Event-free survival by residual cancer burden with pembrolizumab in early-stage TNBC: exploratory analysis from KEYNOTE-522.

BACKGROUND: KEYNOTE-522 demonstrated statistically significant improvements in pathological complete response (pCR) with neoadjuvant pembrolizumab plus chemotherapy and event-free survival (EFS) with neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab in patients with high-risk, early-stage triple-negative breast cancer (TNBC). Prior studies have shown the prognostic value of the residual cancer burden (RCB) index to quantify the extent of residual disease after neoadjuvant chemotherapy. In this preplanned exploratory analysis, we assessed RCB distribution and EFS within RCB categories by treatment group. PATIENTS AND METHODS: A total of 1174 patients with stage T1c/N1-2 or T2-4/N0-2 TNBC were randomized 2 : 1 to pembrolizumab 200 mg or placebo every 3 weeks given with four cycles of paclitaxel + carboplatin, followed by four cycles of doxorubicin or epirubicin + cyclophosphamide. After surgery, patients received pembrolizumab or placebo for nine cycles or until recurrence or unacceptable toxicity. Primary endpoints are pCR and EFS. RCB is a prespecified exploratory endpoint. The association between EFS and RCB was assessed using a Cox regression model. RESULTS: Pembrolizumab shifted patients into lower RCB categories across the entire spectrum compared with placebo. There were more patients in the pembrolizumab group with RCB-0 (pCR), and fewer patients in the pembrolizumab group with RCB-1, RCB-2, and RCB-3. The corresponding hazard ratios (95% confidence intervals) for EFS were 0.70 (0.38-1.31), 0.92 (0.39-2.20), 0.52 (0.32-0.82), and 1.24 (0.69-2.23). The most common first EFS events were distant recurrences, with fewer in the pembrolizumab group across all RCB categories. Among patients with RCB-0/1, more than half [21/38 (55.3%)] of all events were central nervous system recurrences, with 13/22 (59.1%) in the pembrolizumab group and 8/16 (50.0%) in the placebo group. CONCLUSIONS: Addition of pembrolizumab to chemotherapy resulted in fewer EFS events in the RCB-0, RCB-1, and RCB-2 categories, with the greatest benefit in RCB-2. These findings demonstrate that pembrolizumab not only increased pCR rates, but also improved EFS among most patients who do not have a pCR.

Brainstem Neural Circuits Triggering Vertical Saccades and Fixation.

Neurons in the nucleus raphe interpositus have tonic activity that suppresses saccadic burst neurons (BNs) during eye fixations, and that is inhibited before and during saccades in all directions (omnipause neurons, OPNs). We have previously demonstrated via intracellular recording and anatomical staining in anesthetized cats of both sexes that OPNs are inhibited by BNs in the medullary reticular formation (horizontal inhibitory BNs, IBNs). These horizontal IBNs receive monosynaptic input from the caudal horizontal saccade area of the superior colliculus (SC), and then produce monosynaptic inhibition in OPNs, providing a mechanism to trigger saccades. However, it is well known that the neural circuits driving horizontal components of saccades are independent from the circuits driving vertical components. Thus, our previous results are unable to explain how purely vertical saccades are triggered. Here, we again apply intracellular recording to show that a disynaptic vertical IBN circuit exists, analogous to the horizontal circuit. Specifically, we show that stimulation of the SC rostral vertical saccade area produces disynaptic inhibition in OPNs, which is not abolished by midline section between the horizontal IBNs. This excludes the possibility that horizontal IBNs could be responsible for the OPN inhibition during vertical saccades. We then show that vertical IBNs in the interstitial nucleus of Cajal, which receive monosynaptic input from rostral SC, are responsible for the disynaptic inhibition of OPNs. These results indicate that a similarly functioning SC-IBN-OPN circuit exists for both the horizontal and vertical oculomotor pathways. These two IBN-mediated circuits are capable of triggering saccades in any direction.Significance Statement Saccades shift gaze to objects of interest, moving their image to the central retina, where it is maintained for detailed examination (fixation). During fixation, high gain saccade burst neurons (BNs) are tonically inhibited by omnipause neurons (OPNs). Our previous study showed that medullary horizontal inhibitory BNs (IBNs) activated from the caudal superior colliculus (SC) inhibit tonically active OPNs in order to initiate horizontal saccades. The present study addresses the source of OPN inhibition for vertical saccades. We find that OPNs monosynaptically inhibit vertical IBNs in the interstitial nucleus of Cajal during fixation. Those same vertical IBNs are activated by the rostral SC, and inhibit OPN activity to initiate vertical saccades.

Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with metastatic colorectal cancer.

The European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with metastatic colorectal cancer (mCRC), published in late 2022, were adapted in December 2022, according to previously established standard methodology, to produce the Pan-Asian adapted (PAGA) ESMO consensus guidelines for the management of Asian patients with mCRC. The adapted guidelines presented in this manuscript represent the consensus opinions reached by a panel of Asian experts in the treatment of patients with mCRC representing the oncological societies of China (CSCO), Indonesia (ISHMO), India (ISMPO), Japan (JSMO), Korea (KSMO), Malaysia (MOS), the Philippines (PSMO), Singapore (SSO), Taiwan (TOS) and Thailand (TSCO), co-ordinated by ESMO and the Japanese Society of Medical Oncology (JSMO). The voting was based on scientific evidence and was independent of the current treatment practices, drug access restrictions and reimbursement decisions in the different Asian countries. The latter are discussed separately in the manuscript. The aim is to provide guidance for the optimisation and harmonisation of the management of patients with mCRC across the different countries of Asia, drawing on the evidence provided by both Western and Asian trials, whilst respecting the differences in screening practices, molecular profiling and age and stage at presentation, coupled with a disparity in the drug approvals and reimbursement strategies, between the different countries.

Safety Profile of the Concomitant Use of Atorvastatin and Cyclosporine in Renal Transplant Recipients.

Cyclosporine (CyA) and atorvastatin (AT) are often administered concomitantly to treat dyslipidemia in renal transplant recipients. However, CyA greatly increases the plasma concentration of AT; therefore, concomitant use might increase the frequency of statin-induced adverse effects. The aim of this study was to investigate whether concomitant use of CyA and AT increases intolerance of the latter agent in Japanese renal transplantation recipients. We performed a retrospective cohort analysis of renal transplant recipients aged 18 years and older who had concomitantly received AT and CyA, or tacrolimus (Tac) therapy. We defined statin intolerance as a decrease in dose or discontinuation of AT due to adverse effects. We evaluated the incidence of statin intolerance in concomitant therapy with CyA for 100 days after the initial administration of AT in comparison with Tac. A total of 144 renal transplant recipients who received AT and CyA, or Tac between January 2013 and December 2019 were included. There was no statistical difference in the incidence of statin intolerance in both the CyA (1.8%; 1/57 patients) and Tac (3.4%; 3/87 patients) groups. Concomitant use of CyA and AT might not increase the incidence of statin intolerance in Japanese renal transplant recipients.

The 2021 SIIM-FISABIO-RSNA Machine Learning COVID-19 Challenge: Annotation and Standard Exam Classification of COVID-19 Chest Radiographs.

We describe the curation, annotation methodology, and characteristics of the dataset used in an artificial intelligence challenge for detection and localization of COVID-19 on chest radiographs. The chest radiographs were annotated by an international group of radiologists into four mutually exclusive categories, including "typical," "indeterminate," and "atypical appearance" for COVID-19, or "negative for pneumonia," adapted from previously published guidelines, and bounding boxes were placed on airspace opacities. This dataset and respective annotations are available to researchers for academic and noncommercial use.

Formation and evolution of carbonaceous asteroid Ryugu: Direct evidence from returned samples.

Samples of the carbonaceous asteroid Ryugu were brought to Earth by the Hayabusa2 spacecraft. We analyzed 17 Ryugu samples measuring 1 to 8 millimeters. Carbon dioxide-bearing water inclusions are present within a pyrrhotite crystal, indicating that Ryugu's parent asteroid formed in the outer Solar System. The samples contain low abundances of materials that formed at high temperatures, such as chondrules and calcium- and aluminum-rich inclusions. The samples are rich in phyllosilicates and carbonates, which formed through aqueous alteration reactions at low temperature, high pH, and water/rock ratios of <1 (by mass). Less altered fragments contain olivine, pyroxene, amorphous silicates, calcite, and phosphide. Numerical simulations, based on the mineralogical and physical properties of the samples, indicate that Ryugu's parent body formed ~2 million years after the beginning of Solar System formation.

The bacteriostatic effect of erythritol on canine periodontal disease-related bacteria.

Erythritol helps both prevent and improve periodontal disease and is therefore widely used for dental care in humans. However, only a few studies have investigated the effects of erythritol on periodontal disease in animals. We hypothesized that erythritol could be used to prevent and improve periodontal disease also in canines and investigated the effects of erythritol on canine periodontal disease-related pathogenic bacteria using both in vitro and in vivo methods. The effect of erythritol on the proliferation of Porphyromonas gulae, which is reportedly associated with canine periodontal disease, was investigated in vitro. In addition, a 4-week intervention trial using an external gel preparation containing 5% erythritol was performed in canines with mild periodontal disease; changes in the microbiota around periodontal lesions were investigated using next-generation sequencing and bioinformatics analysis. The growth of P. gulae was significantly suppressed by erythritol in vitro. In the intervention study, the Shannon index, an indicator of the species distribution α-diversity, and the occupancy of several canine periodontal disease - related bacteria ( P. gulae, P. cangingivalis) were significantly decreased in periodontal lesions. Based on the results of in vitro and in vivo studies, we conclude that, as in humans, erythritol has bacteriostatic effects against periodontal disease - related bacteria in canines.

The association of hemoglobin drop with in-hospital outcomes in COVID-19 patients.

BACKGROUND: Bleeding events can be critical in hospitalized patients with COVID-19, especially those with aggressive anticoagulation therapy. AIM: We aimed to investigate whether hemoglobin drop was associated with increased risk of acute kidney injury (AKI) and in-hospital mortality among patients with COVID-19. DESIGN: Retrospective cohort study. METHODS: This retrospective study was conducted by review of the medical records of 6683 patients with laboratory-confirmed COVID-19 hospitalized in the Mount Sinai Health system between 1st March 2020 and 30th March 2021. We compared patients with and without hemoglobin drop >3 g/dl during hospitalization within a week after admissions, using inverse probability treatment weighted analysis (IPTW). Outcomes of interest were in-hospital mortality and AKI which was defined as serum creatine change of 0.3 mg/dl increase or 1.5 times baseline. RESULTS: Of the 6683 patients admitted due to COVID-19, 750 (11.2%) patients presented with a marked hemoglobin drop. Patients with hemoglobin drop were more likely to receive therapeutic anticoagulation within 2 days after admissions. Patients with hemoglobin drop had higher crude in-hospital mortality (40.8% vs. 20.0%, P < 0.001) as well as AKI (51.4% vs. 23.9%, P < 0.001) compared to those without. IPTW analysis showed that hemoglobin drop was associated with higher in-hospital mortality compared to those without (odds ratio (OR) [95% confidential interval (CI)]: 2.21 [1.54-2.88], P < 0.001) as well as AKI (OR [95% CI]: 2.79 [2.08-3.73], P < 0.001). CONCLUSIONS: Hemoglobin drop during COVID-19 related hospitalizations was associated with a higher risk of AKI and in-hospital mortality.

Dialogue as therapy: the role of the expert in the ICRP Dialogues.

Science communication is commonly framed as a battle with ignorance and the field of radiological protection is not exempt from this tendency. By correcting deficits in the public's understanding of science, the expert is often imagined to be able to convince the public of its objective safety ('anzen'), thereby inspiring a sense of calm ('anshin'). In the wake of the 2011 Fukushima Daiichi disaster, however, the International Commission on Radiological Protection has sought to break with this tradition by organising a series of participatory seminars in which experts engage those affected by the disaster as equals. Drawing on ethnographic fieldwork, this article suggests that the Dialogue seminars can be best understood using the metaphor of therapy; using it to describe the premise, form, and objectives of the Dialogues with a view to identifying good practice for future radiological protection scenarios.

Hypoxic hepatitis with marked elevation of serum ferritin probably due to activation of intrahepatic macrophages: another form of hypoxic hepatitis hitherto not reported?

BACKGROUND AND STUDY AIMS: Hypoxic hepatitis (HH) is an acute liver injury that develops in patients with underlying diseases, such as heart failure, respiratory failure, septic/toxic shock. However, some patients do not have underlying diseases or episodes which are known to result in HH. Here, we analyzed the clinical characteristics of this particular patient group (called 'unknown HH' hereafter) to understand its pathogenesis. PATIENTS AND METHODS: Between October 2010 and January 2016, 157 consecutive patients with acute liver injury were admitted to our hospital. Among these patients, 15 patients were categorized as unknown HH. Medical histories and blood test results of unknown HH were analyzed. RESULTS: Among 15 patients of unknown HH, 11 were habitual drinkers and all experienced one of digestive symptoms which might result in mild hypovolemia such as vomiting, diarrhea, appetite loss, and epigastralgia. All patients of unknown HH presented marked elevation of serum ferritin concentration paralleled with aspartate transaminase (AST), alanine transaminase (ALT), and lactate dehydrogenase (LDH) concentrations. The serum levels of ferritin, ALT, LDH, and prothrombin time-international normalized ratio (PT-INR) were rapidly decreased during hospitalization and all 15 patients of unknown HH recovered without any complication. CONCLUSIONS: We found the particular group of HH with marked elevation of serum ferritin probably due to intrahepatic macrophage activation. Anti-inflammatory treatments might be effective for this group of hypoxic hepatitis.

Evaluation of the stability of Yamakagashi (Rhabdophis tigrinus) Equine Antivenom after 20 years storage.

In 2000, an equine Yamakagashi (Rhabdophis tigrinus) antivenom (Lot 0001) was testmanufactured as an unapproved drug for treatment of Yamakagashi bites. It was stocked on the premise of super-legal use from the viewpoint of emergency health crisis management. The antivenom showed a strong neutralizing ability against the hemorrhagic and coagulation activity of the Yamakagashi venom in its potency test. One vial of the antivenom can effectively neutralize at least about 4 mg of Yamakagashi venom. Its efficacy has also been confirmed in patients with severe cases of R. tigrinus bite that has been used in emergency. In 2020, this antivenom (Lot 0001) has reached 20 years after its production. To evaluate the integrity and potency of the antivenom, quality control, safety and potency tests had been conducted almost every year since 2012. Physical and chemical tests (property test, moisture content test, insoluble foreign matter test, osmotic pressure ratio test, pH test, protein content test, endotoxin test, sterility test) of the antivenom, showed no significant changes throughout the years, when compared to the results immediately after its production in 2000. All the parameters measured were also within the standard values. In animal safety tests (test for absence of toxicity and pyrogen), there was no change in the test results during the storage period and no abnormalities were observed. The potency test (anti-coagulant activity) after 20 years of the product, showed the same potency as those recorded immediately after production. Therefore, in all of the stability monitoring tests conducted so far, the product did not show any significant change compared to the results immediately after production. This confirms the stability of the product during the stockpiling period to the present, that is, 20 years after production.

Effect of zymosan on feed passage in the digestive tract in chicks.

1. The purpose of the present study was to examine whether zymosan, which is a component of fungi, affects feed passage through the digestive tract in chicks (Gallus gallus).2. Intraperitoneal (IP) injection of 2.5 mg zymosan significantly reduced the crop-emptying rate and this effect was similar to that of 100 µg lipopolysaccharide (LPS). Zymosan affected phenol red transit from the proventriculus.3. Zymosan significantly affected the gene expression of interleukin-1ß (IL-1ß), IL-6, IL-8 and histidine decarboxylase in various regions of the digestive tract.4. The present study suggested that zymosan retarded feed passage through the digestive tract in chick and interleukins and histamine may be participating in this process.

Fibronectin plays a major role in hypoxia-induced lenvatinib resistance in hepatocellular carcinoma PLC/PRF/5 cells.

Resistance to lenvatinib mesylate (LEN), a systemic chemotherapy that can be administered orally, has been a major issue for treatment of hepatocellular carcinoma (HCC). Although HCC is the tumor that most exhibits intratumoral hypoxia, which has been shown to be involved in the development of treatment resistance, there are no reports of LEN resistance in HCC treatment under hypoxia. The purpose of our study was to elucidate the mechanism of treatment resistance to LEN under hypoxia using HCC cell lines. We confirmed LEN resistance under hypoxic conditions in HCC cell lines. There was a significant increase in the IC50 value of PLC/PRF/5 cells from 13.0±0.8 µM in normoxia to 21.3±1.1 µM in hypoxia, but in HepG2 cells, the increase was not significant. To elucidate the LEN resistance mechanism of PLC/PRF/5 cells under hypoxia, we performed microarray analysis and extracted genes that are thought to be related to this mechanism. Furthermore, in-silico analysis confirmed significant changes in the extracellular matrix, and among them, FN1 encoding fibronectin was determined as the hub of the gene cluster. The expression of fibronectin in PLC/PRF/5 cells examined with immunofluorescence staining was significantly elevated in and outside of cells under hypoxia, and tended to decrease when cells were exposed to LEN under normoxia. Furthermore, the fibronectin concentration in the culture solution of PLC/PRF/5 cells examined by ELISA was 2.3 times higher under hypoxia than under normoxia under LEN(-) conditions, and 1.6 times higher under hypoxia than under normoxia under LEN(+) conditions. It is assumed that in PLC/PRF/5 cells, fibronectin is probably suppressed as an indirect effect of LEN under normoxia, but transcription factors such as HIF-1α are induced under hypoxia, thus enhancing the production of fibronectin and attenuating the effect of LEN, resulting in drug resistance. This behavior of fibronectin with LEN exposure under hypoxia is probably specific to PLC/PRF/5 cells. Further studies should verify the combined effective inhibition of fibronectin and the MAPK pathway as a promising therapeutic strategy to enhance the value of LEN in HCC treatment.

Alpelisib plus fulvestrant for PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: final overall survival results from SOLAR-1.

BACKGROUND: Activation of the phosphatidylinositol-3-kinase (PI3K) pathway via PIK3CA mutations occurs in 28%-46% of hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2-) advanced breast cancers (ABCs) and is associated with poor prognosis. The SOLAR-1 trial showed that the addition of alpelisib to fulvestrant treatment provided statistically significant and clinically meaningful progression-free survival (PFS) benefit in PIK3CA-mutated, HR+, HER2- ABC. PATIENTS AND METHODS: Men and postmenopausal women with HR+, HER2- ABC whose disease progressed on or after aromatase inhibitor (AI) were randomized 1 : 1 to receive alpelisib (300 mg/day) plus fulvestrant (500 mg every 28 days and once on day 15) or placebo plus fulvestrant. Overall survival (OS) in the PIK3CA-mutant cohort was evaluated by Kaplan-Meier methodology and a one-sided stratified log-rank test was carried out with an O'Brien-Fleming efficacy boundary of P ≤ 0.0161. RESULTS: In the PIK3CA-mutated cohort (n = 341), median OS [95% confidence interval (CI)] was 39.3 months (34.1-44.9) for alpelisib-fulvestrant and 31.4 months (26.8-41.3) for placebo-fulvestrant [hazard ratio (HR) = 0.86 (95% CI, 0.64-1.15; P = 0.15)]. OS results did not cross the prespecified efficacy boundary. Median OS (95% CI) in patients with lung and/or liver metastases was 37.2 months (28.7-43.6) and 22.8 months (19.0-26.8) in the alpelisib-fulvestrant and placebo-fulvestrant arms, respectively [HR = 0.68 (0.46-1.00)]. Median times to chemotherapy (95% CI) for the alpelisib-fulvestrant and placebo-fulvestrant arms were 23.3 months (15.2-28.4) and 14.8 months (10.5-22.6), respectively [HR = 0.72 (0.54-0.95)]. No new safety signals were observed with longer follow-up. CONCLUSIONS: Although the analysis did not cross the prespecified boundary for statistical significance, there was a 7.9-month numeric improvement in median OS when alpelisib was added to fulvestrant treatment of patients with PIK3CA-mutated, HR+, HER2- ABC. Overall, these results further support the statistically significant prolongation of PFS observed with alpelisib plus fulvestrant in this population, which has a poor prognosis due to a PIK3CA mutation. CLINICALTRIALS. GOV ID: NCT02437318.

Evaluation of the stability of Yamakagashi (Rhabdophis tigrinus) Equine Antivenom after 20 years storage

@#In 2000, an equine Yamakagashi (Rhabdophis tigrinus) antivenom (Lot 0001) was testmanufactured as an unapproved drug for treatment of Yamakagashi bites. It was stocked on the premise of super-legal use from the viewpoint of emergency health crisis management. The antivenom showed a strong neutralizing ability against the hemorrhagic and coagulation activity of the Yamakagashi venom in its potency test. One vial of the antivenom can effectively neutralize at least about 4 mg of Yamakagashi venom. Its efficacy has also been confirmed in patients with severe cases of R. tigrinus bite that has been used in emergency. In 2020, this antivenom (Lot 0001) has reached 20 years after its production. To evaluate the integrity and potency of the antivenom, quality control, safety and potency tests had been conducted almost every year since 2012. Physical and chemical tests (property test, moisture content test, insoluble foreign matter test, osmotic pressure ratio test, pH test, protein content test, endotoxin test, sterility test) of the antivenom, showed no significant changes throughout the years, when compared to the results immediately after its production in 2000. All the parameters measured were also within the standard values. In animal safety tests (test for absence of toxicity and pyrogen), there was no change in the test results during the storage period and no abnormalities were observed. The potency test (anti-coagulant activity) after 20 years of the product, showed the same potency as those recorded immediately after production. Therefore, in all of the stability monitoring tests conducted so far, the product did not show any significant change compared to the results immediately after production. This confirms the stability of the product during the stockpiling period to the present, that is, 20 years after production.

Characteristics of plasma window with various channel diameters for accelerator applications.

Plasma window is a feasible device as an atmosphere-vacuum interface, which can withstand energetic particle beams. It is, however, essential to enlarge the diameter to several tens of millimeters for actual beam passing in the accelerator applications. The pressure separation performance and discharge voltage V current I characteristics should be investigated in detail to design the plasma window for each purpose. Therefore, a cascade arc discharge device with a diameter of up to 20 mm was developed, and its characteristics as a function of diameter were examined. As a result, with an increase in the channel diameter, the discharge pressure that was achieved decreased, whose values were smaller compared with the values by the prediction formula, assuming the viscous gas flow with a constant plasma temperature. It showed that the bulk plasma temperature for the larger discharge channel was low because of the low-current density over the channel. Furthermore, the transition of the V-I slope was observed with an increase in the diameter.

Short communication: Menaquinone-4 (vitamin K2) induces proliferation responses in bovine peripheral blood mononuclear cells.

The effects of vitamin K (VK) on immune cells in ruminants are yet to be fully investigated. The objective of this study was to examine the effects of VK on peripheral blood mononuclear cells (PBMC) in Holstein dairy cows. A cell proliferation assay was performed to evaluate the effect of menaquinone-4 (MK-4, the biologically active form of VK) on immune response of PBMC. The proliferation of PBMC stimulated by MK-4 was significantly higher than that of nonstimulated controls. The expression of T cell-related genes in PBMC, stimulated with MK-4, was assessed by quantitative PCR. No significant changes were observed in the mRNA expression levels of both CD4 and CD8 as helper T cell and cytotoxic T cell markers, respectively. The present study demonstrated that MK-4 positively influenced cow PBMC proliferation and suggested the possibility of bovine-specific immune cell activation. The present study lays a foundation for understanding the physiological role of VK in cattle.