Clinical Treatment Course Research Articles

Low Thrombosis Risk CALR Mutations Confer Higher Risk of Essential Thrombocythemia Progression

Background: Patients (pts) with essential thrombocythemia (ET) face increased risk of thrombosis and the prospect of progression to myelofibrosis (MF) or acute leukemia. ET treatment recommendations from ELN 1 and NCCN 2 are largely governed by the revised IPSET-thrombosis score that identifies 4 risk categories from “very low” to “high” based on age, thrombosis history, and the presence of a JAK2 V617F mutation 3. Pts with CALR-mutated ET are known to have a lower risk of thrombosis than those with a JAK2 mutation, and for this reason, are often considered to have lower risk ET. Yet previous study of pts with clinically diagnosed ET found that CALR mutations may negatively impact progression risk 4. For this reason, we evaluated the impact of driver mutations on the risks of thromboembolic events, disease progression, and overall mortality for a cohort of pts with rigorously defined WHO ET treated at our institution. Methods: Medical records were queried for pts with the diagnosis (dx) of ET, as per ICD, code versions 9-10. The dx of ET and dx date were confirmed by manual review. All pts met the 2022 WHO criteria for ET, including a diagnostic marrow in all cases. Confounding diagnoses, including pre-fibrotic MF, polycythemia vera, or presumed ET in pts lacking a marrow biopsy, were strictly excluded by thorough review of the rich data available. Structured query language supplemented by manual review was used to extract clinical, laboratory, molecular, and marrow findings and treatment course. Overall (OS), MF-free (MFS), and thrombosis-free (TFS) survival were estimated using Kaplan-Meier methods. Univariable and multivariable analysis of post-ET MF (PETMF), thrombosis and mortality risk were performed using Cox proportional-hazards models using IPSET-survival 5 and revised IPSET-thrombosis variables as covariates. Results: The query returned 751 pts but only 338 met our strict criteria for ET with diagnostic marrows and had annotated driver mutations. Of these, 216 (64%) were positive for JAK2 V617F, 85 (25%) CALR, 19 (6%) MPL, and 18 (5%) triple negative (TN). We identified no significant differences among the driver mutation cohorts in dx age, sex, or median follow up duration. Semi-quantitative features of the diagnostic marrow biopsies, including age-adjusted cellularity and reticulin fibrosis score, were not significantly different among the groups. Red cell parameters at dx were mildly higher in the JAK2 pts (HCT, HGB, RBC all with p<0.001), WBC count was highest in TN pts ( p=0.012), and PLT count was not significantly different ( p=0.064). 20-year TFS for JAK2 was 71%, CALR 100%, MPL 90% and TN 83% ( p=0.0027, Figure 1); 20-year MFS for JAK2 was 87%, CALR 48%, MPL 65% and TN 94% ( p=0.00053, Figure 2); 20-year OS for JAK2 was 76%, CALR 86%, MPL 89% and TN 90% ( p=0.66). Multivariable analysis showed that CALR was associated with a significantly higher risk of PETMF as compared to JAK2 (HR 11.52, CI 1.88-70.51, p=0.008), independent of age, sex, WBC, and thrombosis history. Conversely, CALR was associated with a lower risk of thrombosis (HR 0.08, CI 0.01-0.58, p=0.013) when adjusting for sex and revised-IPSET thrombosis parameters. Discussion: We found that although pts with CALR-mutated ET have lower thrombosis risk, they experience higher risk of progression to MF. Current risk models for thrombosis yield treatment recommendations well suited to reducing thrombosis risk 3. With this success, pts are expected to live with ET for decades, thereby exposing them to other ET risks, most notably that of malignant disease progression. These risks are of particular concern for younger pts who suffer the greatest relative risk 6. It is important that thrombosis risk and fibrosis risk are not conflated as our data suggest that pts with low or very low risk CALR-mutated ET can be at higher risk of progression. Our findings reinforce the need for long-term data to guide therapy for ET based not only on the near-term thrombotic risk, but also on the long-term risk of progression.

(Epi)genotype and Timing of Tongue Reduction Predict Safety and Long-Term Outcomes in Beckwith-Wiedemann Syndrome.

Macroglossia is a cardinal feature of Beckwith-Wiedemann syndrome (BWS) with a clinical spectrum where the indication and timing for surgery remain to be validated. This study leverages a cohort of molecularly characterized patients with BWS to correlate epigenetic diagnosis with phenotype and treatment outcome. Patients with BWS seen in consultation for macroglossia from 2009-2022 were reviewed for phenotype, molecular diagnosis, tongue reduction status, timing of surgery (early = under 12 months), and perioperative complications. Two hundred thirty-seven patients were included. Imprinting control region 2 loss of methylation (IC2 LOM) was the most common epigenotype (61%). Paternal uniparental isodisomy for chromosome 11 (pUPD11) comprised a larger proportion of patients undergoing tongue reduction (18%) than those not undergoing surgery (8%, p = 0.024) and was associated with need for repeat surgery (OR 4.49, 95% CI 1.06-18.98, p = 0.041). Complications including wound dehiscence, ventilator associated pneumonia, and unplanned extubation were more common in patients undergoing early surgery (20%) than late surgery (4%, OR 5.70, 95% CI 1.14-28.55, p = 0.034). This study presents one of the largest cohorts correlating molecular diagnosis with clinical course of macroglossia treatment in BWS. Macroglossia in patients with pUPD11 is associated with higher rates of reoperation. Relief of obstructive sleep apnea with early tongue reduction must be weighed against risk of perioperative complications, most of which are non-surgical. This study highlights how molecular diagnosis advances clinical care by risk stratifying clinical outcomes in a center providing integrated multidisciplinary care for the BWS population.

Target Re-Delineation in Daily Online Adaptive Radiotherapy of Bladder Cancer: AI vs. Adapters

The purpose was to assess the quality of artificial intelligence (AI) generated targets in cone-beam CT (CBCT) guided online adaptive radiotherapy (oART) of bladder cancer and compare it to corresponding contours edited by adapters (radiotherapy technicians performing oART routinely). Furthermore, to assess the inter-observer delineation variation in daily target re-delineation in oART of bladder cancer. Ten consecutive patients treated with oART for muscle-invasive bladder cancer from Feb 2020 to Feb 2021 were retrospectively included. One CBCT randomly selected from each of the 10 clinical treatment courses was exported to an emulator, where delineations and oART simulations were carried out. The bladder was automatically segmented (clinical target volume (CTV)) using AI. Seven adapters independently reviewed and, if necessary, manually edited the AI-generated structure. A ground truth structure was first delineated blindly by a senior oncologist, then reviewed by an oART experienced medical physicist, and finally edited to a consensus structure. Planning CT and MR images with reference delineations were available during all simulations and delineations. The AI-generated and adapter-edited CTVs were compared to ground truth using dice similarity coefficient (DSC) and volume difference. The inter-observer variation in adapter-edited CTVs was assessed using coefficient of variation (CV) and the generalized conformity index (CIgen). Cigen was calculated as the ratio of the sum of all overlapping volumes between pairs of observers and the sum of all overlapping and non-overlapping volumes between the same pairs. Nine CTVs (7 adapter-edited, 1 AI-generated, 1 ground truth) were generated per patient. Patient cases included three male and seven females; three had catheter. The ground truth volume ranged from 51.5 to 221.6 cc. The median volume difference compared to ground truth was -4.5 (range, -17.8 - 42.4) cc and -15.5 (range, -54.2 - 4.3) cc for adapter-edited and AI-generated structures, respectively. Corresponding DSC values were 0.87 (range, 0.71 - 0.95) and 0.84 (range, 0.64 - 0.95). The AI-generated CTV was smaller than ground truth for all patients except one and smaller than all adapter-edited CTVs. The largest differences among adapter-edited CTVs were observed in cranial, caudal and posterior directions. The median CV was 0.08 (range, 0.05-0.11) and Cigen was 0.78 (range, 0.71-0.88). Target re-delineations in daily CBCT-based oART of bladder cancer demonstrated small inter-observer variation. Manual adjustment of AI-generated structures resulted in improved accuracy in target delineation compared to ground truth. Efforts to reduce the inter-observer variation, e.g., physician support during the initial fractions and review by a second adapter, have been implemented clinically.

TP53 mutations identify high-risk events for peripheral T-cell lymphoma treated with CHOP-based chemotherapy.

Nodal peripheral T-cell lymphomas (PTCL), the most common PTCLs, are generally treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)-based curative-intent chemotherapy. Recent molecular data have assisted in prognosticating these PTCLs, but most reports lack detailed baseline clinical characteristics and treatment courses. We retrospectively evaluated cases of PTCL treated with CHOP-based chemotherapy that had tumors sequenced by the Memorial Sloan Kettering Integrated Mutational Profiling of Actionable Cancer Targets next-generation sequencing panel to identify variables correlating with inferior survival. We identified 132 patients who met these criteria. Clinical factors correlating with an increased risk of progression (by multivariate analysis) included advanced-stage disease and bone marrow involvement. The only somatic genetic aberrancies correlating with inferior progression-free survival (PFS) were TP53 mutations and TP53/17p deletions. PFS remained inferior when stratifying by TP53 mutation status, with a median PFS of 4.5months for PTCL with a TP53 mutation (n= 21) vs 10.5months for PTCL without a TP53 mutation (n= 111). No TP53 aberrancy correlated with inferior overall survival (OS). Although rare (n= 9), CDKN2A-deleted PTCL correlated with inferior OS, witha median of 17.6months vs 56.7months for patients without CDKN2A deletions. This retrospective study suggests that patients with PTCL with TP53 mutations experience inferior PFS when treated with curative-intent chemotherapy, warranting prospective confirmation.

Is Toxoplasma gondii infection a concern in individuals with rheumatic diseases? Evidence from a case-control study based on serological diagnosis

Toxoplasma gondii infection in clinical cases of rheumatic diseases is increasing, whereas, the relationship between T. gondii infection and rheumatic diseases is still ambiguous and contradictory. Thus, the present case-control study based on serological diagnosis was carried out to identify the underlying relationship between T. gondii infection and rheumatic diseases in China. Serological results showed that rheumatic patients (17.25%, 79/458) had a significantly higher T. gondii seroprevalence than control subjects (10.70%, 49/458) (p = 0.004). However, the difference in T. gondii seroprevalence among clinical rheumatic disease forms was insignificant. Moreover, disease duration not effect the T. gondii seroprevalence in the included clinical rheumatic patients. Three risk factors (presence of cats at home, blood transfusion history, and consumption of raw shellfish) were identified through multivariate analysis to affect the T. gondii seroprevalence in the included clinical rheumatic patients. In conclusion, these results indicate that the latent T. gondii infection in clinical rheumatic patients should cause alarm and attention in the course of future scientific research or clinical treatment.

Clinical Phenotypes and the Clinical Course of Bullous Pemphigoid Receiving Dipeptidyl Pepitidase-4 Inhibitor Treatment: An Analysis of Cases in a Single Japanese Center.

Objective Several studies have shown an increased risk of bullous pemphigoid (BP) when receiving dipeptidyl pepitidase-4 inhibitor (DPP-4i) treatment. The present study explored the associations of DPP-4i treatment with the clinical phenotypes and clinical course of BP. Methods We analyzed data of 146 patients with BP at Tokai University School of Medicine from December 1, 2009, to December 31, 2021. We obtained data by a retrospective medical record review and compared the bullous pemphigoid disease area index (BPDAI) between diabetes patients receiving DPP-4i treatment and those not receiving DPP-4i treatment. We employed multivariable linear regression models to explore the association between the DPP-4i treatment and the BPDAI scores. Results Among 53 BP patients with diabetes, 33 had developed BP during treatment with DPP-4i agents, among which vildagliptin was the most frequently used. The urticaria/erythema scores of the BPDAI were significantly lower in patients who developed BP while receiving DPP-4i treatment than among others. Of note, 69.2% of the patients who stopped DPP-4i treatment experienced complete remission, and the clinical course was more favorable in patients with lower scores for urticaria/erythema than among others. Conclusion These findings suggest that, in patients who developed BP while receiving DPP-4i treatment, a noninflammatory phenotype may indicate a high likelihood that DPP-4i treatment contributes to the development of BP. The discontinuation of DPP-4i should be carefully considered in close consultation with dermatologists.

Brainstem Infarction in Immunodeficiency Identified as Adenosine Deaminase 2 Deficiency: Case Report.

We present the case of a 24-year-old male with CNS granulomatosis due to an immunodeficiency syndrome which was identified as deficiency of adenosine deaminase 2 (DADA2) as a cause of brainstem infarction. Case report and detailed description of the clinical course of diagnosis and treatment. The patient's medical history consisted of an unknown immunodeficiency syndrome. Based on former findings, common variable immunodeficiency (CVID) was diagnosed. The patient suffered from three consecutive brainstem strokes of unknown etiology within 3years. An MRI scan detected gadolinium-enhancing, granulomatous-suspect lesions in the interpeduncular cistern, temporal lobe, and tegmentum. Laboratory analysis was compatible with CVID, with leukopenia and immunoglobulin deficiency. Because granulomatous CNS inflammation was suspected, the patient received methylprednisolone immunosuppressive therapy, which led to partially regressive MRI lesions. However, in contrast to imaging, the patient showed a progressive cerebellar syndrome, indicating plasma exchange therapy and immunoglobulin treatment, which led to rapid symptom amelioration. After a relapse and a further stroke, expanded analysis confirmed DADA2 (and not CVID) as the inflammatory cause for recurrent stroke. After starting the therapy with immunoglobulins and adalimumab, no further strokes occurred. We present the case of a young adult with diagnosis of DADA2 as a cause for recurrent strokes due to vasculitis. This stroke etiology is rare but should be considered as a cause of recurrent stroke of unknown origin in young patients to avoid a disabling disease course by disease-specific treatment options.

Distinct genomic features between osteosarcomas firstly metastasing to bone and to lung

BackgroundOsteosarcoma initially metastasing to bone only shows distinct biological features compared to osteosarcoma that firstly metastasizes to the lung, which suggests us underlying different genomic pathogenetic mechanism. MethodsWe analyzed whole-exome sequencing (WES) data for 38 osteosarcoma with paired samples in different relapse patterns. We also sought to redefine disease subclassifications for osteosarcoma based on genetic alterations and correlate these genetic profiles with clinical treatment courses to elucidate potential evolving cladograms. ResultsWe investigated WES of 12/38 patients with high-grade osteosarcoma (31.6%) with initial bone metastasis (group A) and 26/38 (68.4%) with initial pulmonary metastasis (group B), of whom 15/38 (39.5%) had paired samples of primary lesions and metastatic lesions. We found that osteosarcoma in group A mainly carries single-nucleotide variations displaying higher tumor mutation burden and neoantigen load and more tertiary lymphoid structures, while those in group B mainly exhibits structural variants. High conservation of reported genetic sequencing over time in their evolving cladograms. ConclusionsOsteosarcoma with mainly single-nucleotide variations other than structural variants might exhibit biological behavior predisposing toward bone metastases as well as better immunogenicity in tumor microenvironment.

The clinical impacts of postoperative complications after colon cancer surgery for the clinical course of adjuvant treatment and survival

AimWe investigated whether or not postoperative complications (POCs) themselves have a negative survival impact or indirectly worsen the survival due to insufficient adjuvant chemotherapy in a pooled analysis of two large phase III studies performed in JapanPatients and methodsThe study examined the patients who enrolled in 1304, phase III study comparing the efficacy of 6 and 12 months of capecitabine as adjuvant chemotherapy for stage III colon cancer patients and in 882, a phase III study to confirm the tolerability of oxaliplatin, fluorouracil, and l-leucovorin in Japanese stage II/III colon cancer patients. In our study, POCs were defined as the following major surgical complications: anastomotic leakage, pneumonia, bowel obstruction/ileus, surgical site infection, postoperative bleeding, urinary tract infection, and fistula. Patients were classified as those with POCs (C group) and those without POCs (NC group).ResultsA total of 2095 patients were examined in the present study. POCs were observed in 169 patients (8.1%). The overall survival (OS) rates at 5 years after surgery were 75.3% in the C group and 86.5% in the NC group (p = 0.0017). The hazard ratio of POCs for the OS in multivariate analysis was 1.70 (95% confidence interval, 1.19 to 2.45; p = 0.0040). The time to adjuvant treatment failure (TTF) of adjuvant chemotherapy was similar between the groups, being 68.6% in the C group and 67.1% in the NC group for the 6-month continuation rate of adjuvant chemotherapy. The dose reduction rate of adjuvant chemotherapy and adjuvant treatment suspension rate were also similar between the groups (C vs. NC groups: 45.0% vs. 48.7%, p = 0.3520; and 52.7% vs. 55.0%, p = 0.5522, respectively).ConclusionPOCs were associated with a poor prognosis but did not affect the intensity of adjuvant chemotherapy. These results suggested that POCs themselves negatively influence the survival.

Abstract 5592: Expansion and characterization on ALK positive NSCLC circulating tumor cells isolated using a size based inertial microfluidic Labyrinth device

Abstract Introduction Lung cancer (LC) is the leading cause of cancer deaths. 85% of LC are non-small cell lung cancer (NSCLC). Fusions involving anaplastic lymphoma kinase (ALK) are oncogenic drivers in ~ 7% of NSCLC. Previous studies have shown that drug resistance develops within ~2 years after ALK tyrosine kinase inhibitor targeted therapy. Due to resistance mechanisms and the biological heterogeneity that evolves over the treatment of ALK+ NSCLC, it is important to monitor and study those dynamic changes through the clinical treatment course to understand cancer progression. Circulating tumor cells (CTCs) are rare cells, shed from cancer lesions into the bloodstream. They can be isolated from a patient's peripheral blood sample (~20ml) to enable study of tumor characteristics at multiple time points. They are promising biomarkers that not only offer phenotypic and genotypic information, but also present a potential to expand into patient derived ex vivo tumor models. In this study, we use a high throughput label-free microfluidic device, Labyrinth, developed in the Nagrath lab for cell size based CTC enrichment, followed by expansion of CTCs in organoid models, further molecular characterization, and growth in patient-derived xenograft (PDX) models. Methods Blood samples were collected from patients (n=22), three with known ALK status. CTC isolation was performed using Labyrinth at 2.0 mL/min. A part of the isolated CTCs were immunofluorescently stained for pan cytokeratin (pan CK), CD45, DAPI, epithelial cell adhesion molecule (EpCAM), and vimentin markers for enumeration. Others were processed for expansion in ultralow attachment plates with three types of organoid culture media. The rest of the CTCs were used for molecular characterizations. Growth curves were produced on expanded samples on Day 0, 7, 14, and 21 in different culture conditions. A live/dead assay and in situ hybridization (FISH) were also performed. On Day 7, selected samples were injected into NSG™ mice. Bulk RNA sequencing was conducted on the original tumor, Day 0 and 7 CTCs, and PDX samples. Results The median CTC concentration in this cohort (n=22) was 316.2 CTCs/ml of blood. Isolated CTCs from ALK+ NSCLC patients showed ALK fusions by FISH. We observed that the number of ALK CTCs was reduced over time consistent with decreased tumor size in CT scans. There were significant differences (p<0.05) for vimentin positive CTCs compared to the other three types of CTCs, which indicated a higher prevalence of a mesenchymal state of NSCLC CTCs. One of the two samples successfully developed into PDX after two months. In summary, we demonstrated a successful workflow to enrich and expand CTCs from ALK+ NSCLC patients. The expanded CTCs can be further characterized and can generate tumors in PDX models. Citation Format: Yuru Chen, Shamileh Fouladdel, Harrison Ball, Xu Cheng, Liwei Bao, Habib Serhan, Albert Liu, Bryce Vandenburg, Laura Goo, Nathan Merrill, Aaron Udager, Angel Qin, Sofia D. Merajver, Sunitha Nagrath. Expansion and characterization on ALK positive NSCLC circulating tumor cells isolated using a size based inertial microfluidic Labyrinth device. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5592.

Central retinal vein occlusion associated with Bartonella henselae infection

PurposeTo report the clinical features and treatment course of a case of central retinal vein occlusion (CRVO) as the initial sign of ocular Bartonella henselae (B. henselae) infection.ObservationA 36-year-old male was evaluated for unilateral vision loss. He denied prodromal symptoms but reported prior exposure to fleas. Best corrected visual acuity (BCVA) was 20/400 in the left eye. Clinical examination revealed a CRVO with atypical features including significant peripapillary exudates and peripheral vascular sheathing. Laboratory testing revealed elevated B. henselae IgG titers (1:512) with no abnormalities on hypercoagulability testing. The patient was treated with doxycycline and aflibercept with an excellent clinical response and improvement in BCVA to 20/25 in the left eye two months later.ConclusionCRVO is a rare but sight-threatening complication of ocular bartonellosis and can be the presenting sign of infection, even in the absence of cat exposure or prodromal symptoms.

Clinical manifestation, course and treatment results of Coats disease in children

Purpose: to analyze the clinical manifestations, course, and results of treatment of Coats disease in children. Materials and methods. We performed a retrospective analysis of medical records of 59 patients with Coats retinitis (83 % were boys) who had been comprehensively examined and treated between 2018 and 2021. After the diagnosis was verified, the children were hospitalized for treatment. Retinal laser coagulation was performed on 61 eyes, angiogenesis inhibitors were administered on 1 eye, and 5 eyes received microsurgical interventions. Results. At the time of disease detection, the children’s age varied from 1 to 16 years. In 97 % of cases, the process was unilateral. An improvement of the anatomical condition and the eye-preserving effect were achieved in 87 %. Visual acuity could only be increased in 19 eyes (31.1 %), all with the initial or the advanced stages of Coats retinitis. Proceeding from our experience, the analysis of polymorphism of clinical manifestations, functional prognosis and differentiated approach to treatment depending on the prevailing clinical symptoms, we suggest a new variant of clinical classification of Coats retinitis. Conclusion. In order to ensure a timely diagnosis of the disease, a very thorough examination of patients in the first decade of life is required. Only an early diagnosis and timely treatment can help achieve not only an eye-preserving effect but also functional results.

Research progress of potential factors influencing photodynamic therapy for gastrointestinal cancer.

Gastrointestinal cancer is a malignant tumor of the gastrointestinal tract and its associated digestive organs, including esophageal cancer, gastric cancer, carcinoma of the ampulla, pancreas, bile duct, intestines and rectal cancer. They account for about 30% of global cancer-related incidence and about 40% of mortality. Photodynamic therapy (PDT), as a treatment mode, has been applied to the treatment of gastrointestinal cancer due to potential advantages targeting and potentially lower toxic side effects. However, In the course of clinical treatment, we have found that different patients have various responsiveness to PDT, and even the same patients may have different clinical effects after receiving treatment in different time periods. For influencing factors, traditionally, we only focus on adjusting the dose of photosensitizer and the intensity and time of irradiation,while minimizing other potential factors.Therefore, this paper looks for factors that affect PDT from the patient's own conditions, tumor characteristics and tumor microenvironment(including:tumor acidic microenvironment,tumor hypoxic microenvironment, multi-drug resistance, different tumor characteristics and the immune status of patients) and summarizes how to potentially improve the curative effect of PDT.

Extraskeletal Myxoid Chondrosarcoma: Retrospective Case Series Examining Prognostic Factors, Treatment Approaches, and Oncologic Outcomes.

Extraskeletal myxoid chondrosarcoma (EMC) is an ultrarare soft tissue sarcoma, and a limited number of studies are published regarding its clinical course and efficacy of treatment. The goal of this retrospective case series is to explore patient characteristics, treatment approaches, and oncologic outcomes to help inform future EMC management. All patients with a diagnosis of EMC seen at the University of Michigan Sarcoma Center between 1998 and 2021 were identified. A chart review was performed to analyze demographics, tumor characteristics, treatments, and outcomes. Forty-four patients with EMC were identified. The median follow-up was 49.8 months. The median age at diagnosis was 57 (range: 25 to 79), and 35 patients (80%) were male. Thirty-four patients (77%) had locoregional disease at diagnosis, and 26 patients (59%) ultimately developed metastatic disease. After locoregional curative-intent surgery, 15 patients had documented recurrence, of which 11 were metastatic (73%). Five-year overall survival was 79% for all patients, 86% for locoregional disease, and 58% for metastatic disease; for locoregional disease, 5-year disease-free and metastasis-free survival post-surgery were 43% and 53%, respectively; 1-year progression-free survival for metastatic disease from the start of first-line systemic therapy was 43%. Older age was the only factor statistically associated with improved prognosis, although perioperative radiotherapy, lower histologic grade, and negative margins also had directional associations with outcomes. The data in this patient series are generally consistent with published literature on EMC and demonstrate a high recurrence rate, high propensity for metastasis, and high rate of progression of metastatic disease on systemic therapy.

Gabapentin alleviates myocardial ischemia–reperfusion injury by increasing the protein expression of GABAARδ

Gabapentin is a commonly used analgesic in the clinic to reduce opioid consumption. It is well known that gabapentin can reduce cerebral ischemia-reperfusion injury (IRI). However, it remains unclear whether gabapentin can reduce myocardial IRI. Before the performance of myocardial ischemia and reperfusion (I/R), rats received gabapentin without or with an intravenous injection of PI3K inhibitor (LY294002), or an intraspinal injection of lentivirus-mediated GABAARδ-shRNA. The myocardial IRI were evaluated by calculating the infarction area, arrhythmia score and myocardial apoptosis. The activity of PI3K/Akt and the expression of GABAARδ were quantified by western blotting. The effect of gabapentin on myocardial I/R was further demonstrated in vitro by establishing oxygen-glucose deprivation and reoxygenation in cardiomyocytes. After I/R in vivo, there were significant increases in infarction area, arrhythmia and Bax protein expression in the myocardium, as well as a decrease of GABAARδ in the spinal cord. Meanwhile, I/R also decreased the protein expression of PI3K/Akt and Bcl-2. Gabapentin pretreatment successfully attenuated IRI including reducing the myocardial infarction area and apoptosis. This effect was abolished by both the systemic inhibition of PI3K/Akt and the intraspinal suppression of GABAARδ. However, gabapentin pretreatment failed to prevent cellular injury induced by OGD/R in cardiomyocytes. Therefore, the myocardial protective effect of gabapentin may be attributed to activating PI3K/Akt in the myocardium and upregulating GABAARδ in the spinal cord. Gabapentin achieved a potent protective effect on the myocardium during the course of routine clinical treatment.

Neutrophil Count in Severe Burns Is Useful for Predicting Prognosis.

Burn injuries, particularly extensive severe burns, often have a fatal prognosis. However, many prognostic predictors are based on changes in the clinical course of treatment, and no prognostic predictors can be estimated in the early phases of injury. Using the Burn Index (BI) for evaluations requires familiarity with daily burn treatment, such as being able to evaluate the change from a second degree burn to a third degree burn appropriately. We sought to find a simpler and more quantitative prognostic prediction index. Compared to the Survivor group, neutrophil (P = 0.038) and white blood cell counts were increased significantly in the Non-survivor group (P = 0.004). Neutrophil counts and white blood cell counts correlated positively with the length of hospital stay, total body surface area, Prognostic Burn Index (PBI), and BI. The BI and PBI correlated with patient prognosis, as did neutrophil and white blood cell counts. These results suggested that neutrophil and white blood cell counts in the early phases of burn injuries might be another factor in the prognosis of burn patients in addition to the current predictors.

Epidemiological Investigation of Brucellosis Spondylitis and Optimal Selection of Clinical Drug Compatibility, Treatment Course and Treatment Plan

Background: Brucellosis is a zoonotic endemic disease, the main source of infection is infected cattle, sheep, pigs and their products. In recent years, the global incidence of brucellosis spondylitis has increased year by year, and it has spread from pastoral areas to semi-agricultural and semi-pastoral areas, agricultural areas and cities. It has changed from a mainly occupational disease to a mainly food-borne disease, and it is also a zoonotic specific spinal infectious disease that WHO and governments around the world pay great attention to. Due to the low cure rate and high recurrence rate of traditional drug therapy regimen. Therefore, to carry out epidemiological investigation and Related research on clinical drug therapy of brucellosis spondylitis has practical significance for improving diagnosis rate, cure rate and reducing recurrence rate. Objective: To analyze the epidemiological characteristics of Brucellosis spondylitis and explore the choice of drugs and the best drug treatment plan, so as to provide scientific basis for improving the prevention and control of the disease and treatment effect. Methods: Clinical epidemiodogical materials were collected from 113 patients with brucellar spondylitis. All these patients were divided into 5 different groups according to 5 kinds of drugs adopted respectively, and then the patients were given different course of treatment. Results: In the 113 patients, brucellar spondylitis morbility of female patients were higher than that of male ones, and the morbility of Bashang were higher than that of Baxia. These patients were infected mainly through browsing and breeding beasts. Lumbars were the major focus of infection. It was very comnlon that two adjacent lumbars were involved in concurrently. L4 was the most common infection location and its demolishment was most serious. The curative effect of group treated with doxycycline was better than that of group treated without doxycycline. If the course of treatment Was increased, the curative effect Was not increased obviously. Conclusions: There are characteristic features in clinical epidemiology of brucell spondylitis. Doxycycline + Rifampicin + Sulfamethoxazole was used as the preferred antibiotic. Using antibiotics adequately and jointly by two courses of treatment for a long time is the most reasonable way to treat the disease and prevent the disease from recurrence.

Treatment of superior oblique myokymia with pregabalin. Review of a clinical case

Superior oblique myokymia is a rare idiopathic disease, characterized by sudden, spontaneous, unilateral, rhythmic contractions of the superior oblique muscle and typically presents with monocular oscillopsia and diplopia. This pathological condition most often affects middle‑aged patients without concomitant systemic diseases. The aim of the article was to study the features of the clinical course, diagnosis and methods of treatment of superior oblique myokymia based on a clinical case. A review of a clinical case of superior oblique myokymia in a patient born in 1983 is presented. The diagnosis was established on the basis of clinical manifestations in the form of sudden episodes of vertical oscillopsia and diplopia in the field of vision of the right eye, which occurred both spontaneously during prolonged work at the computer, driving a vehicle, and in response to light stimulation. A 38‑year‑old patient described the disease as the presence of periodic attacks, during which blurred vision, doubling and movement of objects in the field of vision of the right eye occurred for 2 — 3 seconds, after which the vision returned to normal. The number of attacks was up to 100 per day and significantly worsened the patient’s quality of life. During the neurological examination, an episode of vertical oscillopsia with diplopia was revealed when light was directed at the right eye. No other pathological changes were observed in the nervous system, eyes and other systems and organs, which was confirmed by laboratory and instrumental examination methods, examinations and consultations of different specialists. The patient had a positive therapeutic effect in the treatment of superior oblique myokymia with pregabalin at a dose of 150 mg per day. Recommendations to reduce the time spent working at the computer and to adopt a healthy lifestyle were important.
 Thus, superior oblique myokymia is a rare pathological condition manifested by sudden episodes of monocular vertical oscillopsia and diplopia. Pregabalin can be considered as the medication of choice in the treatment of this disease. Further research is needed to establish unified treatment guideline.

Screening of an individualized treatment strategy for an advanced gallbladder cancer using patient-derived tumor xenograft and organoid models.

Gallbladder cancer is a highly aggressive malignancy with poor sensitivity to postoperative radiotherapy or chemotherapy; therefore, the development of individualized treatment strategies is paramount to improve patient outcomes. Both patient-derived tumor xenograft (PDX) and patient-derived tumor organoid (PDO) models derived from surgical specimens can better preserve the biological characteristics and heterogeneity of individual original tumors, display a unique advantage for individualized therapy and predicting clinical outcomes. In this study, PDX and PDO models of advanced gallbladder cancer were established, and the consistency of biological characteristics between them and primary patient samples was confirmed using pathological analysis and RNA-sequencing. Additionally, we tested the efficacy of chemotherapeutic drugs, targeted drugs, and immune checkpoint inhibitors using these two models. The results demonstrated that gemcitabine combined with cisplatin induced significant therapeutic effects. Furthermore, treatment with immune checkpoint inhibitors elicited promising responses in both the humanized mice and PDO immune models. Based on these results, gemcitabine combined with cisplatin was used for basic treatment, and immune checkpoint inhibitors were applied as a complementary intervention for gallbladder cancer. The patient responded well to treatment and exhibited a clearance of tumor foci. Our findings indicate that the combined use of PDO and PDX models can guide the clinical treatment course for gallbladder cancer patients to achieve individualized and effective treatment.

Global attitudes on and the status of enteral nutrition therapy for pediatric inflammatory bowel disease.

Enteral nutrition (EN) is a diet-remission therapy for inflammatory bowel disease (IBD) that plays a more important role in children than adults. EN includes exclusive enteral nutrition (EEN), partial enteral nutrition (PEN), and maintenance enteral nutrition (MEN). However, EEN remains an unstandardized treatment for pediatric IBD. The types and methods of EN differ around the world. The current study reviewed the EN literature on children with IBD. A total of 12 survey studies were identified that analyzed the current state of EN use, including clinical opinions, implementation methods, treatment course, EEN formula, IBD classification, progress, dietary reintroduction, and patient feedback. The findings revealed that EEN has a strong effect on mild to moderate Crohn's disease (CD). The usage rates of this treatment in different sites were ileum/colon (Paris classification L3) > ileum (L1) > upper digestive tract (L4) > colon (L2) > perianal disease (P) > ulcerative colitis (UC) > extraintestinal lesions. The polymeric formula was the most used EN formulation. New EN diets include a CD exclusion diet (CDED), a specific carbohydrate diet (SCD), and a CD treatment-with-eating (CD-TREAT) diet. Children with IBD responded similarly to EEN administered orally or using a feeding tube. Most guidelines recommended 6-8 weeks of EEN treatment to induce remission. Many clinicians preferred to combine drug medications during EEN and recommended that MEN accounts for at least 25-35% of daily caloric intake. EN remains an unstandardized therapy that requires teamwork across disciplines.