The Graded Prognostic Assessment for lung cancer using molecular markers (Lung-molGPA) has not been validated for use with Japanese non-small cell lung cancer (NSCLC) patients with brain metastasis ...(BM) and the factors impacting survival need to be assessed.
We retrospectively analyzed 294 NSCLC patients who were newly diagnosed with BM between 2013 and 2020 and had received radiotherapy for BM initially at the Hokkaido Cancer Center. We evaluated the effect on the prognosis of Lung-molGPA items, the expression of PD-L1 (classified as high, low, and no expression), and the treatment history. The main outcome was the survival measured from the day of the diagnosis of BM, and log-rank tests were performed to evaluate the results.
The median overall survival (OS) times for adenocarcinoma by groups of GPA scores (0‒1.0, 1.5‒2.0, 2.5‒3.0, and 3.5‒4.0) were 5.5, 14.8, 28.3, and 39.0 months (p < 0.0001), respectively. The median survival times for non-adenocarcinoma by groups of GPA scores (0‒1.0, 1.5‒2.0, and 2.5‒3.0) were 3.2, 11.0, and 16.0 months (p = 0.0011), respectively. In adenocarcinoma patients with gene mutations, osimertinib significantly improved the outcome (median OS: 34.2 and 17.6 months with and without osimertinib, respectively (p = 0.0164)). There was no significant difference in the OS between patients who were initially treated with tyrosine-kinase inhibitor for BM and those who initially received radiotherapy (p = 0.5337). In patients tested for PD-L1 expression, the median survival times after the diagnosis of BM were 5.6, 22.5, and 9.3 months for the high-, low- and no-expression groups (p = 0.2198), respectively. Also, in patients with high PD-L1 expressions, those with ICI had survival (median OS, 8.6 months) than those without (median OS, 3.6 months).
We confirmed that Lung-molGPA successfully classified Japanese NSCLC patients with BM by the prognosis. Osimertinib prolonged survival of EGFR-positive NSCLC patients with BM, and ICI was effective in patients with high PD-L1 expressions.
Background
Tri-weekly cisplatin and radiotherapy (CDDP + RT) is a standard of care for locally advanced head and neck squamous cell carcinoma (LA-HNSCC) but is sometimes challenging to complete in ...older patients. Weekly CDDP + RT has shown mild toxicity compared to tri-weekly CDDP + RT for LA-HNSCC and is a promising option for older adults. We aimed to report the treatment outcomes and prognostic factors in patients with LA-HNSCC treated with weekly CDDP + RT.
Methods
We analyzed patients aged ≥ 70 years who started weekly CDDP + RT for LA-HNSCC between July 2006 and October 2022. LA-HNSCC includes cancer in the oropharynx, hypopharynx, or larynx with a clinical stage of 3 or 4 without distant metastases based on the Union for International Cancer Control staging system 8th edition. The radiation dose of 70 Gy was delivered in 35 fractions by 3-dimensional conformal radiotherapy, intensity-modulated radiotherapy, or proton beam therapy. The primary endpoint was the 3-year overall survival (OS), and the secondary endpoints were the 3-year progression-free survival (PFS) and 3-year cause-specific survival (CSS). The Kaplan–Meier method was used to calculate survival rates, and the log-rank test was used to evaluate statistical significance. A Cox proportional hazards model was used for the multivariate analysis of prognostic factors.
Results
The median age of the 49 patients was 72 (range: 70–78) years. The median CDDP dose was 200 (40–280) mg/ m
2
, and 47 patients completed scheduled radiotherapy. Forty-eight patients (98.0%) had a performance status of ≥ 1 at the initial visit. The 3-year OS, PFS, and CSS were 80.9% (95% confidence interval CI: 64.8–90.7), 58.9% (95%CI: 42.7–73.3), and 85.0% (95%CI: 68.7–93.4), respectively. In the multivariate analysis, the cumulative CDDP dose (< 200 or ≥ 200 mg/m
2
) was a significant factor for OS (hazard ratio: 0.29 95% CI 0.08–0.97, p = 0.044). There was one case of early mortality. Grade 3 or higher late adverse events were observed in four patients (8.2%).
Conclusions
Weekly CDDP + RT in older patients led to good survival outcomes with an acceptable rate of adverse events. CDDP should be administered at a dose of at least 200 mg/m
2
in older patients.
Trial registration
Retrospectively registered
Correction: Discover Oncology (2023) 14:226https://doi.org/10.1007/s12672-023-00844-7 After publication an error was found by the authors in the progression-free survival (PFS) analysis. Abstract ...Incorrect The 3-year OS, PFS, and CSS were 80.9% (95% confidence interval CI: 64.8–90.7), 68.3% (95% CI 51.8–81.2), and 85.0% (95% CI 68.7–93.4), respectively. Correct The 3-year OS, PFS, and CSS were 80.9% (95% confidence interval CI: 64.8–90.7), 58.9% (95% CI: 42.7–73.3), and 85.0% (95% CI: 68.7–93.4), respectively. Results Incorrect With a median follow-up period of 36 months (range: 1–156), the 3-year and 5-year OS rates were 80.9% (95% CI 64.8–90.7) and 69.7% (51.6–83.2), respectively (Fig. 1A). Correct With a median follow-up period of 36 months (range: 1–156), the 3-year and 5-year OS rates were 80.9% (95% CI 64.8–90.7) and 69.7% (51.6–83.2), respectively (Fig. 1A).
Glioblastoma is the most common of malignant primary brain tumors and one of the tumors with the poorest prognosis for which the overall survival rate has not significantly improved despite recent ...advances in treatment techniques and therapeutic drugs. Since the emergence of immune checkpoint inhibitors, the immune response to tumors has attracted increasing attention. Treatments affecting the immune system have been attempted for various tumors, including glioblastomas, but little has been shown to be effective. It has been found that the reason for this is that glioblastomas have a high ability to evade attacks from the immune system, and that the lymphocyte depletion associated with treatment can reduce its immune function. Currently, research to elucidate the resistance of glioblastomas to the immune system and development of new immunotherapies are being vigorously carried out. Targeting of radiation therapy for glioblastomas varies among guidelines and clinical trials. Based on early reports, target definitions with wide margins are common, but there are also reports that narrowing the margins does not make a significant difference in treatment outcome. It has also been suggested that a large number of lymphocytes in the blood are irradiated by the irradiation treatment to a wide area in a large number of fractionations, which may reduce the immune function, and the blood is being recognized as an organ at risk. Recently, a randomized phase II trial comparing two types of target definition in radiotherapy for glioblastomas was conducted, and it was reported that the overall survival and progression-free survival were significantly better in a small irradiation field group. We review recent findings on the immune response and the immunotherapy to glioblastomas and the novel role of radiotherapy and propose the need to develop an optimal radiotherapy that takes radiation effects on the immune function into account.
Patients with lung cancer and brain metastases represent a markedly heterogeneous population. Accurate prognosis is essential to optimally individualize care. In prior publications, we described the ...graded prognostic assessment (GPA), but a GPA for patients with small cell lung cancer (SCLC) has never been reported, and in non-small cell lung cancer (NSCLC), the effect of programmed death ligand 1 (PD-L1) was unknown. The 3-fold purpose of this work is to provide the initial report of an SCLC GPA, to evaluate the effect of PD-L1 on survival in patients with NSCLC, and to update the Lung GPA accordingly.
A multivariable analysis of prognostic factors and treatments associated with survival was performed on 4183 patients with lung cancer (3002 adenocarcinoma, 611 nonadenocarcinoma, 570 SCLC) with newly diagnosed brain metastases between January 1, 2015, and December 31, 2020, using a multi-institutional retrospective database. Significant variables were used to update the Lung GPA.
Overall median survival for lung adenocarcinoma, SCLC, and nonadenocarcinoma was 17, 10, and 8 months, respectively, but varied widely by GPA from 2 to 52 months. In SCLC, the significant prognostic factors were age, performance status, extracranial metastases, and number of brain metastases. In NSCLC, the distribution of molecular markers among patients with lung adenocarcinoma and known primary tumor molecular status revealed alterations/expression in PD-L1 50% to 100%, PD-L1 1% to 49%, epidermal growth factor receptor, and anaplastic lymphoma kinase in 32%, 31%, 30%, and 7%, respectively. Median survival of patients with lung adenocarcinoma and brain metastases with 0, 1% to 49%, and ≥50% PD-L1 expression was 17, 19, and 24 months, respectively (P < .01), confirming PD-L1 is a prognostic factor. Previously identified prognostic factors for NSCLC (epidermal growth factor receptor and anaplastic lymphoma kinase status, performance status, age, number of brain metastases, and extracranial metastases) were reaffirmed. These factors were incorporated into the updated Lung GPA with robust separation between subgroups for all histologies.
Survival for patients with lung cancer and brain metastases has improved but varies widely. The initial report of a GPA for SCLC is presented. For patients with NSCLC-adenocarcinoma and brain metastases, PD-L1 is a newly identified significant prognostic factor, and the previously identified factors were reaffirmed. The updated indices establish unique criteria for SCLC, NSCLC-nonadenocarcinoma, and NSCLC-adenocarcinoma (incorporating PD-L1). The updated Lung GPA, available for free at brainmetgpa.com, provides an accurate tool to estimate survival, individualize treatment, and stratify clinical trials.
Peaks due to the rainbow scattering in elastic collisions of Ar+ ions with ground state CH4 molecules were observed in the differential cross section at laboratory energies from 20 to 80 eV ...superimposed on an oscillatory structure which is attributed to the accidental resonant electron transfer between collision partners. The rainbow peaks are clearly seen when the differential cross section is plotted in a reduced form. Indeed, each rainbow peak appears at the reduced scattering angle of about 290 eV-degrees. Classical calculations are fitted to the experimental cross sections with the use of the 12-6-4 potential. This potential contains an adjustable force parameter γ ranging from 1 to 0 according to how the charge-induced dipole interaction has a dominant role in the collision. The best fit is obtained when the potential depth is 2.7 eV and the interatomic distance at the potential well minimum is 2.4 Å for γ = 0.4.
A simple classical treatment of the potential curve fitting to the experimental differential cross section is presented. The classical deflection function is expanded in a triple series of the ...inverse power of the impact parameter. This series holds for any combinations of both repulsive and attractive inverse power potentials stronger than γ-2, and it permits an analytical evaluation of the classical differential cross section. This method is attempted to fit to the differential scattering data of Ar++Ar and Xe++Xe measured by Lorents, Olson and Conklin. Results show fairly good agreement in the neighborhood of the rainbow scattering angle except for the oscillatory interference patterns due to the resonant electron exchange. This method is simple and it may save much numerical labour compared with semiclassical or quantal treatment.
Moduli inflation from modular flavor symmetries Abe, Yoshihiko; Higaki, Tetsutaro; Kaneko, Fumiya ...
The journal of high energy physics,
06/2023, Letnik:
2023, Številka:
6
Journal Article
Recenzirano
Odprti dostop
A
bstract
We study slow-roll inflation model controlled by the modular flavor symmetry. In the model, the modulus field plays a role of inflaton and the introduction of the stabilizer field coupled ...to a modular form in the superpotential produces the inflaton potential. In order to generate the flat direction for the slow-roll inflation, we consider the Kähler potential corrected by the modular form. It is noted that the modulus field perpendicular to the inflaton direction is stabilized during the inflation. The model turns out to be consistent with the current observations and behaves similarly to the
α
-attractor models in some parameter spaces. The inflaton rolls down to the CP-symmetric vacuum at the end of inflation.
The purpose of the present study was to investigate the effects of particle size on the dissolution and oral absorption of cilostazol. Three types of suspensions having different particle size ...distributions were prepared of the hammer-milled, the jet-milled cilostazol crystals and the NanoCrystal® spray-dried powder of cilostazol. In vitro dissolution rate of cilostazol was significantly increased by reducing the particle size. The dissolution curves of the cilostazol suspensions were in good agreement with the simulation based on the Noyes–Whitney equation. The bioavailability of cilostazol after oral administration to dogs was increased with reducing the particle size. While positive food effect on the absorption was observed for the suspensions made of the hammer-milled and the jet-milled crystals, no significant food effect was found for the suspension made of the NanoCrystal® cilostazol spray-dried powder. These results could be qualitatively predicted from the in vitro dissolution data using the bio-relevant media, FaSSIF and FeSSIF. In conclusion, the NanoCrystal® technology is found to be efficient to improve the oral bioavailability of cilostazol and to avoid the food effect on the absorption.
Parkinson's disease (PD) symptoms do not become apparent until most dopaminergic neurons in the substantia nigra pars compacta (SNc) degenerate, suggesting that compensatory mechanisms play a role. ...Here, we investigated the compensatory involvement of activated microglia in the SN pars reticulata (SNr) and the globus pallidus (GP) in a 6‐hydroxydopamine‐induced rat hemiparkinsonism model. Activated microglia accumulated more markedly in the SNr than in the SNc in the model. The cells had enlarged somata and expressed phagocytic markers CD68 and NG2 proteoglycan in a limited region of the SNr, where synapsin I‐ and postsynaptic density 95‐immunoreactivities were reduced. The activated microglia engulfed pre‐ and post‐synaptic elements, including NMDA receptors into their phagosomes. Cells in the SNr and GP engulfed red fluorescent DiI that was injected into the subthalamic nucleus (STN) as an anterograde tracer. Rat primary microglia increased their phagocytic activities in response to glutamate, with increased expression of mRNA encoding phagocytosis‐related factors. The synthetic glucocorticoid dexamethasone overcame the stimulating effect of glutamate. Subcutaneous single administration of dexamethasone to the PD model rats suppressed microglial activation in the SNr, resulting in aggravated motor dysfunctions, while expression of mRNA encoding glutamatergic, but not GABAergic, synaptic elements increased. These findings suggest that microglia in the SNr and GP become activated and selectively eliminate glutamatergic synapses from the STN in response to increased glutamatergic activity. Thus, microglia may be involved in a negative feedback loop in the indirect pathway of the basal ganglia to compensate for the loss of dopaminergic neurons in PD brains.
Main Points
Microglia eliminate glutamatergic synapses from the subthalamic nuclei in basal ganglia outputs in a rat parkinsonism model.
By eliminating synapses, microglia give negative feedback compensating for dopaminergic neuron loss.
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