When is a pathology review indicated in endometrial cancer?

OBJECTIVE: Discrepancies may exist between an original pathology report and formal pathology review, with subsequent implications for treatment. We conducted a study of pathology review in endometrial cancer from a population-based study to identify areas of discrepancy and effect on treatment. METHODS: This was a retrospective cohort study in Ontario, Canada from 1996 to 2000. We identified hysterectomy cases from patients with endometrial cancer that were subject to formal pathology review by a gynecologic pathologist at one of six tertiary care centers. Sarcomas and other rare histologic subtypes with fewer than five cases were excluded. We evaluated discrepancy between original pathology and review by demographics, stage, grade, and risk group. Four risk groups were defined: 1) low (stage I), 2) intermediate (stage I and II), 3) high-risk (stage I and II), and 4) advanced stage (all stage III and IV). Reclassification from one risk group to another upon pathology review represented a potential change in treatment. Factors associated with significant discrepancy were identified by a multivariable logistic regression model. RESULTS: Formal pathology review was available on 450 cases. There were no differences by age, year, or hospital type. The overall discrepancy rate was 42.7% (95% confidence interval 38.2-47.3%). The intermediate-risk group had the highest rate of reclassification into another group (33.1%). The most significant rates of discrepancy were associated with endometrioid grades 2 and 3 tumors and stage IIA disease (39.8%, 50.9%, and 79.6%, respectively). CONCLUSION: There was significant discrepancy between original pathology and formal review in endometrial cancer, with implications for guidelines on pathology review at a population level. LEVEL OF EVIDENCE: III     

Clinical impact of integrated PET/CT on the management of suspected cervical cancer recurrence

OBJECTIVES: To assess the value and clinical impact of integrated PET/CT using (18)F-FDG in the diagnosis and management of women with suspected cervical cancer recurrence. METHODS: Fifty-two patients with cervical cancer with suspected recurrence because of clinical, cytological, biochemical and radiological findings were retrospectively evaluated. A final diagnosis of recurrence was confirmed by histologic tissue biopsy or by further clinical or radiological evidence. The clinical impact of information provided by PET/CT on patient management was assessed on the basis of clinical follow-up data concerning further diagnostic or therapeutic approach. RESULTS: Twenty-eight of 32 positive PET/CT scans (87.5%) were proven to have recurrent disease. Seventeen of 20 negative PET/CT scans (85.0%) had no evidence of disease. The sensitivity, specificity, and accuracy of PET/CT for detecting recurrence were 90.3%, 81.0%, and 86.5% respectively. PET/CT changed the management of 12 patients (23.1%) by changing treatment plan (5 patients), by initiating unplanned treatment strategy (4 patients), or by obviating the need for planned diagnostic procedures (3 patients). Median duration after performing PET/CT and last follow-up was 12 (range: 6-27) months, and the 2-year disease-free survival rate of patients with negative PET/CT scan for recurrence was significantly better than that of patients with positive PET/CT (85.0% vs. 10.9%, P=0002). CONCLUSIONS: In patients with a suspected recurrence of cervical cancer, integrated PET/CT using (18)F-FDG provides good anatomic and functional localization of suspicious lesions, and the better diagnostic interpretation has an impact not only on clinical management and treatment planning of patients, but also on disease-free survival.     

Artificial Neural Network Modelling of the Effect of Vanadium Addition on the Tensile Properties and Microstructure of High-Strength Tempcore Rebars

In high-strength rebar, the various microstructures obtained by the Tempcore process and the addition of V have a complex effect on the strength improvement of rebar. This study investigated the mechanism of strengthening of high-strength Tempcore rebars upon the addition of vanadium through artificial neural network (ANN) modelling. Various V contents (0.005, 0.072 and 0.14 wt.%) were investigated, and a large amount of bainite and V(C, N) were precipitated in the core of the Tempcore rebar in the high-V specimens. In addition, as the V content increased, the number of these fine precipitates (10–30 nm) increased. The precipitation strengthening proposed by the Ashby–Orowan model is a major contributing factor to the yield-strength increase (35 MPa) of the Tempcore rebar containing 0.140 wt.% V. The ANN model was developed to predict the yield and tensile strengths of Tempcore rebar after the addition of various amounts of V and self-tempering at various temperatures, and it showed high reproducibility compared to the experimental values (R-square was 93% and the average relative error was 2.6%). ANN modelling revealed that the yield strength of the Tempcore rebar increased more significantly with increasing V content (0.01–0.2 wt.%.) at relatively high self-tempering temperatures (≥530 °C). These results provide guidelines for selecting the optimal V content and process conditions for manufacturing high-strength Tempcore rebars.     

Initial Abdominal CT and Laboratory Findings Prior to Diagnosis of Crohn’s Disease in Children

PurposeTo identify initial abdominal computed tomography (CT) and laboratory findings prior to a diagnosis of Crohn’s disease (CD) in children.Materials and MethodsIn this retrospective study, patients (≤18 year-old) who were diagnosed with CD from 2004 to 2019 and had abdominal CT just prior to being diagnosed with CD were included in the CD group. Patients (≤18 years old) who were diagnosed with infectious enterocolitis from 2018 to 2019 and had undergone CT prior to being diagnosed with enterocolitis were included as a control group. We assessed the diagnostic performances of initial CT and laboratory findings for the diagnosis of CD using logistic regression and the area under the curve (AUC).ResultsIn total, 107 patients (50 CD patients, 57 control patients) were included, without an age difference between groups (median 13 years old vs. 11 years old, p=0.119). On univariate logistic regression analysis, multisegmental bowel involvement, mesenteric vessel engorgement, higher portal vein/aorta diameter ratio, longer liver longitudinal diameter, lower hemoglobin (≤12.5 g/dL), lower albumin (≤4 g/dL), and higher platelet (>320×10³/µL) levels were significant factors for CD. On multivariate analysis, multisegmental bowel involvement [odds ratio (OR) 111.6, 95% confidence interval (CI) 4.778–2605.925] and lower albumin levels (OR 0.9, 95% CI 0.891–0.993) were significant factors. When these two features were combined, the AUC value was 0.985 with a sensitivity of 96% and specificity of 100% for differentiating CD.ConclusionMultisegmental bowel involvement on CT and decreased albumin levels can help differentiate CD from infectious enterocolitis in children prior to a definite diagnosis of CD.     

Effects of Interleukin-17A on the Early Stages of Arterial Thrombosis in Mice

PurposeInterleukin (IL)-17A has been suggested to play a role in the growth and organization of thrombi. We examined whether IL-17A plays a role in the early stages of thrombosis and whether there are sex differences in the effects of IL-17A.Materials and MethodsWe performed a blinded, randomized, placebo-controlled study to compare time to thrombotic occlusion and sex differences therein between mice treated with IL-17A and those treated with saline using a ferric chloride-induced model. We also assessed thrombus histology, blood coagulation, and plasma levels of coagulation factors.ResultsTime to occlusion values did not differ between the IL-17A group and the control group (94.6±86.9 sec vs. 121.0±84.4 sec, p=0.238). However, it was significantly shorter in the IL-17A group of female mice (74.6±57.2 sec vs. 130.0±76.2 sec, p=0.032). In rotational thromboelastometry, the IL-17A group exhibited increased maximum clot firmness (71.3±4.5 mm vs. 66.7±4.7 mm, p=0.038) and greater amplitude at 30 min (69.7±5.2 mm vs. 64.5±5.3 mm, p=0.040) than the control group. In Western blotting, the IL-17A group showed higher levels of coagulation factor XIII (2.2±1.5 vs. 1.0±0.9, p=0.008), monocyte chemoattractant protein-1 (1.6±0.6 vs. 1.0±0.4, p=0.023), and tissue factor (1.5±0.6 vs. 1.0±0.5, p=0.003).ConclusionIL-17A plays a role in the initial st ages of arterial thrombosis in mice. Coagulation factors and monocyte chemoattractant protein-1 may be associated with IL-17A-mediated thrombosis.     

Friction Properties of Solid Lubricants with Different Multiwalled Carbon Nanotube Contents

Bushes are circular bearings that surround a shaft and help it rotate smoothly. In heavy equipment, bushes are coated with solid lubricants to reduce friction. Although the coating layer of the lubricant has a stable coefficient of friction (CoF), it is important that this should last for a long time. In this study, multiwalled carbon nanotubes (MWCNTs), which have a low CoF, were added to the lubricant to improve its performance. When 2.3 wt% MWCNTs were added to the polymer resin, the dynamic CoF (under a 29 N external load) decreased by 78% in relation to that of the resin without MWCNTs. As the MWCNT content increased, the roughness of the coating decreased, which reduced the CoF. Moreover, MWCNT addition increased the overall tensile strength owing to an increase in the bonding force between the resins. Under a high load of 20 tonnes (t), the MWCNT-based solid lubricant had a CoF of 0.05, lower than commercial MoS₂-based solid lubricants; this was maintained for more than 10,000 cycles in a bush and shaft test. With the MWCNT-based solid lubricant, a lubricating polymer film formed, even on worn bush surfaces. The CoF of the solid lubricant was reduced and the number of cycles with a constant CoF increased when MWCNTs were added owing to the formation of the lubricating polymer film.     

Clinical Characteristics and Risk Factors for Mortality in Critical Coronavirus Disease 2019 Patients 50 Years of Age or Younger During the Delta Wave: Comparison With Patients > 50 Years in Korea

BackgroundNumerous patients around the globe are dying from coronavirus disease 2019 (COVID-19). While age is a known risk factor, risk analysis in the young generation is lacking. The present study aimed to evaluate the clinical features and mortality risk factors in younger patients (≤ 50 years) with a critical case of COVID-19 in comparison with those among older patients (> 50 years) in Korea.MethodsWe analyzed the data of adult patients only in critical condition (requiring high flow nasal cannula oxygen therapy or higher respiratory support) hospitalized with PCR-confirmed COVID-19 at 11 hospitals in Korea from July 1, 2021 to November 30, 2021 when the delta variant was a dominant strain. Patients’ electronic medical records were reviewed to identify clinical characteristics.ResultsDuring the study period, 448 patients were enrolled. One hundred and forty-two were aged 50 years or younger (the younger group), while 306 were above 50 years of age (the older group). The most common pre-existing conditions in the younger group were diabetes mellitus and hypertension, and 69.7% of the patients had a body mass index (BMI) > 25 kg/m². Of 142 younger patients, 31 of 142 patients (21.8%, 19 women) did not have these pre-existing conditions. The overall case fatality rate among severity cases was 21.0%, and it differed according to age: 5.6% (n = 8/142) in the younger group, 28.1% in the older group, and 38% in the ≥ 65 years group. Age (odds ratio [OR], 7.902; 95% confidence interval [CI], 2.754–18.181), mechanical ventilation therapy (OR, 17.233; 95% CI, 8.439–35.192), highest creatinine > 1.5 mg/dL (OR, 17.631; 95% CI, 8.321–37.357), and combined blood stream infection (OR, 7.092; 95% CI, 1.061–18.181) were identified as independent predictors of mortality in total patients. Similar patterns were observed in age-specific analyses, but most results were statistically insignificant in multivariate analysis due to the low number of deaths in the younger group. The full vaccination rate was very low among study population (13.6%), and only three patients were fully vaccinated, with none of the patients who died having been fully vaccinated in the younger group. Seven of eight patients who died had a pre-existing condition or were obese (BMI > 25 kg/m²), and the one remaining patient died from a secondary infection.ConclusionAbout 22% of the patients in the young critical group did not have an underlying disease or obesity, but the rate of obesity (BMI > 25 kg/m²) was high, with a fatality rate of 5.6%. The full vaccination rate was extremely low compared to the general population of the same age group, showing that non-vaccination has a grave impact on the progression of COVID-19 to a critical condition. The findings of this study highlight the need for measures to prevent critical progression of COVID-19, such as vaccinations and targeting young adults especially having risk factors.     

Dromedary camel nanobodies broadly neutralize SARS-CoV-2 variants

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike is a trimer of S1/S2 heterodimers with three receptor-binding domains (RBDs) at the S1 subunit for human angiotensin-converting enzyme 2 (hACE2). Due to their small size, nanobodies can recognize protein cavities that are not accessible to conventional antibodies. To isolate high-affinity nanobodies, large libraries with great diversity are highly desirable. Dromedary camels (Camelus dromedarius) are natural reservoirs of coronaviruses like Middle East respiratory syndrome CoV (MERS-CoV) that are transmitted to humans. Here, we built large dromedary camel V_HH phage libraries to isolate nanobodies that broadly neutralize SARS-CoV-2 variants. We isolated two V_HH nanobodies, NCI-CoV-7A3 (7A3) and NCI-CoV-8A2 (8A2), which have a high affinity for the RBD via targeting nonoverlapping epitopes and show broad neutralization activity against SARS-CoV-2 and its emerging variants of concern. Cryoelectron microscopy (cryo-EM) complex structures revealed that 8A2 binds the RBD in its up mode with a long CDR3 loop directly involved in the ACE2 binding residues and that 7A3 targets a deeply buried region that uniquely extends from the S1 subunit to the apex of the S2 subunit regardless of the conformational state of the RBD. At a dose of ≥5 mg/kg, 7A3 efficiently protected transgenic mice expressing hACE2 from the lethal challenge of variants B.1.351 or B.1.617.2, suggesting its therapeutic use against COVID-19 variants. The dromedary camel V_HH phage libraries could be helpful as a unique platform ready for quickly isolating potent nanobodies against future emerging viruses.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiologic agent of COVID-19 (1, 2) that enters human cells by binding its envelope anchored type I fusion protein (spike) to angiotensin-converting enzyme 2 (ACE2) (3, 4). The SARS-CoV-2 spike is a trimer of S1/S2 heterodimers with three ACE2 receptor-binding domains (RBDs) attached to the distal end of the spike via a hinge region that allows conformational flexibility (4). In the all-down conformation, the RBDs are packed with their long axes contained in a plane perpendicular to the axis of symmetry of the trimer. Transition to the roughly perpendicular up conformation exposes the receptor-binding motif (RBM), located at the distal end of the RBD, which is sterically occluded in the down state. Numerous neutralizing antibodies targeting the spike, particularly its RBD, have been developed to treat COVID-19 using common strategies such as single B cell cloning, animal immunization, and phage display (5–9). Most vaccines, including those that are messenger RNA based, are designed to induce immunity against the spike or RBD (10–12). However, emerging SARS-CoV-2 variants such as D614G, B.1.1.7 (Alpha, United Kingdom), B.1.351 (Beta, South Africa), and P.1 (Gamma, Brazil) have exhibited increased resistance to neutralization by monoclonal antibodies or postvaccination sera elicited by the COVID-19 vaccines (13, 14). Monoclonal antibodies with Emergency Use Authorization for COVID-19 treatment partially (Casirivimab) or completely (Bamlanivimab) failed to inhibit the B.1.351 and P.1 variants. Similarly, these variants were less effectively inhibited by convalescent plasma and sera from individuals vaccinated with a COVID-19 vaccine (BNT162b2) (13). The B.1.617.2 (Delta, India) variant became the prevailing strain in many countries (15). Highly effective and broadly neutralizing antibody therapy is urgently demanded for COVID-19 patients.Due to their small size and unique conformations, camelid V_HH single-domain antibodies (also known as nanobodies) can recognize protein cavities that are not accessible to conventional antibodies (16). To isolate high-affinity nanobodies without a need for further affinity maturation, it is highly desirable to construct large nanobody libraries with great diversity. Dromedary camels have been found as potential natural reservoirs of Middle East respiratory syndrome CoV (MERS-CoV) (17). We speculated that dromedary camels would be an ideal source of neutralizing nanobodies against coronaviruses. In the present study, we built large camel V_HH single-domain antibody phage libraries with a diversity of over 10¹¹ from six dromedary camels (Camelus dromedarius), three males and three females, with ages ranging from 3 mo to 20 y. We used both the SARS-CoV-2 RBD and the stabilized spike ectodomain trimer protein as baits to conduct phage panning for nanobody screening. Among all the binders, we found NCI-CoV-7A3 (7A3), NCI-CoV-1B5 (1B5), NCI-CoV-8A2 (8A2), and NCI-CoV-2F7 (2F7) to be potent ACE2 blockers. In addition, these dromedary camel nanobodies displayed potent neutralization activity against the B.1.351 and B.1.1.7 variants and the original strain (Wuhan-Hu-1). The cryoelectron microscopy (cryo-EM) structure of the spike trimer protein complex with these V_HH nanobodies revealed two distinct nonoverlapping epitopes for neutralizing SARS-CoV-2. In particular, 7A3 recognizes a unique and deeply buried region that extends to the apex of the S2 subunit of the spike. Combined treatment with 7A3 and 8A2 shows more potent protection against various variants in culture and mice infected with the B.1.351 variant. Interestingly, 7A3 alone retains its neutralization activity against the lethal challenge of the B.1.617.2 variant in mice.