Background
After initial response to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), approximately one-third of patients develop central nervous system (CNS) metastases, ...including leptomeningeal metastases (LM). To achieve longer survival, control of CNS metastases is important, but therapeutic options are limited for LM after failure of standard-dose EGFR-TKIs.
Methods
We retrospectively evaluated the efficacy and safety of high-dose erlotinib in
EGFR
-mutant non-small cell lung cancer (NSCLC) patients with refractory LM after failure of standard-dose EGFR-TKIs. Survivals from diagnosis of LM to death were compared in patients with or without high-dose erlotinib.
Results
Between January 2007 and April 2013, we identified 35 patients with
EGFR
-mutant NSCLC, complicated with LM, and 12 underwent high-dose erlotinib, while the other 23 received only standard-dose EGFR-TKIs. In patients receiving high-dose erlotinib, magnetic resonance imaging response was confirmed in 3 (30 %) of 10 evaluable patients. Median time to CNS progression was 2.3 months (95 % confidence interval CI 1.8–5.5 months). Performance status and neurological symptoms improved in 4 (33 %) of 12 and 6 (50 %) of 12 patients, respectively. No severe adverse events (≥grade 3) associated with high-dose erlotinib were observed. Median survival time from diagnosis of LM in patients with high-dose erlotinib was 6.2 months (95 % CI 2.5–8.5 months), and in those without 5.9 months (95 % CI 1.3–7.8 months) (
p
= 0.94).
Conclusion
High-dose erlotinib suggested its efficacy and safety in some patients with refractory LM. It represents a potential therapeutic option against LM after failure of standard-dose EGFR-TKIs, especially to palliate LM-related neurological symptoms.
Trichosporon asahii is a pathogenic yeast that cause trichosporonosis. T. asahii exhibits several colony morphologies, such as white (W)‐ or off‐white (O)‐type, which may affect virulence. In this ...study, we compared the expression pattern of heparin‐binding proteins in various colony morphologies and identified heparin‐binding protein in T. asahii. Surface plasmon resonance analysis revealed that cell surface molecules attached more strongly to heparin in W‐ than O‐type cells. We purified and identified a heparin‐binding protein strongly expressed in W‐type cells using heparin‐Sepharose beads, named it heparin‐binding protein 1 (HepBP1), and expressed Flag‐tagged HepBP1 in mammalian cells. The heparin‐binding ability of Flag‐tagged HepBP1 was confirmed by pulldown assay using heparin‐Sepharose beads. Thus, HepBP1 is a heparin‐binding protein on T. asahii cell surface. These results suggest that several T. asahii cell surface proteins interact with glycosaminoglycans; therefore, they could contribute to infection.
Identification of heparin‐binding proteins HepBP1 and HepBP3 in Trichosporon asahii.
Take‐away
Cell surface molecules (CSM) in Trichosporon asahii interact with heparin.
CSM–heparin interaction is stronger for white‐ than off‐white‐type colonies.
CSM contain more heparin‐binding protein in white‐ than off‐white‐type colonies.
HepBP1 is a heparin‐binding protein strongly expressed in W‐type cells.
Sequences homologous to human herpesvirus 6 (HHV-6) are integrated within the nuclear genome of about 1% of humans, but it is not clear how this came about. It is also uncertain whether integrated ...HHV-6 can reactivate into an infectious virus. HHV-6 integrates into telomeres, and this has recently been associated with polymorphisms affecting MOV10L1. MOV10L1 is located on the subtelomere of chromosome 22q (chr22q) and is required to make PIWI-interacting RNAs (piRNAs). As piRNAs block germline integration of transposons, piRNA-mediated repression of HHV-6 integration has been proposed to explain this association. In vitro, recombination of the HHV-6 genome along its terminal direct repeats (DRs) leads to excision from the telomere and viral reactivation, but the expected "solo-DR scar" has not been described in vivo. Here we screened for integrated HHV-6 in 7,485 Japanese subjects using whole-genome sequencing (WGS). Integrated HHV-6 was associated with polymorphisms on chr22q. However, in contrast to prior work, we find that the reported MOV10L1 polymorphism is physically linked to an ancient endogenous HHV-6A variant integrated into the telomere of chr22q in East Asians. Unexpectedly, an HHV-6B variant has also endogenized in chr22q; two endogenous HHV-6 variants at this locus thus account for 72% of all integrated HHV-6 in Japan. We also report human genomes carrying only one portion of the HHV-6B genome, a solo-DR, supporting in vivo excision and possible viral reactivation. Together these results explain the recently-reported association between integrated HHV-6 and MOV10L1/piRNAs, suggest potential exaptation of HHV-6 in its coevolution with human chr22q, and clarify the evolution and risk of reactivation of the only intact (non-retro)viral genome known to be present in human germlines.
•Rat skeletal muscles have enzymatic activities producing corticosterone except the activity of P450scc.•Pregnenolone sulfate functions as a precursor for the local skeletal muscular corticosterone ...biosynthesis via the sulfate-sulfatase pathway.•Gastrocnemius muscles highly express P45011β rather than that in soleus muscles and P45011β is localized in fast-twitch or type II muscle fibers.•Local synthesized corticosterone might be involved in glucocorticoid-induced muscle atrophy that preferentially occurs in fast muscle.
Adrenal corticosterone plays crucial roles in energy metabolism and immuno-reactivity throughout the body. As we have previously shown that corticosterone biosynthesis in C2C12 myoblasts, we study about corticosterone biosynthesis in rat skeletal muscles. It was found that enzymatic activities producing corticosterone and testosterone except the activity of P450scc in rat skeletal muscle as like as C2C12 cells. The CYP11B mRNA encoding cytochrome P45011β that mediates 11-deoxycorticosterone hydroxylase activity, producing corticosterone was expressed in skeletal muscles. In immunoblotting analysis, cytochrome P45011β protein was expressed in rat muscles and whole organs especially higher levels in adrenal and brain. The localizations of corticosterone content and enzymatic activities involved in the production of corticosterone were preferentially observed in gastrocnemius fibers rather than in soleus fibers. The immunohistochemical analysis showed that the fast-twitch or type II muscle fibers positive to antibody against fast myosin heavy chain were preferentially stained with anti-cytochrome P45011β antibody in the gastrocnemius fiber. In addition, we detected corticosterone biosynthesis from pregnenolone sulfate conjugates in perfusion of the rat hindquarter. Corticosterone is synthesized in rat skeletal muscles and the biosynthesis was localized in the fast-twitch or type II muscle fibers. We speculated that the local synthesized corticosterone might be involved in glucocorticoid-induced muscle atrophy that preferentially occurs in fast muscle fibers, and the initial substrate of the local CORT biosynthesis were supported to be performed from the conjugates such as pregnenolone sulfate circulating in the blood flow.
Patients with chronic kidney disease (CKD) are commonly at high risk of tuberculosis (TB). Conversely, TB rarely causes tubulointerstitial nephritis. A 75-year-old Japanese man who was undergoing ...periodic follow-ups for CKD stage G3aA3 with membranous nephropathy was diagnosed with acute kidney injury (AKI) (estimated glomerular filtration rate eGFR: 15 mL/min/1.73 m2) without prerenal AKI. He reported developing recent-onset cough 3 weeks prior to presenting to us. Renal biopsy revealed acute tubulointerstitial nephritis along with known membranous nephropathy. CD4+ helper T cells comprised most lymphocytes in the tubulointerstitium. Results of the interferon-gamma release assay, sputum smear test, polymerase chain reaction (PCR), and culture test were positive for TB. Chest computed tomography revealed thickening of the left bronchial wall; therefore, a diagnosis of early bronchial TB was made; his urine culture and PCR were negative for TB. At four months after TB treatment with no immunosuppressive therapy, his eGFR improved to 50 mL/min/1.73 m2, and based on this progress, the AKI was diagnosed as tuberculosis-associated tubulointerstitial nephritis (TATIN). Although TATIN typically occurs with chronic or miliary tuberculosis, it is very rare in early bronchial TB. Identification of TATIN is important in kidney diseases of unknown etiology, and treatment with anti-TB drugs is necessary.
It is reported that
(
) infection may be linked to non-digestive tract diseases, such as arteriosclerosis including dyslipidemia, diabetes, obesity, hypertension, and cardiovascular disease. ...Therefore, we reviewed recent studies available in PubMed dealing with the mechanisms of arteriosclerosis due to
infection and the effects of
eradication. Conventional studies suggested that
infection may increase the risk of arteriosclerosis. A large interventional study is required to clarify the causal relationships and the effects of bacterial eradication.
TP53 gene is frequently mutated in gastric cancer (GC), but the relationship with clinicopathological features and prognosis is conflicting. Here, we screened TP53 mutation spectrum of 214 GC ...patients in relation to their clinicopathological features and prognosis.
TP53 nonsilent mutations were detected in 80 cases (37.4%), being frequently occurred as C:G to T:A single nucleotide transitions at 5'-CpG-3' sites. TP53 mutations occurred more frequently in differentiated histologic type than in undifferentiated type in the early stage (48.6% vs. 7%, P=0.0006), while the mutations correlated with venous invasion among advanced stage (47.7% vs. 20.7%, P=0.04). Subset of GC with TP53 hot spot mutations (R175, G245, R248, R273, R282) presented significantly worse overall survival and recurrence free survival compared to others (both P=0.001).
Matched biopsies from GC and adjacent tissues from 214 patients were used for the experiment. All coding regions of TP53 gene (exon2 to exon11) were examined using Sanger sequencing.
Our data suggest that GC with TP53 mutations seems to develop as differentiated histologic type and show aggressive biological behavior such as venous invasion. Moreover, our data emphasizes the importance of discriminating TP53 hot spot mutations (R175, G245, R248, R273, R282) to predict worse overall survival and recurrence free survival of GC patients.
Heparin-induced thrombocytopenia (HIT) involves platelet activation and aggregation caused by heparin or HIT antibodies associated with poor survival outcomes. We report a case of HIT that occurred ...after hemodialysis was started for rapidly progressive glomerulonephritis (RPGN), which was caused by anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV), and ultimately resulted in asymptomatic cerebral infarction.
A 76-year-old Japanese man was urgently admitted to our hospital for weight loss and acute kidney injury (serum creatinine: 12 mg/dL). Hemodialysis therapy was started using heparin for anticoagulation. Blood testing revealed elevated titers of myeloperoxidase anti-neutrophil cytoplasmic antibodies, and renal biopsy revealed crescentic glomerulonephritis with broad hyalinization of most of the glomeruli and a pauci-immune staining pattern. These findings fulfilled the diagnostic criteria for microscopic polyangiitis, and the patient was diagnosed with RPGN caused by AAV. Steroid pulse therapy, intermittent pulse intravenous cyclophosphamide, and oral steroid therapy failed to improve the patient's renal function, and maintenance dialysis was started. However, on day 15, his platelet count had decreased to 47,000/µL, with clotting observed in the hemodialysis catheter. Magnetic resonance imaging of the head identified acute asymptomatic brain infarction in the left occipital lobe, and a positive HIT antibody test result supported a diagnosis of type II HIT. During hemodialysis, the anticoagulant treatment was changed from heparin to argatroban. Platelet counts subsequently normalized, and the patient was discharged. A negative HIT antibody test result was observed on day 622.
There have been several similar reports of AAV and HIT co-existence. However, this is a rare case report on cerebral infarction with AAV and HIT co-existence. Autoimmune diseases are considered risk factors for HIT, and AAV may overlap with other systemic autoimmune diseases. To confirm the relationship between these two diseases, it is necessary to accumulate more information from future cases with AAV and HIT co-existence. If acute thrombocytopenia and clotting events are observed when heparin is used as an anticoagulant, type II HIT should always be considered in any patient due to its potentially fatal thrombotic complications.
Purpose
There is no concrete evidence to support the association between the amount of subcutaneous fat area (SFA) in the central venous port-insertion site (precordium) and port-related ...complications. We aimed to investigate the relationship between SFA in the midclavicular line and postoperative infectious complications in patients undergoing port-insertion surgery.
Methods
This was a single-institute and historical cohort study of 174 patients who underwent first central venous port implantation surgery for chemotherapy between January 2014 and December 2018. SFA in the midclavicular line was measured using preoperative computed tomography scans. The patients were divided into three groups according to SFA amount tertiles, and we investigated the association of SFA with infectious and all-cause complication events within 1 year.
Results
Within a median follow-up of 306 days, the patients with intermediate SFA had significantly higher infection-free survival than those with low and high SFA (low vs. intermediate vs. high: 80.4% vs. 97.7% vs. 83.4%, respectively,
p
=0.034). In contrast, there was no significant difference in the overall complication-free survival among the groups (low vs. intermediate vs. high: 80.4% vs. 88.9% vs. 81.8%, respectively,
p
=0.29). Low SFA was independently associated with high risk of infectious complications (hazard ratio, 9.45; 95% confidence interval, 1.07–83.22,
p
=0.043).
Conclusion
Low SFA in the midclavicular line was an independent risk factor for infectious complications in the chemotherapy setting. This practical indicator can be useful for optimizing patients’ nutritional status and when considering other types of vascular access to support administration of intravenous chemotherapy.
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