Breast cancer in adolescents and young adults has a specific biology and poor patient outcome compared with older patients.

BACKGROUND: We aimed to clarify the features of adolescents and young adults (AYA: younger than 40 years old) breast cancer (BC) compared with other age groups in estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative BC, given the effects of age-related hormonal status. METHODS: The cohorts analyzed were divided into AYA (15-39 years old), perimenopausal (40-54 years old), menopausal (55-64 years old), and old (65+ years old). Clinicopathological and biological features were analyzed using gene set variation analysis and xCell algorithm using transcriptome profiles from large public databases of ER-positive/HER2-negative BC (METABRIC; n = 1353, SCAN-B; n = 2381). RESULTS: In the ER-positive/HER2-negative subtype, pathological lymph node positivity, and Nottingham grade 3 were higher among AYA (all P < 0.001). AYA patients had a trend toward worse disease-specific and overall survival, particularly compared with the perimenopausal group. Estrogen response late signaling decreased with age (all P ≤ 0.001 in both METABRIC and SCAN-B cohorts). AYA was associated with significantly higher BRCAness and DNA repair than the other groups (all P < 0.05 in both cohorts). AYA significantly enriched cell proliferation-related and procancerous gene sets [mTORC1, unfolded protein response, and phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling] when compared with the others (all P < 0.03 in both cohorts). Interestingly, these features have also been observed in tumors <2 cm. Infiltration of CD8+, regulatory, T helper type 2 cells, and M1 macrophages was higher, while M2 macrophages were lower in AYA (all P < 0.03 in both cohorts). Finally, ER-positive/HER2-negative BC in AYA patients has different features of gene mutations, including AHNAK2, GATA3, HERC2, and TG, which were observed at a higher rate in AYA, and KMT2C, which was observed at a lower rate in AYA, compared with other age groups. CONCLUSIONS: ER-positive/HER2-negative BC in AYA was highly proliferative with high immune cell infiltration compared with the other age groups.

Influence of splenomegaly on aortic and liver parenchymal CT numbers during contrast-enhance CT in patients with cirrhosis.

INTRODUCTION: To compare CT (computed tomography) values for enhancement of the abdominal aorta and liver parenchyma during dynamic contrast enhancement (CE) CT in cirrhotic patients with and without splenomegaly (SM). METHODS: We considered 258 patients (83 males and 46 females for the splenomegaly group, and 83 males and 46 females for the control group) for this retrospective study. We measured CT values in the abdominal aorta and hepatic parenchyma during the hepatic arterial (HAP) and portal venous (PVP) phases. The aortic CE at HAP and the hepatic parenchymal CE at PVP were compared between the two groups. For success rate of scans, we also calculated the optimal CE rates (>280 HU in the abdominal aorta and >50 HU in the hepatic parenchyma) for each group. RESULTS: In the SM group, the CE for abdominal aorta was decreased during the aortic phase for a dynamic CE-CT (p < 0.05). When evaluating the success rates, they were found to be 65.1 % and 58.9 % in the SM group and 81.4 % and 72.3 % in the non-SM group (p < 0.05). CONCLUSION: The success rate of scans and CE for the abdominal aorta during the aortic phase exhibited a significant decrease during dynamic CE-CT scans on patients with SM. Patients with SM may have reduced diagnostic ability with typical contrast injection protocols. IMPLICATIONS FOR PRACTICE: It may be necessary to change the injection rates and contrast medium volume during CE-CT depending on the presence or absence of SM.

Safety evaluation of the use of calcineurin inhibitor to prenatal and postpartum women in Japan from a health administrative database.

BACKGROUND: To investigate the use of calcineurin inhibitors (CNIs) in pregnant Japanese women and to evaluate their safety in infants. METHODS: Data were extracted from the claims database of the Japan Medical Data Center. The prevalence of CNIs was evaluated 180 days before pregnancy onset, during pregnancy, and within180-days post partum. We investigated the characteristics of the infants, including the presence of major malformations and their diagnoses, for 1 year after birth. RESULTS: A total of 91,865 pregnancies in 80,049 women were included. Fifty-three women were prescribed CNIs between 180-day before pregnancy onset and 180-day postpartum; 35 of the 53 women were prescribed the drugs during pregnancy, and 10 of their infants were born preterm. Three were diagnosed with major congenital malformations, such as patent ductus arteriosus. Six preterm infants presented with infant respiratory distress syndrome. CONCLUSIONS: No congenital anomalies were clearly attributable to the use of CNIs during pregnancy.

Atezolizumab plus bevacizumab versus lenvatinib or sorafenib in non-viral unresectable hepatocellular carcinoma: an international propensity score matching analysis.

BACKGROUND: A growing body of evidence suggests that non-viral hepatocellular carcinoma (HCC) might benefit less from immunotherapy. MATERIALS AND METHODS: We carried out a retrospective analysis of prospectively collected data from consecutive patients with non-viral advanced HCC, treated with atezolizumab plus bevacizumab, lenvatinib, or sorafenib, in 36 centers in 4 countries (Italy, Japan, Republic of Korea, and UK). The primary endpoint was overall survival (OS) with atezolizumab plus bevacizumab versus lenvatinib. Secondary endpoints were progression-free survival (PFS) with atezolizumab plus bevacizumab versus lenvatinib, and OS and PFS with atezolizumab plus bevacizumab versus sorafenib. For the primary and secondary endpoints, we carried out the analysis on the whole population first, and then we divided the cohort into two groups: non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) population and non-NAFLD/NASH population. RESULTS: One hundred and ninety patients received atezolizumab plus bevacizumab, 569 patients received lenvatinib, and 210 patients received sorafenib. In the whole population, multivariate analysis showed that treatment with lenvatinib was associated with a longer OS [hazard ratio (HR) 0.65; 95% confidence interval (CI) 0.44-0.95; P = 0.0268] and PFS (HR 0.67; 95% CI 0.51-0.86; P = 0.002) compared to atezolizumab plus bevacizumab. In the NAFLD/NASH population, multivariate analysis confirmed that lenvatinib treatment was associated with a longer OS (HR 0.46; 95% CI 0.26-0.84; P = 0.0110) and PFS (HR 0.55; 95% CI 0.38-0.82; P = 0.031) compared to atezolizumab plus bevacizumab. In the subgroup of non-NAFLD/NASH patients, no difference in OS or PFS was observed between patients treated with lenvatinib and those treated with atezolizumab plus bevacizumab. All these results were confirmed following propensity score matching analysis. By comparing patients receiving atezolizumab plus bevacizumab versus sorafenib, no statistically significant difference in survival was observed. CONCLUSIONS: The present analysis conducted on a large number of advanced non-viral HCC patients showed for the first time that treatment with lenvatinib is associated with a significant survival benefit compared to atezolizumab plus bevacizumab, in particular in patients with NAFLD/NASH-related HCC.

Self-sustaining oscillation of two axonemal microtubules based on a stochastic bonding model between microtubules and dynein.

The motility of cilia and flagella plays important physiological roles, and there has been a great deal of research on the mechanisms underlying the motility of molecular motors. Although recent molecular structural analyses have revealed the components of the ciliary axoneme, the mechanisms involved in the regulation of dynein activity are still unknown, and how multiple dyneins coordinate their movements remains unclear. In particular, the mode of binding for axonemal dynein has not been elucidated. In this study, we constructed a thermodynamic stochastic model of microtubule-dynein coupling and reproduced the experiments of Aoyama and Kamiya on the minimal component of axonemal microtubule-dynein. We then identified the binding mode of axonemal dynein and clarified the relationship between dynein activity distribution and axonemal movement. Based on our numerical results, the slip-bond mechanism agrees quantitatively with the experimental results in terms of amplitude, frequency, and propagation velocity, implying that axial microtubule-dynein coupling may follow a slip-bond mechanism. Moreover, the frequency and propagation velocity decayed in proportion to the fourth power of microtubule length, and the critical load of the trigger for the oscillation agreed well with Euler's critical load.

Nonalcoholic steatohepatitis in hepatocarcinoma: new insights about its prognostic role in patients treated with lenvatinib.

BACKGROUND: Hepatocellular carcinoma (HCC) treatment remains a big challenge in the field of oncology. The liver disease (viral or not viral) underlying HCC turned out to be crucial in determining the biologic behavior of the tumor, including its response to treatment. The aim of this analysis was to investigate the role of the etiology of the underlying liver disease in survival outcomes. PATIENTS AND METHODS: We conducted a multicenter retrospective study on a large cohort of patients treated with lenvatinib as first-line therapy for advanced HCC from both Eastern and Western institutions. Univariate and multivariate analyses were performed. RESULTS: Among the 1232 lenvatinib-treated HCC patients, 453 (36.8%) were hepatitis C virus positive, 268 hepatitis B virus positive (21.8%), 236 nonalcoholic steatohepatitis (NASH) correlate (19.2%) and 275 had other etiologies (22.3%). The median progression-free survival (mPFS) was 6.2 months [95% confidence interval (CI) 5.9-6.7 months] and the median overall survival (mOS) was 15.8 months (95% CI 14.9-17.2 months). In the univariate analysis for OS NASH-HCC was associated with longer mOS [22.2 versus 15.1 months; hazard ratio (HR) 0.69; 95% CI 0.56-0.85; P = 0.0006]. In the univariate analysis for PFS NASH-HCC was associated with longer mPFS (7.5 versus 6.5 months; HR 0.84; 95% CI 0.71-0.99; P = 0.0436). The multivariate analysis confirmed NASH-HCC (HR 0.64; 95% CI 0.48-0.86; P = 0.0028) as an independent prognostic factor for OS, along with albumin-bilirubin (ALBI) grade, extrahepatic spread, neutrophil-to-lymphocyte ratio, portal vein thrombosis, Eastern Cooperative Oncology Group (ECOG) performance status and alpha-fetoprotein. An interaction test was performed between sorafenib and lenvatinib cohorts and the results highlighted the positive predictive role of NASH in favor of the lenvatinib arm (P = 0.0047). CONCLUSION: NASH has been identified as an independent prognostic factor in a large cohort of patients with advanced HCC treated with lenvatinib, thereby suggesting the role of the etiology in the selection of patients for tyrosine kinase treatment. If validated, this result could provide new insights useful to improve the management of these patients.

Factors affecting the effect of naldemedine for opioid-induced constipation: a single-institution, retrospective analysis.

Naldemedine is the newest orally available, peripherally selective µ-opioid receptor antagonist blocker approved for opioid-induced constipation (OIC) treatment in adult patients. On the other hand, some patients have insufficient OIC control even with naldemedine. Thus, this retrospective study was conducted to identify factors affecting the effect of naldemedine. The participants were 210 patients who had received naldemedine at our institute between June 2017 and August 2019. Variables associated with alleviation of OIC were extracted from clinical records and used for regression analysis. The effect of naldemedine was determined according to the degree of constipation. The degree of constipation was categorized as grade 0 - 2 with reference to the CTCAE version 5.0. Multivariate ordered logistic regression analysis was conducted to identify factors affecting the effect of naldemedine. Use of naldemedine within 2 days of opioid initiation [odds ratio (OR) =0.346, 95% confidence interval (CI) =0.173-0.693; P = 0.003], concomitant use of anticholinergics (OR = 2.033, 95% CI = 1.150-3.594; P = 0.015), tramadol (OR = 0.488, 95% CI = 0.250-0.953; P =0.036), and chronic non-cancer pain (OR = 0.429, 95% CI = 0.197-0.937; P = 0.034) were identified as significant factors related to the effect of naldemedine.

Predictors of the usefulness of mirogabalin for neuropathic pain: a single-institution retrospective study.

Mirogabalin is a novel, preferentially selective α2δ-1 ligand to treat neuropathic pain. However, this agent is not always effective for patients with neuropathic pain. We therefore attempted to identify factors that could predict the efficacy of mirogabalin. The study comprised 133 patients given mirogabalin for alleviation of neuropathic pain between April and November 2019 at our hospital. Variables were extracted from medical records for regression analysis of factors associated to alleviation of neuropathic pain. We evaluated the effect of mirogabalin at two weeks after administration. Groups were categorized according to degree of improvement: poor, effective, or very effective. Multivariate ordered logistic regression analysis was conducted to identify predictors for the usefulness of mirogabalin. Threshold measures were analysed using receiver operating characteristic (ROC) curves. Maintenance dose [odds ratio (OR) = 0.90; 95% confidence interval (CI) = 0.84-0.98; P = 0.01], concomitant use of opioids (OR = 0.26, 95% CI = 0.08-0.83; P = 0.023) and Neurotropin® (NTP) (OR = 4.78, 95% CI =1.04-21.93; P = 0.044) were factors significantly correlated to the effect of mirogabalin. ROC curve analysis of the effective group indicated a threshold maintenance dose of≤ 20 mg/day (area under the curve [AUC] = 0.53). In conclusion, maintenance dose (≤ 20 mg), concomitant use of opioids and NTP were identified as predictors for the utility of mirogabalin.

Search for η

We measured missing mass spectrum of the ^{12}C(γ,p) reaction for the first time in coincidence with potential decay products from η^{'} bound nuclei. We tagged an (η+p) pair associated with the η^{'}N→ηN process in a nucleus. After applying kinematical selections to reduce backgrounds, no signal events were observed in the bound-state region. An upper limit of the signal cross section in the opening angle cosθ_{lab}^{ηp}<-0.9 was obtained to be 2.2 nb/sr at the 90% confidence level. It is compared with theoretical cross sections, whose normalization ambiguity is suppressed by measuring a quasifree η^{'} production rate. Our results indicate a small branching fraction of the η^{'}N→ηN process and/or a shallow η^{'}-nucleus potential.

Impact of technically qualified surgeons on laparoscopic colorectal resection outcomes: results of a propensity score-matching analysis.

BACKGROUND: The Endoscopic Surgical Skill Qualification System (ESSQS) was introduced in Japan to improve the quality of laparoscopic surgery. This cohort study investigated the short- and long-term postoperative outcomes of colorectal cancer laparoscopic procedures performed by or with qualified surgeons compared with outcomes for unqualified surgeons. METHODS: All laparoscopic colorectal resections performed from 2010 to 2013 in 11 Japanese hospitals were reviewed retrospectively. The procedures were categorized as performed by surgeons with or without the ESSQS qualification and patients' clinical, pathological and surgical features were used to match subgroups using propensity scoring. Outcome measures included postoperative and long-term results. RESULTS: Overall, 1428 procedures were analysed; 586 procedures were performed with ESSQS-qualified surgeons and 842 were done by ESSQS-unqualified surgeons. Upon matching, two cohorts of 426 patients were selected for comparison of short-term results. A prevalence of rectal resection (50·3 versus 40·5 per cent; P < 0·001) and shorter duration of surgery (230 versus 238 min; P = 0·045) was reported for the ESSQS group. Intraoperative and postoperative complication and reoperation rates were significantly lower in the ESSQS group than in the non-ESSQS group (1·2 versus 3·6 per cent, P = 0·014; 4·6 versus 7·5 per cent, P = 0·025; 1·9 versus 3·9 per cent, P = 0·023, respectively). These findings were confirmed after propensity score matching. Cox regression analysis found that non-attendance of ESSQS-qualified surgeons (hazard ratio 12·30, 95 per cent c.i. 1·28 to 119·10; P = 0·038) was independently associated with local recurrence in patients with stage II disease. CONCLUSION: Laparoscopic colorectal procedures performed with ESSQS-qualified surgeons showed improved postoperative results. Further studies are needed to investigate the impact of the qualification on long-term oncological outcomes.

ANTECEDENTES: El Sistema de Certificación de Habilidades Quirúrgicas Endoscópicas (Endoscopic Surgical Skill Qualification System, ESSQS) fue introducido en Japón para mejorar la calidad de la cirugía laparoscópica. En este estudio de cohortes se investigaron los resultados postoperatorios a corto y a largo plazo de las intervenciones laparoscópicas de cáncer colorrectal realizadas por o con la asistencia de cirujanos con certificación en comparación con cirujanos no certificados. MÉTODOS: Todas las resecciones colorrectales laparoscópicas realizadas entre 2010 y 2013 en 11 hospitales japoneses fueron revisadas retrospectivamente. Los procedimientos se clasificaron en función de si habían sido realizados por cirujanos con o sin certificación del ESSQS, y las características clínicas, patológicas y quirúrgicas de los pacientes se utilizaron para emparejar los subgrupos mediante puntuaciones de propensión. Las variables de resultado incluyeron los resultados postoperatorios y a largo plazo RESULTADOS: En total se analizaron 1.428 procedimientos, incluyendo 586 y 842 procedimientos realizados con y sin cirujanos certificados por ESSQS, respectivamente. Tras el emparejamiento, se seleccionaron dos cohortes de 426 pacientes para la comparación de resultados a corto plazo. Se observó una mayor prevalencia de resecciones rectales (50,3% versus 40,1%, P = 0,0001) y un tiempo quirúrgico más corto (230 versus 238 min, P = 0,04) en el grupo ESSQS. Las tasas de complicaciones intra- y postoperatorias y de reoperaciones fueron significativamente más bajas en el grupo ESSQS que en el grupo no ESSQS (1,2%, 4,6% y 1,9% versus 3,6%, 7,5% y 3,9%, P = 0,01; 0,03, y 0,02, respectivamente). Estos hallazgos se confirmaron tras el análisis de emparejamiento por puntaje de propensión. El análisis de regresión de Cox mostró que la no participación de cirujanos certificados con ESSQS (razón de oportunidades, odds ratio, OR 12,3; i.c. del 95%, 1,28-119,1; P = 0,03) se asoció independientemente con la recidiva local en los casos en estadio II. CONCLUSIÓN: Los procedimientos colorrectales laparoscópicos realizados por cirujanos certificados por ESSQS presentaron mejores resultados postoperatorios. Son necesarios más estudios para determinar el impacto de la certificación en los resultados oncológicos a largo plazo.

Safety and efficacy of PD-1/PD-L1 blockade in patients with preexisting antinuclear antibodies.

PURPOSE: Immune checkpoint inhibitors (ICIs) show promising clinical activity in advanced cancers. However, the safety and efficacy of PD-1/PD-L1 blockade in patients with preexisting antinuclear antibodies (ANA) are unclear. METHODS: 191 patients treated with nivolumab, pembrolizumab, atezolizumab, or durvalumab for unresectable advanced cancers between September 2014 and December 2018 were identified retrospectively. Patients were divided into positive (ANA titers ≥ 1:160) and negative ANA groups (ANA titers < 1:160). Development of immune-related adverse events (irAEs), the overall response rate (ORR), and disease control rate (DCR) were monitored. RESULTS: Positive ANA titers were seen in 9 out of 191 patients. Four patients in the positive ANA group and 69 patients in the negative group developed irAEs of any grade without a significant difference between the groups. The development of endocrine, pulmonary, and cutaneous irAEs was not significant, whereas positive ANA was significantly higher in patients who developed colitis (2/9) than in patients who did not (3/182, P = 0.0002). DCR in the positive and negative ANA group was 37.5% and 67.5%, respectively, and was not statistically significant, but had better efficacy in patients without ANA (P = 0.08). ANA-related autoimmune diseases such as SLE, Sjögren's syndrome, MCTD, scleroderma, dermatomyositis, and polymyositis was not induced in either group. However, one patient with preexisting dermatomyositis had a flare up after initiation of atezolizumab. CONCLUSION: Further studies to identify predictive factors for the development of irAEs are required to provide relevant patient care and maximize the therapeutic benefits of ICIs.

Usefulness of real-time elastography for diagnosing lymph node metastasis of skin cancer: does elastography potentially eliminate the need for sentinel lymph node biopsy in squamous cell carcinoma?

BACKGROUND: The metastatic involvement of regional lymph nodes is the most important prognostic factor for overall survival of skin cancer patients. The sonographic technique of freehand real-time tissue elastography (RTE), which displays tissue rigidity as a colour overlay of the tissue image, was developed. OBJECTIVE: Our purpose was to evaluate the benefit of RTE for detecting lymph node metastases of skin cancer non-invasively before operation. METHODS: We first selected lymph nodes of skin cancer patients which had already been diagnosed by biopsy as being reactive or metastatic, and then retrospectively collected images of RTE and B-mode and colour Doppler ultrasound on those lymph nodes performed preoperatively. Twenty-one lymph nodes from 12 patients with squamous cell carcinoma (SCC), 23 lymph nodes from 14 patients with malignant melanoma (MM) and 14 lymph nodes from six patients with extramammary Paget disease (Paget) were investigated. Elastographic images were assessed on a scale of one to four according to the percentage of high elasticity (hard) area (HEA) in the lymph node. RESULTS: In all three skin cancers, lymph nodes evaluated as grade 3 or 4 by RTE were metastatic. All lymph nodes evaluated as grade 1 or 2 by RTE were reactive in SCC, whereas some lymph nodes evaluated as grade 1 or 2 were metastatic in MM and Paget. CONCLUSION: Real-time tissue elastography may aid in distinguishing reactive lymph nodes from metastatic ones especially in SCC.

Evaluation of screening for drug use using postmortem prolactin levels in serum and cerebrospinal fluid.

Prolactin (PRL) levels can usually be controlled by PRL-inhibiting psychiatric drugs that include anti-dopamine agents. However, the use of dopamine (DA) antagonists may lead to hyperprolactinemia under certain clinical conditions. The aim of this study was to investigate postmortem PRL levels as potential markers of drug abuse, especially that of DA antagonists, in autopsy cases. We examined 121 autopsy cases, excluding cases involving acute hypoxia/ischemia, such as asphyxia, because PRL concentrations are reportedly increased under acute hypoxic conditions. Detected drugs were classified as either DA antagonists, stimulants, psychotropic drugs other than DA antagonists, or other non-psychotropic drugs, and many cases had no detected drugs. Samples comprised blood collected from the right heart chamber and cerebrospinal fluid (CSF). PRL protein level was measured by chemiluminescent immunoassay, and PRL gene expression in the anterior pituitary of autopsy cases was analyzed by reverse transcription-polymerase chain reaction. The PRL-positive cell ratio in the anterior pituitary gland was also measured by immunohistochemical analysis. The results indicated that PRL levels in the serum and CSF were higher in DA antagonist cases than in other cases. PRL levels in the serum and CSF also correlated with the PRL gene expression in cases with abuse of DA antagonists. However, no significant difference in the PRL-positive cell ratio in the anterior pituitary gland was evident between any of the classes of drug-detected and drug-undetected cases. These results suggest that postmortem measurements of PRL transcription levels may be useful for diagnosing cases of DA antagonist use.

REDUCTION IN AMBIENT GAMMA DOSE RATE FROM RADIOCESIUM DUE TO SNOW COVER.

In the present study, variations in ambient gamma dose rate associated with snow cover were examined in a radioactive-contaminated site in Fukushima Prefecture, Japan. The ambient gamma dose rates decreased with increasing snow depth. The reduction trends were different between fresh snow (0.1-0.2 g/cm3) and granular snow (0.3-0.4 g/cm3) depending on snow density. Snow cover water content (snow water equivalent) calculated from snow depth and density was a key parameter governing the reduction in the ambient gamma dose rate. The ambient gamma dose rates reduced to 0.6 and 0.5 at 4 g/cm2 and 8 g/cm2 of snow water equivalent, respectively. Based on gamma-ray flux density distributions, the ambient gamma dose rates from the primary gamma rays decreased more compared to those from scattered gamma rays due to snow cover.