bluuebunny/crossref_metadata_2025 huggingface dataset:
TMIC-75. ICAM-1 PROMOTES AN IMMUNOSUPPRESSIVE LANDSCAPE IN GLIOBLASTOMAS BY REGULATING THE PHENOTYPIC POLARIZATION STATE OF TUMOR ASSOCIATED MACROPHAGES
Authors: Gandhi Shreya , Devaraja Kaviya , Mansouri Sheila , Zadeh Gelareh
Published: November 2024

Glioblastoma (GBM) is a fatal adult CNS tumor, with a median overall survival of 12-15 months. Intercellular adhesion molecule 1 (ICAM-1) is a cell adhesion molecule whose expression is significantly greater in the mesenchymal transcriptional subtype of GBMs, whereby it is prognostic. We have previously shown that when ICAM-1 is knocked out in the tumor microenvironment (TME) of immune-competent GBM-bearing mice, these mice showed prolonged overall survival and reduced tumor volume. It is yet to be determined how ICAM-1 expression affects infiltration and functional polarization of tumor-associated macrophages (TAMs) and other immune cells in GBM, and if we can suppress the infiltration of M2-like TAMs into the TME by inhibiting ICAM-1. We used a mouse glioma model with and without knockout (KO) of the ICAM-1 gene and intracranially injected GL261 cells. ICAM-1 KO mice survived longer and had reduced tumor volume relative to wildtype, with survival and volume differences being rescued upon ICAM-1 bone marrow reconstitution. Upon endpoint, we performed cytometry by time-of-flight, and found that ICAM-1 KO tumors harbored a reduction in helper T cells, Tregs, and cytotoxic T cells, but an increased proportion in double-negative T cells relative to ICAM-1 WT tumors. ICAM-1 KO tumors also demonstrated an increased proportion of M1-like TAMs relative to M2-like. These results were validated upon administration of ISIS-3082 to tumor models, an antisense oligonucleotide for which a human-specific form has been fast-track approved for other diseases, that targets ICAM-1 transiently in peripheral immune cells prior to TME infiltration. These findings suggest that ICAM-1 expression influences immune cell infiltration, potentially modulates the functional state of TAMs towards a M1-like state, and that ICAM-1 may be targeted in TAMs to ‘reeducate’ them before entering the TME. This may be translated into clinical practice and combined with standards-of-care to render GBMs more sensitive to treatment.
TMIC-84. MOLECULAR EVOLUTION OF THE TUMOR AND ITS MICROENVIRONMENT AT RECURRENCE
Authors: Hashemi Elaheh , R.L Akshaya , Kumar Anupam , Voong Viva , Wang Lin Lin , Diaz Aaron , Phillips Joanna
Published: November 2024

Changes in the glioma immune microenvironment at recurrence may contribute to disease progression and therapeutic resistance. In prior studies we demonstrated that the circumscribed glioma, pleomorphic xanthoastrocytoma (PXA), was relatively immune enriched including activated cytotoxic CD8+ T cells and Iba1+ microglia/macrophages. While PXA are often low-grade, a significant fraction can recur and progress to higher grade. To determine how the tumor and its immune microenvironment changes with recurrence, we examined a cohort of tumors from patients with multiple resections. Using single-nucleus RNA sequencing (snRNAseq) and spatial molecular imaging we investigate the temporal changes in the tumor and its microenvironment. To begin, we analyzed samples from three patients with paired initial and recurrent tumor. A total of 22,465 immune and non-immune cells were analyzed. Compared to the initial, the recurrent tumor tended to have decreased numbers of T cells and T cells had lower expression of CD2 and GZMA. Pathway analysis for DE genes in TAMs demonstrated enrichment of genes associated with NTRK signaling, while pathways related to aerobic respiration and mitochondrial translation were decreased suggesting a less inflammatory phenotype. Tumor cells at recurrence demonstrated decreased expression of CD274 (PD-L1) and of the chemokine CXCL14, previously identified as a factor driving an anti-tumor CD8+ T cell response. In a cohort of 5 patients with paired initial and recurrent tumors, we observed increased numbers of CD163+ TAMs. Together these data suggest changes in the tumor-associated immune response at recurrence that may be relevant to therapy. Using murine models for the disease we are investigating the factors that regulate these changes.
TMOD-07. DEVELOPMENT AND CHARACTERIZATION OF A SPINAL CORD DIFFUSE MIDLINE GLIOMA MODEL
Authors: Hernandez-Osuna Reyes , Lacalle Andrea , Gonzalez-Huarriz Marisol , Marco-Sainz Javier , Palacios Daniel , Nuin Sara , Morales Sandra , Perez-Larraya Jaime Gallego , Patiño-García Ana , Phoenix Timothy , Hernandez-Lain Aurelio , Lassaletta Alvaro , Blasco Luis , Quincoces Gemma , Collantes Maria , Solano Palma , Alonso Marta M , Labiano Sara
Published: November 2024

Diffuse midline gliomas (DMGs) are very aggressive central nervous system tumors that occur mainly in children and adolescents. Most DMGs develop in the brainstem, but they can also be found in the thalamus and the spinal cord, the latter comprising 4% of all DMGs. Despite advances in current treatments, the outcome for DMG patients remains extremely poor. The success of immunotherapy in other tumors encourages its translation to DMGs, for which the understanding of the tumor immune microenvironment (TIME) is imperative. The field counts with several murine DMG models in the pontine and thalamic locations. However, there is a paucity of spinal cord models. Thus, in this work, we have generated an orthotopic syngeneic model of H3K27M spinal cord DMG by injecting the tumor cells directly into the spinal cord under the T2 vertebra. We monitored tumor growth by bioluminescence and PET using 18F-FDG and 11C-methionine. As the tumor grew, we observed human-like symptoms in the mice, such as hemiplegia and hemiparesis. TIME characterization showed that this tumor model is mainly infiltrated by macrophages and almost devoid of lymphocytes. We are currently delving into the phenotype of these populations by scRNAseq and spatial transcriptomics. In addition, we are comparing our findings with human samples (n=15) to assess whether our model mimics human disease and can serve as a bonafide model of this tumor location. As a proof of concept, treatment of spinal DMG-bearing mice with a TIM-3 antagonist antibody, previously described as effective in pontine DMG-bearing mice, increased the median overall survival. We showed by microPET imaging that anti-TIM-3 administration into the brain ventricles diffuses to the tumor. These results open a path for the characterization of the spinal cord DMG TIME and for testing preclinical treatments in this new model.
TMOD-22. MULTIREGION BIOPSIES AND CORRESPONDING NEUROSPHERE CULTURES REVEAL SPATIAL DIVERGENCE IN GLIOBLASTOMA EVOLUTION
Authors: Salatino Roberto , Geisberg Jacob , Onubogu Ugoma , Romero-Toledo Arantxa , Oakes Banjamin , Szentirmai Oszkar , McDonald Thomas , Michor Franziska , Janiszewska Michalina
Published: November 2024

Spatial organization of normal tissues is key for their function, yet the role of distribution of distinct clones of cancer cells in tumor is not usually studied as a potential vulnerability in cancer. This is of particular interest in glioblastoma (GBM), in which extensive intratumor heterogeneity hampers effectiveness of treatment. To better understand tumor evolution and the complexity of cancer ecosystem in GBM, we performed profiling of biopsies collected from MRI-defined regions of the tumors, spanning the surface, tumor core and deep tumor margins, which drive local recurrence after surgery. To test how spatially distinct biopsies differ in their cancer cell composition and to assess the tumor microenvironment heterogeneity, we took advantage of 5-ALA metabolite fluorescence, which accumulates in GBM cells and allows the surgeon to visualize cancer under blue light. We used it to separate cancer cells (predominantly 5-ALAhigh) from tumor microenvironment (5-ALAlow) and subjected the fractions to bulk and single cell transcriptomics, respectively. We found a gradient of cellular states associated with location in the tumor, with the deep margin samples having more 5-ALAlow cancer cells and generally less defined phenotype. We have also developed neurosphere cultures from our collection of spatially distant biopsies. Despite the selection pressure of the in vitro culture conditions, cells from different regions of the tumor adopted different morphologies, suggesting retention of some of their differential features. The differences between cultures were reflected in metabolism, proliferation, and differential sensitivity to a drug panel. Whole exome sequencing and transcriptomic analysis were also performed to identify the selection bottleneck of culture conditions, establish evolutionary trajectory of the distinct regions and neurosphere cultures, and test how strongly our cultures represent both the 5-ALAhigh and 5-ALAlow subpopulations of GBM cells. Our study identified properties associated with different spatial locations within GBM tumors, which will help uncover the cellular and microenvironmental dependencies that could lead to novel therapeutic targets for this highly heterogeneous tumor.
The Privacy–Equality Synthesis: Framing Reproductive Rights in India
Authors: Pillai Gauri
Published: November 2024

Reproductive rights are typically framed as engaging one’s constitutional right to privacy. However, with increasing contestations around the right to privacy, the right to equality has been proposed as an alternate frame. Often, a choice tends to be constructed between the two. Challenging this, some argue for both privacy and equality to be included in framing constitutional reproductive rights. This approach places emphasis on the combined presence of the two rights. Indian constitutional law offers a third, distinct possibility, moving beyond mere rights addition to reading rights in ‘synthesis’. The synthesis pays close attention to the site of dynamic rights interaction, highlighting the effects of the rights on one another. This method of rights analysis, and its latent potential, remains dormant within constitutional doctrine in India. Resurrecting it, and studying examples of abortion and maternal mortality, I frame reproductive rights through the synthesis between privacy and equality. In functioning as a magnifier, a catalyst and a backstop, the synthesis alters the constitutional imagination of reproductive rights in India while, simultaneously, advancing an insightful paradigm for constitutional reproductive rights globally and rights analyses generally.
Protracted Magma Evolution and Transcrustal Magmatic Plumbing System Architecture at Erta Ale Volcano (Afar, Ethiopia)
Authors: Pin Juliette , Chazot Gilles , France Lydéric , Abily Bénédicte , Gurenko Andrey , Bertrand Hervé , Loppin Alexandra
Published: November 2024

The Afar region is one of the only places on Earth where magmatic continental rifting and associated ongoing break-up processes are exposed onshore. The several active magmatic segments there are characterized by contrasted morphologies, crustal thicknesses, magma production rates, and magma-tectonic styles. In the Erta Ale Range rift segment, extension is magmatically accommodated, making the range the ideal place to study the magmatic behavior of a mature rift segment. Erta Ale Range comprises sub-segments with magma compositions ranging from basalts to rhyolites, but only the Erta Ale Volcano (EAV) sub-segment is active, where only basaltic compositions have been reported so far. Here, we show for the first time protracted differentiation at EAV that is not expressed volcanically at the surface, but is rather accessible via unique cognate gabbroic and microgabbroic blocks, and recorded by mixing with erupted basaltic magmas. These cognate samples record previously unknown mushy and evolved parts of the EAV plumbing system. To constrain their origin and evolution, we measured the major and trace element compositions of the bulk rocks, interstitial glasses, and melt inclusions. We also measured the oxygen isotopic compositions of olivine crystals, interstitial glasses, and melt inclusions. By combining these results with textural relationships and oxy-thermo-barometry calculations, we discuss magma differentiation and storage conditions, as well as magmatic interactions during transport through the crust. Comparison of our results with rhyolite-MELTS thermodynamic models highlights that protracted fractional crystallization is the main process of magma evolution, and when associated with reactive porous flow is capable of forming the evolved compositions observed (up to 75 wt.% SiO2). We also use the model outputs to quantify distinct steps of igneous differentiation in both shallow and deep crustal reservoirs, and we highlight significant interactions with hydrothermally altered wall rocks. We discuss this model within the geological contexts of the Erta Ale Range rift segment and the larger Afar region, and highlight contrasts with mature oceanic systems to argue that the region is not in the final stages of continental break-up.
Deficiency of TET2-mediated KMT2D self-transcription confers a targetable vulnerability in hepatocellular carcinoma
Authors: Jin Yuting , Rao Keqiang , Zheng Jiaojiao , Zhang Xinchao , Luo Yi , He Jing
Published: November 2024

Hepatocellular carcinoma (HCC) has become a leading cause of cancer-related mortality worldwide. Conventional therapies tend to exacerbate comorbidities, liver dysfunction, and relapse, rendering an urgent demand for novel strategy for management of HCC. Here, we reported that DNA dioxygenase TET2 collaborates with histone methyltransferase KMT2D to enable transcription of KMT2D and ARID1A in HCC. Mechanistically, KMT2D and ARID1A are the major epigenetic targets of TET2 through RNA-seq analysis. Moreover, KMT2D recruits TET2 to facilitate self-transcription via oxidation of 5-methylcytosine in promoter, thereby maintaining expression of ARID1A. Physiologically, KMT2D was identified as a tumor suppressor and mediates the antitumor effect of vitamin C in HCC. Tumors with depleted KMT2D present growth advantage over control group. Vitamin C is able to impair tumor growth, which is compromised by deficiency of KMT2D. Furthermore, loss of KMT2D sensitizes HCC tumors to cisplatin with reduced tumor weight and high level of DNA damage. Ultimately, TET2–KMT2D axis correlates with prognosis of patients with HCC. Patients with high amounts of TET2 and KMT2D present better outcome. Our findings not only put forth a heretofore unrecognized mechanism underlying cross-talk between TET2 and KMT2D in mediating self-transcription of KMT2D, but also propose a targetable vulnerability for HCC therapy on the basis of TET2–KMT2D axis.
Partisan belief in new misinformation is resistant to accuracy incentives
Authors: Stein Jonas , Keuschnigg Marc , van de Rijt Arnout
Published: November 2024

One explanation for why people accept ideologically welcome misinformation is that they are insincere. Consistent with the insincerity hypothesis, past experiments have demonstrated that bias in the veracity assessment of publicly reported statistics and debunked news headlines often diminishes considerably when accuracy is incentivized. Many statements encountered online, however, constitute previously unseen claims that are difficult to evaluate the veracity of. We hypothesize that when confronted with unfamiliar content, unsure partisans will form sincere beliefs that are ideologically aligned. Across three experimental studies, 1,344 conservative and liberal US participants assessed the veracity of 20 politically sensitive statements that either confirmed or contradicted social science evidence only known to experts. As hypothesized, analyses show that incentives failed to correct most ideological differences in the perceived veracity of statements. Sixty six to 78% of partisan differences in accuracy assessment persisted even when monetary stakes were raised beyond levels in prior studies. Participants displayed a surprising degree of confidence in their erroneous beliefs, as bias was not reduced when participants could safely avoid rating statements they were unsure about, without monetary loss. These findings suggest limits to the ability of disciplining interventions to reduce the expression of false statements, because many of the targeted individuals sincerely believe them to be true.
Transcriptomic Analysis of the Amygdala in Subjects with Schizophrenia, Bipolar Disorder and Major Depressive Disorder Reveals Differentially Altered Metabolic Pathways
Authors: Zhang Xiaolu , Valeri Jake , Eladawi Mahmoud A , Gisabella Barbara , Garrett Michael R , Vallender Eric J , McCullumsmith Robert , Pantazopoulos Harry , O’Donovan Sinead M
Published: November 2024

Background and Hypothesis

The amygdala, crucial for mood, anxiety, fear, and reward regulation, shows neuroanatomical and molecular divergence in psychiatric disorders like schizophrenia, bipolar disorder and major depression. This region is also emerging as an important regulator of metabolic and immune pathways. The goal of this study is to address the paucity of molecular studies in the human amygdala. We hypothesize that diagnosis-specific gene expression alterations contribute to the unique pathophysiological profiles of these disorders.

Study Design

We used a cohort of subjects diagnosed with SCZ, BPD or MDD, and nonpsychiatrically ill control subjects (n = 15/group), together with our bioinformatic 3-pod analysis consisting of full transcriptome pathway analysis, targeted pathway analysis, leading-edge gene analysis and iLINCS perturbagen analysis.

Study Results

We identified altered expression of metabolic pathways in each disorder. Subjects with SCZ displayed downregulation of mitochondrial respiration and nucleotide metabolism pathways. In comparison, we observed upregulation of mitochondrial respiration pathways in subjects with MDD, while subjects with BPD displayed enrichment of pathways involved in carbohydrate metabolism. Several pathways associated with brain metabolism including immune system processes and calcium ion transport were also differentially altered between diagnosis groups.

Conclusion

Our findings suggest metabolic pathways, including downregulation of energy metabolism pathways in SCZ and upregulation of energy metabolism pathways in MDD, are uniquely altered in the amygdala in these disorders, which may impact approaches for therapeutic strategies.
Continuation versus Interruption of Buprenorphine/Naloxone in Adult Veterans Undergoing Surgery: Examination of Postoperative Pain and Opioid Utilization in a National Retrospective Cohort Study
Authors: Hitt James M. , Elkin Peter L. , de Leon-Casasola Oscar A.
Published: November 2024

Background:

Prescription rates for buprenorphine in opioid use disorder are increasing, and recent guidelines recommend its continuation during and after surgery; however, evidence from clinical outcome studies is limited. The authors tested the hypotheses (1) that perioperative continuation of buprenorphine does not result in higher pain scores and (2) that this approach does not result in higher supplemental postoperative opioid requirements.

Methods:

The Veterans Affairs Corporate Data Warehouse was queried for patients who underwent surgery while being prescribed buprenorphine/naloxone for opioid use disorder between 2010 and 2020. Analysis of the prescription record was used to infer buprenorphine management, and a 3:1 matched control set of patients without buprenorphine prescriptions was generated. The authors examined patients who continued buprenorphine, patients who had buprenorphine interrupted, and control patients. The primary outcome was time-weighted average postoperative pain scores from inpatient and outpatient sources within 72 h of surgery. The secondary outcome was postoperative average daily morphine equivalent opioid requirements within 2 weeks of surgery.

Results:

A total of 1,881 surgical procedures in 1,673 patients taking buprenorphine for opioid use disorder were included; these procedures were matched to 5,748 control patients (5,775 procedures) without a buprenorphine prescription. Among the 1,881 procedures, 1,186 (63%) continued buprenorphine through the perioperative period, while 695 (37%) interrupted buprenorphine. Pain scores (± SD) were clinically similar for all three groups (4.1 ± 1.9 control [n = 3,284], 4.9 ± 2.0 continued buprenorphine [n = 662], and 5.5 ± 1.7 interrupted buprenorphine [n = 419]; P < 0.001). Patients who continued buprenorphine did not require significantly more supplemental opioids as compared to controls (39.7 ± 1.9 mg morphine equivalents/day vs. 36.5 ± 0.7; P = 0.23), and patients who interrupted buprenorphine received more supplemental opioids than those who continued it (74.2 ± 4.5 mg morphine equivalents/day vs. 39.7 ± 1.9, respectively; P < 0.001).

Conclusions:

Continuation of buprenorphine is not associated with higher average pain scores or postoperative opioid requirements, supporting recently published guidelines.
Comparative Analysis of Surgical Outcomes in Separation Surgery vs. Anterior Reconstruction for Metastatic Epidural Spinal Cord Compression
Authors: Amelink Jantijn J.G.J. , Pierik Robertus J.B. , Groot Olivier Q. , Shin John H. , Verlaan Jorrit-Jan , Tobert Daniel G.
Published: November 2024

Study Design.

Retrospectively matched case-control study

Objective.

To compare intraoperative and postoperative outcomes between separation surgery and corpectomy with anterior reconstruction for patients with metastatic epidural spinal cord compression (MESCC).

Summary of Background Data.

The primary goal of surgery for MESCC is to preserve and improve neurological function. Separation surgery may offer a less invasive alternative that still achieves neurological decompression and restores biomechanical stability, enabling surgeons to forego more invasive surgeries, such as corpectomy with anterior reconstruction. However, there is limited literature comparing these two surgical methods.

Methods.

Fifty-six patients aged 18 years or older who underwent either separation surgery followed by stereotactic body radiation therapy (n=28) or corpectomy with anterior reconstruction (n=28) for MESCC from 2017 to 2022 were included. Outcomes included estimated blood loss, operating time, intraoperative blood transfusion and complications. The Mann-Whitney U test was used for continuous data, and Fisher’s exact test for categorical data.

Results.

Patients undergoing separation surgery compared with anterior reconstruction experienced less blood loss (median 500 ml [IQR 300-1,000] vs. 925 ml [IQR 500-1,425]; P=0.036) and shorter operating times (median 214 minutes [IQR 164-281] vs. 286 minutes [IQR 220-328]; P=0.028). Intraoperative blood transfusion occurred in seven patients (25%) in the separation surgery group versus 14 patients (50%) in the anterior reconstruction group (P=0.10). There were no significant differences between both groups with regard to duration of hospitalization, complications, postoperative transfusions, reoperations, or survival (P<0.05).

Conclusion.

Separation surgery was found to have less blood loss and shorter operating times compared with corpectomy with anterior reconstruction. These findings suggest that separation surgery may be a viable therapeutic alternative for MESCC patients currently undergoing more invasive surgical approaches. Future studies should prospectively compare separation surgery and corpectomy with anterior reconstruction to provide additional evidence on their relative effectiveness in managing local tumor control.

Level of evidence:

Treatment benefits, Level IV
Phrenic Nerve Palsy After Posterior Cervical Fusion
Authors: Falconiero Thomas , Viola Anthony , LaGreca Mark , Yeung Caleb M. , Rihn Jeffrey
Published: November 2024

Introduction:

Cervical nerve palsies, most commonly C5, are relatively common following posterior cervical decompression and fusion (PCDF) for the management of cervical myelopathy. However, phrenic nerve palsy following PCDF is a rare complication documented in only one previous case report. The authors present a case of phrenic nerve palsy following PCDF.

Methods and Material:

The patient is a 51-year-old male who presented with cervical myelopathy and radiculopathy as well as cervicalgia of 1 year’s duration. The patient underwent C3–C6 posterior cervical decompression and fusion (PCDF). On postoperative day 5, he was found to have a right C5 nerve palsy, which improved with steroid use and physical therapy. When he returned at 7 weeks postoperatively, the patient had progressive dyspnea. A fluoroscopic exam by pulmonology revealed a right-sided phrenic nerve palsy was the cause of the dyspnea.

Results and Discussion:

Phrenic nerve palsy causing hemi-diaphragmatic paralysis is a rare complication of cervical spine surgery that requires a high degree of suspicion due to the nonspecific signs and symptoms. Our clinical case suggests that surgeons should bear in mind phrenic nerve palsy as a potential complication in patients with respiratory distress following cervical laminectomy.
Performance of the Healthy Aging Brain Care Monitor Self Report in Monitoring Post-Intensive Care Syndrome Among Acute Respiratory Failure Survivors
Authors: Savsani Parth K. , Khan Sikandar H. , Perkins Anthony J. , Wang Sophia , Jawaid Samreen , Moiz Salwa , Monahan Patrick O. , Kroenke Kurt , Gao Sujuan , Khan Babar A.
Published: November 2024

OBJECTIVES:

To describe the performance of the Healthy Aging Brain Care Monitor Self Report (HABC-M SR) in assessment of post-intensive care syndrome (PICS) among Acute Respiratory Failure ICU survivors.

DESIGN:

Secondary data analysis of a randomized controlled trial.

SETTING:

Patients evaluated by a nurse care coordinator in an out-of-hospital setting.

PATIENTS:

English-speaking adults 18 years old or older who were admitted to the ICU with acute respiratory failure requiring invasive or noninvasive mechanical ventilation for greater than or equal to 24 hours.

INTERVENTIONS:

Patients randomized to the intervention arm of the mobile critical care recovery program, a negative trial testing multidisciplinary care to improve quality of life.

MEASUREMENTS AND MAIN RESULTS:

HABC-M SR scale was used to assess PICS in the intervention group at ICU discharge, 3, and 6 months post-discharge. Hospital Anxiety and Depression Scale; Pain, Enjoyment of Life, and General Activity Scale; Timed Up and Go; and Patient-Reported Outcomes Measurement Information System sleep scores were obtained at the same time. Mini-Mental State Examination (MMSE) was administered at baseline and 6 months. ICU survivors reported mild PICS symptoms, which improved over 6 months (mean HABC-M SR scores: baseline [8.5, sd 7.6], 3 mo [5.3 mo, sd 6.6 mo], and 6 mo [5.2 mo, sd 6.9 mo; p < 0.001]). HABC-M SR total score had moderate internal consistency that improved over time (Cronbach’s alpha = 0.78 at baseline and 0.84 at 6 mo). The psychological subscale of HABC-M SR was moderately correlated with standardized scales for mood, pain, and sleep. The cognitive subscale was not significantly correlated with MMSE.

CONCLUSIONS:

While HABC-M SR correlated with mood, physical, and sleep symptoms, the cognitive subscale was less sensitive compared with standardized scales.
Novel immunotherapeutic approaches in lung cancer: driving beyond programmed death-1/programmed death ligand-1 and cytotoxic T-lymphocyte-associated Protein-4
Authors: Resuli Blerina , Kauffmann-Guerrero Diego
Published: November 2024

Purpose of review

In this review, our aim is to highlight the latest novel immunotherapeutic approaches for advanced nonsmall cell lung cancer (NSCLC) beyond anti-programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) and anti- cytotoxic T-lymphocyte-associated Protein-4 (CTLA4).

Recent findings

Immune checkpoint inhibitors (ICIs) revolutionized the treatment of advanced NSCLC. Despite that, patients develop primary or acquired resistance to ICIs. The discovery of novel approaches represents both an unmet need and an opportunity to improve outcomes in these patients.

We summarized the most relevant novel immune checkpoints, many of them in their early phase of testing, to provide a comprehensive overview of the state of the art of immunotherapy in NSCLC beyond PD-1/PD-L1 and CTL-4 inhibitors.
Immune checkpoint inhibitors in driver mutation-positive nonsmall cell lung cancer
Authors: Huber Rudolf M. , Kauffmann-Guerrero Diego
Published: November 2024

Purpose of review

Immune checkpoint inhibitors (ICIs) and targeted therapies have changed the landscape of management of nonsmall cell lung cancer (NSCLC) dramatically. Whereas ICIs in NSCLC without specific driver mutations are well established it is unclear what the place of ICIs in driver mutation-positive NSCLC is. This review summarizes the current view on the use of ICIs in driver mutation-positive NSCLC.

Recent findings

Immune checkpoint inhibition in combination with chemotherapy (and antiangiogenesis) in recurrent driver mutation-positive NSCLC after tyrosine kinase inhibitor therapy may be effective

Currently the role of immune checkpoint inhibitors in driver mutation-positive NSCLC is limited. They can in combination be applied in second and later line settings if no specific therapy is available.
The comparison of clinicopathological characteristics of two distinct manifestations of gastric signet ring cell carcinoma under EUS
Authors: Liu Shanshan , Han Chaoqun , He Qi , Shang Guochen , Jin Yu , Liu Jun , Ding Zhen , Lin Rong
Published: November 2024

Background and Objectives

There are two different endoscopic ultrasonographic manifestations of gastric signet ring cell carcinoma (GSRCC). No studies have been reported on the differences in the clinical profiles of patients based on EUS examination. We aim to study the variations in clinicopathological characteristics between two distinct endoscopic ultrasonographic manifestations of GSRCC.

Methods

A total of 302 patients with GSRCC confirmed by pathological examination who underwent EUS were enrolled in the study. Based on the endoscopic ultrasonographic features, patients were categorized into two groups: type 1, where the entire layer structure disappeared, and type 2, where the layer structure was still present and appeared lymphomatoid. Clinicopathologic features were collected retrospectively and analyzed.

Results

Compared with type 2 patients, type 1 patients tended to develop GSRCC at an older age (P = 0.033) and had higher serum levels of tumor markers and were more likely to experience anemia (P < 0.001) and weight loss (P < 0.001) during the disease progression. Significant increases in the tumor size (P < 0.001), thickness of the affected gastric wall (P < 0.001), and depth of tumor invasion (P < 0.001) were observed in type 1 patients. Furthermore, type 1 patients had higher prevalence of affected blood vessels (P < 0.001), nerves (P < 0.001), lymph nodes (P < 0.001), and peritoneal metastasis (P < 0.001). However, no difference was found in the duration of disease between the two groups, and all deficient mismatch repairs were observed in type 1 patients.

Conclusions

The two distinct endoscopic ultrasonographic manifestations of GSRCC exhibited different clinicopathological characteristics, suggesting that they may represent different subtypes of the disease that require special attention in management strategies.
Lymph Node Inclusion in a Modified Osteomyocutaneous Allograft for Vascularized Composite Allotransplantation: Establishment and Feasibility Assessment in a Pig Model
Authors: Hirsiger Stefanie , Lese Ioana , Arenas Hoyos Isabel , Zubler Cédric , Haberthür David , Hlushchuk Ruslan , Djonov Valentin , Banz Yara , Macek Ana , von Tengg-Kobligk Hendrik , Casoni Daniela , Rieben Robert , Olariu Radu
Published: November 2024

Background:

Representative translational animal models play a key role in vascularized composite allotransplantation (VCA) research. A composite porcine hindlimb flap, previously described, is a relevant preclinical model. However, its bulkiness and the absence of critical immunologic tissues make it less suitable for investigating the unique immunologic features of VCA. We aimed to further develop this model by reducing its bulkiness and by including donor-draining lymph nodes.

Methods:

We conducted an anatomic study by harvesting 11 porcine osteomyocutaneous flaps (4 conventional and 7 modified techniques), which were characterized by computed tomography. Furthermore, 8 allotransplantations were performed in Swiss landrace pigs. After the procedure, animals were assigned to a model development and control group (N = 4 per group). No immunosuppression was given, and animals were followed up until grade 3 rejection.

Results:

With the modified technique, the flap weight was significantly reduced with a mean weight of 831 g, corresponding to 1.8% total body weight versus 1710 g in the conventional technique, representing 4.2% of total body weight (P < 0.0001). The muscle/bone ratio was reduced from 8.24 (conventional) to 2.92 (modified), (P = 0.03). Histologically, graft-draining lymph nodes showed typical changes related to rejection and no signs of ischemia after in vivo transplantation.

Conclusions:

By modifying the surgical technique, the bulkiness of the flap was markedly reduced, without impairing its vascularization and reliably including vascularized graft-draining lymph nodes. Our modified VCA model in the pig presents distinct advantages for surgery as well as immunologic analysis, warranting a large-scale use for experimental reconstructive transplantation studies.
Adherence to antihypertensive medications in Omani patients: a comparison of drug biochemical analysis and the Morisky Medication Adherence Scale
Authors: Al-Ani Abdullah , Al Suleimani Yousuf , Ritscher Sabrina , Toennes Stefan W. , Al-Hashar Amna , Al-Zakwani Ibrahim , Al Za’abi Mohammed , Al Hashmi Khamis
Published: November 2024

Background:

Medication nonadherence is a major risk factor for suboptimal or failed hypertension pharmacologic therapy.

Objective:

To determine the nonadherence rate to antihypertensive medications using high-performance liquid chromatography–tandem mass spectrometry (LC–MS/MS) and the self-reported Morisky Medication Adherence Scale (MMAS).

Methods:

This study used a prospective cross-sectional cohort design. Patients with hypertension aged ≥18 years and prescribed at least one antihypertensive medication were recruited from an outpatient hypertensive clinic at a tertiary healthcare institution in Oman. Adherence was assessed using LC–MS/MS urine analysis and the MMAS.

Results:

In total, 162 patients completed the MMAS questionnaire and provided urine samples for LC–MS/MS analysis. The overall mean age of the cohort was 55 ± 13 years, and 57% of the patients were men. The mean systolic and diastolic blood pressures were 146 ± 18 mmHg and 79 ± 10 mmHg, respectively. Using the MMAS method, 65% of the patients reported nonadherence. However, LC–MS/MS analysis revealed that only 27% of the patients were nonadherent. The adherent group by LC–MS/MS had significantly lower systolic (P = 0.026) and diastolic blood pressures (P < 0.001) than the nonadherent group, whereas no differences were observed using the MMAS method. There was weak or no agreement between the MMAS and LC–MS/MS results (P = 0.142).

Conclusion:

Almost one-fourth of our patients with hypertension were nonadherent to their medications. There was a weak concordance between the MMAS and LC–MS/MS methods in detecting medication nonadherence. Further research into noninvasive convenient adherence scales or methods and their correlations with LC–MS/MS analysis is warranted.
Relationship between blood pressure variability and blood pressure phenotypes: a home blood pressure monitoring study
Authors: Alves Marco A.M. , Bezerra Rodrigo , Dal Pont Christian S. , Mota-Gomes Marco A. , Paiva Annelise M.G. , Barroso Weimar S. , Miranda Roberto D. , Barbosa Eduardo C.D. , Brandão Andréa A. , Lima-Filho José L. , Coca Antonio , Sposito Andrei C. , Feitosa Audes D.M. , Nadruz Wilson
Published: November 2024

Objective:

Home blood pressure (BP) variability (BPV) and BP phenotypes such as white-coat hypertension (WCH), white-coat uncontrolled hypertension (WUCH), masked hypertension (MH) and masked uncontrolled hypertension (MUCH) are predictors of adverse cardiovascular events. This study compared home BPV across BP phenotypes built from abnormal office BP (OBP) and home BP monitoring (HBPM) thresholds defined by three distinct societies [European Society of Hypertension (ESH): OBP ≥ 140/90 mmHg and HBPM ≥ 135/85 mmHg; American College of Cardiology/American Heart Association (ACC/AHA): OBP and HBPM ≥ 130/80 mmHg and Brazilian Society of Cardiology (BSC): OBP ≥ 140/90 mmHg and HBPM ≥ 130/80 mmHg].

Methods:

This cross-sectional study evaluated 51 194 treated (37% men, age = 61 ± 15 years) and 56 100 untreated (41% men, age = 54 ± 16 years) individuals from 1045 Brazilian centers who underwent OBP and HBPM measurements. Systolic and diastolic home BPV were estimated as the: standard deviation, coefficient of variation, and the variability independent of the mean of HBPM.

Results:

Results of adjusted analysis showed that home BPV parameters were significantly greater in individuals with WCH/WUCH according to the BSC criteria, in those with MH/MUCH defined by the ACC/AHA criteria, and tended to be greater in individuals with either MH/MUCH or WCH/WUCH defined by the ESH criteria.

Furthermore, restricted cubic spline analysis showed a U-shaped association between BPV and the difference between OBP and HBPM in treated and untreated individuals.

Conclusion:

Home BPV was greater in WCH/WUCH and/or MH/MUCH depending on the criteria used to define abnormal OBP and HBPM thresholds. These findings underscore the need to standardize abnormal BP criteria in clinical practice.
NEURORETINITIS ASSOCIATED WITH COVID-19 INFECTION AND VARICELLA-ZOSTER VIRUS REACTIVATION
Authors: Gavrić Ana Uršula , Mylemans Evelien Margareta , Valentinčič Nataša Vidovič
Published: November 2024

Purpose:

To report a case of neuroretinitis as the presenting manifestation of COVID-19 infection alongside VZV reactivation, in the absence of other systemic symptoms.

Methods:

A case report.

Results:

A previously healthy 15-year-old male presented with a one-week history of acute unilateral visual loss and clinical findings consistent with neuroretinitis. Diagnostic work-up revealed a positive nasopharyngeal swab PCR for COVID-19 and serology showed the presence of IgM and IgG antibodies for VZV. Following a comprehensive treatment regimen involving intravenous acyclovir, high-dose intravenous steroids and oral doxycycline, rapid and remarkable improvements were observed. The macular star and optic disc swelling regressed, and visual acuity improved from 20/200 to 20/20.

Conclusion:

This case offers valuable insights into the neuroretinitis associated with COVID-19 infection and VZV reactivation.
Risk of zonular dialysis in fellow eye cataract surgeries: multicenter comparative study
Authors: Elhusseiny Abdelrahman M. , Ibrahim S. Nazem , Toma Joseph , Yang Yit C. , Sallam Ahmed B.
Published: November 2024

Purpose:

To evaluate the risk of zonular dialysis (ZD) in fellow eye phacoemulsification cataract surgery and to identify risk factors, including prior first eye ZD.

Setting:

8 United Kingdom National Health Service clinical centers.

Design:

Retrospective database study.

Methods:

Overall risk of ZD in the fellow eye was calculated and the odds ratio (OR) for the various risk factors was reported, including first eye ZD. The main outcome measures were the risk and the predictors of intraoperative ZD in the fellow eye.

Results:

There was a total of 66 288 patients. At the time of the first surgery, the mean age of patients was 75.3 ± 10.2 years and 39.2% were male. Intraoperative ZD occurred during the first eye surgery in 333 patients (0.5%) and the fellow eye in 349 patients (0.5%). The risk of fellow eye developing ZD in patients with first eye ZD was higher than in patients without first eye ZD: 23 of 333 patients (6.9%) vs 326 of 65 955 patients (0.5%) (unadjusted OR 14.9, P < .001). In the adjusted logistic regression model, first eye ZD was the most significant risk factor (OR 13.3, 95% confidence interval [CI] 8.2-21.7). Other significant covariates of ZD in the fellow eye were pseudoexfoliation (OR 6, 95% CI 3.8-9.7), previous pars plana vitrectomy (OR 4.5, 95% CI 1.1-18.5), and poor pupillary dilation (OR 2.2, 95% CI 1.4-3.3).

Conclusions:

The most important risk factor for the development of ZD in the fellow eye during cataract surgery was the occurrence of ZD in the first eye. These findings have implications for patient counseling and surgery allocation.
Ocular shape of cataract with retinitis pigmentosa: case-control study
Authors: Iida Masanobu , Masuda Yoichiro , Ohira Ryo , Ichihara Kosuke , Komatsu Koji , Shiba Takuya , Iwaki Hisaharu , Oki Kotaro , Nakano Tadashi
Published: November 2024

Purpose:

To investigate the anterior segment morphology in cataracts with retinitis pigmentosa (RP).

Setting:

The Jikei University Hospital.

Design:

Retrospective matched case-control study.

Methods:

The analysis included 28 eyes of 28 patients with cataracts and RP and 28 eyes of 28 patients with cataracts but without RP, matched for age and sex. Lens thickness, anterior lens curvature (Front R), posterior lens curvature, anterior chamber depth (ACD), anterior chamber width, central corneal thickness (CCT), white-to-white (WTW) distance, corneal curvature, and axial length (AL) were compared between the groups. Data were obtained from preoperative evaluations conducted before cataract surgery. The same set of comparisons was also conducted for 18 eyes of 18 patients with cataracts and RP and 18 eyes of 18 patients with cataracts but without RP, matched for age, sex, and AL. Cases with missing data, categorized as Emery-Little classification grade 4 or above, or those with a history of acute angle closure were excluded.

Results:

In the age and sex-matched analysis, cataracts with RP showed a significantly thicker lens, steeper Front R, shallower ACD, thinner CCT, and shorter AL. In the analysis matched by age, sex, and AL, cataracts with RP had a thicker lens, steeper Front R, and larger WTW distance.

Conclusions:

Cataracts with RP demonstrated centripetal swelling of the lens, centrifugal corneal thinning, and AL shortening. A decrease in tension between the lens and eyeball wall because of zonular weakness in the RP may lead to swelling of the lens and horizontal flattening of the eyeball.
Effects of Procedural Information, Buzzy, and Multiple Interventions on Pain in Children Undergoing Venipuncture: A Randomized Controlled Trial
Authors: KAHRIMAN Ilknur , MERAL Buket , COLAK Bahar , BEKTAS Meral , KIRBAS Zila Özlem , ARICI Yeliz Kasko
Published: November 2024

Background

Needle-related procedures are commonly performed in childhood and lead to considerable pain.

Purpose

This randomized controlled study was conducted to compare the effects on venipuncture pain of the Buzzy, an informational animated video, multiple interventions, and standard care in children aged 6–12 years.

Methods

One hundred eighty children were assigned to the groups using a computerized randomization program. Pain level was evaluated by the children, parents, and their nurses using the Wong–Baker Faces Pain Scale. The level of agreement among the nurse, parents, and children's pain reports was evaluated. Multivariable regression analysis was performed to identify the factors significantly associated with pain score.

Results

The participants in the Buzzy, video watching, and multiple intervention groups reported lower mean pain scores (child: KW = 28.24, p < .001; parent: KW = 18.51, p < .001; nurse: KW = 44.4, p < .001) than their peers in the control group. Moreover, age was identified as a risk factor affecting pain level (OR = 1.375, 95% CI [1.086, 1.740]; p = .008).

Conclusions

Buzzy and informational videos are potentially effective methods to facilitate venipuncture-related pain management in children. The use of pain management methods during venipuncture is recommended, especially in children younger than 10 years old.
Clinical efficacy and outcomes of calcitriol combined with bisphosphonates in the treatment of postmenopausal osteoporosis: A quasi-experimental study
Authors: Han Kui , Wang Xiaoyan
Published: November 2024

Background:

A quasi-experimental study was conducted to investigate the clinical efficacy and outcomes of calcitriol combined with bisphosphonates in the treatment of postmenopausal osteoporosis (OP).

Methods:

A total of 152 patients with postmenopausal OP from March 2019 to June 2021 were enrolled. The patients who received calcitriol treatment were adopted as the control group, and the patients treated with calcitriol combined with bisphosphonates were considered as the intervention group. The treatment effects of patients were compared, and the pain degree of the joints of the patients was evaluated by Visual Analogue Scale/Score (VAS), the Barthel Index score was used to evaluate the daily living ability of patients, the hand and Oswestry Disability Index (ODI) were used to evaluate the dysfunction before and after treatment, and the bone metabolism indexes, immune cytokines and bone mineral density were detected before and after treatment, and the incidence of adverse reactions was calculated.

Results:

Regarding the therapeutic effects, the intervention group indicated an effective rate of 96.05% while the effective rate was 84.21% in the control group. The total effective rate of treatment in the intervention group was higher than the control group. The VAS, ODI scores, and bone metabolism indexes of the intervention group were significantly lower than the control group at 1, 2, and 3 months after treatment. The Barthel Index scores and bone mineral density of the intervention group were higher than the control group at 1, 2, and 3 months after treatment. The improvement of immune cytokines in the intervention group was significantly better than the control group (P < .05). One patient in the intervention group developed dizziness and 1 patient developed chills, with an adverse reaction rate of 2.63%, while in the control group, 2 patients had fever, and 2 patients developed chills, with an adverse reaction rate of 5.26% (P > .05).

Conclusion:

Calcitriol combined with bisphosphonates has a significant clinical effect in the treatment of postmenopausal OP, which can significantly relieve bone pain in postmenopausal OP patients, enhance abnormal bone metabolism and immune function, and promote bone mineral density and daily living ability.