Efficiency of bladder-sparing strategies for bladder cancer: an umbrella review.

Bladder preservation (BP) has emerged as a clinical alternative to radical cystectomy (RC) for alleviating the substantial physical and psychological burden imposed on localized bladder cancer patients. Nevertheless, disparities persist in the comparative evaluations of BP and RC. We aimed to address the disparities between BP and RC. An umbrella review and meta-analysis were conducted to explore these disparities. We extracted data from meta-analyses and randomized controlled trials (RCTs) selected after searching PubMed, Embase, Web of Science, and the Cochrane Database of Systematic Reviews. Review Manager 5.4.0 and R x64 4.1.3 were used to evaluate the collected data. Our study included 11 meta-analyses and 3 RCTs. In terms of progression-free survival, all the meta-analyses reported that patients with localized bladder cancer who underwent BP exhibited outcomes comparable to those who underwent RC. Meta-analyses regarding the outcomes of cancer-specific survival (CSS) and overall survival (OS) are controversial. To solve these issues, we conducted a pooled analysis of CSS data, which supported the similarity of CSS between BP and RC with no significant heterogeneity [odds ratio (OR): 1.2; 95% confidence interval (CI): 0.71-2.02; I2 = 26%]. Similarly, the pooled OS results extracted from three RCTs indicated the comparability of OS between BP and RC with no significant heterogeneity (OR: 1.12; 95% CI: 0.41-3.07; I2 = 33%). A combination of umbrella review and meta-analysis results suggested that BP had survival rates comparable to those of RC. We suggest that BP may be a more eligible therapy than RC for patients with localized muscle-invasive bladder cancer. This conclusion warrants further validation through randomized controlled trials.

An endothelial-related prognostic index for bladder cancer patients.

BACKGROUND: Within the tumor microenvironment, endothelial cells hold substantial sway over bladder cancer (BC) prognosis. Herein, we aim to elucidate the impact of endothelial cells on BC patient outcomes by employing an integration of single-cell and bulk RNA sequencing data. METHODS: All data utilized in this study were procured from online databases. R version 3.6.3 and relevant packages were harnessed for the development and validation of an endothelial-associated prognostic index (EPI). RESULTS: EPI was formulated, incorporating six genes (CYTL1, FAM43A, GSN, HSPG2, RBP7, and SLC2A3). EPI demonstrated significant prognostic value in both The Cancer Genome Atlas (TCGA) and externally validated dataset. Functional results revealed a profound association between EPI and endothelial cell functionality, as well as immune-related processes. Our findings suggest that patients with low-risk EPI scores are more likely to respond positively to immunotherapy, as indicated by immune checkpoint activity, immune infiltration, tumor mutational burden, stemness index, TIDE, and IMvigor210 analyses. Conversely, individuals with high-risk EPI scores exhibited heightened sensitivity to cisplatin, docetaxel, and gemcitabine treatment regimens. CONCLUSION: We have effectively discerned pivotal genes from the endothelial cell perspective and constructed an EPI for BC patients, thereby offering promising prospects for precision medicine.

Distinctive Craniofacial and Oral Anomalies in MN1 C-terminal Truncation Syndrome.

MN1 C-terminal truncation (MCTT) syndrome was first reported in 2020 and only 28 patients have been recorded to date. Since MCTT syndrome is a newly defined and rare syndrome with many clinical features, the present study reviewed the manifestations and management of oral and dental anomalies. Gene variants of MCTT syndrome and their positive phenotypes were summarised. The phenotypes of variants in two exons differed from each other mainly in the craniomaxillofacial region, including brain MRI abnormalities and palatal morphology. Pathogenic mechanisms, especially in craniofacial and oral anomalies, were discussed. Appropriate treatments in the stomatology and respiratory departments could improve the symptoms of MCTT syndrome. The different sites of MN1 gene variants may influence the clinical symptoms and there may be racial differences in MCTT syndrome. We recommend oral and pulmonary evaluations for the multidisciplinary treatment of MCTT syndrome.

Unraveling the Promise of RET Inhibitors in Precision Cancer Therapy by Targeting RET Mutations.

Over the past decades, the role of rearranged during transfection (RET) alterations in tumorigenesis has been firmly established. RET kinase inhibition is an essential therapeutic target in patients with RET-altered cancers. In clinical practice, initial efficacy can be achieved in patients through the utilization of multikinase inhibitors (MKIs) with RET inhibitory activity. However, the effectiveness of these MKIs is impeded by the adverse events associated with off-target effects. Recently, many RET-selective inhibitors, characterized by heightened specificity and potency, have been developed, representing a substantial breakthrough in the field of RET precision oncology. This Perspective focuses on the contemporary understanding of RET mutations, recent advancements in next-generation RET inhibitors, and the challenges associated with resistance to RET inhibitors. It provides valuable insights for the development of next-generation MKIs and selective RET inhibitors.

A nomogram for prediction of ERCP success in patients with bile duct leaks: a multicenter study.

BACKGROUND: Bile duct leaks (BDLs) are serious complications that occurs after hepatobiliary surgery and trauma, leading to rapid clinical deterioration. Endoscopic retrograde cholangiopancreatography (ERCP) is the first-line treatment for BDLs, but it is not clear which patients will respond to this therapy and which patients will require additional surgical intervention. The aim of our study was to explore the predictors of successful ERCP for BDLs. METHODS: A retrospective analysis was conducted using data from six centers' databases. All consecutive patients who were clinically confirmed as BDLs were included in the study. Collected data were demographics, disease severity, and ERCP procedure characteristics. Univariate and multivariate analysis were used to select independent predictive factors that affect the outcome of ERCP for BDLs, and a nomogram was established. Calibration and ROC curves were used to evaluate the models. RESULTS: Four hundred and forty-eight consecutive patients were clinically confirmed as BDLs and 347 were excluded. In the 101 patients included patients, clinical success was achieved in 78 patients (77.2%). In logistic multivariable regression, two independent factors were negatively associated with the success of ERCP: SIRS (OR, 0.183; 95% CI 0.039-0.864; P = 0.032) and high-grade leak (OR 0.073; 95% CI 0.010-0.539; P = 0.010). Two independent factors were positively associated with the success of ERCP: leak-bridging drainage (OR 4.792; 95% CI 1.08-21.21; P = 0.039) and cystic duct leak (OR 6.193; 95% CI 1.03-37.17; P = 0.046). The prediction model with these four factors was evaluated using a receiver-operating characteristic (ROC) curve, which demonstrated an area under the curve of 0.9351. The calibration curve showed that the model had good predictive accuracy. CONCLUSION: Leak-bridging drainage and cystic duct leak are positive predictors for the success of ERCP, while SIRS and high-grade leak are negative predictors. This prediction model with nomogram has good predictive ability and practical clinical value, and may be helpful in clinical decision-making and prognostication.

Efficacy and safety of neoadjuvant sintilimab in combination with FLOT chemotherapy in patients with HER2-negative locally advanced gastric or gastroesophageal junction adenocarcinoma: an investigator-initiated, single-arm, open-label, phase II study.

BACKGROUND: The addition of immune checkpoint inhibitors to neoadjuvant chemotherapy in operable advanced gastric or gastroesophageal junction (G/GEJ) cancer aroused wide interest. This study was designed to assess the efficacy and safety of neoadjuvant sintilimab, a programmed cell death protein-1 (PD-1) inhibitor, in combination with fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) chemotherapy for HER2-negative locally advanced G/GEJ cancer. METHODS: Eligible patients with clinical stage cT4 and/or cN+M0 G/GEJ cancer were enroled in this phase II study. Patients received neoadjuvant sintilimab (200 mg every 3 weeks) for three cycles plus FLOT (50 mg/m 2 docetaxel, 80 mg/m 2 oxaliplatin, 200 mg/m 2 calcium levofolinate, 2600 mg/m 2 5-fluorouracil every 2 weeks) for four cycles before surgery, followed by four cycles of adjuvant FLOT with same dosages after resection. The primary endpoint was the pathological complete response (pCR) rate. RESULTS: Thirty-two patients were enroled between August 2019 and September 2021, with a median follow-up of 34.8 (95% CI, 32.8-42.9) months. Thirty-two (100%) patients received neoadjuvant therapy, and 29 underwent surgery with an R0 resection rate of 93.1%. The pCR (TRG0) was achieved in 5 (17.2%; 95% CI, 5.8-35.8%) patients, and the major pathological response was 55.2%. Twenty-three (79.3%) patients had T downstaging, 21 (72.4%) had N downstaging, and 19 (65.5%) had overall TNM downstaging. Six (20.7%) patients experienced recurrence. Patients achieving pCR showed better event-free survival (EFS), disease-free survival (DFS), and overall survival (OS) than non-pCR. The estimated 3-year EFS rate, 3-year DFS rate, and 3-year OS rate were 71.4% (95% CI, 57.2-89.2%), 78.8% (95% CI, 65.1-95.5%), and 70.9% (95% CI, 54.8-91.6%), respectively. The objective response rate and disease control rate were 84.4% (95% CI, 68.3-93.1%) and 96.9% (95% CI, 84.3-99.5%), respectively. Twenty-five (86.2%) received adjuvant therapy. The main grade ≥3 treatment-related adverse events (TRAEs) were lymphopenia (34.4%), neutropenia (28.1%), and leukopenia (15.6%). no patients died from TRAE. The LDH level exhibited a better predictive value to pathological responses than PD-L1 and MSI status. CONCLUSIONS: The study demonstrated an encouraging efficacy and manageable safety profile of neoadjuvant sintilimab plus FLOT in HER2-negative locally advanced G/GEJ cancer, which suggested a potential therapeutic option for this population.

Research Note: Preliminary functional analysis of EGF-like domains of Eimeria tenella microneme protein 7 identified in sporozoites and merozoites.

Eimeria tenella, an obligate intracellular apicomplexan parasite, is the major causative agent of chicken coccidiosis. Some epidermal growth factor (EGF)-like domain-containing proteins of other members of apicomplexan parasites have been reported to contribute to parasite survival. To date, however, EGF-like domain-containing proteins of E. tenella are not well studied. In this study, a gene fragment that encodes 4 EGF-like domains of E. tenella microneme protein 7 (EGF-EtMIC7) was amplified and expressed using an Escherichia coli expression system. Following generation of polyclonal antibodies that recognize recombinant EGF-EtMIC7 (rEGF-EtMIC7), the expression of EtMIC7 in sporozoites and merozoites was examined. Moreover, its roles in cellular regulation were investigated. The native EtMIC7 in E. tenella sporozoites and merozoites was detected by using Western blot and indirect immunofluorescence assays. rEGF-EtMIC7 could activate Akt, whereas blockade of EGF receptor (EGFR) failed to induce Akt phosphorylation. Compared with the control group, LMH cells treated with rEGF-EtMIC7 showed increased cell proliferation and expressed higher levels of B cell leukemia/lymphoma 2 (BCL-2). These findings contribute to the better understanding of parasite-host interactions at the molecular level during E. tenella infection.

Aging aggravates liver fibrosis through downregulated hepatocyte SIRT1-induced liver sinusoidal endothelial cell dysfunction.

BACKGROUND: Aging increases the susceptibility to chronic liver diseases and hastens liver fibrosis deterioration, but the underlying mechanisms remain partially understood. The aim of this study was to investigate the effect of aging and chronic liver diseases on hepatocyte Sirtuin 1 (SIRT1) and LSECs and their contribution to liver fibrosis pathogeneses. METHODS: Young (8-12 wk) and aged (18-20 mo) mice were subjected to carbon tetrachloride-induced liver fibrosis. Primary HSCs and LSECs were isolated and cocultured for in vitro experiments. Liver tissues and blood samples from healthy controls and patients with liver fibrosis were analyzed. RESULTS: Downregulated hepatocytes SIRT1 in aged mice increased high mobility group box 1 acetylation, cytoplasmic translocation, and extracellular secretion, causing LSECs dysfunction by means of the toll-like receptor 4/AK strain transforming (AKT)/endothelial nitric oxide synthase pathway, ultimately activating HSCs and increasing susceptibility to liver injury and fibrosis. Adeno-associated virus-mediated overexpression of SIRT1 in hepatocytes suppressed the abovementioned alterations and attenuated carbon tetrachloride-induced liver injury and fibrosis in liver fibrosis mice, and there were no significant differences in liver injury and fibrosis indicators between young and aged mice after SIRT1 overexpression treatment. In vitro experiments demonstrated that SIRT1 overexpression and endothelial nitric oxide synthase agonist YC-1 improved LSECs function and inhibited HSCs activation, mediated by nitric oxide. Similarly, downregulated hepatocytes SIRT1 and LSECs dysfunction were observed in the livers of aged individuals compared to young individuals and were more pronounced in aged patients with liver fibrosis. CONCLUSIONS: Aging aggravates liver fibrosis through downregulated hepatocytes SIRT1-induced LSECs dysfunction, providing a prospective curative approach for preventing and treating liver fibrosis.

Ropivacaine-loaded hydrogels for prolonged relief of chemotherapy-induced peripheral neuropathic pain and potentiated chemotherapy.

Chemotherapy can cause severe pain for patients, but there are currently no satisfactory methods of pain relief. Enhancing the efficacy of chemotherapy to reduce the side effects of high-dose chemotherapeutic drugs remains a major challenge. Moreover, the treatment of chemotherapy-induced peripheral neuropathic pain (CIPNP) is separate from chemotherapy in the clinical setting, causing inconvenience to cancer patients. In view of the many obstacles mentioned above, we developed a strategy to incorporate local anesthetic (LA) into a cisplatin-loaded PF127 hydrogel for painless potentiated chemotherapy. We found that multiple administrations of cisplatin-loaded PF127 hydrogels (PFC) evoked severe CIPNP, which correlated with increased pERK-positive neurons in the dorsal root ganglion (DRG). However, incorporating ropivacaine into the PFC relieved PFC-induced CIPNP for more than ten hours and decreased the number of pERK-positive neurons in the DRG. Moreover, incorporating ropivacaine into the PFC for chemotherapy is found to upregulate major histocompatibility complex class I (MHC-I) expression in tumor cells and promote the infiltration of cytotoxic T lymphocytes (CD8+ T cells) in tumors, thereby potentiating chemotherapy efficacy. This study proposes that LA can be used as an immunemodulator to enhance the effectiveness of chemotherapy, providing new ideas for painless cancer treatment.

Preclinical characterization of danatinib as a novel FLT3 inhibitor with excellent efficacy against resistant acute myeloid leukemia.

The therapeutic benefits of available FLT3 inhibitors for AML are limited by drug resistance, which is related to mutations, as well toxicity caused by off-target effects. In this study, we introduce a new small molecule FLT3 inhibitor called danatinib, which was designed to overcome the limitations of currently approved agents. Danatinib demonstrated greater potency and selectivity, resulting in cytotoxic activity specific to FLT3-ITD and/or FLT3-TKD mutated models. It also showed a superior kinome inhibition profile compared to several currently approved FLT3 inhibitors. In diverse FLT3-TKD models, danatinib exhibited substantially improved activity at clinically relevant doses, outperforming approved FLT3 inhibitors. In vivo safety evaluations performed on the granulopoiesis of transgenic myeloperoxidase (MPO) zebrafish and mice models proved danatinib to have an acceptable safety profile. Danatinib holds promise as a new and improved FLT3 inhibitor for the treatment of AML, offering long-lasting remissions and improved overall survival rates.

When Lymphoma Strikes the Pancreas: A Rare Presentation of Systemic Anaplastic Lymphoma Kinase-Negative Anaplastic Large Cell Lymphoma in a Human Immunodeficiency Virus-Positive Patient.

Anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma (ALCL) is an uncommon subtype of non-Hodgkin lymphoma, with pancreatic involvement being exceedingly rare and documented in only a handful of case reports. We present a unique case of a 31-year-old human immunodeficiency virus (HIV)-positive male with multisite ALK-negative ALCL, who initially presented with a buttock ulcer, leading to a suspicion of primary cutaneous ALCL or lymphomatoid papulosis. However, the discovery of multiple extracutaneous sites, including an atypical pancreatic head involvement, confirmed the diagnosis of systemic ALK-negative ALCL with cutaneous manifestation. The patient received six cycles of brentuximab vedotin + cyclophosphamide-doxorubicin-prednisone (BV + CHP) treatment, achieving a substantial reduction in the size of the pancreatic head mass and no detectable fluorodeoxyglucose (FDG) uptake on positron emission tomography (PET) scan. This case underscores the diagnostic challenges of ALK-negative ALCL in HIV-positive patients with extranodal presentations and demonstrates the potential effectiveness of targeted therapeutic strategies for such cases.

Diffuse large B-cell lymphoma presenting as postmenopausal bleeding.

Key Clinical Message: Endometrial lymphoma is a rare etiology of abnormal uterine bleeding and endometrial thickening, and often shares similar clinical and imaging characteristics with other uterine malignancies such as endometrial carcinoma. Chemotherapy appears adequate for treating primary endometrial lymphoma. Abstract: We report a case of primary endometrial diffuse large B-cell lymphoma to increase awareness of this condition which is essential for correct diagnosis and treatment.

Ginsenoside Rh2 and its octyl ester derivative inhibited invasion and metastasis of hepatocellular carcinoma via the c-Jun/COX2/PGE2 pathway.

BACKGROUND: Liver cancer is a topical global health issue. The treatment of liver cancer meets significant challenges in the high recurrence rate and invasive incidence. Therefore, the treatment strategies that target epithelial-mesenchymal transition (EMT) induced by cyclooxygenase 2 (COX2)/ prostaglandin E2 (PGE2) pathway have become epidemic. Ginsenoside Rh2 has been proved to inhibit the EMT. However, the underlying mechanisms remain unclear. Moreover, the octyl ester derivative of Rh2 (Rh2-O) exhibited superior anti-proliferative and immunomodulatory effects than Rh2 in our previous researches, which indicated that Rh2-O might also exert inhibitory effects on invasion and metastasis. PURPOSE: The aim of current study is to explore the inhibitory effects of Rh2 and Rh2-O on invasion and metastasis of hepatocellular carcinoma, and to investigate whether these effects are dependent on the c-Jun/COX2/PGE2 pathway. STUDY DESIGN: The Huh-7 liver cancer cells and the H22 tumor-bearing mice were treated with Rh2 and Rh2-O. METHOD: In this paper, the inhibitory effects of Rh2 and Rh2-O on invasion and metastasis were tested by wound healing, trans-well assay and tumor-bearing mice, and the involvement of c-Jun/COX2/PGE2 pathway were verified by exogenous PGE2, activation of COX2 and overexpression of c-Jun. RESULTS: The results showed that Rh2 and Rh2-O could efficiently inhibit the invasion and metastasis in a dose-dependent manner (p < 0.05). And the Rh2-O showed stronger effects than Rh2. Moreover, the exogenous PGE2, activation of COX2 by exogenous LPS and the overexpression of c-Jun by transfection all reversed the inhibitory effects of Rh2 and Rh2-O on metastasis or EMT (p < 0.05). CONCLUSION: Rh2 and Rh2-O could inhibit the invasion and metastasis of hepatocellular carcinoma via restraining the EMT, which was mediated by c-Jun/COX2/PGE2 pathway.