Risk factors of immune checkpoint inhibitor-related pneumonitis after neoadjuvant immunochemotherapy for resectable NSCLC.

BACKGROUND: The incidence of checkpoint inhibitor-associated pneumonitis (CIP) in advanced non-small cell lung cancer (NSCLC) has been substantiated through large-scale clinical trials or real-world studies. However, reports on CIP incidence within the context of neoadjuvant immunotherapy for resectable NSCLC remain scarce. This study endeavors to investigate the incidence, risk factors, and outcomes of CIP in patients with resectable NSCLC receiving neoadjuvant immunochemotherapy. METHODS: A retrospective, case-control study was conducted on patients diagnosed with NSCLC stages IIA-IIIB who received neoadjuvant immunochemotherapy between January 2018 and September 2022. Patients were stratified into two groups based on the presence or absence of CIP, facilitating a comparative analysis of clinical characteristics, treatment modalities, physiological indicators, and prognostic outcomes . RESULTS: The study cohort comprised 245 patients, with 11.4% (28/245) experiencing CIP. The median period of CIP onset was 70 (range, 40-221) days. The incidence of severe CIP (grade 3-4) was 3.7% (9/245). Patients with CIP showed a higher all-cause mortality rate of 21.4% (6/28) compared to that of patients without CIP. Those who developed CIP exhibited elevated body mass index (BMI) values (p = 0.028) and increased fibrinogen (FIB) levels (p < 0.001), alongside a significant decrease in both diffusing capacity for carbon monoxide (DLCO)% pred (p = 0.001) and DLCO/VA% pred (p = 0.021) after neoadjuvant therapy compared to pre-indicators. Receiver operating characteristic curve (ROC) analysis showed that the area under the ROC curve of three assessed variables (FIB levels, BMI, DLCO) reached 0.806 in predicting CIP occurrence at an early stage. CONCLUSIONS: This cohort demonstrated that elevated BMI, increased FIB levels, and decreased pulmonary diffusion function after neoadjuvant therapy are risk factors of CIP occurrence. Early assessment and continuous monitoring of these indicators are imperative for the predictive identification of CIP, enhancing patient management and outcomes.

A Radiomic Approach to Access Tumor Immune Status by CD8+TRMs on Surgically Resected Non-Small-Cell Lung Cancer.

PURPOSE: Immunotherapy has made breakthroughs in the treatment of non-small-cell lung cancer (NSCLC); however, only a subset of patients achieved long-term survival, so it is of great importance to find a biomarker of lung cancer thus guide immunotherapy. Studies have shown that the infiltration level of tissue resident memory CD8+ T cells (CD8+ TRMs) is positively correlated with lung cancer prognosis and can be an ideal biomarker for assessing the tumor local immune status. We screened the radiomic features associated with CD8+ TRMs as targets in NSCLC surgical specimens by radiomic approaches, and established a radiomic predictive model to assess the local immune status, which may provide a scientific reference for lung cancer treatment strategies. PATIENTS AND METHODS: We retrospectively analyzed the NSCLC surgical specimens immune cell database and extracted CD8+ TRMs cell data, preoperative CT scan data were achieved. A total of 97 patients containing complete preoperative data were included, radiomic features were extracted from the preoperative CT image data. All the patients were divided into two groups, namely high-CD8+ TRMs infiltrated group and low-CD8+ TRMs infiltrated group, based on the proportion of CD8+ TRMs cells subset in the immune cell population. The most valuable radiomic features and semantic features were extracted and selected, and a neural network model was established to predict the level of CD8+ TRMs cell infiltration level to assess the tumor local immune status. RESULTS: The NSCLC tumor immune status predictive model was built to discriminate high- from low-CD8+ TRMs with an area under the curve (AUC) of 0.788 (95% CI) in the training set and 0.753 (95% CI) in the validation set. CONCLUSION: The radiomic models using CT image data showed a good predictive performance for accessing NSCLC immune status thus has great potential for personalized therapeutic decision making.

Treatment of Central Nervous System Relapse in Acute Promyelocytic Leukemia by Venetoclax: A Case Report.

Extramedullary relapse of acute promyelocytic leukemia is a rare phenomenon and is associated with a poor prognosis, with the central nervous system being the most common site of relapse. The current treatments are still limited. Venetoclax, a selective inhibitor of BCL2, is a small molecule that can cross the blood-brain barrier and shows a potential efficacy in the treatment of chronic lymphocytic leukemia with central nervous system involvement. Although venetoclax has also been used in the treatment of acute myeloid leukemia in recent years, there are no reports of its use in the treatment of central nervous system relapse in acute promyelocytic leukemia. Here, we report a case of central nervous system relapse in acute promyelocytic leukemia that achieved complete remission after oral treatment with venetoclax. The presence of venetoclax in the patient's CSF was confirmed by testing CSF and plasma by mass spectrometry. The concentration of venetoclax in CSF was approximately 1/300 of that in plasma trough concentration. The treatment experience in this case demonstrates the potential ability of venetoclax to treat of central nervous system relapse/involvement in acute promyelocytic leukemia, thus providing a new treatment option for this kind of patient.

Dynamic monitor of CT scan within short interval in invasive pulmonary aspergillosis for nonneutropenic patients: a retrospective analysis in two centers.

BACKGROUND: In nonneutropenic patients with underlying respiratory diseases (URD), invasive pulmonary aspergillosis (IPA) is a life-threatening disease. Yet establishing early diagnosis in those patients remains quite a challenge. METHODS: A retrospective series of nonneutropenic patients with probable or proven IPA were reviewed from January 2014 to May 2018 in Department of Respiratory Medicine of two Chinese hospitals. Those patients were suspected of IPA and underwent lung computed tomography (CT) scans twice within 5-21 days. The items required for IPA diagnosis were assessed by their host factors, mycological findings and CT scans according to the European Organization for Research and Treatment of Cancer (EORTC) and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (MSG) criteria (EORTC/MSG criteria). RESULTS: Together with the risk factors, mycological findings and nonspecific radiological signs on first CT, ten patients were suspected of IPA. With the appearance of cavities on second CT scan in the following days, all patients met the criteria of probable or possible IPA. Except one patient who refused antifungal treatment, nine patients received timely antifungal treatment and recovered well. One of the nine treated IPA cases was further confirmed by pathology, one was confirmed by biopsy. CONCLUSIONS: Dynamic monitor of CT scan provided specific image evidences for IPA diagnosis. This novel finding might provide a noninvasive and efficient strategy in IPA diagnosis with URD.

Different roles of matrix metalloproteinase 2 in osteolysis of skeletal dysplasia and bone metastasis (Review).

Matrix metalloproteinase 2 (MMP2) is a well­characterized protein that is indispensable for extracellular matrix remodeling and other pathological processes, such as tumor progression and skeletal dysplasia. Excessive activation of MMP2 promotes osteolytic metastasis and bone destruction in late­stage cancers, while its loss­of­function mutations result in the decreased bone mineralization and generalized osteolysis occurring progressively in skeletal developmental disorders, particularly in multicentric osteolysis, nodulosis and arthropathy (MONA). Either upregulation or downregulation of MMP2 activity can result in the same osteolytic effects. Thus, different functions of MMP2 have been recently identified that could explain this observation. While MMP2 can degrade bone matrix, facilitate osteoclastogenesis and amplify various signaling pathways that enhance osteolysis in bone metastasis, its role in maintaining the number of bone cells, supporting osteocytic canalicular network formation and suppressing leptin­mediated inhibition of bone formation has been implicated in osteolytic disorders caused by MMP2 deficiency. Furthermore, the proangiogenic activity of MMP2 is one of the potential mechanisms that are associated with both pathological situations. In the present article, the latest research on MMP2 in bone homeostasis is reviewed and the mechanisms underlying the role of this protein in skeletal metastasis and developmental osteolysis are discussed.

Efficacy of Pyrotinib in a Heavily Pretreated Patient with Lung Adenocarcinoma Harboring HER2 Amplification and Exon 20 Insertions: A Case Report.

The clinical benefits of HER2 inhibitors in patients with non-small cell lung cancer (NSCLC) have been limited. There is a paucity of effective therapies in NSCLC after developing resistance to initial anti-HER2 therapy. Herein, we presented the clinical benefit of pyrotinib in a 53-year-old patient with advanced lung adenocarcinoma whose circulating tumor DNA (ctDNA) analysis of pleural effusion revealed the coexistence of HER2 exon 20 p.Y772_A775dup (mutation ratio: 38.86%) and HER2 amplification (copy number: 4.5) following failures of multiple therapies including afatinib and ado-trastuzumab emtansine (T-DM1). Notably, pyrotinib treatment induced rapid and marked improvement of clinical symptoms, and partial response was observed after 8 weeks. CtDNA monitoring during the treatment showed that the mutation ratio of HER2 decreased to 7.99%, and the amplification disappeared. The patient achieved a progression-free survival of 7.5 months after treatment with pyrotinib. Thus, pyrotinib may be a new treatment strategy for the subgroup of lung adenocarcinoma patients, with coexistence of HER2 exon 20 p.Y772_A775dup and HER2 amplification even after failures of multiple anti-HER2 therapies. It also indicated the value of capture-based next-generation sequencing to monitor and guide therapy.

Modified algorithm for managing postoperative osteomyelitis following fracture fixation with Cierny-Mader type.

BACKGROUND: No standardized protocol has been suggested in the treatment of postoperative osteomyelitis following fracture fixation. Our team evaluates the clinical efficacy of the modified algorithm for managing postoperative osteomyelitis following fracture fixation with Cierny-Mader type. METHODS: Ninety-five wounds were reviewed from March 2009 to February 2016 in our hospital. Sixty-one wounds were treated by the modified algorithm as follows: stable hardware + bone not healed Cierny-Mader 1 type = remove hardware, temporary stabilize; stable hardware + bone not healed Cierny-Mader 2 type = retain hardware ; stable hardware + bone not healed Cierny-Mader for type 3 and type 4 = remove hardware, temporary stabilize/Ilizarov technique; unstable hardware + bone not healed = remove hardware, temporary stabilize/Ilizarov technique; and stable hardware + bone healed = remove hardware. Thirty-four wounds were treated by the conventional algorithm. Autodermoplasty, flap transfer, myocutaneous flap, and other methods including antibiotic irrigation and drug delivery system were used in wound repair. RESULTS: The patients treated with modified algorithm had a significantly reduced recurrence (P < 0.01) and increased results of negative bacterial cultures (P < 0.01); however, a decrease in the number of retained hardware cases was observed (P < 0.05). For those treated with tissue reconstruction, there was no significance (P > 0.05) compared with the conventional group. CONCLUSIONS: The modified algorithm for the postoperative osteomyelitis following fracture fixation according to the stability of the hardware and Cierny-Mader type represents a good clinical efficacy in the management of postoperative osteomyelitis. This procedure is simple and shows promising results; more clinical evidence is needed to confirm the existing findings and optimize the treatment of postoperative osteomyelitis following fracture fixation.

A 60-Year-Old Man With Right Lung Mass Presents With Cough.

CASE PRESENTATION: A 60-year-old Chinese man was admitted to our hospital with chronic cough for > 2 months. His cough was paroxysmal and nonirritating, occasionally productive with some small amounts of white phlegm. He had had a low-grade fever for half a month. There were no night sweats, joint swelling on limbs, pain, rash, or any other discomfort. The patient denied weight loss and decreased appetite.

Primary thoracic neuroblastoma in an adult: A rare case report.

RATIONALE: Neuroblastoma is one of the most common malignant tumors in childhood, which mainly occurs in adrenal glands and peripheral sympathetic nerve system. Neuroblastoma occurring in adulthood is rare, and adults with neuroblastoma arising from thorax are exceedingly rare. A case of neuroblastoma that originated from thorax was reported, and was treated by resection operation. PATIENT CONCERNS: A 46-year-old woman was admitted to our hospital with left side chest pain for 5 days. Laboratory examinations were all normal. Chest computerized tomogram (CT) showed a lesion with clear boundary that was located at the left dorsal pleura. The nature of the mass was heterogeneous, showing slight heterogeneous enhancement after contrast and there was no obvious necrosis. DIAGNOSES: Based on the morphologic and immunohistochemical features, the tumor diagnosis was favorable for neuroblastoma. INTERVENTIONS: A resection operation was carried out. OUTCOMES: Three years postoperative, no sign of recurrence or metastasis has been observed. LESSONS: Primary neuroblastoma in adulthood is rare and has poor prognosis. Resection can be an important treatment option, and combining with other methods like chemotherapy, stem cell transplantation, the survival rate may be improved.

Angiosarcoma originating in the anterior mediastinum: A case report.

RATIONALE: Angiosarcomas are malignant vascular tumors, and angiosarcoma occurring in the anterior mediastinum is rare. Here we report a case of angiosarcoma that originated in the anterior mediastinum treated with surgery, followed by radiotherapy and synchronous chemotherapy. PATIENT CONCERNS: A 56-year-old female was admitted to our hospital with chest pain for 3 days. Chest computerized tomogram (CT) examination showed a heterogeneous mass in the anterior superior mediastinum, and after injection of contrast agent, the mass showed obvious heterogeneous enhancement. Magnetic resonance imaging (MRI) with T1 weighted image (T1WI) showed isointensity and T2 weighted image (T2WI) showed heterogeneous signal intensity, the mass showed an obvious heterogeneously enhancement after intravenous administration of contrast material. DIAGNOSIS AND INTERVENTIONS: Surgical resection operation was carried out. According to its morphologic and immunohistochemic feature of tumor cells which expressing CD31, CD34, and ERG, the tumor was categorized as an angiosarcoma. After operation, the patient received radiotherapy and synchronous chemotherapy. OUTCOMES: At present, 8 months postoperatively, no signs of recurrence have been observed. LESSONS: Although angiosarcoma in anterior mediastinum is rare, when a mass located in this area, a more careful immunohistological analysis should be performed to avoid overlooking the presence of angiosarcoma.

Immunomodulatory properties of graphene oxide for osteogenesis and angiogenesis.

BACKGROUND: The osteo-immunomodulatory properties of biomaterials play an important role in the outcomes of bone regeneration. Graphene oxide (GO) has been widely applied in many research fields due to its unique properties. However, the immunomodulatory properties of GO as a biomaterial for bone tissue engineering are still unclear. MATERIALS AND METHODS: In this study, we evaluated the Inflammatory response of RAW264.7 cells influenced by GO. Then the osteogenic differentiation of BMSCs, and angiogenic differentiation of human umbilical vein endothelial cells (HUVECs) by stimulation with GO/RAW 264.7-conditioned culture medium were accessed. We also further investi gated the possible mechanisms underlying the osteo- and angio-immunomodulatory effects of GO. RESULTS: Our results showed that GO stimulates the secretion of oncostatin M, tumor necrosis factor alpha and other factors through the nuclear factor-κB pathway. GO/RAW264.7-conditioned medium promoted the osteogenic differentiation of BMSCs, stimulated upregulation of the HUVECs of vascular-related receptors, and promoted their tube formation in vitro. CONCLUSION: In conclusion, our research shows that GO, as a biomaterial, can induce the formation of a beneficial osteo-immunomodulatory environment and is a promising biomaterial for bone tissue engineering.

Local delivery of HMGB1 in gelatin sponge scaffolds combined with mesenchymal stem cell sheets to accelerate fracture healing.

Fracture nonunion and delayed union continue to pose challenges for orthopedic surgeons. In the present study, we combined HMGB1 gelatin sponges with MSC sheets to promote bone healing after surgical treatment of rat tibial fractures. The HMGB1 gelatin sponge scaffolds supported the expansion of mesenchymal stem cells (MSCs) and promoted the osteogenic differentiation of MSCs and MSC sheets. Lentiviral vectors were then used to overexpress HMGB1 in MSCs. The results indicated that HMGB1 promotes the osteogenic differentiation of MSCs through the STAT3 pathway. Both siRNA and a STAT3 inhibitor downregulated STAT3, further confirming that HMGB1 induces the osteogenic differentiation of MSCs partly via the STAT3 signal pathway. In a rat tibial osteotomy model, we demonstrated the ability of HMGB1 gelatin sponge scaffolds to increase bone formation. The addition of MSC sheets further enhanced fracture healing. These findings support the use of HMGB1-loaded gelatin sponge scaffolds combined with MSC sheets to enhance fracture healing after surgical intervention.

[Medical imaging in tumor precision medicine: opportunities and challenges].

Tumor precision medicine is an emerging approach for tumor diagnosis, treatment and prevention, which takes account of individual variability of environment, lifestyle and genetic information. Tumor precision medicine is built up on the medical imaging innovations developed during the past decades, including the new hardware, new imaging agents, standardized protocols, image analysis and multimodal imaging fusion technology. Also the development of automated and reproducible analysis algorithm has extracted large amount of information from image-based features. With the continuous development and mining of tumor clinical and imaging databases, the radiogenomics, radiomics and artificial intelligence have been flourishing. Therefore, these new technological advances bring new opportunities and challenges to the application of imaging in tumor precision medicine.

Biological activity and magnetic resonance imaging of superparamagnetic iron oxide nanoparticles-labeled adipose-derived stem cells.

INTRODUCTION: No comparative study of adipose-derived stem cells (ADSCs) and bone marrow mesenchymal stem cells (BMSCs) by using superparamagnetic iron oxide nanoparticles (SPIOs)-labeling and magnetic resonance imaging (MRI) has been performed. METHODS: We studied the biological activity and MRI of ADSCs by labeling them with SPIOs and comparing them with BMSCs. After incubating the cells in culture medium with different levels of SPIOs (control group: 0 µg/ml; Groups 1 to 3: 25, 50, and 100 µg/ml) for 24 hours, we compared ADSCs with BMSCs in terms of intracellular iron content, labeling efficiency, and cell viability. Stem cells in the culture medium containing 50 µg/ml SPIOs were induced into osteoblasts and fat cells. Adipogenic and osteogenic differentiation potentials were compared. R2* values of MRI in vitro were compared. RESULTS: The results showed that labeling efficiency was highest in Group 2. Intracellular iron content and R2* values increased with increasing concentrations of SPIOs, whereas cell viability decreased with increasing concentrations of SPIOs, and adipogenic and osteogenic differentiation potentials decreased. However, we found no significant difference between the two kinds of cells for any of these indexes. CONCLUSIONS: ADSCs can be labeled and traced as easily as BMSCs in vitro. Given their abundance and higher proliferative capacity, as was previously shown, ADSCs may be better suited to stem cell therapy than are BMSCs.

Contrast-enhanced multiple-phase imaging features in hepatic epithelioid hemangioendothelioma.

AIM: To investigate and review the contrast-enhanced multiple-phase computed tomography (CEMP CT) and magnetic resonance imaging (MRI) findings in patients with pathologically confirmed hepatic epithelioid hemangioendothelioma (HEHE). METHODS: Findings from imaging examinations in 8 patients (5 women and 3 men) with pathologically confirmed HEHE were retrospectively reviewed (CT images obtained from 7 patients and MR images obtained from 6 patients). The age of presentation varied from 27 years to 60 years (average age 39.8 years). RESULTS: There were two types of HEHE: multifocal type (n = 7) and diffuse type (n = 1). In the multifocal-type cases, there were 74 lesions on CT and 28 lesions on MRI with 7 lesions found with diffusion weighted imaging; 18 (24.3%) of 74 lesions on plain CT and 26 (92.9%) of 28 lesions on pre-contrast MRI showed the target sign. On CEMP CT, 28 (37.8%) of 74 lesions appeared with the target sign and a progressive-enhancement rim and 9 (12.2%) of 74 lesions displayed progressive enhancement, maintaining a state of persistent enhancement. On CEMP MRI, 27 (96.4%) of 28 lesions appeared with the target sign with a progressive-enhancement rim and 28 (100%) of 28 lesions displayed progressive-enhancement, maintaining a state of persistent enhancement. In the diffuse-type cases, an enlarged liver was observed with a large nodule appearing with persistent enhancement on CEMP CT and MRI. CONCLUSION: The most important imaging features of HEHE are the target sign and/or progressive enhancement with persistent enhancement on CEMP CT and MRI. MRI is advantageous over CT in displaying these imaging features.

Toxic effects of iron oxide nanoparticles on human umbilical vein endothelial cells.

Iron oxide nanoparticles (IONPs) have been employed for hyperthermia treatments, stem cell therapies, cell labeling, and imaging modalities. The biocompatibility and cytotoxic effects of iron oxide nanoparticles when used in biomedical applications, however, are an ongoing concern. Endothelial cells have a critical role in this research dealing with tumors, cardiovascular disease and inflammation. However, there is little information dealing with the biologic effects of IONPs on the endothelial cell. This paper deals with the influence of dextran and citric acid coated IONPs on the behavior and function of human umbilical vein endothelial cells (HUVECs). After exposing endothelial cells to IONPs, dose-dependent effects on HUVECs viability, cytoskeleton and function were determined. Both citric acid and dextran coated particles appeared to be largely internalized by HUVECs through endocytosis and contribute to eventual cell death possibly by apoptosis. Cytoskeletal structures were greatly disrupted, as evidenced by diminished vinculin spots, and disorganized actin fiber and tubulin networks. The capacity of HUVECs to form a vascular network on Matrigel™ diminished after exposure to IONPs. Cell migration/invasion were inhibited significantly even at very low iron concentrations (0.1 mM). The results of this study indicate the great importance of thoroughly understanding nanoparticle-cell interactions, and the potential to exploit this understanding in tumor therapy applications involving IONPs as thermo/chemoembolization agents.

[Magnetic resonance signal detection of superparamagnetic iron oxide nanoparticles and its biological effects on endothelial cells].

OBJECTIVE: To investigate the magnetic resonance (MR) signal changes of superparamagnetic iron oxide (SPIO) and its biological effects on endothelial cells. METHODS: The citric-acid coated SPIO was synthesized by co-precipitation method. The human umbilical vein endothelial cells (HUVECs) were incubated with SPIO for 24 h in culture medium at iron concentration of 0.01, 0.05, 0.10, 0.15 mg/ml (experimental groups), and the cells incubated without SPIO served as control groups. The uptake efficiency of intracellular iron was measured by Prussian blue staining, and the cell viability was monitored by Calcein-AM method. The cell cytoskeleton (F-actin and tubulin), adherence and migration capacity were measured by immunofluorescence staining. The iron oxide nanoparticles distribution and the cellular organelle change were monitored by transmission electron microscopy (TEM). Quantification of particle uptake was measured by atomic absorption spectrometry. The MR signal of endothelial cells after labeling was monitored by Philips 3.0 T MR scanner. RESULTS: SPIO was uptaken by HUVECs in a concentration-dependence manner. Compared with the control group, cell viability was decreased along with the increase of iron concentration. Compared with the control group, the cell cytoskeleton was markedly disorganized and the FAK spot was bigger and sparser.The nanoparticles were mainly existed in lysosomes, and the higher concentration of SPIO, the more lysosomes and vacuoles presented in the cells. The iron content per cell was (55.86 +/-9.935) pg when the SPIO concentration was 0.15 mg/ml. The MR image showed that the cells labeled with SPIO resulted in the decrease of MR signal. CONCLUSION: The cells labeled with SPIO can be detected by MR. The cell viability, cytoskeleton, adherence and migration capacity of HUVECs are affected by citric-acid coated SPIO in a concentration-dependent manner.

[Treatment of acute and chronic osteomyelitis with negative pressure wound therapy].

OBJECTIVE: To investigate the treatment of acute and chronic osteomyelitis with negative pressure wound therapy. METHOD: Thirty cases of acute and chronic osteomyelitis were treated with negative pressure wound therapy, assisted with debridement, autodermoplasty and myo-cutaneous flap surgery. RESULTS: No evidence of relapse was found in all cases treated with negative pressure wound therapy. All the patients were followed up, range from 6 to 23 months, the average was 13.6 months. CONCLUSION: The negative pressure wound therapy maybe a simple, effective and inexpensive method, and could be one of the favorable therapy in the treatment of acute and chronic osteomyelitis.