bluuebunny/crossref_metadata_2025 huggingface dataset:
Mapping of Pelvic Ring Injuries From High-Energy Trauma Using Unfolded CT Image Technology
Authors: Mills Andrew T. , LaRoque Michael C. , Thomas Claire N. , George Albert V. , Albright Patrick A. , Cole Peter A.
Published: February 2023

Objectives:

High-energy pelvic ring injuries are associated with significant morbidity and mortality, elevating the importance of injury pattern identification. The purpose of this study was to use a novel 3D computed tomography (CT) unfolding process to both evaluate high-energy pelvic ring injures and to produce injury frequency maps based on injury patterns.

Methods:

Patients 18–65 years of age presenting to a level 1 trauma center with pelvic ring injuries between 2016 and 2020 were identified. Of the 482 patients reviewed, 355 were excluded primarily due to having a low energy mechanism, inadequate radiographs, or an isolated fracture. Unfolded pelvic CT images were created using syngo.via CT Bone Reading software. Pelvic ring injury frequency maps were created using the unfolded pelvic CT images and a previously described mapping technique.

Results:

One hundred twenty-seven patients analyzed had a mean age of 32.7 years. The most common mechanisms of injury (MOI) were motor vehicle collision (30.7%) and fall from height (23.6%). The breakdown of pelvic ring injuries included LC1 = 44.1%, LC2 = 7.1%, LC3 = 14.2%, APC1 = 2.4%, APC2 = 15.0%, APC3 = 5.5%, and VS = 11.8%, with OTA/AO-61B = 74.0% and OTA/AO-61C = 26.0%. Pelvic ring mapping revealed that articular and bony injuries varied markedly between the different types of pelvic ring disruptions, both in type and location.

Conclusions:

Pelvic ring injury frequency maps created from unfolded CT images reflect consistent injury patterns providing distinctive information based on force vector mechanisms. Unfolded CT images allow for a novel way to visualize pelvic ring injuries which yield greater comprehension of failure patterns with implications for treatment.
Anterior Hook Plating of Patella Fractures: A Biomechanical Analysis and Clinical Series
Authors: Alley Maxwell C. , Kain Michael , Mitchell Sean , Walker Brock J. , Jones Clifford B. , Tornetta Paul
Published: February 2023

Objectives:

To compare anterior hook plating with established fixation constructs biomechanically and report outcomes and complications in a cohort of patella fractures treated with the technique.

Design:

Laboratory-based biomechanical study and clinical multicenter retrospective cohort study.

Setting:

2 US Level 1 trauma centers.

Patients/Participants:

51 patients (28 M and 23 F) with 30 simple transverse and 21 comminuted patella fractures. Thirty-six cadaveric patellae were used for the biomechanical study.

Intervention:

Biomechanical—dorsal plating was compared with cerclage wiring and modified tension band cable fixation in a comminuted patella fracture model in 36 cadaveric patellae. Constructs were tested at 0° and 45 degrees of flexion. Clinical—we reviewed a consecutive series of patella fractures in 2 centers for outcome and complications.

Main Outcome Measurements:

Biomechanical—construct stiffness. Clinical—reduction, union, complications, and range of motion.

Results:

Stiffness was greatest in dorsal plating at both 0° and 45 degrees. Dorsal plating (976 N, 1643 N) > modified tension band (317 N, 297 N) > cerclage (89.8 N, 150.3 N) at 0 and 45 degrees, respectively. 51 patients with patella fractures had them fixed with dorsal 2.7-mm mini fragment plates including a distal to proximal lag screw through the plate from the nose of the patella. 9 cases were small distal fragments not easily managed with screws and cables. All patients were followed up to union. There were 2 infections (1 superficial and 1 deep with nonunion), and 5 had implant removal (9.8%).

Conclusions:

Dorsal plating is biomechanically and clinically superior to modified tension band and cerclage techniques in comminuted patella fractures. This method allows for fixation of small distal pole fractures.

Level of Evidence:

Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.
Diagnosis of Occult Infection Using Fracture-Related Infection Criteria at the Time of Nonunion Repair
Authors: Shah Nihar S. , Simpson Nana A. , Frederickson Matthew , Dowell Evan , Doyle Matt , Sabbagh Ramsey S. , Sagi H. Claude
Published: February 2023

Objectives:

To apply the recently developed fracture-related infection criteria to patients presenting for repair of fracture nonunion and determine the incidence and associated organisms of occult infection in these patients.

Design:

Retrospective study.

Setting:

Tertiary referral trauma center.

Patients and Participants:

Patients presenting with fracture nonunion after operative intervention.

Main Outcome Measurements:

Demographic variables, injury characteristics, culture results, and physical examination and laboratory values at the time of presentation.

Results:

A total of 270 nonunion patients were identified. Sixty-eight percent (n = 184) had no clinical or laboratory signs of infection at presentation before nonunion repair. After operative intervention, 7% of these clinically negative patients (n = 12/184) had positive intraoperative cultures indicating occult infection. The most common organisms causing occult infection were low-virulence coagulase-negative Staphylococcus (83%) and Cutibacterium acnes (17%). Thirty-two percent of patients (n = 86/270) presented with clinical and/or laboratory signs of infection at presentation before nonunion repair, with 19% of these patients (n = 16/86) having negative cultures. The most common organisms in this group of patients with positive clinical signs and intraoperative cultures were methicillin-resistant Staphylococcus Aureus (21%) and gram-negative rods (29%). Patients with nonunion of the tibia were significantly more likely to have high-virulence organism culture results (P < 0.001).

Conclusions:

Based on this analysis, occult infection occurs in 7% of patients presenting with nonunion and no clinical or laboratory signs of infection. We recommend that all patients should be carefully evaluated for infection with intraoperative cultures regardless of presentation. Organisms associated with occult infection at the time of nonunion repair were almost exclusively of low virulence (CoNS and C. Acnes) and were more likely to present in the upper extremity. Patients with nonunion of the tibia were more likely to have infection secondary to high-virulence organisms and demonstrate clinical or laboratory signs of infection at the time of presentation.

Level of Evidence:

Diagnostic Level IV. See Instructions for Authors for a complete description of levels of evidence.
Outcomes After Acute Versus Staged Fixation of Complete Articular Tibial Plafond Fractures
Authors: Flanagan Christopher D. , Lufrano Reuben C. , Mesa Lazaro , Watson David , Shah Anjan R. , Maxson Benjamin J. , Infante Anthony , Donohue David , Downes Katheryne , Sanders Roy W. , Mir Hassan R.
Published: February 2023

Objective:

To determine the outcomes after acute versus staged fixation of complete articular tibial plafond fractures.

Design:

Retrospective cohort study.

Setting:

Single Level 1 Trauma center.

Participants:

98 skeletally mature patients with OTA/AO 43C type fractures who underwent definitive fixation with plate and screw constructs and had a minimum 6 months of follow-up.

Intervention:

Acute open reduction internal fixation (aORIF) versus staged (sORIF) definitive fixation.

Main Outcome Measurement:

Rates of wound dehiscence/necrosis and deep infection.

Results:

Acute (N = 40) versus staged (N = 58) ORIF groups had comparable rates of vascular disease, renal disease, and substance/nicotine use, but aORIF patients had higher rates of diabetes mellitus (10% vs. 0%, P < 0.001), which correlated with higher American Society of Anaesthesiologist scores (>American Society of Anaesthesiologist 3: 37.5% vs. 13.8%, P = 0.02). Both groups achieved anatomic/good reductions, as determined by postoperative CT scans, at rates greater than 90%; however, the sORIF group required modestly longer operative times to achieve this outcome (aORIF vs. sORIF: 121 vs. 146 minutes, P = 0.02). Postoperatively, both groups had similar rates of wound dehiscence (2.5% vs. 6.9%, P = 0.65), superficial infections (10% vs. 17.2%, P = 0.39), and deep infections (10% vs. 8.6%, P = 0.99). While the injury pattern itself required free flap coverage in 1 patient in each group, unplanned free flap coverage occurred in 10.0% and 10.3% of aORIF and sORIF groups, respectively. Overall, rates of unplanned reoperations, excluding ankle arthrodesis, did not differ between groups (aORIF vs. sORIF:12.5% vs. 25.9%, P = 0.13).

Conclusions:

In select patients managed by fellowship-trained orthopaedic traumatologists, acute definitive pilon fixation can produce acceptable outcomes.

Level of Evidence:

Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.
Outcomes of double-incision posterior knee release for severe knee flexion contracture
Authors: Musielak Bartosz , Al-Saad Salwan R. , Jóźwiak Marek , Koch Aleksander , Shadi Milud
Published: February 2023

Many surgical solutions for knee flexiondeformity in the pediatric population alter the anatomical bony alignment in the distal femur. Posterior knee capsule release has been presented as an alternative surgical procedurethat maintains the anatomical shape of relevant bones while solving the issue of knee flexion contracture. The aim of this study is to assess the results of a double-incision posteriorknee capsulotomy release performed on pediatric patients with neuromuscular or congenital severe knee flexion deformity. Thirty cases (24 patients, mean age 7.4 years) of severe knee flexion contractures were retrospectively analyzed in a cohort of varying underlying conditions (including spina bifida, muscular dystrophy, cerebral palsy, sclerodermia, and congenital patellar dislocations). Posterior knee release was performed through medial and lateral short incisions with subsequent serial casting. Range and pace of correction as well as the complication rate were recorded. Follow-up information (>1 year) included functionality (FMS scale) and pain (Kujala/Knee Injury Osteoarthritis Score [KOOS]) scales. Significant correction in the knee position was achieved in all analyzed knees (from mean 40.2° to 0.7°; P < 0.01). Twenty-nine out of 30 cases achieved correction by 7 days postoperatively (average number of casts: 1.93 ± 1.05). Overall complication rate in the analyzed cohort reached 6.7% (2/30 cases; double metaphyseal fracture and arthrofibrosis). At follow-up (22.3 months on average), functional ambulation and pain parameters improved drastically, with no further complications observed. Double-incision posterior knee release is an effective method of knee contracture release, which does not affect the axial alignment of the distal femoral bone. Thus, posterior knee release should be considered as potential alternatives to osteotomies and eight-plate corrections, which are currently the basic methods of knee contracture treatment.
A Comparison Between 3 Functional Hip Scores for Evaluation of the Pediatric Hip
Authors: Huebschmann Nathan A. , Masrouha Karim Z. , Dib Aseel , Moscona Leon , Castañeda Pablo
Published: February 2023

Background:

This investigation aimed to determine the degree of correlation among 3 functional scales for evaluating the hip in pediatric patients and determine the correlation between measures of global function and outcome.

Methods:

We performed a prospective study of 173 consecutive patients (Mage = 13 ± 3 y) being followed for developmental dysplasia of the hip (n = 122, 71%), slipped capital femoral epiphysis (n = 31, 18%), or Legg-Calve-Perthes disease (n = 20, 12%). We evaluated patients clinically, and we compiled scores for the Iowa Hip Score (IHS), Harris Hip Score (HHS), and Children’s Hospital Oakland Hip Evaluation Scale (CHOHES). Patients concomitantly completed the Pediatric Outcomes Data Collection Instrument (PODCI) at the same clinic visit. We assessed Global Functioning Scale the and the Sports and Physical Functioning Core Scale of the PODCI. We determined the degree of correlation between the functional hip scales and between each scale and the PODCI scales using Spearman rank correlation coefficients.

Results:

The correlations between the IHS, HHS, and CHOHES scores were robust (IHS and HHS ρ = 0.991; IHS and CHOHES ρ = 0.933; HHS and CHOHES ρ = 0.938; all P < 0.001). The correlation between the Global Functioning Scale of the PODCI and the 3 hip scores was ρ = 0.343 for the IHS, ρ = 0.341 for the HHS, and ρ = 0.352 for the CHOHES (all P < 0.001). The correlation between the sports and physical functioning core scale of the PODCI and the 3 hip scores was ρ = 0.324 for the IHS, ρ = 0.329 for the HHS, and ρ = 0.346 for the CHOHES (all P < 0.001).

Conclusions:

In a pediatric population with diverse hip pathology, there was a very strong correlation between scores on the IHS, HHS, and CHOHES. However, none of these 3 most commonly used hip scores correlated strongly with the global functioning scale or sports and physical functioning core scale of the PODCI. The most frequently used scores to determine the outcome of pediatric patients with hip pathology correlate strongly with each other but do not necessarily relate to global functional results.

Level of Evidence:

Level IV.
Facet Distraction and Dysphagia: A Prospective Evaluation of This Common Postoperative Issue Following Anterior Cervical Spine Surgery
Authors: Kanhere Arun P. , Paziuk Taylor , Lambrechts Mark J. , Issa Tariq Z. , Karamian Brian A. , Mazmudar Aditya , Tran Khoa S. , Purtill Caroline , Mangan John J. , Vaccaro Alexander R. , Kepler Christopher K. , Schroder Gregory D. , Hilibrand Alan S. , Rihn Jeffrey A.
Published: February 2023

Study Design.

Prospective cohort study.

Objective.

Our primary study was to investigate whether the degree of postoperative facet and disk space distraction following anterior cervical discectomy and fusion (ACDF) affects the rate of postoperative dysphagia.

Summary of Background Data.

Although ACDF is safe and well tolerated, postoperative dysphagia remains a common complication. Intervertebral disk space distraction is necessary in ACDF to visualize the operative field, prepare the endplates for fusion, and facilitate graft insertion. However, the degree of distraction tolerated, before onset of dysphagia, is not well characterized ACDF.

Materials and Methods.

A prospective cohort study was conducted of 70 patients who underwent ACDF between June 2018 and January 2019. Two independent reviewers measured all preoperative and postoperative radiographs measured for interfacet distraction distance and intervertebral distraction distance, with intrareviewer reproducibility measurements after one month. For multilevel surgery, the level with the greatest distraction was measured. Primary outcomes were numerical dysphagia (0–10), Eating Assessment Tool 10, and Dysphagia Symptom Questionnaire score collected at initial visit and two, six, 12, and 24 weeks postoperatively.

Results.

A total of 70 patients were prospectively enrolled, 59 of whom had adequate radiographs. An average of 1.71 (SD: 0.70) levels were included in the ACDF construct. Preoperatively, 13.4% of patients reported symptoms of dysphagia, which subsequently increased in the postoperative period at through 12 weeks postoperatively, before returning to baseline at 24 weeks. Intrareviewer and interreviewer reliability analysis demonstrated strong agreement. There was no relationship between interfacet distraction distance/intervertebral distraction distance and dysphagia prevalence, numerical rating, Eating Assessment Tool 10, or Dysphagia Symptom Questionnaire.

Conclusions.

Patients who had an ACDF have an increased risk of dysphagia in the short term, however, this resolved without intervention by six months. Our data suggests increased facet and intervertebral disk distraction does not influence postoperative dysphagia rates.

Level of Evidence:

3.
Increased Cellular Expression of Interleukin-6 in Patients With Ossification of the Posterior Longitudinal Ligament
Authors: Saito Hideki , Yayama Takafumi , Mori Kanji , Kumagai Kosuke , Fujikawa Hitomi , Chosei Yuya , Imai Shinji
Published: February 2023

Study Design.

We performed histologic, immunohistochemical, immunoblot examination and suspension array analyses of cytokine expression in cultured cells derived from human cervical ossification of the posterior longitudinal ligament (OPLL).

Objective.

To determine the roles of interleukin-6 (IL-6) during the maturation of osteoblasts and chondrocytes associated with the development of OPLL.

Summary of Background Data.

Ectopic OPLL affects ~3% of the general population, with a higher incidence in Asian ethnic groups. Alterations in cytokine profiles may influence osteoblast differentiation, but the mechanisms and signaling pathways associated with the ossification process remain unclear.

Methods.

Samples were collected from 14 patients with OPLL who had undergone spinal surgery and seven with cervical spondylotic myelopathy without OPLL. Tissue sections were used for histologic and immunohistochemical studies, and primary cells from ligamentum samples were used for cytokine array and immunoblotting. A suspension array was used to measure the concentrations of 27 inflammatory cytokines or growth factors.

Results.

Suspension array and immunoblot analyses revealed significantly elevated levels of IL-6 in OPLL patients. Alterations in IL-6 concentrations were found to alter the expression of the genes Sox9, Runx2, and SIRT1. In addition, immunohistochemical analysis revealed that these factors are present in mesenchymal cells within the degenerative portion of the ligament matrix that is adjacent to the ossification front.

Conclusions.

IL-6 plays a profound role in the osteoblast differentiation process along with the induction of chondrocyte hypertrophy and cell apoptosis in the early stages of ossification in OPLL. These changes in cytokine profiles are essential factors for regulation of the ectopic ossified plaque in OPLL.
Global Sagittal Spinal Compensation for Dropped Head Alignment
Authors: Nishimura Hirosuke , Endo Kenji , Sawaji Yasunobu , Suzuki Hidekazu , Aihara Takato , Murata Kazuma , Konishi Takamitsu , Yamauchi Hideya , Ueshima Tomoyuki , Yamamoto Kengo
Published: February 2023

Study Design.

This is a retrospective radiographic study of a consecutive series of cases in patients with dropped head syndrome (DHS) at a single tertiary referral center.

Objective.

The aim was to clarify the compensation among parameters of spinal sagittal alignment in patients with DHS.

Summary of Background Data.

The treatment strategy for DHS should vary according to the types of global sagittal spinal alignment. However, theoretical evidence in consideration of spinal sagittal compensation against the dropped head condition is lacking.

Materials and Methods.

One hundred sixteen patients diagnosed with isolated neck extensor myopathy were enrolled. Radiographic measurements were made, including parameters of spinal sagittal alignment. The patients were divided into three groups according to sagittal spinal balance: C7SVA (sagittal vertical axis) ≥ +50 mm (P-DHS; positive imbalanced DHS), −50 mm ≤C7SVA <+50 mm (B-DHS; balanced DHS), and C7SVA <−50 mm (N-DHS; negative imbalanced DHS). Correlations among the various spinal parameters were analyzed.

Results.

Among all types of DHS, there was no correlation between C2-C7 angle (C2-C7A) and T1 slope. In B-DHS, other correlations among the adjacent spinal segments were maintained. In N-DHS, there was no correlation between C2-C7A and TK, and in P-DHS, there was also no correlation between TK and lumbar lordosis.

Conclusions.

The loss of compensation at the cervicothoracic junction was observed in all DHS types. B-DHS showed decompensation only at the cervicothoracic junction. N-DHS presented additional decompensation of the thoracic spine, and P-DHS showed decompensation between the thoracic and lumbar spine. Evaluation of global sagittal spinal balance is important for determining global spinal compensation associated with DHS and when considering treatment strategy.
Knockdown of circ-PIP5K1A overcomes resistance to cisplatin in ovarian cancer by miR-942-5p/NFIB axis
Authors: Sheng Hui , Wang Xueling
Published: February 2023

Cisplatin (DDP)-based chemotherapy is the main chemotherapeutic agent for ovarian cancer (OC) treatment. Circular RNA PIP5K1A (circ-PIP5K1A) was found to promote OC tumorigenesis. However, whether circ-PIP5K1A was involved in DDP resistance in OC remains unclear. Levels of circ-PIP5K1A, microRNA (miR)-942-5p, and nuclear factor I B (NFIB) were detected using quantitative real-time PCR and Western blot assays. In-vitro experiments were conducted by using cell counting kit-8, cell colony formation, 5-ethynyl-2′-deoxyuridine, flow cytometry, and transwell assays, respectively. In-vivo assay was performed using murine xenograft model. The binding interaction between miR-942-5p and circ-PIP5K1A or NFIB was confirmed using dual-luciferase reporter assay. Exosomes were obtained from culture media by the use of commercial kits and qualified by transmission electron microscopy and Western blot. Circ-PIP5K1A was highly expressed in DDP-resistant OC tissues and cells. Circ-PIP5K1A knockdown could constrain the proliferation, migration, and invasion, as well as increase apoptosis and sensitivity to DDP in DDP-resistant OC cells. Mechanistically, circ-PIP5K1A acted as a sponge for miR-942-5p to positively regulate NFIB expression. Moreover, rescue experiments demonstrated that the anticancer and DDP sensitization effects caused by circ-PIP5K1A silencing in DDP-resistant OC cells were achieved through the miR-942-5p/NFIB axis. Importantly, circ-PIP5K1A silencing enhanced DDP efficacy and impeded tumor growth in OC in vivo. Additionally, we also found that circ-PIP5K1A was packaged into exosomes and could be internalized by surrounding cells. Circ-PIP5K1A knockdown reduced the resistance to DDP in OC via regulating miR-942-5p/NFIB axis. Besides that, circ-PIP5K1A was packaged into exosomes and exosomal circ-SKA3 could mediate intercellular communication between OC cells. These findings provided a promising therapeutic target for OC.
Case series report: radiation-induced oropharyngeal carcinoma
Authors: Salman Saeed , Doweck Ilana , Taha Tarek , Billan Salem
Published: February 2023

The incidence of radiation-induced secondary primary tumors (SPTs) is estimated to be between 1 and 20%. The oropharynx is not a common site for postradiotherapy head and neck SPTs. We describe the cases of eight patients, each with an SPT of the oropharynx. These developed after a long median latency of 17.7 years with each receiving two-dimensional radiation therapy and delivery of at least 5000 cGy per pharynx, except for one who was treated with IMRT. Tumor histological commonalities revealed squamous cell carcinoma p16 negative staining, local invasion, and limited lymphatic spread, with posterior wall of the oropharynx and the base of the tongue being the most common locations. Limited and challenging treatment options have been reported such as surgery, reirradiation, or clinical trials. Radiation-induced SP oropharyngeal carcinoma has unique clinical and pathological features. Patients with this disease have limited treatment options, which should be discussed in a multidisciplinary tumor board meeting. For this population, lifelong follow-up may help in early diagnosis and improve outcomes.
M2 macrophage-derived exosomal miR-1911-5p promotes cell migration and invasion in lung adenocarcinoma by down-regulating CELF2-activated ZBTB4 expression
Authors: Guan Bingfeng , Dai Xiaofeng , Zhu Yan , Geng Qing
Published: February 2023

Lung adenocarcinoma (LUAD) is one of the most aggressive, lethal cancers, comprising around 40% of lung cancer cases. Metastases are the primary cause of LUAD deaths. The mechanism underlying metastatic LUAD and tumor microenvironment remain largely unknown. To explore the effect of M2 macrophage-derived exosomes on LUAD progression. Quantitative-PCR (q-PCR) and western blot were used to measure the expression of RNAs and proteins separately. Co-culture experiments wound healing and Transwell invasion assays were performed to evaluate the effect of M2 macrophage-derived exosomes on LUAD cell migration and invasion. RNA pulldown and luciferase reporter, RNA-binding immunoprecipitation (RIP), and mRNA stability assays were conducted to explore the downstream mechanism of exosomal microRNA-1911-5p (miR-1911-5p). M2 macrophage-derived exosomes accelerated the migration and invasion of LUAD cells. M2 macrophages-secreted exosomal miR-1911-5p enhanced cell migration and invasion in LUAD. Mechanically, miR-1911-5p targeted CUGBP- and ETR-3-like family 2 (CELF2) to downregulate zinc finger and BTB domain containing 4 (ZBTB4) in LUAD. Additionally, miR-1911-5p promoted LUAD progression via ZBTB4. The present study demonstrated that M2 macrophage-derived exosomal miR-1911-5p facilitates the migration and invasion of LUAD cells by inhibiting CELF2-activated ZBTB4, which might offer insight into LUAD treatment.
FXR1 facilitates axitinib resistance in clear cell renal cell carcinoma via regulating KEAP1/Nrf2 signaling pathway
Authors: Huang Haipeng , Zhang Jiange , Jiang Peng , Xu Xiaolong , Huang Fu , Zhao Binli , Wang Xiaoming , Zhou Liquan
Published: February 2023

Axitinib is emerging as a first-line combination treatment drug for metastatic renal cell carcinoma, but the acquired resistance significantly bothers the treatment efficacy. This article is to investigate the impact of fragile X mental retardation autosomal homolog 1 (FXR1) and its mechanistic involvement with Kelch-like epoxy chloropropan-associated protein 1 (KEAP1)/NF-E2-related factor 2 (Nrf2) pathway on cell resistance to axitinib in clear cell renal cell carcinoma (ccRCC). Establishment of axitinib resistance cells (786-O, Caki-1, 786-O/axitinib, or Caki-1/axitinib) was made, and the cells were then transfected with sh-FXR1, or co-transfected with sh-FXR1 and sh-KEAP1. The quantitative real-time PCR (qRT-PCR) and western blotting assays were employed to measure the expression of FXR1, KEAP1, Nrf2, LC3 II/I, Beclin 1, p62, MDR-1, and MRP-1. In addition, the binding between FXR1 and KEAP1 was verified by RNA-immunoprecipitation and RNA pull-down assays, and FXR1-dependent KEAP1 mRNA degradation was determined. Herein, FXR1 was demonstrated to be overexpressed in ccRCC cells, and showed higher expression in 786-O/axitinib and Caki-1/axitinib cells. Mechanistically, FXR1 enriched KEAP1 mRNA, and pulled downed by biotinylated KEAP1 probes. Results of RNA stability assay reveled that KEAP mRNA stability was suppressed by FXR1. Furthermore, knockdown of FXR1 promoted cell apoptosis and showed a restrained feature on cell resistance to axitinib. Of note, KEAP1 knockdown suppressed cell autophagy, oxidative stress, resistance to axitinib, and promoted apoptosis, despite FXR1 was downregulated in ccRCC cells. In conclusion, FXR1 played an encouraging role in ccRCC cell resistance to axitinib by modulating KEAP/Nrf2 pathway.
Outcomes from treatment of metastatic renal-cell carcinoma following failure of first-line anti-VEGF/VEGFR therapy: real-life evidence on the change of the treatment paradigm
Authors: Bamias Aristotelis , Zakopoulou Roubini , Tzannis Kimon , Sakellakis Minas , Koutsoukos Konstantinos , Kyriazoglou Anastasios , Panagiotou Aikaterini , Armylagos Stylianos , Rokas Konstantinos , Gotzias Dimitrios , Boulouta Anna , Bozionelou Vassiliki , Stravodimos Konstantinos , Varkarakis Ioannis , Mavroudis Dimitrios , Dimopoulos Meletios-Athanasios
Published: February 2023

Recently approved agents for post-vascular endothelial growth factor/post-vascular endothelial growth factor receptor (VEGF/VEGFR) inhibitors treatment of metastatic renal-cell carcinomas (mRCC), such as axitinib, nivolumab, and cabozantinib were shown to improve prognosis and substituted everolimus in this setting. We studied practice patterns, efficacy, and tolerability of these agents in a real-world series of Greek patients. We included patients with mRCC who received everolimus, axitinib, or nivolumab after progression on first-line anti-VEGF/VEGFRs therapy. Patients were stratified into three groups. Group A received nivolumab with or without cabozantinib at some point in their disease. Group B received axitinib but without nivolumab or cabozantinib. Group C received only everolimus among the four approved agents. Overall, 131 patients were included in the analysis. Everolimus and nivolumab were mainly used in the second line, while axitinib and cabozantinib were mostly used in the third and fourth lines. Median overall survival (OS) from first-line initiation was 8.7 [95% confidence interval (CI), 4–not reached], 3.6 (95% CI, 2–6), and 2.1 years (95% CI, 1.4–2.6) for Group A, B, and C, respectively (P < 0.001). Median OS from the initiation of second-line therapy was 3.5, 2.7, and 1.3 years, respectively (P < 0.001). There was no impact of first-line agent or treatment timing on survival. International Metastatic Renal Cell Carcinoma Database Consortium risk stratification was associated with OS. Toxicities observed were within expected frequencies. Grade ≥3 events were rare. Adoption of modern standards in everyday treatment of mRCC results in prolongation of survival. Real-world datasets are the new landmarks of survival for future research.
Durable complete remission with local therapies after neoadjuvant and adjuvant nivolumab in recurrent/metastatic head and neck cancer
Authors: Cabezas-Camarero Santiago , Iglesias-Moreno María Cruz , Cerezo Druet Elena , Sotelo Miguel J. , Merino-Menéndez Salomé , Cabrera-Martín María Nieves , Plaza-Hernández José Carlos , Pérez-Segura Pedro
Published: February 2023

Up to 10–15% of patients with first-line recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) present with platinum-refractory disease. The anti-PD1 nivolumab is the first therapeutic option in this setting achieving a 19.2% objective response rate and a 7.7-month median overall survival (OS). Given the poor prognosis of platinum-refractory patients, those showing slow progressive disease with no functional status deterioration should maintain nivolumab beyond progression in the absence of severe or unmanageable toxicities. Another strategy is to use local therapies such as radiotherapy and surgical tumor resection in cases of oligometastatic or oligoprogressive disease. Both strategies may significantly improve disease control and OS in these populations. We present the case of a patient with platinum-refractory disease treated with first-line nivolumab beyond progression who achieved a durable complete response after palliative radiation and surgical resection of five tumor lesions. To our knowledge, this is the first reported case of an R/M HNSCC treated with such a strategy outside a clinical trial and contributes to the evidence for combining anti-PD1 agents and local therapies in selected patients with R/M HNSCC.
High expression of SDC1 in stromal cells is associated with good prognosis in colorectal cancer
Authors: Li Zhejie , He Shujin , Liu Jianli , Zhi Xiao , Yang Lili , Zhang Junjun , Zhao Ran , Zhang Renya , Li Lei , Wang Wei
Published: February 2023

We have previously reported that patients with high Syndecan 1 (SDC1) expression in colorectal cancer (CRC) cells have a favorable prognosis, and we also found that stromal cells showed upregulation of SDC1, but the clinical significance is unclear. The expression of SDC1 in the stroma cells was assessed by immunohistochemistry using a tissue microarray comprising representative cores from 513 CRC patients. The correlation between the expression of SDC1 in the stroma cells and the clinicopathological features of patients was analyzed. The data showed that the expression of SDC1 in the stroma cells was correlated with the degree of differentiation (P = 0.012) and tumor location (up or down) (P = 0.005). Also, CRCs patients with high expression of SDC1 in the stromal cells have a good prognosis (P = 0.0369). Accumulating evidence indicates that SDC1, whether in tumor cells or stromal cells, plays a tumor-suppressor role in CRCs.
Successful osimertinib rechallenge after severe thrombocytopenia caused by osimertinib combined with sitagliptin: a case report
Authors: Tan Xinyuan , Chen She , He Liu , Huang Minling , Zhang Xiaoshan
Published: February 2023

Osimertinib is recommended as the first-line treatment of advanced non-small cell lung cancer (NSCLC) in adults. The most commonly reported adverse events for osimertinib are skin effects, diarrhea, nausea, decreased appetite, fatigue, paronychia, and stomatitis. Severe thrombocytopenia is rarely reported. We present a case of severe thrombocytopenia in a 70-year-old NSCLC patient caused by osimertinib combined with sitagliptin. After remission of thrombocytopenia, the patient was well tolerated with osimertinib re-administration in the absence of sitagliptin. We speculated that declined platelet count might be related to the interaction between osimertinib and sitagliptin by acting with a synergistic effect on platelets. Osimertinib rechallenge can be considered after discontinuing drugs that may contribute to platelet decline if possible, and making a careful assessment of complete blood count and risk of bleeding.
Circular RNA circ_0003028 regulates cell development through modulating miR-498/ornithine decarboxylase 1 axis in hepatocellular carcinoma
Authors: Zhang Tao , Sun Qikai , Shen Chao , Qian Yeben
Published: February 2023

Circular RNA has been revealed to participate in multiple biological functions and contribute to various diseases’ progression. This study aims to clarify the role of circ_0003028 and its potential molecular mechanism in hepatocellular carcinoma (HCC). The levels of circ_0003028, miR-498, and ornithine decarboxylase 1 (ODC1) mRNA were examined by quantitative real-time PCR. The cell proliferation ability was detected via 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide, colony formation, and 5-ethynyl-2′-deoxyuridine assays. The apoptotic rate was evaluated through flow cytometry. The migration and invasion capacity was tested by using wound healing assay and transwell assay. The protein levels of E-cadherin, N-cadherin, and vimentin were measured by western blot assay. The ceRNA regulatory mechanism of circ_0003028 was observed via dual-luciferase reporter and RNA pull-down assays. The mice xenograft models were constructed to confirm the oncogenicity of circ_0003028 in HCC in vivo. Circ_0003028 and ODC1 were upregulated, whereas miR-498 was downregulated in HCC tissues and cells. Circ_0003028 knockdown inhibited cell proliferation and metastasis, and promoted apoptosis. MiR-498 was a direct target of circ_0003028, and inhibition of miR-498 reversed the inhibitory effect of circ_0003028 silencing on HCC progression. Moreover, ODC1 was a direct target of miR-498 and ODC1 overexpression abated the anticancer roles of miR-498 in HCC. Additionally, circ_0003028 regulated ODC1 expression by sponging miR-498. Finally, we found that circ_0003028 could induce epithelial-mesenchymal transition of HCC cells by exosome pathway. In brief, the results demonstrated that circ_0003028 exerted tumourigenicity roles via miR-498/ODC1 signaling axis, providing a promising biomarker and therapeutic target for HCC.
Stat3 shRNA delivery with folate receptor-modified multi-functionalized graphene oxide particles for combined infrared radiation and gene therapy in hepatocellular carcinoma
Authors: Chen Xuyang , Zhang Ling , Wang Xiaoqin , Xu Libo , Sun Jicheng , Liu Yiran , Liu Xiaorui , Kalvakolanu Dhan V , Guo Baofeng
Published: February 2023

As a vital oncogene, a variety of inhibitors targeting Stat3 and its various upstream signaling pathways has been explored. Since small molecules, peptidomimetics and other peptide inhibitors usually lead to side effects and difficult administration, gene therapeutics that have characteristics of low toxicity and high targeting, make them an attractive alternative for targeting Stat3. A major challenge to this approach is the lack of safe delivery systems for in-vivo applications. Among the various siRNA delivery systems, nanoparticles emerge as a new tool for gene delivery with high biocompatibility, low cost, and minimal toxicity. In this study, we developed a graphene oxide (GO)-based nanocarrier, GO-polyethyleneimine (PEI)-polyethylene glycol (PEG)-folic acid (FA), as a tool targeting for Stat3-specific shRNA to mouse hepatoma cells in vitro and in vivo. Infrared photothermal therapy was combined in vivo since GO has the characteristic of infrared absorbability. Our results suggest a significant tumor growth inhibition after treatment with GO-PEI-PEG-FA-sh-Stat3 combined with infrared photothermal therapy. Thus, GO-PEI-PEG-FA appears to be a novel nano-transformer that could be used in the clinics in future.
Phase II study of gemcitabine, cisplatin, and bevacizumab for first recurrent and refractory ovarian clear cell carcinoma Kansai Clinical Oncology Group-G1601
Authors: Ito Kimihiko , Nakagawa Mio , Shimokawa Mototsugu , Hori Kensuke , Tashima Lena , Goto Mayako , Yanagida Satoshi , Suzuki Jiro , Kaya Ryusuke , Kawabata Ayako , Yamada Kyosuke , Park Jongmyung , Nasu Hiroki , Nishio Shin , Kondo Eiji , Kaneda Michiko , Tsubamoto Hiroshi , Arakawa Atsushi , Nagasawa Takayuki , Motohashi Takashi
Published: February 2023

Patients with advanced ovarian clear cell carcinoma (CCC) have a poor prognosis in the absence of an effective standard treatment. Combination therapy with gemcitabine, cisplatin, and bevacizumab (GPBev) is promising for ovarian CCC. Thus, we conducted a multi-institutional, phase II trial in Japan to examine the efficacy and safety of GPBev for CCC. This is the first study on the use of GPBev for CCC. Eighteen patients (median age, 56.5 years) with pathologically confirmed first recurrent or refractory CCC and having evaluable regions, as assessed using RECIST, were recruited between January 2017 and May 2019. Gemcitabine (1000 mg/m2), cisplatin (40 mg/m2), and bevacizumab (10 mg/kg) were administered intravenously on days 1 and 15, every 28 days, for 6–10 cycles, until disease progression or intolerable toxicity. The primary endpoint was overall response rate (ORR). The secondary endpoints included disease control rate (DCR) and adverse events (AEs). Fifteen patients (83.3%) completed 6–10 cycles of treatment; three patients (two with AEs and one with progressive disease) did not. The ORR was 61.1% [complete response (CR) 3 and partial response (PR) 8] and DCR was 88.9% (CR 3, PR 8, and stable disease 5). Grade 3 and 4 hematological AEs were observed in 16.7 and 5.6% of the patients, respectively. Nonhematological AEs of grades 3 and 4 were observed in 27.8 and 5.6% of the patients, respectively. GPBev is a promising therapy for CCC owing to the high ORR and acceptable toxicity for the first recurrence and refractory CCC.
Sustained antitumor response to lenvatinib with weekend-off and alternate-day administration in chemotherapy-refractory thymic carcinoma: a case report
Authors: Sunaga Noriaki , Miura Yosuke , Sakurai Reiko , Ohshima Sohei , Uno Shogo , Muto Sohei , Sato Mari , Tsurumaki Hiroaki , Yatomi Masakiyo , Koga Yasuhiko , Ohtaki Yoichi , Nagashima Toshiteru , Okano Naoko , Kubo Nobuteru , Maeno Toshitaka , Hisada Takeshi
Published: February 2023

Lenvatinib is a multitargeted kinase inhibitor and maintaining its dose intensity has been shown to be beneficial in patients with thyroid and hepatocellular carcinomas. However, most patients require lenvatinib interruption and dose reduction due to the high incidence of adverse events (AEs). Lenvatinib was recently approved in Japan for patients with unresectable thymic carcinoma; however, real-world evidence of its clinical benefit is limited. Here, we report the case of chemotherapy-refractory thymic carcinoma in a patient who was administered a starting dose of lenvatinib using a 5-day on/2-day off (weekend-off) protocol, followed by alternate-day administration after fatigue onset derived from overt or subclinical hypothyroidism. Consequently, the patient exhibited a durable response to lenvatinib, with a 17-month progression-free survival without any severe or intolerable AEs. The present case suggests that maintaining lenvatinib dose intensity using such alternative administration regimens contributes to favorable clinical outcomes in thymic carcinoma.
Single-step assembly of lipid-gelatin-epigallocatechin-3-gallate hybrid nanoparticles for cancer therapy
Authors: Song Juan , Yu Xudong , Lv Chengzhi , Wang Dong
Published: February 2023

Objective

Novel core-shell lipid-gelatin-epigallocatechin-3-gallate hybrid nanoparticles (LGE-N) were prepared to increase the stability and antitumor efficacy of epigallocatechin-3-gallate (EGCG).

Methods

The LGE-N was prepared by a single-step double-emulsion method, in which EGCG-gelatin nanoparticles were formed and stabilized in the inner phase by gelatinization. The cytotoxicity of EGCG solution (EGCG-S) and LGE-N were assessed by a standard 3-(4, 5-dimethylthiazol- 2-yl)-2, 5-diphenyltetrazolium bromide assay.

Results

The obtained LGE-N had a spherical shape, with relatively high encapsulation efficiency (92.30 ± 1.63%), drug loading capacity (11.09 ± 0.62%) and controlled drug release. In-vitro cytotoxicity studies revealed that LGE-N exhibited a lower half maximal inhibitory concentration compared with EGCG-S in MCF-7 (a breast carcinoma cell line) cells. When labeled with a fluorescent probe, Dir, LGE-N was shown to accumulate much more in tumor. In addition, the LGE-N achieved potent antitumor efficacy at a dose of 5 mg/kg in 4T1-implanted mice.

Conclusion

Our study highlights the unique EGCG-entrapped lipid-gelatin hybrid nanoparticles, which may be a powerful strategy for further cancer therapy.
STK25: a viable therapeutic target for cancer treatments?
Authors: Chen Ke-qian , Lei Guan-lan , Ke Bo-yi , Chen Lu , Wang Zong-bao , Wang Shu-zhi
Published: February 2023

Serine/threonine protein kinase 25 (STK25) is a critical regulator of ectopic lipid storage, glucose and insulin homeostasis, fibrosis, and meta-inflammation. More and more studies have revealed a strong correlation between STK25 and human diseases. On the one hand, STK25 can affect glucose and fatty acid metabolism in normal cells or tumors. On the other hand, STK25 participates in autophagy, cell polarity, cell apoptosis, and cell migration by activating various signaling pathways. This article reviews the composition and function of STK25, the energy metabolism and potential drugs that may target STK25, and the research progress of STK25 in the occurrence and development of tumors, to provide a reference for the clinical treatment of tumors.
Association Between Length of Storage of Transfused Packed RBC Units and Outcome of Surgical Critically Ill Adults: A Subgroup Analysis of the Age of Blood Evaluation Randomized Trial*
Authors: Lehr Anab Rebecca , Hébert Paul , Fergusson Dean , Sabri Elham , Lacroix Jacques
Published: February 2023

Objectives:

The Age of Blood Evaluation (ABLE) study reported no clinical benefit in fresher compared with standard delivery RBC units (length of storage: 6.9 ± 4.1 vs 22.0 ± 8.4 d, respectively). Perioperative patients are often anemic, at risk of blood loss, and more exposed to RBC transfusions. We address the question whether fresh RBC units are safer than standard delivery RBC units in perioperative ICU patients.

Design:

Subgroup analysis of surgical nontrauma adults enrolled in the ABLE randomized controlled trial.

Setting:

ICUs.

Patients:

Three hundred twenty surgical patients among the 2,510 ICU adults recruited in the ABLE study who had a request for a first RBC transfusion in the first week in ICU stay and an anticipated length of mechanical ventilation greater than or equal to 48 hours. We included perioperative patients but excluded elective cardiac surgery and trauma.

Interventions:

Surgical participants were allocated to receive either RBC units stored less than or equal to 7 days or standard issue RBC.

MEASUREMENTS AND MAIN RESULTS:

The primary outcome was 90-day all-cause mortality. One hundred seventy-two perioperative patients were allocated to the fresh and 148 to the standard group. Baseline data were similar. The length of storage was 7.2 ± 6.4 in fresh and 20.6 ± 8.4 days in standard group (p < 0.0001). The 90-day mortality was 29.7% and 28.4%, respectively (absolute risk difference: 0.01; 95% CI –0.09 to 0.11; p = 0.803). No significant differences were observed for all secondary outcomes, including 6-month mortality, even after adjustment for age, country, and Acute Physiology and Chronic Health Evaluation score.

Conclusions:

There was no evidence that fresh red cells improved outcomes as compared to standard issue red cells in critically ill surgical patients, consistent with other patients enrolled in the ABLE trial.
The Status Quo of Continuing Medical Education in South-East Asia and Eastern Mediterranean Regions: A Scoping Review of 33 Countries
Authors: Vakani Farhan Saeed , Uebel Kerry , Balasooriya Chinthaka , Demirkol Apo
Published: February 2023

Introduction:

Continuing medical education is a process of continuous learning to maintain physicians' competence and professional performance. Efforts to make continuing medical education (CME) programs mandatory in the South-East Asia Region by linking credits to the renewal of registration have met with mixed success. However, there are no recent reviews on the CME status in regions with a large number of developing countries. This review aims to map the practices and regulation of the CME activities in the South-East Asia and Eastern Mediterranean regions.

Methods:

A scoping review was undertaken using a modified Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews checklist. A search was conducted within PubMed, Embase, Web of Science, Scopus databases, and national medical and health council websites.

Results:

Evidence on the provision of CME is available for all but seven of the 33 countries in both regions. Fourteen countries of varying income levels have implemented mandatory CME linked to the renewal of registration. They have statutory bodies governing CME and allocating credits, with most requiring a large number of hourly based activities for the renewal of registration and evidence of a wide range of local providers.

Conclusions:

Financial resources, a thorough organizational structure and standards, and a wide range of local CME providers seem to promote the implementation of mandatory CME in most of these countries.