Physical Signs and Clinical Findings Before Death in Ill Elderly Patients.

Few studies have examined variations in both the physical signs and clinical findings in the final days and hours before the death of elderly patients. We determined the physical signs and clinical findings in patients who were at least 75 years old or were diagnosed with cancer with impending death and examined the association of these parameters with the profile and timing of their endocardiography (ECG) and oxygen saturation (SpO2) changes prior to death. In this prospective, observational study, between April 2014 and June 2017, we enrolled elderly patients who were admitted to the Respiratory Medicine Ward in our hospital and were near death, which was determined based on certain symptoms such as a loss of oral intake. We recorded their physical signs (oral intake, consciousness level, and respiration with mandibular movement) 4 times a day from admission to death. We evaluated their changes in ECG and in SpO2 levels for up to 24 hours preceding death. For the 70 patients who died in our ward, we found a loss of oral intake at 6 days, consciousness impairment at 1.3 days, and then respiration with mandibular movement at 12 hours before death were the most consistent findings before death. When we analyzed the ECG and SpO2 changes during impending death, 83% of the patients showed undetectable SpO2 levels followed by a loss of heart rate. The loss of P wave in the ECG was characterized as process on impending death. Respiration with mandibular movement was one of the specific signs of impending death in ill elderly patients. The monitoring of ECG and SpO2 levels may be a useful tool to predict the impending time of death.

A new rapid method for detecting epidermal growth factor receptor mutations in non-small cell lung cancer.

Mutations in the epidermal growth factor receptor (EGFR) gene are associated with a favorable clinical response to the EGFR tyrosine kinase inhibitors gefitinib and erlotinib in non-small cell lung cancer (NSCLC). We present here, a new method for the rapid detection of the two most common EGFR mutations (delE746-A750 and L858R) from clinical samples. The methodology involves the combination of newly designed mutation-specific primers and a novel real-time PCR machine with an innovative thermo-control mechanism that enables ultrarapid PCR. We evaluated this method using a cell mixture composed of various ratios of lung cancer cells harboring mutated or wild-type EGFR, lung cancer tissues obtained by surgery, and a cytology sample obtained by bronchoscopy from a lung cancer patient. In the cell mixture analysis, our method detected 0.1% of cells with delE746-A750 and 1% of cells with L858R among cells with wild-type EGFR. In 143 lung cancer tissues, the result of this assay was concordant with those of direct sequencing in 138 samples. The five samples with discordant results were tested using a PCR-Invader assay and the result matched those of our method at 100%. We also successfully detected EGFR mutations in the lavage obtained from a lung cancer patient. The turnaround time for this method was <10 min, and all steps could be accomplished in <50 min after sample collection. Thus, our novel PCR method offers a rapid, simple, and less expensive test for EGFR mutations and can be applied as a point-of-care diagnostic test.

Imatinib mesylate (STI571) enhances amrubicin-induced cytotoxic activity through inhibition of the phosphatidylinositol 3-kinase/Akt pathway in small cell lung cancer cells.

Small cell lung cancer (SCLC) is characterized by autocrine mechanisms. Stem cell factor (SCF) and its receptor c-kit can activate Akt and extracellular signal-regulated kinase (Erk) pathways. Imatinib mesylate (STI571) can inhibit c-kit tyrosine kinase activity, but clinical trials have resulted in failure. We investigated the possibility of SCF/c-kit-targeted therapy against SCLC. Using c-kit-positive SCLC cells (H209 and H69 cells) and SCF as a model of the autocrine mechanisms, the effects of SCF, LY294002, PD98059 or STI571 on Akt and Erk were assessed by Western blot analysis. The cell growth inhibitions of cisplatin, etoposide irinotecan and amrubicin (AMR) with or without SCF, LY294002, PD98059 or STI571 were evaluated by MTT assay. Treatment with SCF activated Akt and Erk and the activations were inhibited by STI571 in H209 but not in H69 cells. LY294002 and PD98059 inhibited SCF-induced Akt and Erk activation in H209 cells, respectively. STI571 alone did not exert growth inhibition in the SCF-treated cells. In H209 cells, SCF decreased the cytotoxicity of AMR, but not of other drugs. In H69 cells, SCF did not affect sensitivity to any drugs. LY294002 but not PD98059 restored or enhanced AMR-sensitivity in SCF-treated H209 or untreated H69 cells, respectively. STI571 restored the AMR-sensitivity of SCF-treated H209 cells to the basal level. If the SCF/c-kit contributes to Akt activation in vivo, the combination of STI571 and AMR may be effective against SCLC. Additionally, using a combination of AKT inhibitors and AMR may be a promising treatment in the future.

[Acute bird-related hypersensitivity pneumonitis: radiological findings in a case in the early phase after onset].

A 71-year-old woman was admitted to our hospital four times because of high fever and dyspnea from September to November in 2007. We treated her with antibiotics on her first two admissions. HOwever, we suspected hypersensitivity pneumonitis on the third admission because she suffered from fever and dyspnea soon after she had been discharged and returned home. She recovered only with the oxygen therapy on the last two admissions. Computed tomography of the chest showed early phase localized consolidation but changed to ground-glass opacities spreading over the entire lung field later during her third and fourth admissions. Bronchial alveolar lavage showed increases in total cell count, lymphocytes and IgA of pigeon-dropping extracts' and budgerigar-dropping extracts. TBLB showed epithelioid cell granulomas without caseous necrosis and alveolar septal inflammation. Inhalation challenge test using freeze-dried pigeon-dropping extracts was positive, therefore we finally established a diagnosis of acute bird related hypersensitivity pneumonitis. This is apparently the first report of acute bird-related hypersensitivity pneumonitis showing localized consolidation initially and later changing to diffuse ground-glass opacities. These radiological observations are significant in considering the onset and the progression of this disease.

Synergistic cell growth inhibition by the combination of amrubicin and Akt-suppressing tyrosine kinase inhibitors in small cell lung cancer cells: implication of c-Src and its inhibitor.

Small cell lung cancer (SCLC) is one of the intractable malignancies. The goal of this study was to clarify whether Akt activity is involved with chemo-resistance and to improve the sensitivity of SCLC cells to the current standard chemotherapeutic drugs with agents that are expected to suppress Akt activity through tyrosine kinase inhibition. Although Akt activity seemed to be involved with the sensitivity of SCLC cells to chemotherapeutic agents (cisplatin, etoposide, SN38 and amrubicin), in Akt-activated N417 cells, only amrubicin exerted synergistic cell growth inhibition when combined with an Akt inhibitor, LY294002. A non-specific tyrosine kinase inhibitor, genistein, suppressed Akt and showed synergistic interaction in combination with amrubicin in N417 cells. Among tyrosine kinases (insulin-like growth factor I receptor, c-Kit and c-Src), only c-Src was activated in N417 cells compared with Akt-inactive H209 cells. A c-Src-specific inhibitor, PP2, and a clinically available multi-tyrosine kinase inhibitor, dasatinib, suppressed Akt activity in parallel with c-Src inhibition. Both PP2 and dasatinib exerted synergistic growth inhibition of N417 cells in the combination with amrubicin. In immunohistochemical analysis, c-Src was expressed in 17 of 19 of the SCLC tumor tissues. These observations suggested that Akt suppression enhances the cytotoxicity of amrubicin, and for the purpose of Akt suppression, c-Src is a promising target in SCLC.