Anticentromere antibodies are the most potent antinuclear antibodies in reducing live birth outcomes after ICSI.

RESEARCH QUESTION: How, and to what extent, do anticentromere antibodies (ACA) reduce live birth outcomes after ICSI? STUDY DESIGN: Retrospective cohort study of infertile women aged 30-43 years who underwent ICSI between September 2016 and March 2021. Women with a history or current diagnosis of symptomatic connective tissue disease were excluded. Immunofluorescence staining detected antinuclear antibodies (ANA). Staining pattern and titre (cut-off, 1:160) were used to divide infertile women into three groups: positive for ACA (ACA+) (n = 28); positive for ANA other than ACA (ANA+) (n = 77); and negative for both ACA and ANA (control) (n = 3723). RESULTS: Cumulative live birth rate (CLB) was lowest in ACA+ (7%, 31% and 46% in ACA+, ANA+ and control, respectively) (ACA+ versus control, P < 0.0001; ACA+ versus ANA+, P = 0.011; ANA+ versus control, P = 0.012). A small impairment in meiosis I and a larger impairment in meiosis II, fertilization and embryo cleavage caused the decrease. Multiple pronuclei formation increased (RR versus control, 5.33; 95% CI 4.26 to 6.65) and good-quality blastocyst development decreased (RR 0.34; 95% CI 0.22 to 0.53). Multiple logistic regression analysis showed that ACA was associated with CLB outcome (OR 0.08, 95% CI 0.02 to 0.36); the other four ANA staining patterns were not. CONCLUSIONS: The effect of ACA on live birth outcomes is strongest after ICSI among ANA, primarily through the impairment of meiosis II and subsequent stages. Repeated ICSI failure and eggs with multiple pronuclei may warrant specific testing for ACA.

Impact of Travel Distance on Surgical Outcomes of Patients Surgically Treated for Non-Small Cell Lung Cancer: A Single-Center Study in Ehime, Japan.

Travel burden is a poor prognostic factor for many cancers worldwide because it hinders optimal diagnosis and treatment planning. Currently, the impact of travel burden on survival after surgery for non-small cell lung cancer (NSCLC) in Japan is largely unexplored. We examined the impact of travel distance on the postoperative outcomes of patients with NSCLC in Ehime Prefecture, Japan. The data of 1212 patients who underwent surgical resection for NSCLC were retrospectively reviewed. Patients were divided into quartiles based on the travel distance from their home to the hospital (≤ 13 km, 13-40 km, 40-57 km, and > 57 km) in Ehime Prefecture. We found no significant differences among the quartiles in baseline clinicopathological characteristics, including sex, smoking status, histology, surgical procedure, clinical stage, and pathological stage. Overall survival (OS) and relapse-free survival (RFS) also were not significantly different among the travel distance quartiles. We conclude that travel distance did not impact OS or RFS among patients with NSCLC who underwent surgical resection at our institution.

The Impact of Sequestration on Artemisinin-Induced Parasite Clearance in Plasmodium falciparum Malaria in Africa.

BACKGROUND: Artemisinin-resistant Plasmodium falciparum is spreading in Southeast Asia and Africa. In vivo susceptibility to artemisinin is studied by looking at the rate of decline of peripheral parasitemia (parasite clearance half-life). However, parasites that are adhered/sequestered to the endothelium and undetectable in the peripheral blood are not considered in the estimation of parasite clearance. Here, we evaluated the influence of sequestration on in vivo artemisinin efficacy in Uganda, where artemisinin resistance is spreading. METHODS: We analyzed 133 patients with P. falciparum malaria included in an in vivo study on artemisinin efficacy in northern Uganda in 2018 and 2019. The parasite clearance half-life was estimated from peripheral parasitemia after artemisinin monotherapy. P. falciparum histidine-rich protein 2 (PfHRP2) was measured in pretreatment plasma. The number of sequestered parasites was estimated from PfHRP2 concentration and peripheral parasitemia. RESULTS: The estimated number of sequestered parasites per plasma volume ranged from 0 to 2 564 000/µL. Inflammation, thrombocytopenia, and dyslipidemia were significantly associated with sequestration independent of peripheral parasitemia. The median parasite clearance half-lives were 1.65 hours in patients infected with Pfkelch13 wild-type parasites (n = 104) and 3.95 hours in those with A675V artemisinin-resistant mutant (n = 18). In the multivariable model for the wild-type population, 1 000 000/µL of sequestered parasites were estimated to delay parasite clearance by 16.8% (95% confidence interval, 5.1%-28.5%), although it was not clear in the A675V population. CONCLUSIONS: In patients with P. falciparum malaria without artemisinin-resistant mutations, intensive sequestration delays parasite clearance after treatment, which may contribute to reduced artemisinin efficacy.

EGFR Mutation is a Prognostic Factor in Lung Cancer Patients with Pleural Dissemination Detected During or After Surgery.

BACKGROUND: Primary lung tumors are sometimes resected when either pleural dissemination (PD) or malignant pleural effusion (MPE) exists. This study clarified the prognostic factors for non-small cell lung cancer (NSCLC) with either PD and MPE, or both, detected during or after surgery. PATIENTS AND METHODS: We examined patients with NSCLC from a multicenter database who had either PD, MPE, or both, detected during or after surgery between 2005 and 2015. Hazard ratios and 95% confidence intervals were estimated using the Cox proportional hazards model adjusted for potential confounding factors. RESULTS: Among 9463 registered patients, PD, MPE, or both, were found in 114 patients with NSCLC during or after surgery. Primary tumor resection and exploratory thoracotomy were performed in 65 and 49 patients, respectively. In univariate analysis, adenocarcinoma, clinically undetected lymph node metastasis (c-N0 or unknown), EGFR mutation, and combination of chemotherapy or tyrosine kinase inhibitors after surgery were better prognostic factors for overall survival (OS), whereas in the multivariate analysis, adenocarcinoma, clinically undetected lymph node metastasis, and EGFR mutation were favorable independent prognostic factors in OS. Additionally, limited to patients with EGFR mutation, patients with primary lung tumor resection showed a significantly better 5-year OS than those with exploratory thoracotomy (86.4 vs. 44.8%; p < 0.001). CONCLUSION: Our findings show that surgical resection of primary tumors could improve the prognosis of patients with PD, MPE, or both, detected during or after surgery when the tumors harbor an EGFR mutation.

Predictive value of EGFR mutation in non-small-cell lung cancer patients treated with platinum doublet postoperative chemotherapy.

The mutation status of tumor tissue DNA (n = 389) of resected stage II-III non-squamous non-small-cell lung cancer (Ns-NSCLC) was analyzed using targeted deep sequencing as an exploratory biomarker study (JIPANG-TR) for the JIPANG study, a randomized phase III study of pemetrexed/cisplatin (Pem/Cis) vs vinorelbine/cisplatin (Vnr/Cis). The TP53 mutation, common EGFR mutations (exon 19 deletion and L858R), and KRAS mutations were frequently detected. The frequency of the EGFR mutation was significant among female patients. Patients with an EGFR mutation-positive status had a significantly shorter recurrence-free survival (RFS) time (24 mo vs not reached) (HR, 1.64; 95% CI, 1.22-2.21; P = .0011 for EGFR mutation status). Multivariable analysis identified both the pathological stage and EGFR mutation status as independent prognostic factors for RFS (HR, 1.78; 95% CI, 1.30-2.44; P = .0003 for disease stage; and HR, 1.57; 95% CI, 1.15-2.16; P = .0050 for EGFR mutation status). This study demonstrated that the EGFR mutation has either a poor prognostic or predictive impact on a poor response to postoperative chemotherapy with platinum doublet chemotherapy for stage II-III Ns-NSCLC patients. This result supports a role for mandatory molecular diagnosis of early-stage Ns-NSCLC for precision oncology and signifies the importance of adjuvant for the 3rd generation tyrosine kinase inhibitor rather than platinum-based chemotherapy. This study is registered with the UMIN Clinical Trial Registry (UMIN 000012237).

A Case of Mediastinal Localized Malignant Pleural Mesothelioma Successfully Treated by Chemotherapy and Conversion Surgery.

Localized malignant mesothelioma is a rare disease and little is known about its treatment strategy. We herein report a case of localized malignant pleural mesothelioma that had infiltrated into the anterior mediastinum, which was successfully treated using chemotherapy and conversion surgery. A 63-year-old man with a mediastinal tumor was referred to our hospital. Pathologic analysis of the biopsy specimen showed malignant mesothelioma. Significant tumor shrinkage by cisplatin and pemetrexed was observed and he underwent radical surgery via a median sternotomy. The patient has been disease free for 12 months.

Tumor mutation burden as a biomarker for lung cancer patients treated with pemetrexed and cisplatin (the JIPANG-TR).

The JIPANG study is a randomized phase III study of pemetrexed/cisplatin (Pem/Cis) versus vinorelbine/cisplatin (Vnr/Cis) for completely resected stage II-IIIA non-squamous non-small cell lung cancer (Ns-NSCLC). This study did not meet the primary endpoint (recurrence-free survival, RFS) but Pem/Cis had a similar efficacy to Vnr/Cis with a better tolerability. Tumor mutation burden (TMB) is thought to have a predictive value of immune checkpoint inhibitors. However, the relevance of TMB to cytotoxic chemotherapy remains unknown. This exploratory study investigates the relationship between tumor mutation profiles and clinical outcome of Pem/Cis. Formalin-fixed, paraffin-embedded tumor tissues (n = 389) were obtained from the patients. Mutation status of tissue DNA was analyzed by targeted deep sequencing. Epidermal growth factor receptor (EGFR) mutations were detected frequently in Ns-NSCLC (139/374). Patients without any EGFR mutations experienced longer RFS in the Pem/Cis arm versus Vnr/Cis arms. Pem/Cis in patients with high TMB (≥12-16 mut/Mb) tended to have improved survival. In patients with wild-type EGFR, TMB ≥ 12 mut/Mb was significantly associated with improved RFS with Pem/Cis versus Vnr/Cis (not reached vs 52.5 months; hazard ratio (HR) 0.477). It could be proposed that TMB was predictive of RFS benefit with Pem/Cis versus Vnr/Cis in Ns-NSCLC. Further investigation is required to determine whether TMB combined with EGFR mutation status could be used as a predictive biomarker.

Therapeutic Outcomes of 15 Postoperative Bronchopleural Fistulas Including Seven Endoscopic Interventions.

Therapeutic approaches to bronchopleural fistula (BPF) closure after lung resection are surgical or endoscopic interventions. We evaluated therapeutic outcomes to determine the optimal approach. We reviewed 15 patients who had developed BPF after lung resection for thoracic malignant diseases at our institution in the 10 years since 2008. The patients were 11 men and 4 women (mean age 68 years). We performed one pneumonectomy, 6 lobectomies, 7 segmentectomies, and one partial resection for malignant diseases. The median interval from lung resection to the BPF diagnosis was 46 days. The BPF-associated mortality rate was 26.7% (4/15). The rate of successful BPF closure was 66.6% (10/15). The endoscopic and surgical intervention success rates were 14.2% (1/7) and 69.2% (9/13), respectively (p<0.01). Of 5 patients who had failed BPF treatments, 4 died, and one transferred out without BPF closure. The therapeutic outcomes were related to preoperative comorbidities, performance status at the BPF diagnosis, time intervals from lung resection to BPF diagnosis, and presence of active pneumonia. The difference between endoscopic and surgical outcomes was nonsignificant, although the surgical intervention success rate was somewhat higher. The selection of endoscopic or surgical intervention for BPF does not significantly affect therapeutic outcomes.

Feasibility Trial of Oral UFT after Platinum-based Adjuvant Chemotherapy in Patients with Resected Non-small Cell Lung Cancer.

We evaluated the feasibility of maintenance treatment using UFT (a combination of tegafur and uracil) after adjuvant platinum-based chemotherapy in patients with resected lung cancer. A prospective feasibility trial was conducted. Between 2010 and 2014, UFT was administered for 2 years sequentially after platinum-based adjuvant chemotherapy in 24 patients with resected Stage IIA-IIIA non-small cell lung cancer. The safety of UFT and the rate of treatment completion were then evaluated. The prior platinum-based chemotherapy regimens consisted of cisplatin+vinorelbine in 16 patients, carboplatin+paclitaxel in 5 and carboplatin+S-1 in one. During the subsequent UFT administration, a total of 3 patients required a dose reduction because of Grade 1 blood-stained sputum, Grade 2 numbness, and Grade 2 constipation, in one patient each. Eleven patients underwent the planned 2-year UFT administration, but 12 patients could not because of the recurrence of lung cancer in 5 patients, metachronous malignancy in one, and toxicities in 6. The completion rate for UFT administration was 64.7% (11/17). The most common type of toxicity was gastrointestinal toxicities. All of the toxicities were grade 1 or 2, and no severe toxicities were observed. UFT treatment after platinum-based chemotherapy was revealed to be feasible.

Changes in Post-Operative Complication and Mortality Rates after Lung Cancer Resection in the 20-Year Period 1995-2014.

We reviewed post-operative complication and mortality rates from 1995 through 2014 and evaluated the changes in those rates across that 20-year period. Two thousand and three hundred sixteen patients with lung cancer underwent resection at our institution between 1995 and 2014. This timespan was divided into four 5-year periods. Each patient's age, Charlson comorbidity index score, and extent of surgery in each 5-year period were summarized, and the changes in these factors over the 20-year span were evaluated. The complication and mortality rates were calculated for each 5-year period, and the changes in those rates over the 20-years were evaluated. The number of patients with higher Charlson comorbidity index scores increased during the 20-year period. Of the 455 patients who developed complications, 97 developed life-threating complications. There were 16 post-operative deaths and 23 in-hospital deaths. There were no significant changes in the complication rate or mortality rate during the 20-year period. Both rates were significantly correlated with the extent of resection. Although the number of patients with comorbidities increased in the 20-year period, the post-operative complication and mortality rates, as well as in-hospital mortality, did not change significantly.

A Case of Mediastinal Cystic Lymphangioma.

A 35-year-old Japanese man's routine chest radiography revealed an abnormal opacity. Chest computed tomography and magnetic resonance imaging showed a 5.5 cm in dia. cystic tumor located at the left anterior mediastinum. The tumor was suspected to be an asymptomatic thymic cyst, and we chose observation for the tumor. At the 3-year follow up, the cystic tumor had gradually enlarged to 7.5 cm in dia. and we thus performed a surgical resection via left video-assisted thoracic surgery. An immunohistochemical analysis showed that the cystic tumor was not a thymic cyst but rather a mediastinal cystic lymphangioma. Mediastinal cystic lymphangiomas are very rare, and they are difficult to diagnose preoperatively. Complete surgical resection is proposed for the treatment of such tumors.

A rare case of inflammatory myofibroblastic tumor of the diaphragmatic parietal pleura with dissemination.

Inflammatory myofibroblastic tumor (IMT) is a rare neoplasm that occurs at different sites in the body. Pleural IMT in particular is especially rare. IMTs infrequently tend to have malignancy. We report a rare case of advanced diaphragmatic parietal pleural IMT with dissemination. A 30-year-old woman complained of right upper abdominal pain. Computed tomography showed a large lobulated mass over the right diaphragm, but no disseminated nodules were noted. Intraoperatively, we found the primary tumor arising from the diaphragmatic parietal pleura and a dozen disseminated nodules, and we removed them completely. The histopathological and immunohistochemical diagnosis was IMT.

Lipid profile and atherogenic indices soon after birth in Japanese preterm infants.

AIM: The intra-uterine environment affects the risk of development of cardiovascular disease in adulthood. The aim of this study was to determine the influence of prematurity and foetal growth restriction on lipid metabolism, by assessing atherogenic indices soon after birth in preterm infants. METHODS: Blood samples were collected within 20 min of birth from 80 preterm infants with a gestational age of ≤35 weeks. Serum total cholesterol (TC), low-density lipoprotein cholesterol (LDLc), high-density lipoprotein cholesterol (HDLc), apolipoprotein-A1 (apoA1) and apolipoprotein-B (apoB) levels were measured. The ratio of TC/HDLc, LDLc/HDLc and apoB/apoA1 were also calculated. Correlations between these indices and gestational age, birth weight and the standard deviation (SD) score for birth weight were also determined. RESULTS: Gestational age, birth weight and SD score for birth weight were negatively correlated with the TC/HDLc, LDLc/HDLc and apoB/apoA1 ratios. CONCLUSION: In preterm infants, prematurity and poor foetal growth may influence lipid and apolipoprotein metabolism and affect atherogenic indices at birth.

Preclinical evaluation of microRNA-34b/c delivery for malignant pleural mesothelioma.

The microRNA-34s (miR-34s) have p53 response elements in their 5'-flanking regions and demonstrate tumor-suppressive functions. In malignant pleural mesothelioma (MPM), we previously reported that expression of miR-34b and miR-34c (miR-34b/c) was frequently downregulated by methylation in MPM cell lines and primary tumors. The forced overexpression of miR-34b/c showed significant antitumor effects with the induction of apoptosis in MPM cells. In this study, we examined the in vivo antitumor effects of miR-34b/c using adenovirus vector on MPM. We subcutaneously transplanted NCI-H290, a human MPM cell line, into BALB/C mice and injected adenovirus vector expressing miR-34b/c, luciferase driven by the cytomegalovirus promoter (Ad-miR-34b/c or Ad-Luc), or PBS control into tumors over 5mm in diameter. A statistically significant growth inhibition of the tumor volume was observed in the Ad-miR-34b/c group from day 6 onward compared to the Ad-Luc group. The inhibition rate of Ad-miR-34b/c, compared to the tumor volume treated with Ad-Luc, was 58.6% on day 10 and 54.7% on day13. Our results indicate that adenovirus-mediated miR-34b/c gene therapy could be useful for the clinical treatment of MPM.

[Pulmonary non-tuberculous mycobacteriosis complicated with lung cancer].

A 54-year-old man with pulmonary non-tuberculous mycobacteriosis( pulmonary NTM) who had been treated by antituberculous chemotherapy, developed a new nodule of 1.3 cm in size in the segment 1/2 of the right upper lobe. The cavity of 3.5 cm in size in the segment 6 of the right lower lobe from which Mycobacterium intracellulare was bronchoscopically detected, was suspected to be pulmonary NTM lesion. Since lung cancer was highly suspected by radiological examinations, right upper lobectomy and S6 segmentectomy were performed. Pathological diagnosis for the right upper lobe nodule was adenocarcinoma.

Suitable Patient Selection and Optimal Timing of Treatment for Persistent Air Leak after Lung Resection.

OBJECTIVES: The choice of therapeutic intervention for postoperative air leak varies between institutions. We aimed to identify the optimal timing and patient criteria for therapeutic intervention in cases of postoperative air leaks after lung resection. METHODS: This study utilized data from a prospective multicenter observational study conducted in 2019. Among the 2187 cases in the database, 420 cases with air leaks on postoperative day 1 were identified. The intervention group underwent therapeutic interventions, such as pleurodesis or surgery, while the observation group was monitored without intervention. A comparison between the intervention group and the observation group were analyzed using the cumulative distribution and hazard functions. RESULTS: Forty-six patients (11.0%) were included in the intervention group. The multivariate analysis revealed that low body mass index (p = 0.019), partial resection (p = 0.010), intraoperative use of fibrin glue (p = 0.008), severe air leak on postoperative day 1 (p < 0.001), and high forced expiratory volume in 1 s (p = 0.021) were significant predictors of the requirement for intervention. The proportion of patients with persistent air leak in the observation group was 20% on postoperative day 5 and 94% on postoperative day 7. The hazard of air leak cessation peaked from postoperative day 3 to postoperative day 7. CONCLUSIONS: This research contributes valuable insights into predicting therapeutic interventions for postoperative air leaks and identifies scenarios where spontaneous cessation is probable. A validation through prospective studies is warranted to affirm these findings.

Low serum carnitine level is associated with increased urinary carnitine excretion in late pregnancy.

BACKGROUND: Carnitine is essential for fatty acid metabolism. Free carnitine (FCA) is excreted in the urine in the glomerulus, but is partly reabsorbed by a carnitine transporter. The mechanism underlying the decrease in serum carnitine level during pregnancy is unclear. OBJECTIVE: To investigate whether low carnitine level is associated with increased renal excretion in pregnant women. METHODS: We recruited 43 healthy pregnant and 25 non-pregnant women. Total carnitine (TCA) and FCA levels were measured using the enzymatic cycling method, and the acylcarnitine (ACA) level was calculated. Fractional excretion (FE) was calculated as carnitine clearance divided by creatinine clearance. RESULTS: The mean TCA, FCA, and ACA levels were lower at 12 weeks of gestation in pregnant than non-pregnant women (P < .001); the levels decreased further at 36 weeks, reaching 39%, 36%, and 52% of those in non-pregnant women, respectively (P < .001). The FEs were 3-4-fold higher in pregnant women than non-pregnant women. Pregnant women had a lower serum FCA/TCA ratio than non-pregnant women (0.788 ± 0.098 vs 0.830 ± 0.074, respectively; P < .05), whereas the urine FCA/TCA ratio was similar between the groups. CONCLUSION: Low carnitine level is associated with increased renal excretion during late pregnancy.

Benign Mesothelial Cells in transbronchial biopsy specimens: A potential diagnostic pitfall for lung cancer.

Bronchoscopy is a common diagnostic procedure used to identify lung cancer. Specimens acquired through transbronchial biopsy are pivotal in the diagnosis and molecular characterization of this disease. The occurrence of benign mesothelial cells during a transbronchial biopsy (TBB) is relatively rare. Furthermore, these lesions can sometimes be erroneously identified as malignant, potentially resulting in unwarranted or inappropriate treatment for patients with and without lung cancer. In this retrospective analysis, we examined 619 TBB cases at our institute from 2019 to 2021. Benign mesothelial cells were identified via immunohistochemical studies in eight (1.3%) of 619 cases. These cells were classified into three patterns based on their cellular morphology: monolayer, lace, and cobblestone. Recognizing this phenomenon during the procedure is crucial to accurately distinguish benign mesothelial cells from their cancerous counterparts.

Silenced expression of NFKBIA in lung adenocarcinoma patients with a never-smoking history.

Nuclear factor of κ-light polypeptide gene enhancer in B cells inhibitor α (NFKBIA), which is a tumor suppressor gene, was found to be silenced in lung adenocarcinomas. We examined NFKBIA expression, mutations in the EGFR and K-ras genes, and EML4-ALK fusion in 101 resected lung adenocarcinoma samples from never-smokers. NFKBIA expression was evaluated using immunohistochemistry. NFKBIA expression was negative in 16 of the 101 samples (15.8%). EGFR and K-ras mutations and EML4-ALK fusion were detected in 61 (60.5%), 1 (1.0%), and 2 (2.0%) of the 101 samples, respectively, in a completely mutually exclusive manner. Negative NFKBIA expression was observed significantly more frequently among the tumors with none of the three genetic alterations compared to those with such alterations (p = 0.009). In addition, negative NFKBIA expression was significantly more frequent among the EGFR-wild type samples compared to the EGFR-mutant samples (p = 0.013). In conclusion, NFKBIA expression was silenced in adenocarcinomas without EGFR/K-ras mutations or EML4-ALK fusion, suggesting that the silencing of NFKBIA may play an important role in the carcinogenesis of adenocarcinomas independent of EGFR/K-ras mutations or EML4-ALK fusion.