bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of Time to Onset and Outcome of Lung Adverse Events Related to Pembrolizumab Using Marketing Surveillance
Authors: Kanbayashi Yuko , Kobayashi Momoko , Anzai Miku , Shimizu Tadashi , Uchida Mayako
Published: October 2023

Background: Pembrolizumab has been widely used in patients since its release, but detailed information on lung-specific adverse events (AEs) from post-marketing monitoring has not been reported. Objectives: This study was undertaken to determine the risk of pembrolizumab-induced lung AEs, time to onset, and post hoc outcomes using the Japanese Adverse Drug Event Report database. Method: We analyzed data for the period between April 2004 and March 2022. Data on lung AEs were extracted and the relative risks of AEs were estimated using reporting odds ratios. Results: We analyzed 2,021,907 reports and identified 15,306 reports of AEs caused by pembrolizumab, including 3,004 lung AEs. Signals were detected for 14 lung AEs. Interstitial lung disease was the most frequently reported (62.3%) and included fatal cases. A histogram of median time to onset showed occurrence ranging from 2 to 73 days, but some cases of interstitial lung disease occurred after 2 years of administration. The AEs showing the highest fatality rates were interstitial lung disease, respiratory failure, and pneumonia aspiration. Conclusions: This study focused on lung AEs caused by pembrolizumab as post-marketing AEs. Some cases could potentially involve serious outcomes, so patients should be monitored for signs of AE onset not only at the start of administration but also over an extended period, especially for interstitial lung disease.
Truth or Trend – Misinformation Spreading Fast on TikTok: A Cross-Sectional Analysis of Onychomycosis Content
Authors: Waterton Kelita A. , Lipner Shari R.
Published: October 2023

Background: Onychomycosis is the most frequently diagnosed nail condition in clinical practice. With the growing popularity of TikTok and online health information-seeking behavior, it is imperative to understand onychomycosis-related content on this platform. Objective: Our objective was to assess content and quality of the most popular onychomycosis-related content on TikTok. Methods: We queried TikTok for videos using the search terms “onychomycosis” and “nail fungus” for the top 100 videos by view count, with DISCERN scoring used to rate videos for quality. Results: Average DISCERN score was 1.77 and dermatologists posted videos with the highest mean score (2.56). Most of the videos were educational (72%) and/or related to treatment (69%). Home remedies were recommended more often (58%) than FDA-approved therapies (7%). Physician versus nonphysician posted videos had higher mean DISCERN score (2.28 vs. 1.44) (p < 0.001), greater view number (1,209,953 vs. 343,993) (p < 0.05), and more often discussed medical therapy (p < 0.05). Conclusion: While social media is a valuable resource for providing medical information to an interminable audience, there are significant shortcomings. Therefore, we recommend that dermatologists advise patients against relying on social media for medical information and consider using social media to provide accessible evidence-based health education on onychomycosis.
Cx43 Facilitates Mesenchymal Transition of Endothelial Cells Induced by Shear Stress
Authors: Zhou En , Zhou Jing , Bi Changlong , Zhang Zongqi
Published: October 2023

Objectives: This study aimed to determine the function of Cx43 in the endothelial-to-mesenchymal transition (EndMT) process of endothelial cells (ECs) and to explore the potential signaling pathways underlying these functions. Methods: ECs were extracted from rat aorta. ECs were transfected with Cx43 cDNA and Cx43 siRNA and then exposed to 5 or 12 dyne/cm2. Immunofluorescence staining was used to detect the expression of SM22α, Cx43, and acetylated α-tubulin in ECs. Western blotting was used to detect the protein expression of α-SMA, CD31, Cx43, H1-calponin, Ift88, and p-smad3 in ECs. Results: The expression of αSMA, SM22α, and Cx43 was significantly increased, and CD31 was markedly decreased in ECs treated with laminar shear stress at 5 dyn/cm2. The Cx43 cDNA transfection could induce the expression of SM22α or H1-calponin and attenuate CD31 expression in ECs. Also, Cx43 overexpression harms cilia formation in ECs exposed to 5 dyn/cm2, accompanied with the regulated Ift88 and smad signaling. Conclusions: This study found that laminar shear stress at 5 dyn/cm2 would increase the expression of Cx43 to facilitate the EndMT process of ECs, associated with morphological changes in primary cilia and the decreased expression of Ift88 in ECs.
Evaluation of Time to Onset and Outcome of Cardiac Adverse Events Associated with Nilotinib using Post-Marketing Surveillance
Authors: Kanbayashi Yuko , Kojima Asuka , Wakabayashi Haruka , Shimizu Tadashi , Uchida Mayako
Published: October 2023

Introduction: Cardiac adverse events (CAEs) have become a concern as serious adverse events (AEs) of nilotinib administration. No reports have described the incidence of CAEs associated with nilotinib in Japanese patients. Thus, we conducted this study to evaluate the risk of nilotinib-induced CAEs, time to onset, incidence rates, and post hoc outcomes using the Japanese Adverse Drug Event Report database. Methods: We analysed data for the period between April 2004 and March 2022. Data on CAEs were extracted, and relative risk of AEs was estimated using the reporting odds ratio. Results: We analysed 2,021,907 reports and identified 3,545 reports of AEs caused by nilotinib. Of these, 511 reports involved CAEs. Signals were detected for 19 CAEs. Of these, electrocardiogram QT prolonged was the most frequently reported (30.9%). Fatal outcomes were observed in eight AEs: cardiac failure, atrial fibrillation, acute myocardial infarction, pericardial effusion, myocardial infarction, cardiac arrest, pericarditis, and cardiac tamponade. Of these, acute myocardial infarction, myocardial infarction, pericarditis, and cardiac tamponade exhibited mortality rates >10%. A histogram of median times to onset showed nilotinib-associated AEs occurring 3–485 days after nilotinib administration. Conclusion: We focused on CAEs caused by nilotinib as post-marketing AEs. Some cases resulted in serious outcomes. Patients should be monitored for signs of onset of these AEs not only at the start of administration but for a long period of time.
Allergen Differences and Correlation Analysis in Siblings Diagnosed with Respiratory Allergic Diseases
Authors: Liu Liping , Wang Weihua , Sun Yuemei , Li Guangrun
Published: October 2023

Introduction: Many parents of children with allergies are worried whether their subsequent children will have allergic reactions to the same allergens. Much of the current research on sibling allergens has been focused on twins; however, in real life, very few children are twins. Our study provides an opportunity to initially explore the sensitivity to allergens in siblings diagnosed with respiratory allergic diseases. Methods: Siblings diagnosed with bronchial asthma and/or allergic rhinitis in the Outpatient Department of Allergy Department of Yantai Yuhuangding Hospital from January 2018 to December 2021 were selected. The siblings were divided into elder group and younger group. Data of gender, age, feeding history, serum total IgE (TIgE), absolute eosinophil counts, and allergen-specific IgE (sIgE) were collected and analyzed. The sIgEs of allergens were divided into six categories and analyzed. Results: A total of 98 sibling pairs of patients were included in this study. There were no differences in the positive rates of the different types of allergens, TIgE values, and the absolute eosinophil values between the elder and younger groups and between different genders. Logistic regression analysis indicated that the elder siblings allergic to dust mites, fungi, weed pollens, or food had a statistically significant increased risk of having their younger sibling sensitive to these types of allergens (all p <0.05), and the risk of allergy to dust mites, weed pollens, and tree pollens of younger group increased with age (all p <0.05). Except for the sIgE values of dust mites, the sIgE values of the other allergens were significantly correlated between the two groups (all p <0.05). Conclusion: The positive rates of different allergens were similar between siblings. Elder siblings with dust mites, fungi, weed pollen, or food allergen positivity will have younger siblings sensitive to the same types of allergens.
El papel de los antibióticos inhalados en la era de los moduladores de CFTR de alta eficacia
Authors: Elborn J. Stuart , Blasi Francesco , Burgel Pierre-Régis , Peckham Daniel
Published: October 2023

Las infecciones bacterianas recurrentes y crónicas son frecuentes en pacientes con fibrosis quística (FQ), y contribuyen al deterioro de la función pulmonar. Los antibióticos constituyen la base del tratamiento de las exacerbaciones e infecciones bacterianas crónicas en la FQ. Los antibióticos inhalados son eficaces para tratar infecciones bacterianas respiratorias crónicas y erradicar a Pseudomonas aeruginosa de las vías respiratorias, con efectos adversos sistémicos limitados. En la última década, los moduladores del regulador de la conductancia transmembrana de la fibrosis quística (CFTR) de alta eficacia se han convertido en una nueva opción terapéutica que corrige/reabre parcialmente el transporte de cloruro en pacientes con mutaciones específicas del CFTR, restaurando la hidratación del moco y mejorando el aclaramiento mucociliar. La reciente combinación triple de moduladores CFTR está aprobada para ∼80–90% de la población con FQ, y reduce significativamente las exacerbaciones pulmonares y mejora los síntomas respiratorios y la función pulmonar. Los moduladores de CFTR han puesto en el centro de atención del tratamiento sintomático a la medicina personalizada/de precisión, al dirigirse a defectos de CFTR específicos del genotipo. Aunque son muy eficaces, no normalizan por completo la fisiología pulmonar, no detienen la inflamación ni resuelven el daño pulmonar crónico, como las bronquiectasias. Es probable que el impacto de estos nuevos fármacos en la salud pulmonar cambie el tratamiento futuro de las infecciones pulmonares crónicas en pacientes con FQ. Este artículo revisa el papel de los antibióticos inhalados en la era de los moduladores de CFTR.
La terapia con moduladores para la fibrosis quística puede revertir las bronquiectasias quísticas
Authors: Middleton Peter G. , Simmonds Nicholas J.
Published: October 2023

Las bronquiectasias suelen considerarse progresivas e irreversibles, por lo que los casos de regresión o reversión constituyen un paso importante para comprender los mecanismos fisiopatológicos subyacentes. El tratamiento de la fibrosis quística (FQ), causada por variantes patogénicas en el gen regulador de la conductancia transmembrana de la fibrosis quística (CFTR), es un ejemplo de éxito en la medicina personalizada. El reciente desarrollo de terapias moduladoras de CFTR ha revolucionado la atención médica. En cuestión de semanas se observan mejoras espectaculares en la función pulmonar, la producción de esputo, el desempeño durante el día y la calidad de vida. Sin embargo, en la actualidad se desconoce el efecto de la exposición a largo plazo al elexacaftor + tezacaftor + ivacaftor (ETI) sobre las anomalías estructurales. En esta serie de casos se describen tres adultos con FQ que han mostrado mejoría progresiva de los cambios cilíndricos, varicosos y, lo más importante, quísticos en bronquiectasias tras un tratamiento prolongado con ETI. Esto plantea la interesante cuestión de la reversibilidad de las bronquiectasias, así como los mecanismos implicados en el mantenimiento y la progresión de las bronquiectasias en relación con la FQ.
Expanding the Spectrum of Extracorporeal Strategies in Small Infants with Hyperammonemia
Authors: Ceschia Giovanni , Parolin Mattia , Longo Germana , Ronco Claudio , Vidal Enrico
Published: October 2023

Hyperammonemia is a life-threatening condition mainly due to the neurotoxicity of ammonia. Ammonia scavengers may be insufficient, and extracorporeal treatment may be required. Continuous treatments are preferred, and a high-dose continuous renal replacement therapy (CRRT) must be prescribed to ensure a fast ammonia depletion. Many of the children with hyperammonemia are newborns, with lower blood volume than older children. The majority of the CRRT systems are adult-based, with large extracorporeal priming volumes and inadequate UF control. Recent strides have been made in the development of CRRT systems more suitable for young children with smaller sets to use in adult machines and dedicated monitors for neonates and infants. The main advantage of the machines for adults is the higher dialysis fluid flows, however with greater hemodynamic risks. Pediatric monitors have been designed to reduce the extracorporeal volume and to increase the precision of the treatment. However, they have substantial limitation in clearance performances. In this review, we discuss on current strategies to provide CRRT in newborns and small infants with hyperammonemia. We also presented our experience with the use of CARPEDIEM™ implemented in a CVVHDF modality, boosting the diffusive clearance with a post-replacement convective mechanism.
Primary Cutaneous Marginal Zone Lymphoma following Repeated Inflammation Caused by Hair Dyeing
Authors: Lee Jun Hyo , Jo Ui Hyeon , Kim Tae Min , Suh Dae Hun
Published: October 2023

Primary cutaneous marginal zone lymphoma (PCMZL) is a rare form of B-cell lymphoma that primarily affects the skin. Chronic antigen stimulation has been implicated in its development, with cases associated with various triggers. We present a case of PCMZL following chronic inflammation caused by long-term hair dyeing. A 75-year-old woman with a history of repeated inflammation and itching after hair dyeing for 30 years presented with persistent red-to-violaceous patches and plaques on her scalp. Despite receiving topical corticosteroid treatment for 10 years, the lesions remained. Pathological examinations confirmed the diagnosis of PCMZL. The patient achieved complete remission after radiotherapy. This case underscores the potential link between chronic inflammation and the development of PCMZL.
Current Treatment Practices for Adult Patients with Constipation in Japan
Authors: Kessoku Takaomi , Misawa Noboru , Ohkubo Hidenori , Nakajima Atsushi
Published: October 2023

Background: The prevalence of constipation in Japan is estimated to be 2–5%. Constipation is a disease found in older adults. In particular, Japan is an aging society, with 65% of men and 80.5% of women aged 65 years or older accounting for the majority of its population. Chronic constipation may be associated with survival, cardiovascular events, decreased quality of life, and death. This study summarizes the recent findings regarding constipation treatment practice in Japan. Summary: Until recently, the diagnosis of constipation was mainly based on medical interviews; however, with the recent development of handheld ultrasound devices, both physicians and nurses can easily and objectively diagnose fecal retention. Magnesium oxide and stimulant laxatives have been the mainstay treatments; however, since 2012, more than five new drugs for treating constipation have become available in Japan. Key Messages: Magnesium oxide is less effective in patients who use acid-secretion inhibitors and patients who have undergone total gastrectomy and should be cared for hypermagnesemia. In addition, regular use of stimulant laxatives may lead to colonic inertia and decreased bowel movements; therefore, they should be used only occasionally. The following is an overview of the different uses of conventional and newer laxatives for treating constipation.
A 37-Year-Old Man with Myofibroblast Sarcoma Combined with Pleural Maculopathy: Case Report
Authors: Tu Di-Wei , Zhang Ting-Wei , Wang Ying-Ying , Kang Di , Li Hong-Bo
Published: October 2023

Myofibroblastic sarcoma (MS) is a malignant tumor of soft tissue or bone that can occur in children or adults, with a high rate of recurrence and metastasis. We report a case of low-grade malignant MS of the left shoulder, diagnosed based on pathological examination and immunohistochemical staining. However, the patient had unexplained pleural maculopathy. The patient passed away 6 months after the diagnosis of myofibroblast sarcoma due to multiple metastases throughout the sarcoma. Combined with the patient’s history, ancillary findings, and after MDT discussion, the patient was ultimately considered to have a high probability of myofibroblast sarcoma combined with pleural maculopathy. In conclusion, when a patient is diagnosed with myofibroblast sarcoma in combination with pleural macula, in the absence of other causative factors, a deep tissue biopsy of the pleura should be actively performed to confirm the diagnosis.
Durability of the Blood Pressure Effects of Renal Pelvic Denervation in Patients with Hypertension during a 12-Month Observation
Authors: Weber Michael A. , Hering Dagmara , Nikoleishvili David , Imedadze Avtandil , Dughashvili Gvantsa , Klimiashvili Zurab , Bekaia Eter , Shengelia Tamar , Kabalava Mamuka , Goguadze Otar , Emukhvari Tamar , Druker Vitaly , Buelna Terry , Heuser Richard , Hashemian Shima , Provanzano Robert
Published: October 2023

Introduction: We previously completed a trial of renal pelvic denervation for treating hypertension that reduced blood pressure by the 2-month primary endpoint. However, information on the durability of effectiveness is a critical requirement for device therapy and we now report data up to 12 months. Methods: This was an open-label, single-arm feasibility study in patients with increased blood pressure despite taking an average of 2.7 medications. The key endpoint reported here was ambulatory blood pressure at 12 months following renal pelvic denervation. Results: In the 17 patients (mean age: 56) studied, there was a reduction from the baseline of 148 + 8.7 mm Hg in the primary endpoint of mean daytime systolic blood pressure at 12 months of 19.1 (26.7, 11.6) mm Hg, p < 0.001, as compared with the 2-month result of 19.4 (24.9, 14.0) mm Hg. The 24-h systolic blood pressure fell by 19.3 (26.7, 11.9), p < 0.001, and nighttime systolic fell by 18.7 (27.5, 9.8), p < 0.001, mm Hg at 12 months. Diastolic pressures also fell significantly from baseline at 12 months. As well, automated office systolic blood pressure was reduced from the baseline of 156.5 ± 12.3 by 24.8 (33.2, 16.8) mm Hg, p < 0.001, at 12 months as compared with 22.4 (31.5, 13.3) at 2 months. All blood pressure changes at 12 months were not different from those at 2 months, thus confirming the durability of the procedure. There were no serious procedural, clinical, or laboratory adverse events related to the intervention. Serum creatinine fell from 1.03 ± 0.22 to 0.82 ± 0.16 mg/dL, and estimated glomerular filtration rate rose from 79.6 ± 17.8 to 96.3 ± 16.4 mL/min/1.73 m2 by 12 months, again sustaining effects seen at 2 months. Conclusion: These findings provide evidence that the significant blood pressure-lowering effects of renal pelvic denervation are durable and safe for at least 1 year and provide the basis for a pivotal randomized blinded trial to further define the safety and effectiveness of this procedure.
Prognostic Potential of the Prognostic Nutritional Index in Non-Small Cell Lung Cancer Patients Receiving Pembrolizumab Combination Therapy with Carboplatin and Paclitaxel/Nab-Paclitaxel
Authors: Nishihara-Kato Fuyumi , Imai Hisao , Tsuda Takeshi , Wasamoto Satoshi , Nagai Yoshiaki , Kishikawa Takayuki , Miura Yosuke , Ono Akihiro , Yamada Yutaka , Masubuchi Ken , Osaki Takashi , Nakagawa Junichi , Umeda Yukihiro , Minemura Hiroyuki , Kozu Yuki , Taniguchi Hirokazu , Ohta Hiromitsu , Kaira Kyoichi , Kagamu Hiroshi
Published: October 2023

Introduction: Pembrolizumab (Pemb) therapy in conjunction with carboplatin and paclitaxel (PTX)/nab-PTX has been efficacious in treating non-small cell lung cancer (NSCLC). However, the response predictors of this combination therapy (Pemb-combination) remain undetermined. We aimed to evaluate whether Glasgow prognostic score (GPS), neutrophil-to-lymphocyte ratio (NLR), body mass index (BMI), platelet-to-lymphocyte ratio (PLR), and prognostic nutritional index (PNI) are potential factors in prognosticating the response to Pemb-combination therapy in advanced NSCLC patients. Methods: We retrospectively recruited 144 NSCLC patients receiving first-line treatment with Pemb-combination therapy from 13 institutions between December 1, 2018, and December 31, 2020. GPS, NLR, BMI, PLR, and PNI were assessed for their efficacy as prognostic indicators. Cox proportional hazard models and the Kaplan-Meier method were used to compare the progression-free survival (PFS) and overall survival (OS) of the patients. Results: The treatment exhibited a response rate of 63.1% (95% confidence interval [CI]: 55.0–70.6%). Following Pemb-combination administration, the median PFS and OS were 7.3 (95% CI: 5.3–9.4) and 16.5 (95% CI: 13.9–22.1) months, respectively. Contrary to PNI, NLR, GPS, BMI, and PLR did not display substantially different PFS in univariate analysis. However, multivariate analysis did not identify PNI as an independent prognostic factor for PFS. Furthermore, univariate analysis revealed that GPS, BMI, and PLR exhibited similar values for OS but not NLR and PNI. Patients with PNI ≥45 were predicted to have better OS than those with PNI <45 (OS: 23.4 and 13.9 months, respectively, p = 0.0028). Multivariate analysis did not establish NLR as an independent prognostic factor for OS. Conclusion: The PNI evidently predicted OS in NSCLC patients treated with Pemb-combination as first-line therapy, thereby validating its efficiency as a prognostic indicator of NSCLC.
Hepatic Artery Anomalies in Pancreaticoduodenectomy: Outcomes from a High-Volume Center
Authors: Frigerio Isabella , Capelli Giulia , Chiminazzo Valentina , Spolverato Gaya , Lorenzoni Giulia , Mancini Silvia , Giardino Alessandro , Regi Paolo , Girelli Roberto , Butturini Giovanni
Published: October 2023

Introduction: Hepatic artery anomalies (HAA) may have an impact on surgical and oncological outcomes of patients undergoing pancreaticoduodenectomy (PD). Methods: Patients who underwent PD at our institution between July 2015 and January 2020 were retrospectively reviewed and classified into two groups: group 1, with presence of HAA, and group 2, with no HAA. A weighted logistic regression model was employed to assess the association between HAA and postoperative complications, and to assess the association between HAA and R status in patients with pancreatic cancer. Results: 502 patients were considered for analysis, with 75 (15%) of them in group 1. They had either an accessory (n = 28, 40.8%) or replaced (n = 26, 36.6%) right hepatic artery. Most patients underwent surgery for a malignancy (n = 451; 90%); among them, vascular resection was performed in 69 cases (15%). The presence of a HAA was reported at preoperative imaging only in 4 cases (5%) and the aberrant vessel was preserved in 72% of patients. At weighted multivariable logistic regression analysis, HAA were not associated to higher odds of morbidity (odds ratio [OR]: 0.753, 95% confidence interval [CI]: 0.543–1.043) nor to R1 status in case of pancreatic cancer (OR: 1.583, 95% CI: 0.979–2.561). Conclusion: At our institution, the presence of HAA does not have an impact on postoperative outcomes or affects oncological clearance after PD. Hospitals’, surgeons’, volume and systematic review of preoperative imaging are all factors that help reduce possible adverse events.
Two Cases of Anti-D Alloimmunization in D-Negative Thai Patients as a Result of the Asian-Type DEL on Transfused Red Cells
Authors: Suksard Kanyapon , Luangtrakool Komon , Rungroung Thongbai , Chamsai Sutthisak , Saetam Pradermchai , Kittisares Kulvara , Permpikul Parichart , Kittivorapart Janejira
Published: October 2023

Introduction: DEL is known to be one of the weakest D variants, which can be detected by the adsorption-elution technique or by molecular study. Currently, in Thailand, we do not routinely test for DEL variants serologically or genetically among serologic RhD-negative blood donors. Case Presentation: We reported 2 cases of alloimmunization after transfused with Rh DEL, RHD*DEL1 allele, in the Thai population. The first case was a 73-year-old male with anemia who presented with post-cardiac arrest and septic shock. The patient was group B, RhD-negative, and was transfused with RhD-negative red blood cells (RBCs). Antibody screening and identification found that the patient developed anti-D and anti-Mia during the admission course. The second case was a 38-year-old woman with pseudomyxoma peritonei who developed anti-D after receiving four units of RhD-negative RBCs during cytoreductive surgery with hyperthermic intraperitoneal chemotherapy. Both patients did not receive anti-D immunoglobulin and had no previous history of anti-D detection. We retrospectively investigated and found two units of RHD*DEL1 among the RBCs transfused to these patients. Discussion: Previous reports of several cases of anti-D alloimmunization in RhD-negative recipients transfused by RHD*DEL1, an Asian-type DEL, are limited only to East Asia. We first identified 2 patients with anti-D alloimmunization after receiving the RHD*DEL1 RBCs in the Thai population. This raises concern about Rh DEL screening among D-negative Thai blood donors and whether to remove DEL units from the D-negative inventory to improve patient safety.
Neratinib as Extended Adjuvant Treatment of HER2-Positive/HR-Positive Early Breast Cancer Patients in Germany, Austria, and Switzerland: Interim Results of the Prospective, Observational ELEANOR Study
Authors: Harbeck Nadia , Wrobel Denise , Zaiss Matthias , Terhaag Jürgen , Guth Dagmar , Distelrath Andrea , Zahn Mark-Oliver , Würstlein Rachel , Lorenz Andreas , Bartsch Rupert , Breitenstein Urs , Schwitter Michael , Balic Marija , Jackisch Christian , Müller Volkmar , Rinnerthaler Gabriel , Schmidt Marcus , Zaman Khalil , Schinköthe Timo , Resch Anna , Valenti Roberta , Lueftner Diana
Published: October 2023

Introduction: Prognosis of patients diagnosed with HER2+ early breast cancer (eBC) has substantially improved, but distant recurrences impacting quality of life and survival still occur. One treatment option for extended adjuvant treatment of patients with HER2+/HR+ eBC is neratinib, available in Europe for patients who completed adjuvant trastuzumab-based therapy within 1 year. The ELEANOR study is investigating the real-world use of neratinib in Germany, Austria, and Switzerland. Results from an interim analysis of the first 200 patients observed for ≥3 months are reported. Methods: The primary objective of this prospective, multicenter, observational study is to assess patient adherence to neratinib (defined as the percentage of patients taking neratinib on ≥75% prescribed days). Secondary objectives are patient characteristics and treatment outcomes. Results: At cut-off (May 2, 2022), a total of 202 patients had been observed for ≥3 months, with neratinib treatment documented for 187 patients (median age: 53.0 years; 67.9% at increased risk of disease recurrence). In total, 151 (80.7%) patients had received prior neoadjuvant treatment; of these, 82 (54.3%) patients achieved a pathologically complete response. Neratinib was initiated at a median 3.6 months after trastuzumab-based treatment, with 36.4% starting at a dose <240 mg/day. Treatment is ongoing for 46.0% of patients, with median treatment duration of 11.2 (interquartile range 0.9–12.0) months. Diarrhea was the most common adverse event (78.6% any grade, 20.3% grade ≥3); pharmacologic prophylaxis was used in 85.6% of patients. Conclusions: The pattern of anti-HER2 pretreatment observed reflected the current treatment for HER2+/HR+ eBC in Germany, Austria, and Switzerland. These interim results suggest that neratinib as an extended adjuvant is a feasible option after various anti-HER2 pretreatments and that its tolerability can be managed and improved with proactive diarrhea management.
Indication for a Pneumocystis Prophylaxis Therapy in Patients with Vascular Anomalies Treated with PIK3/AKT/mTOR Pathway Inhibitors: Experts’ Opinion and Systematic Review from the Literature
Authors: Navarro Maxime , Allemang-Trivalle Aude , Leducq Sophie , Jonville-Bera Annie-Pierre , Maurier Anaïs , Zejli Tarik , Edée Afi-Emiliène , Harchaoui Emilie , Giraudeau Bruno , Maruani Annabel
Published: October 2023

Background: Vascular anomalies (VAs) are increasingly being treated with PI3K/AKT/mTOR pathway inhibitors. These drugs have immunosuppressive properties and thus theoretically overexpose patients to opportunistic infections, especially Pneumocystis jirovecii pneumonia (PJP). PJP prophylaxis use lacks consensus. We aimed to investigate the prevalence of PJP in patients receiving mTOR/PI3K/AKT inhibitors for VAs and determine any indication for pneumocystis prophylaxis in this population. Methods: The study was conducted in 2 parts: (1) we sent a survey to a panel of international experts of VAs asking about their use of pneumocystis prophylaxis drugs and (2) we performed a systematic review of the literature of all published cases of patients receiving these drugs for VA to estimate the prevalence of PJP in this population. Results: Answers from 68 experts were analyzed: 21 (30.9%) answered they always add PJP prophylaxis when prescribing mTOR inhibitors, 20 (29.4%) case-by-case, and 27 (39.7%) never. For the systematic review, among 3,053 reports screened, 217 were included involving 1,189 patients (1,143 received sirolimus, 38 everolimus, 4 alpelisib, 4 miransertib). Among the 1,189 cases, 2 (0.2%) PJP were reported: one under sirolimus and one under everolimus. Thus, the prevalence of PJP was estimated at 0.88 cases/1,000 patients under sirolimus (95% CI: −0.84 to 2.59) and 26.31 cases/1,000 under everolimus (95% CI: −24.58 to 77.18). Patients with PJP never received prophylaxis drugs. We found no PJP cases under alpelisib and miransertib. PJP prophylaxis was given in 218 (18.3%) cases, more frequently for children (91.3 vs. 77.2% in the non-prophylaxis group, p = 0.012), mostly trimethoprim-sulfamethoxazole (186 patients, 85.3%). Conclusion: Our study shows that even if PJP is a rare event, it may occur in patients with VAs treated with an mTOR inhibitor. Although our results cannot allow for revising guidelines, prophylaxis with TMP-SMX might be appropriate for a subgroup of patients with risk factors for PJP.
The Language-Cognition Interface in Atypical Development: Support for an Integrative Approach
Authors: Stanford Emily , Delage Hélène
Published: October 2023

Background: Links between the mastery of complex syntax and more general cognitive abilities (e.g., working memory [WM] and attention) are widely reported for both typically developing children and children with atypical language development, such as developmental language disorder (DLD). These observations have resulted in debates about whether the locus of breakdown in populations with known syntactic impairment is situated in a specific language system or a more general cognitive system. Recently, a hybrid model of language acquisition, the parallel combination approach (PCA), in which both domain-specific and domain-general processes contribute to language development, was put forward. Summary: Our review, which is the first to examine the validity of the PCA, compares a body of our own work investigating the language-cognition interface in various populations: children with specific learning difficulties, attention deficit hyperactivity disorder (ADHD), and DLD. We report findings from two cross-sectional studies (studies 1 and 2), one priming study (study 3), and two training studies (studies 4 and 5). The results confirm a close link between WM, attention, and syntax, in line with domain-general approaches to language impairment. However, certain findings within this review also reveal that impaired general skills can be found alongside intact syntax, providing support for domain-specific approaches. While these results may initially appear contradictory, we argue that they are perfectly in line with the predictions made by the PCA. Key Messages: Study 1 confirms that clinicians should assess syntax in children with specific learning difficulties to avoid the missed diagnosis of comorbid DLD. Studies 2 and 3 offer perspectives on the differential diagnosis of ADHD and DLD and highlight the advantages of using probe tests and dynamic assessment when evaluating children with suspected syntactic impairment. Studies 4 and 5 describe a novel, empirically validated WM training program that has been shown to lead to syntactic improvements in clinical markers of DLD. Finally, the PCA is also clinically relevant as it underscores that children with the same diagnostic label can present dissimilar cognitive profiles with different sources of breakdown. Collectively, the various studies highlight the intricacy of the relationship between syntax and cognition, which cannot be easily described by traditional single-disciplinary frameworks.
Fluoride Exposure in Community Prevention Programmes for Oral Health Using Nail Clippings and Spot Urine Samples: A Systematic Review and Meta-Analysis
Authors: Eskandari Fatemeh , Kumah Elizabeth Adjoa , Azevedo Liane , Stephenson John , John Sherley , Zohoori Fatemeh Vida
Published: October 2023

Due to practical difficulties in quantifying fluoride exposure in populations, practical and accurate biomarkers can play a major role in the surveillance of fluoride. Among different fluoride biomarkers, spot urine and nail clippings have gained more attention due to their ease of acquisition. However, there is no robust consensus about the accuracy of these biomarkers for the estimation of fluoride exposure. This systematic review and meta-analysis aimed to synthesise evidence on the association between fluoride exposure and the fluoride concentration of spot urine and nail clippings. This review was conducted and reported using the PRISMA Statement. Nine databases (Medline, CINAHL, Web of Science, Scopus, ScienceDirect, Sage Journals Online, Campbell Collaboration, Cochrane Collaboration, and Embase); search engines (Google and Google Scholar); and grey literature were searched up to September 2022. All screening, data extraction, and quality assessments were conducted in duplicate. All experimental and observational research studies that reported the correlation between fluoride exposure and fluoride concentrations of spot urine and/or nail clippings were included. The Mixed-Methods Appraisal tool was used to assess the methodological quality of the included studies. A random effect meta-analysis was carried out to determine the relationship between fluoride exposure and fluoride concentration of biomarkers (i.e., spot urine and nail clippings). Forty-four studies met the inclusion criteria. A total of 694,578 participants were included in this review. Twenty-five studies were included in the meta-analysis. The primary meta-analysis showed a moderate correlation of 0.674 (95% confidence interval [CI]: 0.623–0.725, n = 25) between fluoride intake and fluoride concentration of spot urine and a strong correlation of 0.938 (95% CI: 0.520–1.355, n = 11) between fluoride intake and the fluoride concentration of nail clippings in all age groups. The findings of secondary meta-analyses showed a strong positive correlation between fluoride intake and fluoride/creatinine ratio of spot urine in children (0.929; 95% CI: 0.502–0.991; n = 2). In conclusion, spot urine and nail clippings have the potential to be employed as non-invasively obtained biomarkers in populations. However, due to the scarcity of high quality, relevant studies, more research is needed to establish the validity of these biomarkers.
Intravitreal Injection of Bevacizumab for the Prevention of Postoperative Proliferative Vitreoretinopathy in High-Risk Patients Selected by Laser Flare Photometry
Authors: Gahon Marie , Luc Amandine , Zessler Astrid , Pastor Geoffrey , Angioi-Duprez Karine , Thilly Nathalie , Berrod Jean-Paul , Conart Jean-Baptiste
Published: October 2023

Introduction: To evaluate the effect of an intravitreal injection of bevacizumab at the time of rhegmatogenous retinal detachment (RRD) surgery, on postoperative proliferative vitreoretinopathy (PVR) in high-risk patients selected by laser flare photometry. Methods: This single-center observational retrospective cohort study included 137 consecutive patients who underwent pars plana vitrectomy and gas tamponade for primary RRD with increased aqueous flare between July 2016 and June 2021. From June 2019, an intravitreal injection of bevacizumab was administered as an adjunct to RRD repair. Patients who underwent surgery before this time and who did not receive intravitreal bevacizumab served as controls. The main outcome was the rate of retinal redetachment due to PVR. Results: The median flare value was 22.0 (16.5–36.5) pc/ms in the control group and 28.2 (19.7–41.0) pc/ms in the bevacizumab group (p = 0.063). Eyes treated with bevacizumab were more likely to have macula-off RRD (p = 0.003), grade B PVR (p = 0.038), and worse visual acuity (p = 0.004) than controls. The rate of PVR redetachment was significantly lower in the bevacizumab group (11.1%) than in the control (30.1%) (p = 0.012). This difference was more pronounced after adjusting for potential confounding factors (p = 0.005); the risk of developing PVR was 4.5-fold higher in controls (95% CI, 1.6–12.8). After adjustment, the final median visual acuity was also significantly higher in eyes treated with bevacizumab (p = 0.025). Conclusion: This pilot study provides preliminary evidence that bevacizumab may reduce the risk of PVR-related recurrent RRD and improve visual outcomes in high-risk patients selected by laser flare photometry.
Pediatric Macrocorticotropinoma: Do They Differ from Microcorticotropinoma?
Authors: Yami Channaiah Chethan , Memon Saba Samad , Sarathi Vijaya , Lila Anurag Ranjan , Sankhe Shilpa , Arya Sneha , Karlekar Manjiri , Patil Virendra Ashokrao , Shah Nalini , Bandgar Tushar
Published: October 2023

Introduction: Cushing’s disease (CD) due to macrocorticotropinoma (MC) in children and adolescents is a rare entity with limited information regarding its characteristics. The objective of the study is to describe the clinical, biochemical, imaging, management, outcome, and genetic characteristics of children and adolescents with CD due to MC and compare them with those of microcorticotropinoma (mc). Methods: This retrospective study was conducted at a single tertiary care center. Thirty-two patients with CD and MC (maximum tumor dimension ≥10 mm on imaging) and 65 patients with mc (<10 mm on imaging) aged ≤20 years at presentation were enrolled. Results: Nineteen girls and 13 boys with MC presented at a median (IQR) age of 14.5 (12.0–17.9) years. Patients with MC had higher body mass index-standard deviation score (BMI-SDS) (3.70 ± 2.60 vs. 2.59 ± 2.01, p = 0.04), more frequent neuro-ophthalmic symptoms (25% vs. 9% p = 0.04) and short stature (59% vs. 34%, p = 0.049) but less frequent livid striae (53% vs. 77%, p = 0.01), hypokalemia (12% vs. 36%, p = 0.04), and lower cortisol (nmol/L) to corticotropin (pmol/L) ratio (41.20 vs. 55.74, p = 0.04) than those with mc. The remission (59% vs. 64%, p = 1.0) and relapse (53% vs. 37%, p = 0.26) rates after first-line surgery and remission rate after radiotherapy (RT) were comparable between the two cohorts, whereas time to remission after RT (27 vs. 13 months, p = 0.05) was longer in the MC group. A patient with MC had a pathogenic germline variant in CDH23. Conclusion: In this large monocentric series of pediatric CD, frequent mass effect symptoms and short stature, higher BMI-SDS, less frequent livid striae, and hypokalemia with lower effective cortisol secretion characterize the MC cohort. The outcomes of surgery and RT were similar between the groups except for a longer time to remission after RT in the MC cohort. Germline variants are rare (4%) in pediatric MC.
Regulation of the Endogenous Opiate Signaling Pathway against Oxidative Stress and Inflammation: A Considerable Approach for Exploring Preclinical Treatment of Parkinson’s Disease
Authors: Zhu Wei , Neuwirth Lorenz S. , Cadet Patrick
Published: October 2023

Introduction: Oxidative stress and inflammation are major factors contributing to the progressive death of dopaminergic neurons in Parkinson’s disease (PD). Recent studies have demonstrated that morphine’s biosynthetic pathway, coupled with nitric oxide (NO) release, is evolutionarily conserved throughout animals and humans. Moreover, dopamine is a key precursor for morphine biosynthesis. Method: The present study evaluated a series of preclinical experiments to evaluate the effects of low-level morphine treatment upon neuro-immune tissues exposed to rotenone and 6-OHDA as models of PD, followed by an 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide cell proliferation assay and cell/tissue computer-assisted imaging analyses to assess cell/neuronal viability. Results: Morphine at normal physiological concentrations (i.e., 10−6 M and 10−7 M) provided neuroprotection, as it significantly inhibited rotenone and 6-OHDA dopaminergic insults; thereby, reducing and/or forestalling cell death in invertebrate ganglia and human nerve cells. To ensure that morphine caused this neuroprotective effect, naloxone, a potent opiate receptor antagonist, was employed and the results showed that it blocked morphine’s neuroprotective effects. Additionally, co-incubation of NO synthase inhibitor L-NAME also blocked morphine’s neuroprotective effects against rotenone and 6-OHDA insults. Conclusions: Taken together, the present preclinical study showed that while morphine can attenuate lipopolysaccharide-induced inflammation and cell death, both naloxone and L-NAME can abolish this effect. Preincubation of morphine precursors (i.e., L-3,4-dihydroxyphenylalanine, reticuline, and trihexyphenidyl [THP] at physiological concentrations) mimics the observed morphine effect. However, high concentrations of THP, a precursor of the morphine biosynthetic pathway, induced cell death, indicating the physiological importance of morphine biosynthesis in neural tissues. Thus, understanding the morphine biosynthetic pathway coupled with a NO signaling mechanism as a molecular target for neuroprotection against oxidative stress and inflammation in other preclinical models of PD is warranted.
Life of the B10 Mouse: A View from the Hair Follicles and Tissue Stem Cells
Authors: Sugaya Kimihiko
Published: October 2023

In our series of studies, the changes in the skin characteristics of mice caused by aging were investigated in correlation with the stem cells for keratinocytes and melanocytes in the natural hair cycle until middle age. The aim of the present review was to investigate these characteristics of hair follicles (HFs) at older age and complete the analysis of these changes as a study throughout the mouse lifetime. In addition, stem cells for keratinocytes and melanocytes were evaluated for changes in skin characteristics caused by aging. Postnatal day 200 (P200) appears to be the age of complete maturation of skin and the onset of aging with regard to HFs. Keratin 15-positive keratinocyte stem cells complete their localization as a quantitatively sufficient amount of progenitor in the hair bulge region and orchestrate the regeneration of hairs in every anagen phase thereafter. Although their frequency is low, an unusual structure of HFs, curved HFs, appear for the first time at P200. Thereafter, abnormal hair curvature continues to increase throughout life. In contrast, HF characteristics derived from melanocytes begin to show a high frequency of hypopigmented hair bulbs at P200 and appear to lead to a significant increase in the number of white hairs. Curved HFs and white hairs were considered biomarkers of aging in mice. The number of tyrosinase-related protein 2-positive melanocyte stem cells in the hair bulge is extremely low and may be one cause underlying not only the induction of melanocyte-derived characteristics by aging but possibly also that of keratinocyte-derived characteristics. These results provide insight into the mechanisms of the actions of stem cells on hair regeneration through the aging process.
Kinesin Family Member B18 Is Related to Gastric Mucin Phenotype and Contributes to Gastric Cancer Progression by Regulating Epithelial-Mesenchymal Transition
Authors: Ishikawa Akira , Yasumatsu Ryo , Fukui Takafumi , Kido Aya , Katsuya Narutaka , Sentani Kazuhiro , Kuraoka Kazuya , Oue Naohide , Suzuki Takahisa , Oka Shiro , Kotachi Takahiro , Tanabe Kazuaki , Ohdan Hideki , Ashktorab Hassan , Smoot Duane , Yasui Wataru
Published: October 2023

Introduction: Gastric cancer (GC) remains a common health concern worldwide and is the third leading cause of death in Japan. It can be broadly classified into gastric and intestinal mucin phenotypes using immunohistochemistry. We previously reported numerous associations of kinesin family member (KIF) genes and mucin phenotypes with GC. However, no previous studies have reported on the importance of KIF18B in GC using immunostaining. Thus, in this study, we investigated the expression and functions of KIF18B, which is highly expressed in gastric mucin phenotype GC. Methods: We performed RNA-seq of gastric and intestinal mucin type GCs, and clinicopathological studies of the KIF18B we found were performed using 96 GC cases. We also performed functional analysis using GC-derived cell lines. Result: RNA-seq showed the upregulation of matrisome-associated genes in gastric mucin phenotype GC and a high expression of KIF18B. KIF18B was detected in 52 of the 96 GC cases (54%) through immunohistochemistry. Low KIF18B expression was significantly associated with poor overall survival (p < 0.01). Other molecules that were significantly associated with KIF18B were MUC5AC and claudin 18; these were also significantly associated with the gastric mucin phenotype. KIF18B small interfering RNA (siRNA)-transfected GC cells showed greater growth and spheroid colony formation than the negative control siRNA-transfected cells. Furthermore, expression of snail family transcriptional repressor 1 and cadherin 2 was significantly increased and that of cadherin 1 was significantly decreased in KIF18B siRNA-transfected GC cells. Conclusion: These findings not only suggest that KIF18B may be a useful prognostic marker, but also provide insight into the pathogenesis of the GC phenotype.