Identifying prognostic biomarkers for palbociclib add-on therapy in fulvestrant-resistant breast cancer using cell-free DNA sequencing.

BACKGROUND: The FUTURE trial (UMIN000029294) demonstrated the safety and efficacy of adding palbociclib after fulvestrant resistance in patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced and metastatic breast cancer (ABC/MBC). In this planned sub-study, cancer panel sequencing of cell-free DNA (cfDNA) was utilized to explore prognostic and predictive biomarkers for further palbociclib treatment following fulvestrant resistance. MATERIALS AND METHODS: Herein, 149 cfDNA samples from 65 patients with fulvestrant-resistant disease were analysed at the time of palbociclib addition after fulvestrant resistance (baseline), on day 15 of cycle 1, and at the end of treatment using the assay for identifying diverse mutations in 34 cancer-related genes. RESULTS: During the course of treatment, mutations in ESR1, PIK3CA, FOXA1, RUNX1, TBX3, and TP53 were the most common genomic alterations observed. Analysis of genomic mutations revealed that before fulvestrant introduction, baseline PIK3CA mutations were marginally lower in metastatic aromatase inhibitor (AI)-treated patients compared to adjuvant AI-treated patients (P = 0.063). Baseline PIK3CA mutations were associated with poorer progression-free survival [hazard ratio: 1.62, P = 0.04]. Comparative analysis between baseline and early-changing gene mutations identified poor prognostic factors including early-changing MAP3K1 mutations (hazard ratio: 4.66, P = 0.04), baseline AR mutations (hazard ratio: 3.53, P = 0.04), and baseline PIK3CA mutations (hazard ratio: 3.41, P = 0.02). Notably, the relationship between ESR1 mutations and mutations in PIK3CA, MAP3K1, and TP53 weakened as treatment progressed. Instead, PIK3CA mutations became correlated with TP53 and FOXA1 mutations. CONCLUSIONS: Cancer panel testing for cfDNA identified prognostic and predictive biomarkers for palbociclib add-on therapy after acquiring fulvestrant resistance in patients with HR+/HER2- ABC/MBC.

High-Resolution Detection of Translocation of Oral Bacteria to the Gut.

Ectopic enrichment of oral microbes in the gut is a notable alteration in gut microbial balance. These microbes are likely delivered from the oral cavity with saliva and food; however, evidence of oral-gut microbial transmission is insufficient and needs further investigation. In this observational study, we examined 144 pairs of saliva and stool samples collected from community-dwelling adults to verify the oral-gut microbial link and identify the relevant influencing factors on the increased abundance of oral microbes within the gut. The bacterial composition of each sample was determined using PacBio single-molecule long-read sequencing of the full-length 16S ribosomal RNA gene and amplicon sequence variant (ASV) analysis. Although the bacterial compositions of salivary and gut microbiota were distinctly different, at least 1 ASV was shared between salivary and gut microbiota in 72.9% of subjects. Shared ASVs accounted for 0.0% to 63.1% (median 0.14%) of the gut microbiota in each subject and frequently included abundant Streptococcus salivarius and Streptococcus parasanguinis. Their total relative abundance in the gut was significantly higher in older subjects or those with dental plaque accumulation. The gut microbiota with ≥5% of shared ASVs displayed a higher abundance of Streptococcus, Lactobacillus, and Klebsiella and a lower abundance of Faecalibacterium, Blautia, Megamonas, and Parabacteroides. Our study presents evidence for the translocation of oral bacteria to the gut in community-dwelling adults and suggests that aging and dental plaque accumulation contribute to an increased abundance of oral microbes in the gut, which might be relevant to the compositional shift in the gut commensals.

Risk factors for persistent positive anticardiolipin antibodies in women with recurrent pregnancy loss.

Antiphospholipid syndrome (APS) is an established cause of recurrent pregnancy loss (RPL). It is necessary to detect persistently positive antiphospholipid antibodies to diagnose APS. This study aimed to explore risk factors for persistent anticardiolipin (aCL) positivity. Women with a history of RPL or with a history of one or more intrauterine fetal deaths after 10 weeks underwent examinations to determine the causes of RPL, including antiphospholipid antibodies. If aCL-IgG or aCL-IgM antibodies were positive, retests were performed at least 12 weeks apart. Risk factors for persistent aCL antibody positivity were retrospectively investigated. The number and percentage of cases above the 99th percentile were 74/2399 (3.1%) for aCL-IgG, and 81/2399 (3.5%) for aCL-IgM. Of the initially tested cases, 2.3% (56/2399) for aCL-IgG and 2.0% (46/2289) for aCL-IgM were ultimately positive above the 99th percentile in retests. Retest values after 12 weeks were significantly lower than the initial values for both IgG and IgM immunoglobulin classes. Initial aCL antibody titers were significantly higher in the persistent-positive group than in the transient-positive group for both IgG and IgM immunoglobulin classes. The cut-off values for predicting persistent positivity of aCL-IgG antibodies and aCL-IgM antibodies were 15 U/mL (99.1 percentile) and 11 U/mL (99.2 percentile), respectively. The only risk factor for persistently positive aCL antibodies is a high antibody titer during the initial test. When the aCL antibody titer in the initial test exceeds the cut-off value, therapeutic strategies can be defined in subsequent pregnancies without waiting for 12 weeks.

Periodontitis Is Associated with Chronic Obstructive Pulmonary Disease.

Although they are known to share pathophysiological processes, the relationship between periodontitis and chronic obstructive pulmonary disease (COPD) is not fully understood. The aim of the present study was to test the hypothesis that periodontitis is associated with a greater risk of development of COPD, when smoking is taken into account. The analysis in a 5-y follow-up population-based cohort study was based on 900 community-dwelling Japanese adults (age: 68.8 ± 6.3 [mean ± SD], 46.0% male) without COPD aged 60 or older with at least 1 tooth. Participants were classified into 3 categories according to baseline periodontitis severity (no/mild, moderate, and severe). COPD was spirometrically determined by a fixed ratio of <0.7 for forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) and by FEV1/FVC below the lower limit of normal. Poisson regression was used to calculate the relative risk (RR) of developing COPD according to the severity of periodontitis. The population attributable fraction (PAF) was also calculated. During follow-up, 22 (2.4%) subjects developed COPD. Compared with no/mild periodontitis subjects, a significantly increased risk of COPD occurred among severe periodontitis subjects (RR = 3.55; 95% confidence interval [CI], 1.18 to 10.67), but no significant differences were observed between the no/mild and moderate categories (RR = 1.48; 95% CI, 0.56 to 3.90). After adjustment for potential confounders, including smoking intensity, the relationship between severe periodontitis and risk of COPD remained significant (RR = 3.51; 95% CI, 1.15 to 10.74). Likewise, there was a positive association of periodontitis severity with risk of COPD ( P for trend = 0.043). The PAF for COPD due to periodontitis was 22.6%. These data highlight the potential importance of periodontitis as a risk factor for COPD.

Swallowing disorders and 1-year functional decline in community-dwelling older adults receiving home care.

The purpose of this study was to clarify the effect of swallowing disorders on functional decline in community-dwelling older adults receiving home care. This was a 1-year follow-up survey of 176 individuals ≥60 years living at home and receiving homecare services, without total dependence in basic daily living activities, in two mid-sized municipalities in Fukuoka, Japan. Functional decline was measured using the Barthel index (BI), and the primary outcome was total dependence in basic daily living activities (BI ≤ 20 points). Swallowing function was assessed using cervical auscultation, and the primary predictor was swallowing disorders. Logistic regression models were used to assess univariate and multivariate associations between baseline swallowing function and functional decline during follow-up. During follow-up 16 (9.1%), the participants became totally dependent in basic daily living activities. The participants with swallowing disorders had 6.41 times higher odds of total dependence in basic daily living activities compared to participants with normal swallowing function. After adjusting for potential confounders, swallowing disorders were significantly associated with higher odds of total dependence in basic daily living activities (odds ratio = 5.21, 95% confidence interval = 1.33-20.44). Regarding swallowing disorders, the corresponding population attributable fraction (%) of the incidence of total dependence in basic daily living activities was 50.4%. The current findings demonstrated that swallowing disorders were associated with greater risk of functional decline in basic daily living activities among older adults living at home and receiving home nursing care. Maintenance and improvement of swallowing function may prevent late-life functional decline.

Oral mycobiome in community-dwelling elderly and its relation to oral and general health conditions.

OBJECTIVE: Oral fungal infection is generally associated with dysbiosis related to antibiotic use, immunodeficiency, or frailty. However, fungal colonization in a typical population without apparent symptoms and its associated conditions are poorly understood. In this study, oral fungal colonization in community-dwelling and independently living elderly populations was evaluated and factors affecting fungal colonization were analyzed. SUBJECTS AND METHODS: The subjects (410; 181 males and 229 females) were 75-99 years of age; those under prior antibiotic use were excluded. Fungal populations in the saliva were evaluated by PCR-based molecular techniques. Body mass index (BMI), smoking habits, and oral health conditions were examined. RESULTS: Salivary fungal amounts exceeded 104  CFU/ml in 63 (15.4%) of 410 subjects. Candida albicans was most frequently detected (98.4%), followed by Candida glabrata (54.0%), and Candida dubliniensis (38.1%) in those subjects with fungi at 104  CFU/ml or over. Fungi at 104  CFU/ml or over in the presence of C. glabrata or C. dubliniensis was significantly associated with low BMI. CONCLUSIONS: Candida albicans, C. glabrata, and C. dubliniensis dominated the oral mycobiome in Japanese community-dwelling elderly. Lower BMI might signify compromised health status and thus could result in susceptibility to specific candidiasis by C. glabrata and C. dubliniensis.

Low-dose gonadotropin-releasing hormone agonist therapy (draw-back therapy) for successful long-term management of adenomyosis associated with cerebral venous and sinus thrombosis from low-dose oral contraceptive use.

The authors report a case of cerebral venous and sinus thrombosis (CVST) in a patient receiving a low-dose estrogen-progestin combination (oral contraceptives, OCs) for uterine adenomyosis. She was switched to gonadotropin-releasing hormone agonist (GnRHa) draw-back therapy, which was successfully administered long-term. CASE: The patient was a 38-year-old nulligravida with a history of smoking. She presented to this hospital with dysmenorrhea and postmenstrual lower abdominal pain. Adenomyosis was diagnosed using ultrasound and magnetic resonance imaging. She was instructed to stop smoking and was administered low-dose OCs. CVST occurred 18 months later. OC therapy was halted, and only antiplatelet therapy was administered. After six months, her chief complaint symptoms intensified, therefore GnRHa draw-back therapy was administered after obtaining informed consent. No uterine enlargement was observed, and the abdominal pain resolved. During 2.5 years of therapy, her bone density levels remained within normal limits. CVST did not recur and no other thromboses were observed.

Posterior teeth occlusion and dysphagia risk in older nursing home residents: a cross-sectional observational study.

The total number of natural teeth was related to swallowing function among older adults; however, limited information is available regarding the impact of occluding pairs of teeth on swallowing function. This study aimed to examine the association between posterior teeth occlusion and dysphagia risk in older nursing home residents. This cross-sectional study included 238 residents aged ≥60 years from eight nursing homes in Aso City, Japan. Swallowing function was evaluated using the modified water swallowing test (MWST); the primary outcome was dysphagia risk (MWST score ≤3). Posterior teeth occlusion was assessed using number of functional tooth units (FTUs), determined based on number and location of the remaining natural and artificial teeth on implant-supported, fixed or removable prostheses. Univariate and multivariate logistic regression analyses were performed to examine the association between posterior teeth occlusion and dysphagia risk, adjusted for the covariates of number of natural teeth, demographic characteristics, comorbidities, physical function, body mass index and cognitive function. Of the 238 subjects, 44 (18·5%) were determined to be at risk of dysphagia based on the MWST scores. The odds ratio (OR) of dysphagia risk decreased in subjects with higher total FTUs [OR = 0·92, 95% confidence interval (CI) 0·87-0·98]. After adjusting for covariates, this association remained significant (OR = 0·90, 95% CI 0·84-0·97). Loss of posterior teeth occlusion was independently associated with dysphagia risk in older nursing home residents. Maintaining and restoring posterior teeth occlusion may be an effective measure to prevent dysphagia.

Acetaldehyde production by major oral microbes.

OBJECTIVES: To assess acetaldehyde (ACH) production by bacteria constituting the oral microbiota and the inhibitory effects of sugar alcohols on ACH production. MATERIALS AND METHODS: The predominant bacterial components of the salivary microbiota of 166 orally healthy subjects were determined by barcoded pyrosequencing analysis of the 16S rRNA gene. Bacterial ACH production from ethanol or glucose was measured using gas chromatography. In addition, inhibition by four sugars and five sugar alcohols of ACH production was assayed. RESULTS: Forty-one species from 16 genera were selected as predominant and prevalent bacteria based on the following criteria: identification in ≥95% of the subjects, ≥1% of mean relative abundance or ≥5% of maximum relative abundance. All Neisseria species tested produced conspicuous amounts of ACH from ethanol, as did Rothia mucilaginosa, Streptococcus mitis and Prevotella histicola exhibited the ability to produce ACH. In addition, xylitol and sorbitol inhibited ACH production by Neisseria mucosa by more than 90%. CONCLUSIONS: The oral microbiota of orally healthy subjects comprises considerable amounts of bacteria possessing the ability to produce ACH, an oral carcinogen. Consumption of sugar alcohols may regulate ACH production by oral microbes.

Microbial community in persistent apical periodontitis: a 16S rRNA gene clone library analysis.

AIM: To characterize the microbial composition of persistent periapical lesions of root filled teeth using a molecular genetics approach. METHODOLOGY: Apical lesion samples were collected from 12 patients (23-80 years old) who visited the Kyushu University Hospital for apicectomy with persistent periapical lesions associated with root filled teeth. DNA was directly extracted from each sample and the microbial composition was comprehensively analysed using clone library analysis of the 16S rRNA gene. Enterococcus faecalis, Candida albicans and specific fimA genotypes of Porphyromonas gingivalis were confirmed using polymerase chain reaction (PCR) analysis with specific primers. RESULTS: Bacteria were detected in all samples, and the dominant findings were P. gingivalis (19.9%), Fusobacterium nucleatum (11.2%) and Propionibacterium acnes (9%). Bacterial diversity was greater in symptomatic lesions than in asymptomatic ones. In addition, the following bacteria or bacterial combinations were characteristic to symptomatic lesions: Prevotella spp., Treponema spp., Peptostreptococcaceae sp. HOT-113, Olsenella uli, Slackia exigua, Selemonas infelix, P. gingivalis with type IV fimA, and a combination of P. gingivalis, F. nucleatum, and Peptostreptococcaceae sp. HOT-113 and predominance of Streptococcus spp. On the other hand, neither Enterococcus faecalis nor C. albicans were detected in any of the samples. CONCLUSION: Whilst a diverse bacterial species were observed in the persistent apical lesions, some characteristic patterns of bacterial community were found in the symptomatic lesions. The diverse variation of community indicates that bacterial combinations as a community may cause persistent inflammation in periapical tissues rather than specific bacterial species.

Does surgery improve live birth rates in patients with recurrent miscarriage caused by uterine anomalies?

We found that congenital uterine anomalies have a negative impact on reproductive outcome in recurrent-miscarriage couples, being associated with further miscarriage with a normal embryonic karyotype. There has been no study comparing live birth rates between patients with and without surgery. We conducted a prospective study to prove that surgery for a bicornuate or septate uterus might improve the live birth rate. A total of 170 patients with congenital uterine anomalies suffering two or more miscarriages were examined. The live birth rate after ascertainment of anomalies, cumulative live birth rate and infertility rate, were compared between patients with and without surgery. In patients with a septate uterus, the live birth rate (81.3%) at the first pregnancy after ascertainment of anomalies with surgery tended to be higher than that (61.5%) in those without surgery. The infertility rates were similar in both groups, while the cumulative live birth rate (76.1%) tended to be higher than without surgery (60.0%). Surgery showed no benefit in patients with a bicornuate uterus for having a baby, but tended to decrease the preterm birth rate and the low birth weight. The possibility that surgery has benefits for having a baby in patients with a septate uterus suffering recurrent miscarriage could not be excluded.

Squamous-lined cyst of the pancreas: Radiological-pathological correlation.

Pancreatic cystic lesions are increasingly being detected incidentally because of the increased use of cross-sectional imaging. Squamous-lined cysts of the pancreas (lymphoepithelial cyst, epidermoid cyst, and dermoid cyst) are rare cystic lesions lined with squamous epithelium. Distinguishing squamous-lined cysts from other cystic lesions of the pancreas is important to avoid unnecessary surgery, because squamous-lined cysts of the pancreas have no malignant potential. The purpose of this review is to describe findings on computed tomography and magnetic resonance imaging and the histopathological characteristics of squamous-lined cysts, and to summarize the key points of differential diagnosis for pancreatic cystic lesions.

Molecular characterization of fungal populations on the tongue dorsum of institutionalized elderly adults.

OBJECTIVES: To characterize the global composition of oral fungal populations in frail elderly adults and to investigate the relationship with their health status. MATERIALS AND METHODS: We investigated the fungal populations on the tongue dorsum in 291 institutionalized elderly adults by molecular PCR-based techniques using internal transcribed spacer regions of nuclear ribosomal DNA. RESULTS: Quantitative PCR analysis showed that fungi were present on the tongue dorsum of 128 subjects at ≥10(4) CFU per sample, and 35 of them exceeded 10(5) CFU per sample. Length heterogeneity-PCR analysis and nucleotide sequence determinations showed that Candida albicans was most frequently detected in those subjects with fungi at ≥10(4) CFU per sample (105 subjects), followed by Candida dubliniensis (78), Malassezia restricta (57), and Candida tropicalis (45). Statistical analysis revealed that those subjects with ≥10(5) CFU of fungi other than C. albicans per sample had an increased risk of fever (≥7 febrile days per 12 months) compared with subjects with <10(5) CFU per sample, after adjustment for other fever-associated confounding factors. CONCLUSIONS: These data demonstrate that the oral cavity of the elderly is inhabited by a diverse array of fungi not limited to typical Candida species and they suggest that the diversity in distribution is associated with health status.

Endovascular treatment of intractable bleeding from a traumatic pseudoaneurysm of the internal maxillary artery.

Traumatic pseudoaneurysms of the internal maxillary artery (IMA) are rare and difficult to treat. A 58-year-old man with a traumatic pseudoaneurysm of the IMA presented with intractable nasal and oral hemorrhage during dual antiplatelet therapy. Transcatheter artery embolization with N-butyl cyanoacrylate (NBCA) completely occluded the pseudoaneurysm. Transcatheter artery embolization with NBCA is a feasible and effective treatment because of its shorter treatment time and lower incidence of recurrence.

Gasless laparoscopically assisted myomectomy using a wound retraction system.

INTRODUCTION: The purpose of this study was to elucidate the feasibility of gasless laparoscopically assisted myomectomy (LAM) using a wound retraction system. This method treats symptomatic uterine myomas by combining laparoscopy with a mini-laparotomy to enucleate myoma nodules and to close the uterine myometrium. METHODS: This study includes 275 patients who underwent gasless LAM. For patients with fewer than three myoma nodules, the location of the largest nodule was classified as anterior, fundal, or posterior. The operative outcomes, intraoperative and postoperative courses, and complications were examined. RESULTS: All operations were performed satisfactorily, and no conversions to laparotomy were required. None of the patients developed serious complications. The mean blood loss and operating time were 190.3 mL and 152.2 minutes, respectively. The mean myoma size was 8.9 cm, and the mean number of myomas per patient was 2.8. The average postoperative hospital stay was 5.7 days. There were no significant differences in resected myoma size, blood loss, and surgical duration with respect to the location of the largest nodule. CONCLUSION: Gasless LAM with a wound retractor is feasible and allows surgeons to perform myomectomy safely and cost-effectively, without requiring advanced laparoscopic surgical skills and while maintaining minimum invasiveness.