Let $V$ be a bounded domain with smooth boundary in $\R^n$, and $D^*V$ denote its disc cotangent bundle. We compute symplectic homology of $D^*V$, in terms of relative homology of loop spaces on the closure of $V$. We use this result to show that Floer-Hofer capacity of $D^*V$ is between $2r(V)$ and $2(n+1)r(V)$, where $r(V)$ denotes inradius of $V$. As an application, we study periodic billiard trajectories on $V$.
Abstract Cerebrospinal fluid tumor-derived DNA (CSF-tDNA) analysis is a promising approach for monitoring the neoplastic processes of the central nervous system. We applied a lung cancer-specific sequencing panel (CAPP-Seq) to 81 CSF, blood, and tissue samples from 24 lung cancer patients who underwent lumbar puncture (LP) for suspected leptomeningeal disease (LMD). A subset of the cohort ( N = 12) participated in a prospective trial of osimertinib for refractory LMD in which serial LPs were performed before and during treatment. CSF-tDNA variant allele fractions (VAFs) were significantly higher than plasma circulating tumor DNA (ctDNA) VAFs (median CSF-tDNA, 32.7%; median plasma ctDNA, 1.8%; P < 0.0001). Concentrations of tumor DNA in CSF and plasma were positively correlated (Spearman’s ρ, 0.45; P = 0.03). For LMD diagnosis, cytology was 81.8% sensitive and CSF-tDNA was 91.7% sensitive. CSF-tDNA was also strongly prognostic for overall survival (HR = 7.1; P = 0.02). Among patients with progression on targeted therapy, resistance mutations, such as EGFR T790M and MET amplification, were common in peripheral blood but were rare in time-matched CSF, indicating differences in resistance mechanisms based on the anatomic compartment. In the osimertinib cohort, patients with CNS progression had increased CSF-tDNA VAFs at follow-up LP. Post-osimertinib CSF-tDNA VAF was strongly prognostic for CNS progression (HR = 6.2, P = 0.009). Detection of CSF-tDNA in lung cancer patients with suspected LMD is feasible and may have clinical utility. CSF-tDNA improves the sensitivity of LMD diagnosis, enables improved prognostication, and drives therapeutic strategies that account for spatial heterogeneity in resistance mechanisms.
We present the case of a 34-year-old Japanese man with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer and brain metastases. After central nervous system (CNS) disease progression with alecintib and brigatinib, treatment with lorlatinib resulted in a good intracranial response. In this case, we investigated brain penetration ratio of brigatinib using cerebrospinal fluid and paired serum samples, and the ratio was 0.012. Further, we investigated resistance mechanisms via next-generation sequencing (NGS) using lung biopsy at lung cancer diagnosis and brain biopsy sample at progressive disease of brigatinib. No apparent resistance mechanism of known ALK resistance, such as ALK mutations, amplifications, epithelial-mesenchymal transition (EMT) and bypass pathway activation were detected. Taken together, we speculate that the low CNS penetration rate of brigatinib confers CNS progression. Further studies are warranted to reveal the resistance mechanism and propose a treatment strategy for CNS progression in ALK-positive patients.
Background: Reduced insulin secretion is linked to diabetes and cardiovascular disease (CVD), but its role in non-diabetic CVD patients is unclear. The homeostasis model assessment of β-cell function (HOMA-β) measures pancreatic β-cell function. This study investigated the association between HOMA-β and adverse cardiovascular events in non-diabetic CVD patients.
Treatment with tacrolimus requires strict control of the whole-blood concentration in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). In patients undergoing cord blood transplantation (CBT), there is a negative correlation between volume of distribution of tacrolimus and hemoglobin levels, which reflect the red blood cell (RBC) count. In this study, we evaluated the influence of the conditioning regimen (myeloablative and reduced-intensity conditioning) or donor source (cord blood, bone marrow, and peripheral blood stem cells) on the pharmacokinetics of tacrolimus in patients undergoing HSCT, including those undergoing CBT. We also examined applicability of dosing strategy of tacrolimus considering the RBC count. We retrospectively analyzed clinical data-including whole-blood tacrolimus concentrations-from patients with HSCT. The observation period spanned from first continuous intravenous infusions until switch to oral medication, transfer to another hospital, relapse, or death. Population pharmacokinetic analysis was performed on whole-blood tacrolimus concentrations obtained from therapeutic drug monitoring during the observation period. Patient characteristics and laboratory data were evaluated as covariates. We enrolled 91 patients undergoing HSCT (CBT: n = 56; bone marrow transplantation: n = 22; and peripheral blood stem cell transplantation: n = 13); 58 and 33 patients received myeloablative conditioning and reduced-intensity conditioning, respectively. Whole-blood tacrolimus concentrations were accurately captured (n = 1,658 measurements) using a one-compartment and additive error model. The conditioning regimen and donor source did not have an impact on the pharmacokinetics of tacrolimus. Therefore, these factors were not considered when forming the dosing strategy. Nevertheless, a negative correlation between volume of distribution and hemoglobin level was confirmed, indicating that monitoring the RBC count is useful in assessing the dosing strategy. A tacrolimus dosing strategy that considers the variability in hemoglobin levels applies to all patients undergoing HSCT.
Neurotoxicity is a rare and intolerable adverse effect of ceftriaxone therapy. In most cases, it has been diagnosed on the basis of medical history rather than quantitative blood and cerebrospinal fluid testing. We report the case of a woman aged 78 years with ceftriaxone-associated encephalopathy. She regularly underwent hemodialysis. The patient received intravenous ceftriaxone at a dose of 1 g/day for 10 days for a urinary tract infection, and her consciousness level began to deteriorate during the therapy. Five days after ceftriaxone discontinuation, her symptoms rapidly improved. Thus, ceftriaxone-associated encephalopathy was suspected. Ceftriaxone levels in the blood and cerebrospinal fluid were high while the patient had disturbed consciousness. This case showed that ceftriaxone levels were related to ceftriaxone-associated encephalopathy. Therefore, the estimation of ceftriaxone levels may facilitate an accurate diagnosis.
Aims and Scope: For more than 50 years, clinical pharmacologists, clinical and pharmaceutical researchers, drug development specialists, physicians, nurses, and other medical professionals have relied on The Journal of Clinical Pharmacology (JCP) for original research, special reviews, commentaries, and case reports on all phases of drug development from absorption, disposition, metabolism, excretion interactions, and preferred uses through post-marketing evaluations.
Let $(M,ω)$ be an aspherical symplectic manifold, which is closed or convex. Let $U$ be an open set in $M$, which admits a circle action generated by an autonomous Hamiltonian $H \in C^\infty(U)$, such that each orbit of the circle action is not contractible in $M$. Under these assumptions, we prove that the Hofer-Zehnder capacity of $U$ is bounded by the Hofer norm of $H$. The proof uses a variant of the energy-capacity inequality, which is proved by the theory of action selectors.
