Synthesis of Fused Tricyclic Amines Bearing Tetrasubstituted Carbons Using an Alkylation-Cyclization-Isomerization-3-aza-Cope Cascade Reaction.

A new cascade reaction sequence that involves alkylation, cyclization, isomerization, and 3-aza-Cope rearrangement was discovered. The stereogenic centers of the starting piperidines were transferred to the bicyclic enamine products, and a range of electron-withdrawing groups on the alkyne moieties, from ketones to amides, were tolerated under the reaction conditions. The bicyclic enamines underwent trifluoroacetic acid (TFA)-mediated cyclization to form tricyclic amines bearing tetrasubstituted carbons.

Relationship between instrumental activities of daily living decline during hospitalization and one-year mortality in elderly patients with heart failure: A multi-center prospective cohort study.

BACKGROUND: It remains unclear whether instrumental activities of daily living (IADL) decline during hospitalization is related to mortality rates. This study examined the relationship between IADL decline during hospitalization and the one-year mortality rate in elderly heart failure (HF) patients. METHODS: Five hundred seventy-six consecutive patients who were hospitalized for acute decompensated HF and underwent rehabilitation were divided into groups based on changes in IADL during hospitalization: IADL maintained and IADL decline. IADL was assessed by the National Center for Geriatrics and Gerontology-Activities of Daily Living Scale (NCGG-ADL). IADL decline was defined as Δ NCGG-ADL ≤ -1 point. The primary outcome was one-year all-cause mortality rate after discharge. Outcomes were examined using the Kaplan-Meier method with the log-rank test and Cox proportional hazards models using the existing prognostic risk factors for HF. RESULTS: Of 576 patients, 20% (n = 113) had IADL decline during hospitalization, and 9.2% (n = 35) and 6.0% (n = 18) died of all-cause and cardiovascular disease within one year after discharge, respectively. The IADL-decline group had significantly higher one-year all-cause mortality rates after adjusting for risk factors (hazard ratio: 1.923, 95% confidence interval 1.085-3.409; P = 0.023). Among the IADL subcategories, outdoor activity items such as "go out by oneself," "take a bus or train," and "shop for necessities" were more likely to change from independent to dependent during hospitalization. CONCLUSION: IADL decline during hospitalization was associated with an increased all-cause mortality rate at one-year after discharge in elderly HF patients.

p-Methoxy- and 2,4-Dimethoxybenzyl N-Acetylcarbamate Potassium Salts: Versatile Reagents for N-Alkylacetamide and p-Methoxy- and 2,4-Dimethoxybenzyl Carbamates.

The acetamide moiety is a general functional group present in many natural and pharmaceutical products. Herein, we report two new reagents, p-methoxybenzyl N-acetylcarbamate potassium salt (PM-BENAC-K) and 2,4-dimethoxybenzyl N-acetylcarbamate potassium salt (2,4-DM-BENAC-K), which are refined versions of the benzyl N-acetylcarbamate potassium salt (BENAC-K). These compounds, which we reported as simple equivalents of N-acetamide nucleophiles, are stable and easy-to-handle powders that react with a variety of alkyl halides and sulfonates to afford substituted products in good yields. The products were transformed into N-alkylacetamides after p-methoxybenzyloxycarbonyl (Moz) or 2,4-dimethoxybenzyloxycarbonyl (Dmoz) cleavage under mild acidic conditions. The acetyl groups in the substituted products of PM- and 2,4-DM-BENAC-Ks were removed using K2CO3 in methanol to afford Moz- and Dmoz-protected amines, respectively. Hence, the new BENAC-Ks acted as versatile equivalents of both N-acetamide and Moz/Dmoz-protected nitrogen nucleophiles and can be used in synthetic studies of natural and pharmaceutical products.

Determination of Severe Peach Allergens, Gibberellin-Regulated Protein, and Lipid Transfer Protein, Using Monoclonal Antibodies.

In this study, monoclonal antibodies against two major fruit allergens-gibberellin-regulated protein (GRP) and lipid transfer protein (LTP)-were established. Sandwich enzyme-linked immunosorbent assays (ELISAs) for the quantification of peach GRP and LTP were constructed using these antibodies. Both ELISAs reacted with the respective antigens when heated at 100ºC for 20 min, but not when reduced with sodium sulfite, indicating that GRP and LTP are heat-stable, while disulfide bonds play an important role in their native steric structures. GRP and LTP in peaches and peach-containing foods were quantified by these ELISAs. In both cases, there were few differences among peach cultivars normally available on the market; however, concentrations were higher when the peach was ripe. GRP was localized in the pulp of the peach, while LTP was present in the peel. They could be quantified in peach-containing beverages, as well as in dried and canned peaches. GRP in Japanese apricots could also be determined using this ELISA, as its amino acid sequence is the same as that of peach GRP. Then, high concentrations of GRP were detected in umeboshi, a traditional Japanese pickled apricot. Peach leaves were found to have a high LTP content, accordingly, LTP was also observed in lotions containing peach leaf extract. The ability to quantitatively detect GRP and LTP in this study will, therefore, contribute to the improvement of component-resolved diagnoses and quality of life in patients allergic to peaches.

Discharge disposition and 1-year readmission in acute-phase hospitalized patients with heart failure: a retrospective observational multi-center study.

Patients hospitalized for acute heart failure (HF) tend to experience declines in physical function and activities of daily living (ADL) due to bed rest and restricted mobilization. This could result in some patients being transferred to rehabilitation hospitals. This study aims to examine the relationship between discharge disposition and 1-year readmission and mortality rates in HF patients. Nine hundred fifty six consecutive HF patients who were hospitalized for acute decompensated HF and underwent rehabilitation were divided into two groups: home (returned home) or transfer (transferred to rehabilitative or long-term care hospital units due to decline in physical function and/or ADL) groups. The primary and secondary outcomes were 1-year readmission and mortality rates after discharge, respectively. Of the 956 patients, 8.6% (n = 82) were transferred to rehabilitative or long-term care hospital units. Over a 1-year follow-up period, all-cause and HF readmission rates were 50.1% (n = 479) and 27.2% (n = 260), respectively. The transfer group had significantly lower readmission rates compared to home group after adjusting for the pre-existing risk factors (hazard ratio for all-cause and HF readmission: 0.600 and 0.552, 95% CI 0.401-0.897 and 0.314-0.969; P = 0.013 and P = 0.038, respectively). There was no significant relationship between discharge disposition and all-cause mortality rate. Low ADL defined as Barthel index < 60 points was identified as a predictor of all-cause and HF readmission among the home group (odds ratio for all-cause and HF readmission rates: 2.156 and 1.847, 95% CI 1.026-4.531 and 1.036-2.931; P = 0.043 and P = 0.037, respectively). This multi-center study demonstrated that HF patients transferred to rehabilitative or long-term care hospital units after an acute hospitalization had a significantly decreased 1-year all-cause and HF readmission rates compared to patients who returned to their home. These findings may help in selecting a discharge disposition for older HF patients with ADL decline.

Immunological and nutritional predictive factors in patients receiving pembrolizumab for the first-line treatment of non-small cell lung cancer.

PURPOSE: Immune checkpoint inhibitors (ICIs) have prolonged the survival of patients with various carcinomas, including non-small cell lung cancer (NSCLC), and have caused a paradigm shift in cancer treatment. Although programmed death-ligand 1 (PD-L1) expression in tumor cells is a predictive marker of therapeutic efficacy, additional predictive markers are required. This study aimed to explore the role of immunological and nutritional parameters in the prediction of treatment response. METHODS: Patients diagnosed with NSCLC and treated with pembrolizumab were examined retrospectively. Body weight was measured 4-6 weeks before the start of the first treatment, immediately before treatment, and 4-6 weeks after the start of the first treatment. Progression-free survival (PFS) was defined as the time from the start of pembrolizumab treatment to the last follow-up date or until disease progression. Statistical analyses were performed to confirm the association between various factors and association between these factors and PFS. RESULTS: Thirty-eight patients with advanced NSCLC were included. We observed a significant association of weight loss and PD-L1 expression with PFS in the multivariate analysis. A significant correlation was found between the advanced lung cancer inflammation index and neutrophil-to-lymphocyte ratio. A weight loss of > 5% after the start of treatment was significantly associated with worse PFS. CONCLUSIONS: Weight loss is an important negative prognostic factor in patients with NSCLC receiving immunotherapy. Weight maintenance may be important for good ICI treatment efficacy, and future interventions in cancer cachexia are expected to further enhance the treatment efficacy of ICIs.

Investigation of the sensitization rate for gibberellin-regulated protein in patients with Japanese cedar pollinosis.

BACKGROUND: Pollen-food allergy syndrome (PFAS) usually manifests as an itching sensation in the mouth and throat immediately after eating fresh fruits and vegetables. However, some patients with PFAS experience systemic symptoms including anaphylaxis. In Europe, cypress gibberellin-regulated protein (GRP) has been noted to cause allergenicity and exhibit cross-reactivity with peach GRP. Japanese cedar (Cryptomeria japonica), classified in the cypress family, is the primary causative substance among all environmental allergens in Japan. However, studies on the prevalence of GRP sensitization in patients with cedar pollinosis are lacking. OBJECTIVE: This study examined the prevalence of GRP sensitization in patients with Japanese cedar pollinosis. METHODS: We enrolled 52 patients who had requested sublingual immunotherapy treatment with mild-to-severe rhinitis during spring, and had a JCP-specific immunoglobulin E (IgE) levels of >0.7 UA/mL. Peach GRP was purified using affinity chromatography with a monoclonal antibody column. Specific IgE levels to peach GRP were measured using an enzyme-linked immunosorbent assay. Samples exhibiting absorbance at 450 nm of over mean plus three standard deviations of the negative control value were defined as positive. Sera from three patients with severe peach allergy were used as positive controls. RESULTS: Eleven sera from 52 patients with JCP-induced allergic rhinitis were positive for peach GRP. CONCLUSION: Twenty percent of patients with cedar pollinosis were sensitized to peach GRP. Well-powered studies are needed to clarify whether these patients are at an increased risk for systemic symptoms or whether they primarily demonstrate only localized symptoms.

Biomimetic Construction of a syn-2,7-Dimethyloxepane Ring via 7-Endo Cyclization.

syn-2,7-Dimethyloxepane is a unique structure observed in natural ladder-shaped polycyclic ethers (LSPs), such as Caribbean ciguatoxins, gymnocin-B, and brevisulcenal-F that exhibit potent biological activities. Thus, the successful construction of this seven-membered ring is desirable, but its ring strain and the 1,3-repulsion between its two methyl groups makes this process difficult. Herein, we prepared syn-2,7-dimethyloxepanes via 7-endo cyclizations of vinyl epoxides that break Baldwin's rules. Such a biomimetic approach to syn-2,7-dimethyloxepanes has not yet been reported; however, we achieved this challenging cyclization with the aid of a cis-olefin tether and an unsubstituted vinyl group. The NO-ring fragment of gymnocin-B was also prepared from one of these 7-endo cyclized products, demonstrating the potential application of this strategy in constructing bioactive LSPs.

Relationship between average daily rehabilitation time and decline in instrumental activity of daily living among older patients with heart failure: A preliminary analysis of a multicenter cohort study, SURUGA-CARE.

BACKGROUND: Limitation of instrumental activity of daily living (IADL) is independently associated with an adverse prognosis in older heart failure (HF) patients. AIMS: This multicenter study aims to examine the relationship between average daily rehabilitation time (ADRT) and risk of IADL decline during acute hospitalization in older patients with HF. METHODS: Four hundred eleven older patients who were hospitalized due to acute HF and underwent rehabilitation were divided into three groups based on the tertile of the ADRT: short, intermediate, and long groups. IADL was assessed by the National Center for Geriatrics and Gerontology Activities of Daily Living (NCGG-ADL) scale. Change in NCGG-ADL (Δ NCGG-ADL) was calculated by subtracting the pre-hospitalization score from the at-discharge score and IADL decline was defined as Δ NCGG-ADL < = -1 point. Logistic regression analysis was carried out examining the association between ADRT and occurrence of IADL decline. RESULTS: The ADRT was 23.9, 32.0, and 38.6 minutes in short, intermediate, and long group, respectively. The proportion of patients with IADL decline during hospitalization was 21% among all subjects and short group had the highest proportion of IADL decline (33%) and long group had the lowest proportion (14%). The long group had significantly lower odds of IADL decline compared with the short group (OR:0.475, 95% CI:0.231-0.975, P = 0.042). Among the items of NCGG-ADL scale, significant decreases in the "go out by oneself", "travel using a bus or train", "shop for necessities", "vacuum", and "manage medication" were observed at discharge compared to pre-hospitalization in the short group (p<0.01, p<0.01, p<0.01, p<0.05, and p<0.05). CONCLUSIONS: The present study demonstrated that short of ADRT may be associated with the risk of IADL decline during hospitalization in older patients with HF.

Fulminant amebic colitis in a patient with concomitant cytomegalovirus infection after systemic steroid therapy: A case report.

BACKGROUND: Amebic colitis is an infection caused by Entamoeba histolytica and most commonly observed in regions with poor sanitation. It is also seen as a sexually transmitted disease in developed countries. While amebic colitis usually has a chronic course with repeated exacerbations and remissions, it may also manifest as a fulminant form that rapidly progresses and leads to severe, life-threatening complications, such as intestinal perforation, peritonitis, and sepsis, that have a high mortality rate. CASE SUMMARY: A 68-year-old man was admitted to our hospital with chest pain and acute dyspnea. He was diagnosed with acute coronary syndrome, acute heart failure, and bacterial pneumonia. His respiratory condition worsened despite receiving intensive care and intravenous antibiotics. On the fifth day of hospitalization, he was diagnosed with acute respiratory distress syndrome and was started on steroid therapy. He subsequently developed bloody stools and was diagnosed with cytomegalovirus (CMV) enterocolitis based on biopsy results and a peripheral blood CMV pp65 antigenemia test result. Although we started antiviral therapy with ganciclovir, which was successful in reducing his antigen titers, he continued to have bloody diarrhea. Three weeks after initiation of ganciclovir therapy and six weeks after his admission, the patient died from intestinal perforation. We only posthumously diagnosed him with amebic colitis and CMV enterocolitis based on autopsy findings of transmural necrosis of the entire colon with massive ameba infiltration. CONCLUSION: We urge clinicians to consider Entamoeba histolytica infection if severe colitis progresses after steroid therapy. Preemptive treatment is recommended then.

Long-term response to osimertinib in elderly patients with lung adenocarcinoma harbouring de novo EGFR T790M: a case report and literature review.

Osimertinib is a potent and irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that selectively acts on both EGFR-sensitive and EGFR T790M-resistant mutations. Patients with pre-treatment EGFR T790M mutations (de novo EGFR T790M) respond poorly to existing EGFR-TKIs, whereas osimertinib has positive effects. However, the safety data for first-line osimertinib treatment in patients aged >75 years are insufficient. We treated two elderly patients with de novo EGFR T790M mutations with osimertinib as the first-line therapy. We found that the first-line treatment with osimertinib was safe and resulted in a long-term response in elderly patients with de novo EGFR T790M-mutated lung adenocarcinoma.

Transbronchial needle aspiration with endobronchial ultrasonography and ultrathin bronchoscopy for peripheral pulmonary lesions.

BACKGROUND: Although the efficacy of lung cancer treatment has improved, it is dependent on a reliable diagnosis via bronchoscopy. Transbronchial biopsy using ultrathin bronchoscopy can help detect small peripheral pulmonary lesions (PPLs), with a high diagnostic yield. However, the diagnosis rate using forceps biopsy when the radial endobronchial ultrasonography (rEBUS) probe is adjacent to a lesion tends to be low. Transbronchial needle aspiration (TBNA) may improve the diagnostic yield from adjacent lesions. Recently, PeriView FLEX, a new TBNA needle that can be inserted into ultrathin bronchoscopes, has become available. We examined whether TBNA with PeriView FLEX and forceps biopsy improved adjacent lesion diagnosis when using ultrathin bronchoscopes. METHODS: We retrospectively examined 51 consecutive patients who underwent TBNA and forceps biopsy using ultrathin bronchoscopes under rEBUS for small PPLs at the Hakodate Goryoukaku Hospital between November 2019 and August 2020. The histological diagnosis rate using TBNA and forceps biopsy, TBNA alone, or forceps biopsy alone was compared between cases where the rEBUS probe was "Within" and "Adjacent To" the lesions. RESULTS: The diagnosis rate using TBNA and forceps biopsy was 86.3% (95.7% vs. 78.6%; p = 0.08) for all lesions (Within cases vs. Adjacent To cases). The corresponding rate using TBNA alone was 68.6% (69.6% vs. 67.9%; p = 0.57), and that using forceps biopsy alone was 72.5% (91.3% vs. 57.1%; p = 0.0067). CONCLUSIONS: Forceps biopsy with TBNA during ultrathin bronchoscopy for small PPLs improved the diagnostic yield when lesions were adjacent to the rEBUS probe.

Gold(I)-Catalyzed Cyclization-3-Aza-Cope-Mannich Cascade and Its Application to the Synthesis of Cephalotaxine.

The discovery of a new gold(I)-catalyzed cascade reaction involving cyclization onto a vinylammonium, 3-aza-Cope rearrangement, and Mannich cyclization is reported. A variety of fused nitrogen heterocycles were prepared from simple cyclic tertiary amines using 1-5 mol % of a AuCl(PPh3)/Ag[C5(CN)5] cocatalyst system. The developed reaction was used in a study aimed at synthesizing cephalotaxine. A five-step operation from norhydrastinine provided demethylcephalotaxinone in 39.1% overall yield, which was transformed to (-)-cephalotaxine in two steps.

Pseudomesotheliomatous carcinoma of lung adenocarcinoma diagnosed using transesophageal ultrasound-guided bronchoscopic aspiration.

Endoscopic ultrasound with bronchoscope-guided fine-needle aspiration (EUS-B-FNA), a minimally invasive procedure, may be useful for the diagnosis of pseudomesotheliomatous (PMC) carcinoma because a sufficient amount of tissue can be obtained for diagnosis. This is the first report of PMC diagnosed using EUS-B-FNA. Our findings suggest that EUS-B-FNA may reduce the risk of dissemination for PMC.

Long-term response to afatinib in an elderly patient with uncommon epidermal growth factor receptor mutation-positive lung adenocarcinoma.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors are the standard treatment for patients with non-small cell lung cancer (NSCLC) harboring EGFR mutations. Uncommon mutations, excluding exon 19 deletions and exon 21 L858R, comprise 7%-23% of EGFR mutation-positive NSCLC. The treatment of uncommon EGFR mutation-positive NSCLCs is controversial. Here, we present the case of an 81-year-old man who was diagnosed with lung adenocarcinoma cStage IVA harboring the uncommon EGFR L861Q mutation. The patient received oral afatinib treatment (40 mg/day). One month after the initiation of afatinib treatment, Common Terminology Criteria for Adverse Events version 4.0 grade 2 stomatitis was observed. It improved upon afatinib withdrawal. After 10 days of withdrawal, afatinib treatment was resumed at a reduced dose of 20 mg/day. Subsequently, the patient continued treatment with afatinib. A partial response to afatinib treatment was maintained for 49 months until primary tumor regrowth. Afatinib treatment was continued after disease progression, but the patient died of bacterial pneumonia 59 months after initiation of afatinib treatment. Several studies have previously reported a large number of compound mutations with uncommon mutations, and that compound mutation-induced cells are most susceptible to afatinib. This suggests the efficacy of afatinib in clinical practice and that afatinib may be safely administered to elderly patients with appropriate dose reductions.

Spontaneous pneumothorax during nintedanib therapy in patients with systemic sclerosis-associated interstitial lung disease.

Interstitial lung disease (ILD) is a common complication of systemic sclerosis (SSc). Nintedanib, an antifibrotic drug, has recently been approved for treating SSc-ILD. Although there have been no reports suggesting the development of pneumothorax with nintedanib use, its safety in patients with impaired lung function is unclear. We observed the development of refractory spontaneous pneumothorax during nintedanib therapy in two patients with SSc-ILD and impaired lung function. Nintedanib use for SSc-ILD, an extensive disease, may therefore increase the risk of pneumothorax. In addition, pneumothorax is more likely to be refractory in these cases; initiation of nintedanib treatment and follow-up should be considered carefully.

Sedation with fentanyl and midazolam without oropharyngeal anesthesia compared with sedation with pethidine and midazolam with oropharyngeal anesthesia in ultrathin bronchoscopy for peripheral lung lesions.

BACKGROUND: In advanced lung cancer, precision medicine requires repeated biopsies via bronchoscopy at therapy change. Since bronchoscopies are often stressful for patients, sedation using both fentanyl and midazolam is recommended in Europe and America. In Japan, bronchoscopies are generally orally performed under midazolam and oropharyngeal anesthesia. Nasal intubation creates a physiological route to the trachea, causing less irritation to the pharynx than intubation via the oral cavity; however, the necessity of oropharyngeal anesthesia remains unclear. We aimed to compare the safety, patient discomfort, and diagnostic rates for oropharyngeal anesthesia and sedation with pethidine and midazolam (Group A) and sedation with midazolam and fentanyl without oropharyngeal anesthesia (Group B) for ultrathin bronchoscopy of peripheral pulmonary lesions (PPLs) via nasal intubation. METHODS: We retrospectively reviewed 74 consecutive potential lung cancer patients who underwent ultrathin bronchoscopies at the Hakodate Goryoukaku Hospital between July 2019 and June 2020. We reviewed the following: diagnostic rates; cumulative doses of lidocaine, midazolam, and fentanyl; hemodynamic changes; procedural complications in both groups. Pharyngeal anesthesia in group A was administered by spraying 2% (w/v) lidocaine into the pharynx. The chi-squared test was used for statistical analyses. RESULTS: There were no significant changes in hemodynamic parameters and complications. The mean level of discomfort for bronchoscopic examinations was significantly lower in Group B (2.39 vs. 1.64; P = 0.014), with no significant inter-group difference in the diagnostic yields for PPLs (63.0% vs. 71.4%; P = 0.46). CONCLUSIONS: Our findings indicate the advantages of sedation with fentanyl and midazolam without oropharyngeal anesthesia for ultrathin bronchoscopy through nasal intubation.

Lung adenocarcinoma with tumor resolution and dystrophic calcification after salvage surgery following immune checkpoint inhibitor therapy: A case report.

A clinical trial of immune checkpoint inhibitors for advanced non-small cell lung cancer reported an overall survival plateau with a long tail to the survival curve, suggesting that immune checkpoint inhibitors prolong survival. However, little evidence supports the efficacy of immune checkpoint inhibitors as neoadjuvant chemotherapy. We performed salvage surgery on a patient who was treated with an anti-programmed cell death protein-1 (PD-1) antibody and whose tumor size had not changed over time. A 69-year-old Japanese female with advanced lung adenocarcinoma was initially administered pembrolizumab therapy; however, owing to the development of various immune-related adverse events (irAEs), the patient was switched to chemotherapy following steroid therapy. The tumor continued to shrink and calcification within the tumor increased. We performed salvage surgery following which the tumor cells disappeared and necrosis and calcification were detected in the tumor. We concluded that if calcification develops within the tumor and tumor shrinkage is maintained after treatment with anti-PD-1 drugs, the calcification may be dystrophic owing to drug-induced tumor necrosis, and salvage surgery might be beneficial in removing the tumor. KEY POINTS: SIGNIFICANT FINDINGS OF THE STUDY: If calcification develops within the tumor and tumor shrinkage is maintained after treatment with anti-PD-1 drugs, the calcification may be dystrophic owing to tumor necrosis caused by drug effects, and salvage surgery might be beneficial in removing the tumor. WHAT THIS STUDY ADDS: This study showed the efficacy of immune checkpoint inhibitors as neoadjuvant chemotherapy to be followed by salvage surgery for unresectable advanced lung adenocarcinoma.