Changes in oral health status in terminal cancer patients during the last weeks of life.

BACKGROUND: Many studies have shown deterioration of the oral health environment in palliative care patients; however, most of these studies are cross-sectional. In this longitudinal observational study, we aimed to determine the oral symptoms and how they change in palliative care patients. METHODS: The participants were 82 patients (37 men, 45 women) admitted to two palliative care units in Japan between January 2018 and December 2021. The oral condition was evaluated once a week from the time of admission using the Oral Health Assessment Tool (OHAT) and performance status (PS). Friedman tests were performed on the OHAT and PS scores at 1, 2, and 3 weeks before the week of death. In addition, the Bonferroni method was used to determine how many weeks before death the changes occurred. RESULTS: PS continuously deteriorated from three weeks before death. The total OHAT score 2 weeks before death (3.44±2.10) was significantly different compared to that in the week of death (4.37±2.45). In terms of oral conditions, the properties of the saliva changed, and dry mouth became obvious. CONCLUSIONS: The results of this study revealed that the oral environment of palliative care patients became significantly dry 2 weeks before death, suggesting that it may be useful for predicting the stage of death.

The efficacy of prophylactic prochlorperazine injections at the initiation of opioid injections in preventing opioid-induced nausea and vomiting among patients with end-stage cancer.

Objectives: Antiemetics have been widely recommended for treating opioid-induced nausea and vomiting (OINV). According to a previous study, the use of prophylactic prochlorperazine at the initiation of treatment with oral oxycodone was ineffective in preventing OINV. This study examined whether prochlorperazine injection prevents OINV and induces drowsiness in patients with end-stage cancer (a different patient population from the previous study). Methods: Patients with end-stage cancer who received opioid injections for more than 5 days between April 2017 and March 2020 were classified into two groups: the opioid and prochlorperazine injection group and opioid alone group. Their systemic conditions were evaluated on the basis of the performance status and the palliative performance scale, a prognostic indicator. Results: Of 325 patients who received opioid treatment during the study period, 156 patients met the inclusion criteria. Of these, 103 patients and 53 patients were classified into the opioid and prochlorperazine injection group (prochlorperazine) and opioid alone groups (placebo) , respectively. There was no significant difference in characteristics, age, gender, performance status, or palliative performance scale results between the 2 groups. OINV developed in 4 patients in the opioid and prochlorperazine injection groups and in 1 patient in the opioid alone group. Given that sleep disturbance develops in many patients with end-stage cancer who had a specific condition, it is difficult to conclude regarding the relationship between prochlorperazine injection and drowsiness, although this study examined this relationship. Conclusions: As with the previous study, prophylactic prochlorperazine injection was ineffective in preventing OINV in patients who received opioid injections.

Complete Genomic Sequence of the Clinical Isolate Legionella pneumophila Serogroup 1 Strain 80-045 from Japan.

We report the complete genomic sequence of Legionella pneumophila serogroup 1 strain 80-045, isolated from autopsy lung tissue of the first patient diagnosed with Legionnaires' disease in Japan.

Development of a Multiplex-PCR Serotyping Assay for Characterizing Legionella pneumophila Serogroups Based on the Diversity of Lipopolysaccharide Biosynthetic Loci.

Legionella pneumophila, which is the main cause of Legionnaires' disease, comprises at least 15 serogroups (SGs). We show here the diversity of lipopolysaccharide biosynthetic loci among serogroups and describe the development of a PCR serotyping assay for 15 SGs based on the sequences of LPS biosynthetic loci. Using this multiplex-PCR (M-PCR) system, serogroups were detected using primers that specifically amplify the sequences of SG1, SG2, SG5, SG7, SG8, SG9, SG11, SG13, SG3/15, and SG6/12. When PCR products of the expected sizes were not detected, we used primers that identified SG4/10/14. The PCR serotyping system specifically amplified the sequences corresponding to SGs of 238 L. pneumophila strains. This method will be very useful for conducting epidemiological studies and investigating outbreak of Legionnaires' disease.

Multicentric prospective study of effect of dietary intake on quality of life for patients with end-stage cancers.

OBJECTIVE: Impaired dietary intake (DI) contributes to deterioration of quality of life (QOL) in patients with end-stage diseases, including cancer, but the effects of DI on QOL specifically in terminal cancer has not been widely studied. Here, we evaluated the relationship between DI and QOL in patients with end-stage cancers. METHODS: We evaluated the energy amount of DI, performance status (PS) and QLQ-C15-PAL score of cancer patients with short prognoses in multicentre survey and analysed the parameters that influence QOL. RESULTS: We recruited 33 patients in this study. In univariate analysis, DI was significantly associated with PS (P=0.002, r=-0.531), physical functioning (P=0.003, r=-0.503), fatigue (P=0.038, r=-0.362), and appetite loss (P=0.004, r=-0.490). CONCLUSIONS: Improved DI could contribute to QOL of patients with end-stage cancers.

Interleukin-8 and clinical symptoms can be prognostic indicators for advanced cancer patients with cachexia.

OBJECTIVES: Prognostic prediction is a significant tool for selecting appropriate treatment in advanced cancer patients with cachexia, at a time when it is important to offer high-quality palliative care and improve quality of life until death. In this retrospective study, we investigated the prognostic potential of serum cytokine level and various clinical symptoms by analyzing the pathological conditions and metabolic dynamics of cachexia in advanced cancer patients. METHODS: One hundred and fifty-three advanced cancer patients who underwent palliative care and died at the Department of Surgery and Palliative Medicine, Fujita Health University Nanakuri Memorial Hospital between 1 January 2004 and 30 June 2007 were eligible for the study. We simultaneously assessed their blood factors and clinical symptoms at admission. All patients were divided into two groups according to median survival time to analyze the risk factors for prognosis. RESULTS: Multivariate analysis revealed the following independent prognostic factors: interleukin (IL)-8 (odds ratio [OR]=4.17, 95% confidence interval [CI]=1.52-11.41, p=0.002), general fatigue (OR=1.22, 95%CI=1.03-1.45, p=0.019), anorexia (OR=1.19, 95%CI=1.04-1.37, p=0.008), dyspnea (OR=1.19, 95%CI=1.02-1.38, p=0.024), depression (OR=1.28, 95%CI=1.11-1.47, p<0.001), nausea (OR=1.25, 95%CI=1.05-1.48, p=0.007), dry mouth (OR=1.19, 95%CI=1.01-1.40, p=0.032), and overall assessment score (OR=1.05, 95%CI=1.02-1.09, p<0.001). Patients with low IL-8 (<1.347 pg/ml) and low overall assessment score (<26) had significantly better prognosis (both p<0.0001). CONCLUSIONS: High IL-8 level and clinical symptoms can be prognostic indicators for advanced cancer patients with cachexia.

Distribution of lag-1 Alleles, ORF7, and ORF8 Genes of Lipopolysaccharide and Sequence-Based Types Among Legionella pneumophila Serogroup 1 Isolates in Japan and China.

Approximately 85% of cases of Legionnaires' disease are caused by Legionella pneumophila serogroup 1. In this study, we analyzed the distribution of lag-1 alleles, ORF 7 and ORF 8 genes of lipopolysaccharide (LPS) and sequence-based types of 616 L. pneumophila serogroup 1 strains isolated in Japan (206 clinical, 225 environmental) and China (13 clinical and 172 environmental). The lag-1 gene was harbored by significantly more of the clinical isolates compared with the environmental isolates (90.3 vs. 19.1% and 61.6 vs. 3.0%, respectively; both P < 0.001). ORF 7 genes were detected in 51.0% of Japanese clinical and 36.0% of Japanese environmental (P = 0.001) isolates, as well as 15.3% of Chinese clinical and 9.9% of Chinese environmental isolates (P = 0.544). ORF 8 genes were detected in 12.1% of Japanese clinical and 5.8% of Japanese environmental (P = 0.017) isolates, as well as 7.7% of Chinese clinical and 3.4% of Chinese environmental isolates (P = 0.388). The Japanese and Chinese isolates were assigned to 203 and 36 different sequence-types (ST), respectively. ST1 was predominant. Most isolates with the same ST also had the same lag-1, ORF 7, and ORF 8 gene subgroups. In conclusion, the lag-1 was present in most of the clinical isolates, but was absent from most of the environmental isolates from both China and Japan, regardless of the water source and SBT type. PCR-based serotyping and subgrouping methods can be used to define a hierarchy of virulence genotypes that require stringent surveillance to prevent human disease.

Molecular-targeted therapy for advanced anaplastic thyroid cancer combined with nutritional support.

Management of anaplastic thyroid cancer (ATC) is often difficult because of its aggressive characteristics. Molecular-targeted therapy was recently introduced as an alternative therapeutic strategy for ATC; lenvatinib is a molecular-targeted agent that is currently indicated only in Japan for the treatment of ATC. Here we report the case of an 86-year-old Japanese woman with ATC who was treated with lenvatinib at our hospital and exhibited a remarkable response. Computed tomography showed tumor shrinkage by day 8 and stable disease until day 32. She maintained activities of daily living (ADLs) until shortly before her death. The patient's resting energy expenditure and body composition were analyzed at the time of admission. Potential toxicity risk of lenvatinib was evaluated based on these data. Enteral nutrition for oral intake was supplied to compensate for her lack of dietary intake and to improve metabolism for the purpose of suppressing lenvatinib toxicity. She also engaged in physical rehabilitation to avoid developing sarcopenia, which is thought to be a risk factor of molecular-targeted therapy toxicity, and to maintain her activity level. We emphasize the importance of a team approach for providing an appropriate treatment regimen to maintain ADLs, which includes nutritional support, physical rehabilitation, and aggressive therapy with lenvatinib.

Legionella pneumophila and Other Legionella Species Isolated from Legionellosis Patients in Japan between 2008 and 2016.

The Legionella Reference Center in Japan collected 427 Legionella clinical isolates between 2008 and 2016, including 7 representative isolates from corresponding outbreaks. The collection included 419 Legionella pneumophila isolates, of which 372 belonged to serogroup 1 (SG1) (87%) and the others belonged to SG2 to SG15 except for SG7 and SG11, and 8 isolates of other Legionella species (Legionella bozemanae, Legionella dumoffii, Legionella feeleii, Legionella longbeachae, Legionella londiniensis, and Legionella rubrilucens). L. pneumophila isolates were genotyped by sequence-based typing (SBT) and represented 187 sequence types (STs), of which 126 occurred in a single isolate (index of discrimination of 0.984). These STs were analyzed using minimum spanning tree analysis, resulting in the formation of 18 groups. The pattern of overall ST distribution among L. pneumophila isolates was diverse. In particular, some STs were frequently isolated and were suggested to be related to the infection sources. The major STs were ST23 (35 isolates), ST120 (20 isolates), and ST138 (16 isolates). ST23 was the most prevalent and most causative ST for outbreaks in Japan and Europe. ST138 has been observed only in Japan, where it has caused small-scale outbreaks; 81% of those strains (13 isolates) were suspected or confirmed to infect humans through bath water sources. On the other hand, 11 ST23 strains (31%) and 5 ST120 strains (25%) were suspected or confirmed to infect humans through bath water. These findings suggest that some ST strains frequently cause legionellosis in Japan and are found under different environmental conditions.IMPORTANCELegionella pneumophila serogroup 1 (SG1) is the most frequent cause of legionellosis. Our previous genetic analysis indicated that SG1 environmental isolates represented 8 major clonal complexes, consisting of 3 B groups, 2 C groups, and 3 S groups, which included major environmental isolates derived from bath water, cooling towers, and soil and puddles, respectively. Here, we surveyed clinical isolates collected from patients with legionellosis in Japan between 2008 and 2016. Most strains belonging to the B group were isolated from patients for whom bath water was the suspected or confirmed source of infection. Among the isolates derived from patients whose suspected infection source was soil or dust, most belonged to the S1 group and none belonged to the B or C groups. Additionally, the U group was discovered as a new group, which mainly included clinical isolates with unknown infection sources.

Molecular mechanisms of Streptococcus pneumoniae-targeted autophagy via pneumolysin, Golgi-resident Rab41, and Nedd4-1-mediated K63-linked ubiquitination.

Streptococcus pneumoniae is the most common causative agent of community-acquired pneumonia and can penetrate epithelial barriers to enter the bloodstream and brain. We investigated intracellular fates of S. pneumoniae and found that the pathogen is entrapped by selective autophagy in pneumolysin- and ubiquitin-p62-LC3 cargo-dependent manners. Importantly, following induction of autophagy, Rab41 was relocated from the Golgi apparatus to S. pneumoniae-containing autophagic vesicles (PcAV), which were only formed in the presence of Rab41-positive intact Golgi apparatuses. Moreover, subsequent localization and regulation of K48- and K63-linked polyubiquitin chains in and on PcAV were clearly distinguishable from each other. Finally, we found that E3 ligase Nedd4-1 was recruited to PcAV and played a pivotal role in K63-linked polyubiquitin chain (K63Ub) generation on PcAV, promotion of PcAV formation, and elimination of intracellular S. pneumoniae. These findings suggest that Nedd4-1-mediated K63Ub deposition on PcAV acts as a scaffold for PcAV biogenesis and efficient elimination of host cell-invaded pneumococci.

Effects of Combined Treatment with Branched-Chain Amino Acids, Citric Acid, L-Carnitine, Coenzyme Q10, Zinc, and Various Vitamins in Tumor-Bearing Mice.

A functional dietary supplement (FDS) containing Coenzyme Q10, branched-chain amino acids and L-carnitine was administered to tumor-bearing mice, investigating its effects on tumor and muscle tissues. Experiment (A): B16 melanoma cells were implanted subcutaneously into the right side of the abdomen of 8- to 9-week-old C57BL/6J mice. The mice were divided into two groups: a FDS group that received oral administration of FDS (n=10), and a control group that received oral administration of glucose (n=10). The moribund condition was used as the endpoint, and median survival time was determined. Experiment (B): On day 21 after tumor implantation, tumors, soleus muscle, gastrocnemius muscle, and suprahyoid muscles were collected. Tumor and muscle weight and other aspects were evaluated in each group: FDS group (n=15) and control group (n=15). The median survival time was comparable (21 d in the FDS group vs. 18 d in the control group, p=0.30). However, cumulative food intake was significantly higher in the FDS group than the control group (p=0.011). Metastasis of melanoma to the lung was observed in the control group but not in the FDS group (p=0.043). The weight of the suprahyoid muscles was significantly higher in the FDS group than in the control group (p=0.0045). The weight of the tumor was significantly lower in the FDS group than in the control group (p=0.013). The results possibly suggest oral administration of FDS in tumor-bearing mice enhances the maintenance of suprahyoid muscles, resulting in an extended feeding period and suppression of tumor growth and metastasis.

A Clinical Study on Administration of Opioid Antagonists in Terminal Cancer Patients: 7 Patients Receiving Opioid Antagonists Following Opioids among 2443 Terminal Cancer Patients Receiving Opioids.

There have been few detailed reports on respiratory depression due to overdoses of opioids in terminal cancer patients. We investigated the situation of treatment with opioid antagonists for respiratory depression that occurred after administration of opioid at optimal doses in terminal cancer patients, to clarify pathological changes as well as causative factors. In 2443 terminal cancer patients receiving opioids, 7 patients (0.3%) received opioid antagonists: 6, morphine (hydrochloride, 5; sulfate, 1); 1, oxycodone. The median dosage of opioids was 13.3 mg/d, as converted to morphine injection. Respiratory depression occurred on this daily dose in 4 patients and after changed dose and route in 3 patients. Opioids were given through the vein in 6 patients and by the enteral route in 1 patient. Concomitant drugs included nonsteroidal anti-inflammatory drugs in 3 patients and zoledronic acid in 2 patients. In morphine-receiving patients, renal functions were significantly worsened at the time of administration of an opioid antagonist than the day before the start of opioid administration. These findings indicate that the proper use of opioids was safe and acceptable in almost all terminal cancer patients. In rare cases, however, a risk toward respiratory depression onset is indicated because morphine and morphine-6-glucuronide become relatively excessive owing to systemic debility due to disease progression, especially respiratory and renal dysfunctions. At the onset of respiratory depression, appropriate administration of an opioid antagonist mitigated the symptoms. Thereafter, opioid switching or continuous administration at reduced dosages of the same opioids prevented the occurrence of serious adverse events.

Variation and association of fibronectin-binding protein genes fnbA and fnbB in Staphylococcus aureus Japanese isolates.

Fibronectin-binding proteins A and B (FnBPA and FnBPB) mediate adhesion of Staphylococcus aureus to fibrinogen, elastin and fibronectin. FnBPA and FnBPB are encoded by two closely linked genes, fnbA and fnbB, respectively. With the exception of the N-terminal regions, the amino acid sequences of FnBPA and FnBPB are highly conserved. To investigate the genetics and evolution of fnbA and fnbB, the most variable regions, which code for the 67th amino acids of the A through B regions (A67-B) of fnbA and fnbB, were focused upon. Eighty isolates of S. aureus in Japan were sequenced and 19 and 18 types in fnbA and fnbB, respectively, identified. Although the phylogeny of fnbA and fnbB were found to be quite different, each fnbA type connected with a specific fnbB type, indicating that fnbA and fnbB mutate independently, whereas the combination of both genes after recombination is stable. Hence those fnbA-fnbB combinations were defined as FnBP sequence types (FnSTs). Representative isolates of each FnST were assigned distinct STs by multilocus sequence typing, suggesting correspondence of FnST with genome lineage. Linkage disequilibrium (LD) analysis of the A67-B region revealed that subdomains N2, N3 and FnBR1 form a LD block in fnbA, whereas N2 and N3 form two independent LD blocks in fnbB. N2-N3 three-dimensional structural models indicated that not only the variable amino acid residues, but also well-conserved amino acid residues between FnBPA and FnBPB, are located on the surface of the protein. These results highlight a molecular process of the FnBP that has evolved by mingled mutation and recombination with retention of functions.

Distribution of monoclonal antibody subgroups and sequence-based types among Legionella pneumophila serogroup 1 isolates derived from cooling tower water, bathwater, and soil in Japan.

Legionella pneumophila serogroup (SG) 1 is the most frequent cause of legionellosis. This study analyzed environmental isolates of L. pneumophila SG 1 in Japan using monoclonal antibody (MAb) typing and sequence-based typing (SBT). Samples were analyzed from bathwater (BW; n = 50), cooling tower water (CT; n = 50), and soil (SO; n = 35). The distribution of MAb types varied by source, with the most prevalent types being Bellingham (42%), Oxford (72%), and OLDA (51%) in BW, CT, and SO, respectively. The ratios of MAb 3/1 positive isolates were 26, 2, and 14% from BW, CT, and SO, respectively. The environmental isolates from BW, CT, and SO were divided into 34 sequence types (STs; index of discrimination [IOD] = 0.973), 8 STs (IOD = 0.448), and 11 STs (IOD = 0.879), respectively. Genetic variation among CT isolates was smaller than seen in BW and SO. ST1 accounted for 74% of the CT isolates. The only common STs between (i) BW and CT, (ii) BW and SO, and (iii) CT and SO were ST1, ST129, and ST48, respectively, suggesting that each environment constitutes an independent habitat.