzirano
Odprti dostop
Histologic transformation (HT) is a poorly understood event in patients with marginal zone lymphoma (MZL). The aim of this study was to analyze incidence and risk factors for HT in a large series of ...MZL patients.
The studied cohort included 340 MZL patients diagnosed and treated between 1995 and 2012: 157 extranodal MZLs mucosa-associated lymphoid tissue (MALT) lymphoma, 46%, 85 splenic MZLs (SMZLs, 25%) and 37 nodal MZLs (NMZLs, 11%). Sixty-one patients (18%) had bone marrow infiltration at presentation, with or without detectable involvement of peripheral blood, but without other involved sites; they were considered clonal B-cell lymphocytosis of marginal zone origin (CBL-MZ).
With a median follow-up of 4.8 years, the median overall survival and progression-free survival of the whole population were 14.5 and 5 years, respectively. HT was observed in 13 cases 3.8%, 95% confidence interval (95% CI) 2%–6.5%. Elevated lactate dehydrogenase (LDH) at diagnosis was associated with the risk of HT (P = 0.019). HT occurred in 5% of SMZLs, 4% of MALT lymphomas, 3% of NMZLs and 3% of CBL-MZ (P = 0.974). The risk of HT was 5% (95% CI 3–9%) at 5 and 10 years after diagnosis and 10% (95% CI 5%–20%) at 12 years. At the time of HT, most patients had high LDH and B symptoms. At a median follow-up of 12 months after HT, 4 of 13 patients died, all for lymphoma-related causes, with a 2-year post-transformation survival rate of 57% (95% CI 13%–86%).
In this large retrospective series, the risk of HT across all MZL types appeared lower than the one reported for follicular lymphoma.
The ultrahigh-pressure (UHP) whiteschists of the Brossasco-Isasca unit (Dora-Maira Massif, Western Alps) provide a natural laboratory in which to compare results from classical pressure ...(P)–temperature (T) determinations through thermodynamic modelling with the emerging field of elastic thermobarometry. Phase equilibria and chemical composition of three garnet megablasts coupled with Zr-in-rutile thermometry of inclusions constrain garnet growth within a narrow
P
–
T
range at 3–3.5 GPa and 675–720 °C. On the other hand, the zircon-in-garnet host-inclusion system combined with Zr-in-rutile thermometry would suggest inclusion entrapment conditions below 1.5 GPa and 650 °C that are inconsistent with the thermodynamic modelling and the occurrence of coesite as inclusion in the garnet rims. The observed distribution of inclusion pressures cannot be explained by either zircon metamictization, or by the presence of fluids in the inclusions. Comparison of the measured inclusion strains with numerical simulations shows that post-entrapment plastic relaxation of garnet from metamorphic peak conditions down to 0.5 GPa and 600–650 °C, on the retrograde path, best explains the measured inclusion pressures and their disagreement with the results of phase equilibria modelling. This study suggests that the zircon-garnet couple is more reliable at relatively low temperatures (< 600 °C), where entrapment conditions are well preserved but chemical equilibration might be sluggish. On the other hand, thermodynamic modelling appears to be better suited for higher temperatures where rock-scale equilibrium can be achieved more easily but the local plasticity of the host-inclusion system might prevent the preservation of the signal of peak metamorphic conditions in the stress state of inclusions. Currently, we cannot define a precise threshold temperature for resetting of inclusion pressures. However, the application of both chemical and elastic thermobarometry allows a more detailed interpretation of metamorphic
P
–
T
paths.
Polarized Raman spectroscopy was applied to garnet hosts which exhibit anomalous birefringence around inclusions of zircon and quartz to elucidate the spatial distribution of the anisotropic strain ...fields in the vicinity of the host-inclusion boundary. We show that there is a direct relationship between the stress-induced birefringence and the Raman scattering generated by the fully symmetric phonon modes (the
A
1g
modes in cubic crystals). Our experimental results coupled with selected finite element models show that the ratio between the measured Raman peak intensity collected in cross and parallel polarized scattering geometries of totally symmetric modes represents a useful tool to constrain the radial stress profile in the host around the inclusions. Further, we demonstrate how group-theoretical considerations and tensor analysis of the morphic effect (external-field-induced change of the symmetry) on the phonons and the optical properties of the host can help to derive useful information on the symmetry of the stress field. Finally, we show experimentally that, under the same amount of applied stress, this approach is more sensitive than the commonly used approach of measuring differences in phonon frequencies and provides better opportunities to map the spatial variations of strain. This approach is an alternative technique to study structural phenomena associated with anomalous birefringence in host crystals surrounding stressed inclusions and could be applied to other systems in which similar optical effects are observed.
In metastatic colorectal cancer (mCRC), KRAS is the only validated biomarker used to select patients for administration of epidermal growth factor receptor (EGFR)-targeted therapies. To identify ...additional predictive markers, we investigated the importance of HER2, the primary EGFR dimerisation partner, in this particular disease.
We evaluated the HER2 gene status by fluorescence in situ hybridisation (FISH) in 170 KRAS wild-type mCRC patients treated with cetuximab or panitumumab.
Depending on HER2 gene copy number status, patients showed three distinct cytogenetic profiles: 4% of patients had HER2 gene amplification (R:HER2/CEP17 ≥ 2) in all neoplastic cells (HER2-all-A), 61% of patients had HER2 gain due to polysomy or to gene amplification in minor clones (HER2-FISH+*), and 35% of patients had no or slight HER2 gain (HER2-FISH-). These subgroups were significantly correlated with different clinical behaviours, in terms of response rate (RR; P=0.0006), progression-free survival (PFS; P<0.0001) and overall survival (OS; P<0.0001). Patients with HER2-all-A profile experienced the worst outcome, patients with HER2-FISH- profile showed an intermediate behaviour and patients with HER2-FISH+* profile were related to the highest survival probability (median PFS in months: 2.5 vs 3.9 vs 7.6, respectively; median OS in months: 4.2 vs 9.7 vs 13, respectively).
HER2 gene copy number status may influence the clinical response to anti-EGFR-targeted therapy in mCRC patients.
Diamonds and their inclusions are unique fragments of deep Earth, which provide rare samples from inaccessible portions of our planet. Inclusion-free diamonds cannot provide information on depth of ...formation, which could be crucial to understand how the carbon cycle operated in the past. Inclusions in diamonds, which remain uncorrupted over geological times, may instead provide direct records of deep Earth's evolution. Here, we applied elastic geothermobarometry to a diamond-magnesiochromite (mchr) host-inclusion pair from the Udachnaya kimberlite (Siberia, Russia), one of the most important sources of natural diamonds. By combining X-ray diffraction and Fourier-transform infrared spectroscopy data with a new elastic model, we obtained entrapment conditions, P
= 6.5(2) GPa and T
= 1125(32)-1140(33) °C, for the mchr inclusion. These conditions fall on a ca. 35 mW/m
geotherm and are colder than the great majority of mantle xenoliths from similar depth in the same kimberlite. Our results indicate that cold cratonic conditions persisted for billions of years to at least 200 km in the local lithosphere. The composition of the mchr also indicates that at this depth the lithosphere was, at least locally, ultra-depleted at the time of diamond formation, as opposed to the melt-metasomatized, enriched composition of most xenoliths.
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