Trastuzumab deruxtecan in previously treated patients with HER2-positive metastatic breast cancer: updated survival results from a phase II trial (DESTINY-Breast01).

BACKGROUND: Primary analysis of the multicenter, open-label, single-arm, phase II DESTINY-Breast01 trial (median follow-up 11.1 months) demonstrated durable antitumor activity with trastuzumab deruxtecan (T-DXd) in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (mBC) previously treated with trastuzumab emtansine (T-DM1). We report updated cumulative survival outcomes with a median follow-up of 26.5 months (data cut-off 26 March 2021). PATIENTS AND METHODS: Patients with HER2-positive mBC resistant or refractory to T-DM1 received T-DXd 5.4 mg/kg intravenously every 3 weeks until disease progression, unacceptable adverse events, or withdrawal of consent. The primary endpoint was confirmed objective response rate (ORR) by independent central review (ICR). Secondary endpoints included overall survival (OS), duration of response (DoR), progression-free survival (PFS), and safety. RESULTS: The ORR by ICR was 62.0% [95% confidence interval (CI) 54.5% to 69.0%] in patients who received T-DXd 5.4 mg/kg every 3 weeks (n = 184). Median OS was 29.1 months (95% CI 24.6-36.1 months). Median PFS and DoR were 19.4 months (95% CI 14.1-25.0 months) and 18.2 months (95% CI 15.0 months-not evaluable), respectively. Drug-related treatment-emergent adverse events (TEAEs) were observed in 183 patients (99.5%), and 99 patients (53.8%) had one or more grade ≥3 TEAEs. Adjudicated drug-related interstitial lung disease/pneumonitis occurred in 15.8% of patients (n = 29), of which 2.7% (n = 5) were grade 5. CONCLUSIONS: These updated results provide further evidence of sustained antitumor activity of T-DXd with a consistent safety profile in heavily pretreated patients with HER2-positive mBC.

Abemaciclib plus a nonsteroidal aromatase inhibitor as initial therapy for HR+, HER2- advanced breast cancer: final overall survival results of MONARCH 3.

BACKGROUND: In MONARCH 2, the addition of abemaciclib to fulvestrant significantly improved both progression-free survival (PFS) and overall survival (OS) in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) with disease progression on prior endocrine therapy. In MONARCH 3, the addition of abemaciclib to a nonsteroidal aromatase inhibitor (NSAI) as initial therapy for HR+, HER2- ABC significantly improved PFS. Here, we present the prespecified final OS results for MONARCH 3. PATIENTS AND METHODS: MONARCH 3 is a randomized, double-blind, phase III study of abemaciclib plus NSAI (anastrozole or letrozole) versus placebo plus NSAI in postmenopausal women with HR+, HER2- ABC without prior systemic therapy in the advanced setting. The primary objective was investigator-assessed PFS; OS was a gated secondary endpoint, and chemotherapy-free survival was an exploratory endpoint. RESULTS: A total of 493 women were randomized 2 : 1 to receive abemaciclib plus NSAI (n = 328) or placebo plus NSAI (n = 165). After a median follow-up of 8.1 years, there were 198 OS events (60.4%) in the abemaciclib arm and 116 (70.3%) in the placebo arm (hazard ratio, 0.804; 95% confidence interval 0.637-1.015; P = 0.0664, non-significant). Median OS was 66.8 versus 53.7 months for abemaciclib versus placebo. In the subgroup with visceral disease, there were 113 OS events (65.3%) in the abemaciclib arm and 65 (72.2%) in the placebo arm (hazard ratio, 0.758; 95% confidence interval 0.558-1.030; P = 0.0757, non-significant). Median OS was 63.7 months versus 48.8 months for abemaciclib versus placebo. The previously demonstrated PFS benefit was sustained, and chemotherapy-free survival numerically improved with the addition of abemaciclib. No new safety signals were observed. CONCLUSIONS: Abemaciclib combined with an NSAI resulted in clinically meaningful improvement in median OS (intent-to-treat population: 13.1 months; subgroup with visceral disease: 14.9 months) in patients with HR+ HER2- ABC; however, statistical significance was not reached.

Diagnosis of ultrafast surface dynamics of thin foil targets irradiated by intense laser pulses.

The temporal modulation of an electron bunch train accelerated from a foil target irradiated by an intense laser pulse is studied by measuring the coherent transition radiation (CTR) from the rear surface of a target. We experimentally obtained CTR spectra from a 1 µm thick foil target irradiated at a maximum intensity of 6.5 × 1019 W/cm2. Spectral redshifts of the emitted radiation corresponding to increases in laser intensity were observed. These measurements were compared with the theoretical calculation of CTR spectra considering ultrafast surface dynamics, such as plasma surface oscillation and relativistically induced transparency. Plasma surface oscillations induce a spectral redshift, while relativistic transparency causes a spectral blueshift. Both effects are required to find reasonable agreement with the experiment over the entire range of laser intensities.

Long-term efficacy and safety of addition of carboplatin with or without veliparib to standard neoadjuvant chemotherapy in triple-negative breast cancer: 4-year follow-up data from BrighTNess, a randomized phase III trial.

BACKGROUND: Primary analyses of the phase III BrighTNess trial showed addition of carboplatin with/without veliparib to neoadjuvant chemotherapy significantly improved pathological complete response (pCR) rates with manageable acute toxicity in patients with triple-negative breast cancer (TNBC). Here, we report 4.5-year follow-up data from the trial. PATIENTS AND METHODS: Women with untreated stage II-III TNBC were randomized (2 : 1 : 1) to paclitaxel (weekly for 12 doses) plus: (i) carboplatin (every 3 weeks for four cycles) plus veliparib (twice daily); (ii) carboplatin plus veliparib placebo; or (iii) carboplatin placebo plus veliparib placebo. All patients then received doxorubicin and cyclophosphamide every 2-3 weeks for four cycles. The primary endpoint was pCR. Secondary endpoints included event-free survival (EFS), overall survival (OS), and safety. Since the co-primary endpoint of increased pCR with carboplatin plus veliparib with paclitaxel versus carboplatin with paclitaxel was not met, secondary analyses are descriptive. RESULTS: Of 634 patients, 316 were randomized to carboplatin plus veliparib with paclitaxel, 160 to carboplatin with paclitaxel, and 158 to paclitaxel. With median follow-up of 4.5 years, the hazard ratio for EFS for carboplatin plus veliparib with paclitaxel versus paclitaxel was 0.63 [95% confidence interval (CI) 0.43-0.92, P = 0.02], but 1.12 (95% CI 0.72-1.72, P = 0.62) for carboplatin plus veliparib with paclitaxel versus carboplatin with paclitaxel. In post hoc analysis, the hazard ratio for EFS was 0.57 (95% CI 0.36-0.91, P = 0.02) for carboplatin with paclitaxel versus paclitaxel. OS did not differ significantly between treatment arms, nor did rates of myelodysplastic syndromes, acute myeloid leukemia, or other secondary malignancies. CONCLUSIONS: Improvement in pCR with the addition of carboplatin was associated with long-term EFS benefit with a manageable safety profile, and without increasing the risk of second malignancies, whereas adding veliparib did not impact EFS. These findings support the addition of carboplatin to weekly paclitaxel followed by doxorubicin and cyclophosphamide neoadjuvant chemotherapy for early-stage TNBC.

Machine learning to predict incident radiographic knee osteoarthritis over 8 Years using combined MR imaging features, demographics, and clinical factors: data from the Osteoarthritis Initiative.

OBJECTIVE: To develop a machine learning-based prediction model for incident radiographic osteoarthritis (OA) of the knee over 8 years using MRI-based cartilage biochemical composition and knee joint structure, demographics, and clinical predictors including muscle strength and symptoms. DESIGN: Individuals (n = 1,044) with baseline Kellgren Lawrence (KL) grade 0-1 in the right knee from the Osteoarthritis Initiative database were analyzed. 3T MRI at baseline was used to quantify knee cartilage T2, and Whole-Organ Magnetic Resonance Imaging Scores (WORMS) were obtained for cartilage, meniscus, and bone marrow. The outcome was set as true if a subject developed KL grade 2-4 OA in the right knee over 8 years (n = 183) and false if the subject remained at KL 0-1 over 8 years (n = 861). We developed and compared three models: Model 1: 112 predictors based on OA risk factors; Model 2: top ten predictors based on feature importance score from Model 1 and clinical relevance; Model 3: Model 2 without the imaging predictors. We compared the models using the area under the ROC curve derived from hold-out data. RESULTS: The 10-predictor model (Model 2, that includes cartilage and meniscus WORMS scores and cartilage T2) had a slightly lower AUC (0.772) compared to the model with 112 predictors (Model 1: AUC = 0.792, p = 0.739); and had a significantly higher AUC compared to the model without MR imaging predictors (Model 3, AUC = 0.669, p = 0.011). CONCLUSIONS: A 10-predictor model including MRI parameters coupled with demographics, symptoms, muscle, and physical activity scores provides good prediction of incident radiographic OA over 8 years.

A phase II randomized trial of cobimetinib plus chemotherapy, with or without atezolizumab, as first-line treatment for patients with locally advanced or metastatic triple-negative breast cancer (COLET): primary analysis.

BACKGROUND: Resistance to standard chemotherapy in metastatic triple-negative breast cancer (mTNBC) is associated with upregulation of the mitogen-activated protein kinase (MAPK) pathway. Cobimetinib, an MAPK/extracellular signal-regulated kinase (MEK) inhibitor, may increase sensitivity to taxanes and programmed death-ligand 1 inhibitors. COLET is a three-cohort phase II study evaluating first-line cobimetinib plus chemotherapy, with or without atezolizumab, in patients with locally advanced or mTNBC. PATIENTS AND METHODS: Patients were ≥18 years with locally advanced or mTNBC. Following a safety run-in, patients in cohort I were randomized 1:1 to cobimetinib (60 mg, D3-D23 of each 28-day cycle) or placebo, plus paclitaxel (80 mg/m2, D1, 8, and 15). Additional patients were randomized (1:1) to cohort II or III to receive cobimetinib plus atezolizumab (840 mg, D1 and D15) and either paclitaxel (cohort II) or nab-paclitaxel [cohort III (100 mg/m2, D1, D8, and D15)]. Primary endpoints were investigator-assessed progression-free survival (PFS) (cohort I) and confirmed objective response rate (ORR) (cohorts II/III). Safety and tolerability were also assessed. RESULTS: In the expansion stages, median PFS was 5.5 months for cobimetinib/paclitaxel versus 3.8 months for placebo/paclitaxel in cohort I [hazard ratio 0.73; 95% confidence interval (CI) 0.43-1.24; P = 0.25]. In cohort I, ORR was 38.3% (95% CI 24.40-52.20) for cobimetinib/paclitaxel and 20.9% (95% CI 8.77-33.09) for placebo/paclitaxel; ORRs in cohorts II and III were 34.4% (95% CI 18.57-53.19) and 29.0% (95% CI 14.22-48.04), respectively. Diarrhea was the most common grade ≥3 adverse events across all cohorts. CONCLUSIONS: Cobimetinib added to paclitaxel did not lead to a statistically significant increase in PFS or ORR, although a nonsignificant trend toward a numerical increase was observed. Cobimetinib plus atezolizumab and a taxane did not appear to increase ORR. This demonstrates the potential activity of a combinatorial MEK inhibitor, chemotherapy, and immunotherapy in this difficult-to-treat population.

Adjuvant abemaciclib combined with endocrine therapy for high-risk early breast cancer: updated efficacy and Ki-67 analysis from the monarchE study.

BACKGROUND: Adjuvant abemaciclib combined with endocrine therapy (ET) previously demonstrated clinically meaningful improvement in invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) in hormone receptor-positive, human epidermal growth factor receptor 2-negative, node-positive, high-risk early breast cancer at the second interim analysis, however follow-up was limited. Here, we present results of the prespecified primary outcome analysis and an additional follow-up analysis. PATIENTS AND METHODS: This global, phase III, open-label trial randomized (1 : 1) 5637 patients to adjuvant ET for ≥5 years ± abemaciclib for 2 years. Cohort 1 enrolled patients with ≥4 positive axillary lymph nodes (ALNs), or 1-3 positive ALNs and either grade 3 disease or tumor ≥5 cm. Cohort 2 enrolled patients with 1-3 positive ALNs and centrally determined high Ki-67 index (≥20%). The primary endpoint was IDFS in the intent-to-treat population (cohorts 1 and 2). Secondary endpoints were IDFS in patients with high Ki-67, DRFS, overall survival, and safety. RESULTS: At the primary outcome analysis, with 19 months median follow-up time, abemaciclib + ET resulted in a 29% reduction in the risk of developing an IDFS event [hazard ratio (HR) = 0.71, 95% confidence interval (CI) 0.58-0.87; nominal P = 0.0009]. At the additional follow-up analysis, with 27 months median follow-up and 90% of patients off treatment, IDFS (HR = 0.70, 95% CI 0.59-0.82; nominal P < 0.0001) and DRFS (HR = 0.69, 95% CI 0.57-0.83; nominal P < 0.0001) benefit was maintained. The absolute improvements in 3-year IDFS and DRFS rates were 5.4% and 4.2%, respectively. Whereas Ki-67 index was prognostic, abemaciclib benefit was consistent regardless of Ki-67 index. Safety data were consistent with the known abemaciclib risk profile. CONCLUSION: Abemaciclib + ET significantly improved IDFS in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative, node-positive, high-risk early breast cancer, with an acceptable safety profile. Ki-67 index was prognostic, but abemaciclib benefit was observed regardless of Ki-67 index. Overall, the robust treatment benefit of abemaciclib extended beyond the 2-year treatment period.

Pembrolizumab plus chemotherapy as neoadjuvant treatment of high-risk, early-stage triple-negative breast cancer: results from the phase 1b open-label, multicohort KEYNOTE-173 study.

BACKGROUND: The phase Ib KEYNOTE-173 study was conducted to assess the safety and preliminary antitumor activity of neoadjuvant chemotherapy plus pembrolizumab in high-risk, early-stage, non-metastatic triple-negative breast cancer (TNBC). PATIENTS AND METHODS: Six pembrolizumab plus chemotherapy regimens were evaluated (cohorts A-F). All cohorts received a pembrolizumab 200-mg run-in dose (cycle 1), then eight cycles of pembrolizumab in combination with a taxane with or without carboplatin for 12 weeks, and then doxorubicin and cyclophosphamide for an additional 12 weeks before surgery. Primary end points were safety and recommended phase II dose (RP2D); secondary end points were pathological complete response (pCR) rate, objective response rate, and event-free and overall survival. Exploratory end points were the relationship between outcome and potential biomarkers, such as tumor programmed death ligand 1 (PD-L1) expression (combined positive score) and stromal tumor-infiltrating lymphocyte levels (sTILs). RESULTS: Sixty patients were enrolled between 18 February 2016, and 28 February 2017. Dose-limiting toxicities occurred in 22 patients, most commonly febrile neutropenia (n = 10 across cohorts). Four cohorts (B, C, D, F) did not meet the RP2D threshold; two cohorts did (A, E). The most common grade ≥3 treatment-related adverse event was neutropenia (73%). Immune-mediated adverse events and infusion reactions occurred in 18 patients (30%) and were grade ≥3 in six patients (10%). The pCR rate (ypT0/Tis ypN0) across all cohorts was 60% (range 49%-71%). Twelve-month event-free and overall survival rates ranged from 80% to 100% across cohorts (100% for four cohorts). Higher pre-treatment PD-L1 combined positive score, and pre- and on-treatment sTILs were significantly associated with higher pCR rates (P = 0.0127, 0.0059, and 0.0085, respectively). CONCLUSION: Combination neoadjuvant chemotherapy and pembrolizumab for high-risk, early-stage TNBC showed manageable toxicity and promising antitumor activity. In an exploratory analysis, the pCR rate showed a positive correlation with tumor PD-L1 expression and sTIL levels. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02622074.

Recurrence following hemithyroidectomy in patients with low- and intermediate-risk papillary thyroid carcinoma.

BACKGROUND: This study evaluated the incidence, patterns and risk factors for recurrence after hemithyroidectomy in patients with low- and intermediate-risk papillary thyroid carcinoma (PTC), and verified the predictive role of the risk staging systems in current use. METHODS: The clinicopathological characteristics and risk categories were analysed according to recurrence in patients who underwent hemithyroidectomy for low- and intermediate-risk conventional PTC, and were followed up for at least 24 months. Five risk staging systems were used to stratify risk: the 2015 American Thyroid Association (ATA) system; Age, Metastases, Extent and Size (AMES) system; Metastases, Age, Complete resection, Invasion and Size (MACIS) system; Grade, Age, Metastases, Extent and Size (GAMES) system; and the eighth AJCC system. RESULTS: The study included 561 patients; 93·9 per cent of the study population (527 of 561) had a papillary thyroid microcarcinoma 1 cm or smaller in size. At a mean follow-up of 83 months, 25 patients (4·5 per cent) had recurrence; among these patients, 23 (92%) presented with a remaining thyroid lobe. Multifocality was significantly associated with recurrence in univariable and multivariable analyses (adjusted hazard ratio 3·16, 95 per cent c.i. 1·25 to 7·98; P = 0·015). Disease-free survival (DFS) varied according to multifocality (P = 0·010). The five risk staging systems were not associated with recurrence, and their Harrell's C-index ranged from 0·500 to 0·531. DFS rates did not differ between the risk categories in each system. CONCLUSION: Although the recurrence rate after hemithyroidectomy in patients with low- and intermediate-risk PTC was low, meticulous follow-up focusing on the remaining thyroid lobe is needed for early detection and timely management of recurrence. The risk scoring systems in current use have no predictive role in these patients.

ANTECEDENTES: Este estudio evaluó la incidencia, patrones y factores de riesgo de recidiva tras hemitiroidectomía en pacientes con carcinoma papilar de tiroides (papillary thyroid carcinoma, PTC) de riesgo bajo e intermedio y verificó el papel predictivo de los sistemas de estadificación del riesgo utilizados en la actualidad (risk staging systems, RSSs). MÉTODOS: Se analizaron las características clinicopatológicas y las categorías de riesgo en base a la recidiva en 561 pacientes que fueron sometidos a hemitiroidectomía por PTC convencional de riesgo bajo e intermedio y seguidos durante ≥ 24 meses. Para estratificar el riesgo se utilizaron cinco RSSs, incluyendo el sistema de la American Thyroid Association (ATA) de 2015; la edad, las metástasis, la extensión y el tamaño del sistema AMES; las metástasis, la edad, la resección completa, la invasión y el tamaño del sistema GAMES; y la octava edición de la American Joint Committee on Cancer system (AJCC). RESULTADOS: La proporción de la población de estudio con microcarcinoma papilar de tiroides de tamaño ≤ 1 cm fue 93,9% (527/561). A los 83 meses de seguimiento, 25 pacientes (4,5%) presentaron recidiva y entre estos pacientes, 23 (92%) no habían sido sometidos a tiroidectomía total. La multifocalidad se asoció significativamente con la recidiva en los análisis univariado y multivariable con un cociente de riesgos instantáneos (hazard ratio, HR) ajustado de 3,163; i.c. del 95% 1,253-7,983; P = 0,015. La supervivencia libre de enfermedad (disease-free survival, DFS) varió según la multifocalidad (P = 0,010). Los cinco RSSs no se asociaron con la recidiva, y su índice C de Harrell fue 0,500-0,531. Las DFSs no fueron diferentes entre las categorías de riesgo de cada RSS. CONCLUSIÓN: La tasa de recidiva tras hemitiroidectomía en pacientes con PTC de riesgo bajo e intermedio fue baja. Sin embargo, es necesario efectuar un seguimiento meticuloso, centrándose en el lóbulo tiroideo restante, para la detección precoz y el tratamiento oportuno de la recidiva. Los RSSs que se utilizan en la actualidad no tienen valor predictivo en estos pacientes.

Calcium dosage in the lipid emulsion used to treat verapamil toxicity.

No Abstract Keywords.

Environmental impacts of nanomaterials.

Nanotechnology is currently one of the highest priority research fields in many countries due to its immense potentiality and economic impact. Nanotechnology involves the research, development, production, and processing of structures and materials on a nanometer scale in various fields of science, technology, health care, industries, and agriculture. As such, it has contributed to the gradual restructuring of many associated technologies. However, due to the uncertainties and irregularities in shape, size, and chemical compositions, the presence of certain nanomaterials may exert adverse impacts on the environment as well as human health. Concerns have thus been raised about the destiny, transport, and transformation of nanoparticles released into the environment. A critical evaluation of the current states of knowledge regarding the exposure and effects of nanomaterials on the environment and human health is discussed in this review. Recognition on the potential advantages and unintended dangers of nanomaterials to the environment and human health is critically important to pursue their development in the future.

The effect of low-volatile organic compounds, water-based paint on aggravation of allergic disease in schoolchildren.

Whether indoor painting aggravates preexisting allergic diseases remains unclear. We aimed to evaluate the impact of new classroom painting on aggravation of asthma, allergic rhinitis (AR), and atopic dermatitis (AD) in children. Studied school was previously painted with conventional water-based paint 20 years ago and had natural ventilation system. We identified a total of 172 children aged 10-12 years with allergic diseases in 17 classrooms, which were allocated to newly painted rooms with low-volatile organic compounds (VOC), water-based paint, or existing rooms. After painting, there was no intervention or internal airflow to influence indoor air environment in both classrooms. We prospectively assessed the symptom severity and serious events of allergic diseases between both classrooms at baseline and after one and eight weeks after painting. At one and eight weeks, there were no significant changes in the Childhood Asthma Control Test scores, the fractional nitric oxide levels, lung function in asthmatic children in either classroom. There were also no significant changes in the severity score of AR or AD, or serious events in all allergic diseases. These findings suggest classroom painting with this new paint at the levels encountered in this study might not be a major aggravating factor for school-aged children with allergic diseases.

Diagnostic assessment of intraoperative cytology for papillary thyroid carcinoma: using a decision tree analysis.

PURPOSE: The aim of this study was to elucidate the cytological characteristics and the diagnostic usefulness of intraoperative cytology (IOC) for papillary thyroid carcinoma (PTC). In addition, using decision tree analysis, effective features for accurate cytological diagnosis were sought. METHODS: We investigated cellularity, cytological features and diagnosis based on the Bethesda System for Reporting Thyroid Cytopathology in IOC of 240 conventional PTCs. The cytological features were evaluated in terms of nuclear score with nuclear features, and additional figures such as presence of swirling sheets, psammoma bodies, and multinucleated giant cells. The nuclear score (range 0-7) was made via seven nuclear features, including (1) enlarged, (2) oval or irregularly shaped nuclei, (3) longitudinal nuclear grooves, (4) intranuclear cytoplasmic pseudoinclusion, (5) pale nuclei with powdery chromatin, (6) nuclear membrane thickening, and (7) marginally placed micronucleoli. RESULTS: Nuclear scores in PTC, suspicious for malignancy, and atypia of undetermined significance cases were 6.18 ± 0.80, 4.48 ± 0.82, and 3.15 ± 0.67, respectively. Additional figures more frequent in PTC than in other diagnostic categories were identified. Cellularity of IOC significantly correlated with tumor size, nuclear score, and presence of additional figures. Also, IOCs with higher nuclear scores (4-7) significantly correlated with larger tumor size and presence of additional figures. In decision tree analysis, IOCs with nuclear score >5 and swirling sheets could be considered diagnostic for PTCs. CONCLUSIONS: Our study suggests that IOCs using nuclear features and additional figures could be useful with decreasing the likelihood of inconclusive results.

Overall accuracy of cervical cytology and clinicopathological significance of LSIL cells in ASC-H cytology.

OBJECTIVE: The aims of this study were (i) to investigate the diagnostic accuracy of Papanicolaou (Pap) smears and (ii) to evaluate the clinicopathological significance of the presence of low-grade squamous intraepithelial lesion (LSIL) cells in atypical squamous cells cannot exclude high-grade squamous intraepithelial lesion (HSIL) (ASC-H) cytology. METHODS: We retrospectively reviewed paired cytological and histological findings from 3141 patients. ASC-H cytology was classified as either ASC-H or LSIL with some features suggestive of the presence of a concurrent HSIL (LSIL-H). Clinicopathological characteristics were evaluated through a retrospective study and meta-analysis. RESULTS: The accuracy of the cytological diagnosis was 93.7% (2942 of 3141 cases). The positive predictive value (PPV) of ASC-H for cervical intraepithelial neoplasia grade 2 or worse (CIN 2+ ) was 51.4%. In cases of LSIL-H, CIN 2+ histology was more prevalent in the pre-menopausal period (19-44 years) than in peri- and postmenopausal periods (older than 45 years) (P = 0.024). There was no difference in the ability of LSIL-H and ASC-H to predict CIN 2+. CONCLUSION: The Pap smear is a good cervical cancer screening method. Although there was no difference in the predictive value for CIN 2+ between LSIL-H and ASC-H, the presence of definite LSIL cells was more predictive of CIN 2+ in younger patients than in older patients.

Enhanced risk of illness during the 1918 influenza pandemic after previous influenza-like illnesses in three military populations.

The reasons for the unprecedented mortality during the 1918 influenza pandemic remain poorly understood. We examined morbidity records from three military cohorts from years prior to and during the 1918 pandemic period to assess the effects of previous respiratory illnesses on experiences during the pandemic. Clinical registers and morbidity lists were examined to identify all medical encounters for acute respiratory illnesses in students at two U.S. military officer training academies and Australian soldiers deployed in Europe. Influenza-like illness prior to the major pandemic wave of 1918 predisposed Australian soldiers [relative risk (RR) 1·37, 95% confidence interval (CI) 1·18-1·60, P < 0·0001] and US officer trainees at West Point (RR 3·10, 95% CI 2·13-4·52, P < 0·0001) and Annapolis (RR 2·03, 95% CI 1·65-2·50, P < 0·0001) to increased risks of medically treated illnesses in late 1918. The findings suggest that susceptibility to and/or clinical expressions of the 1918 pandemic influenza virus depended on previous experiences with respiratory infectious agents. The findings are consistent with observations during the 2009 pandemic in Canada and may reflect antibody-dependent enhancement of influenza infection.

The TLR4-associated phospholipase D1 activation is crucial for Der f 2-induced IL-13 production.

BACKGROUND: House dust mites (HDMs) are the most important source of indoor aeroallergens that contribute to the rising incidence of allergic diseases such as allergic asthma. The major HDM, Der f 2, induces inflammatory cytokine expression. Little is known about the signaling pathway involved. OBJECTIVE: We wanted to define the Der f 2 signaling pathway from its receptor to the transcription factor responsible for IL-13 expression and production. METHODS: Human bronchial epithelial cells were stimulated with Der f 2. The release and gene expression of IL-13 were measured by means of ELISA and RT-PCR, respectively. In the airway inflammation mouse model, airway responses were assessed using ELISA, histology, BAL fluid, and methacholine responsiveness. RESULTS: Here, we show that Der f 2 binds to TLR4 and induces IL-13 expression and production. In the airway inflammation mouse model, Der f 2-induced IL-13 production significantly decreased with treatment of TAK-242, a novel TLR4 inhibitor. Activation of TLR4 by Der f 2 requires the recruitment and activation of Syk, which leads to phosphorylation of PLCγ and membrane translocation of PKCα. p38 MAPK is then activated by PKCα and stimulates PLD1 activity by phosphorylating the Thr147 residue of PLD1. PLD1 activation enhanced binding of ROCK1 to ATF-2 and leads to increased expression of IL-13. CONCLUSION: Our data extend the knowledge for a variety of possible roles of PLD1 in allergic disorders including asthma pathogenesis and suggest possible candidacy of PLD1 as a molecular target for novel therapeutic approaches.

Clinical impact of microscopic extrathyroidal extension in patients with papillary thyroid microcarcinoma treated with hemithyroidectomy.

BACKGROUND: Pathologically confirmed microscopic extrathyroidal extension (ETE) is often identified after hemithyroidectomy in patients with papillary thyroid microcarcinoma (PTMC). Without the presence of microscopic ETE, these patients would be optimal candidates for hemithyroidectomy. AIM: The present study aimed at evaluating the clinical impact of microscopic ETE on the recurrence of PTMC treated with hemithyroidectomy. SUBJECTS AND METHODS: We compared the clinicopathological characteristics and 5-year outcomes for 262 PTMC patients without ETE and 86 with microscopic ETE who were treated with hemithyroidectomy between January 2004 and December 2010. RESULTS: The mean tumour size was larger (0.67 vs. 0.54 cm, p < 0.001) and the proportion of tumours measuring ≥0.5 cm was higher (84.9 vs. 66.8 %, p = 0.001) in patients with microscopic ETE as compared with patients without ETE. Occult multifocal disease was more frequent in patients with microscopic ETE than in those without ETE (14.0 vs. 6.5 %, p = 0.030). However, the recurrence rate was not different between the two groups during the mean 55.8-month follow-up period. In addition, univariate and multivariate analyses revealed no meaningful association between recurrence and microscopic ETE in patients with PTMC treated with hemithyroidectomy. CONCLUSIONS: Although microscopic ETE was associated with large tumour size and multifocal disease, its clinical impact on disease recurrence was not significant in PTMC patients treated with hemithyroidectomy. Therefore, microscopic ETE identified after hemithyroidectomy would not be an absolute indication for completion thyroidectomy in patients with PTMC.

Extraocular muscle injury during endoscopic sinus surgery: a series of 10 cases at a single center.

BACKGROUND: Extraocular muscle (EOM) injury is a rare but serious complication of endoscopic sinus surgery (ESS). The aim of this study is to describe the clinical characteristics and course of EOM injury occurring during ESS. DESIGN: Retrospective case series. METHODS: Medical records and CT images of patients who suffered from EOM injury after ESS between 2006 and 2012 were retrospectively reviewed. Patient demographics, endoscopic anatomy, type of surgery (primary or revision), predisposing risk factors, site and extent of injury on CT imaging, and associated complications were evaluated. In addition, data regarding ophthalmologic management and clinical outcomes were collected. RESULTS: Ten patients with EOM injuries after ESS were included in this study. One patient was undergoing revision ESS. All patients sustained medial rectus muscle injury and one patient suffered concurrent ipsilateral inferior rectus muscle injury. A microdebrider was used in nine cases. Right-sided injury (90% of patients) was more prevalent than left-sided injury, and 70% of injured medial rectus muscles were completely transected. After subsequent strabismus surgery, 8/9 patients regained binocular single vision in primary gaze despite residual diplopia in some gaze positions. CONCLUSION: Although proper ophthalmologic surgery after EOM injury may improve deviation in the primary gaze position, none of the patients regained normal EOM movement. Therefore, prevention of this complication through adequate surgical technique and precautions is important.