Revealing the oncogenic role of elevated GNL3L expression in esophageal squamous cell carcinoma: insights into the STAT3 pathway.

Background: Esophageal squamous cell carcinoma (ESCC) patients carries a poor prognosis, with limited effective therapeutic targets. This study aimed to clarify the clinical significance of guanine nucleotide-binding protein like 3-like (GNL3L) protein expression in ESCC and its role in malignant progression. Methods: GNL3L expression and associated cancer-promoting pathways in ESCC were interrogated via bioinformatics analysis through use of The Cancer Genome Atlas (TCGA) database. Subsequent verification of GNL3L protein expression in ESCC, coupled with clinical data, was conducted through immunohistochemistry and followed by a comprehensive prognostic analysis. We further investigated potential signaling pathways facilitating ESCC progression, employing a combination of bioinformatics analysis and immunohistochemical (IHC) experiments. Results: Bioinformatics analysis unveiled a significant elevation in GNL3L expression, particularly in gastrointestinal tumors and ESCC. Immunohistochemistry confirmed elevated GNL3L expression in ESCC tissues. Regression analysis established a correlation between elevated GNL3L expression and advanced tumor node metastasis (TNM) stage, with high expression associated with poor prognosis in patients with ESCC. Our integrated approach of bioinformatics and IHC analysis indicated a potential role of the signal transducers and activators of transcription 3 (STAT3) signaling pathway in ESCC progression. Conclusions: High GNL3L expression significantly contributes to the malignant progression of ESCC. This study further elucidates the mechanisms driving ESCC progression and offers possible insights for more effective diagnosis and treatment strategies.

The efficacy-associated biomarkers for immune checkpoint inhibitors in gastrointestinal cancer: a literature review.

Background and Objective: Immune checkpoint inhibitors (ICIs) have been widely applied and studied in the treatment of gastrointestinal (GI) cancers, and have achieved good results. However, in clinical practice, it has been observed that only some patients respond well to ICIs, and some patients may experience various degrees of adverse reactions during the treatment. Timely evaluation of the potential therapeutic effects and adverse reactions of ICIs for patients has important clinical significance. This review aimed to summarize recent progress regarding efficacy-associated biomarkers for ICIs in GI cancer. Methods: The literature on ICI treatment in GI cancers was searched in the PubMed, Embase, and Cochrane Library databases for publications up to April 2023. Key Content and Findings: Clinical practice and research has gradually revealed some biomarkers related to the treatment of GI cancers with ICIs, which can be roughly divided into three types: biomarkers that predict the effectiveness of ICIs treatment, biomarkers associated with resistance to ICIs, and biomarkers associated with immune related adverse events (irAEs). This review article provides a literature review on biomarkers related to the efficacy of ICIs in the treatment of GI cancers. Conclusions: According to existing clinical research results, there are multiple biomarkers that can be used for predicting and monitoring the efficacy and risk of adverse events of ICIs in the treatment of digestive system malignant tumors.

High albumin-bilirubin grade predicts worse short-term complications in gastric cancer patients with metabolic syndrome: a retrospective study.

Background: Preoperative albumin-bilirubin (ALBI) grade has been proposed and applied in recent years to evaluate the prognosis of liver cancer, but its role in gastric cancer (GC) is still unclear. This research aimed to examine the prognostic value of ALBI grade after gastrectomy among patients with GC complicated with metabolic syndrome (MetS). Methods: There were 628 patients who received radical resection for GC. Laboratory data and short-term results were collected prospectively, and preoperative ALBI grades were calculated from the albumin and bilirubin levels. The appropriate ALBI cutoff value was calculated by receiver operating characteristic (ROC) curve analysis, which we used to put patients into high (>-2.54) and low (≤-2.54) ALBI grade groups. The differences between the short-term complication rates of the two groups were analyzed with the chi-square test. Results: Of the included patients, 133 (21.2%) and 495 (78.8%) had high and low ALBI grades, respectively. A high ALBI grade (P=0.001), body mass index (BMI) ≥25 kg/m2 (P=0.001), and hypertension (P=0.018) were independent risk factors for postoperative complications. In GC patients with and without MetS, the high ALBI subgroup showed more overall complications than the low ALBI subgroup (P=0.028 and P=0.001). Among GC patients with MetS, those with a high ALBI grade showed a higher incidence of serious complications than those with a low ALBI grade (P=0.001); a similar, nonsignificant trend occurred in non-MetS patients (P=0.153). Conclusions: The preoperative ALBI grade is important in the prognosis of GC patients with MetS after gastrectomy. GC patients with MetS can lower their incidence of serious complications by adjusting their preoperative ALBI grade.

A narrative review of the evolving role of immunotherapy in the management of esophageal and gastric cancer.

Background and Objective: Despite recent advances in the multidisciplinary management of esophagogastric cancer, overall prognosis remains poor. There is a need for improved treatment options, along with predictive biomarkers that improve therapeutic decision-making. Methods: We conducted an extensive review of immunotherapy articles in the PubMed database between December 2013 and October 2021. Articles in English were included. We included phase 1, 2, and 3 clinical trials for immunotherapy review, and prospective, retrospective, and meta-analyses for biomarker review. Key Content and Findings: Initial studies of immunotherapy were performed in patients with relapsed refractory metastatic disease and demonstrated a modest survival benefit. Subsequent studies have evaluated the use of these agents in combination with first line chemotherapy for metastatic disease. Finally, recent data indicates that immunotherapy in the adjuvant setting after concurrent chemoradiation and surgery improves disease free survival. Both microsatellite instability high (MSI-H) status and Epstein-Barr virus (EBV) positivity predict response to immunotherapy, but many patients without these biomarkers still benefit. The predictive impact of programmed cell death-ligand 1 (PD-L1) expression and tumor mutational burden (TMB) have been variable, and the optimal cutoff point for these biomarkers remains poorly defined. Conclusions: While immunotherapy agents have demonstrated clinical benefit and are now incorporated into the current standard of care, novel immunotherapy approaches such as dual immunotherapy combinations, chimeric antigen receptor (CAR) T cells, and tumor vaccines need to be further investigated. As the era of precision medicine beckons, refined biomarkers to predict benefit are needed.

CXCR2 Mediates Distinct Neutrophil Behavior in Brain Metastatic Breast Tumor.

Brain metastasis is one of the main causes of mortality among breast cancer patients, but the origins and the mechanisms that drive this process remain poorly understood. Here, we report that the upregulation of certain CXCR2-associated ligands in the brain metastatic variants of the breast cancer cells (BrM) dynamically activate the corresponding CXCR2 receptors on the neutrophils, thereby resulting in the modulation of certain key functional neutrophil responses towards the BrM. Using established neutrophil-tumor biomimetic co-culture models, we show that the upregulation of CXCR2 increases the recruitment of Tumor-Associated Neutrophils (TANs) towards the BrM, to enable location-favored formation of Neutrophil Extracellular Traps (NETs). Inhibition of CXCR2 using small molecule antagonist AZD5069 reversed this behavior, limiting the neutrophil responses to the BrM and retarding the reciprocal tumor development. We further demonstrate that abrogation of NETs formation using Neutrophil Elastase Inhibitor (NEI) significantly decreases the influx of neutrophils towards BrM but not to their parental tumor, suggesting that CXCR2 activation could be used by the brain metastatic tumors as a mechanism to program the tumor-infiltrating TANs into a pro-NETotic state, so as to assume a unique spatial distribution that assists in the subsequent migration and invasion of the metastatic tumor cells. This new perspective indicates that CXCR2 is a critical target for suppressing neutrophilic inflammation in brain metastasis.

Locally Advanced Primary Small Cell Carcinoma of the Breast: A Case Report and Review of Current Evidence.

Small-cell breast carcinoma (SCBC) is a very rare type of aggressive breast cancer constituting less than 1% of all breast cancers. The WHO classification categorizes this tumor as small-cell neuroendocrine carcinoma, and its prognosis is usually worse as compared to invasive breast cancers. We report a 64-year-old Caucasian female who presented with a large fungating left breast mass. Biopsy of the mass revealed small-cell carcinoma of the breast, negative for all 3 receptors (estrogen, progesterone, and Her2/neu). Imaging studies were negative for distant metastasis. She was subsequently treated after multidisciplinary discussion utilizing neoadjuvant chemotherapy with platinum agents and etoposide, modified radical mastectomy with axillary lymph node dissection, and adjuvant radiation therapy. Since she has triple-negative small-cell breast cancer, she will be followed with active surveillance without hormonal therapy. With less than 100 cases reported and in the absence of evidence-based standard treatment guidelines, we have reviewed various case series reported in the literature. We further discuss various chemotherapy regimens used previously, adverse prognostic factors of breast neuroendocrine tumors, common receptor status, and genetic mutations found in SCBC.

CNS Involvement in a Patient with Chronic Myeloid Leukemia.

Inspite of medication compliance, some chronic myeloid leukemia (CML) patients will relapse/progress into an accelerated phase or blast crisis. Central nervous system (CNS) involvement is a rare manifestation of such a relapse. Here, we report a case of 23-year-old female who was diagnosed with CML in the accelerated phase and subsequently treated with imatinib. She developed early relapse in her CNS, and her treatment was switched to dasatinib and intrathecal chemotherapy with cytarabine and methotrexate. Her CNS disease went into remission, and she underwent matched unrelated donor (MUD) hematopoietic stem cell transplant (HSCT). We discuss various mechanisms of treatment failure, importance of vigilance for symptoms and signs of treatment failure/relapse, indications for use of different tyrosine kinase inhibitors (TKIs), and management of blast crises in CML.

Comprehensive review of implications of COVID-19 on clinical outcomes of cancer patients and management of solid tumors during the pandemic.

Coronavirus disease-2019 (COVID-19) has emerged as a novel infection which has spread rapidly across the globe and currently presents a grave threat to the health of vulnerable patient populations like those with malignancy, elderly, and immunocompromised. Healthcare systems across the world are grappling with the detrimental impact of this pandemic while learning about this novel disease and concurrently developing vaccines, strategies to mitigate its spread, and treat those infected. Cancer patients today face with a unique situation. They are susceptible to severe clinically adverse events and higher mortality from COVID-19 infection as well as morbidity and mortality from their underlying malignancy. Conclusion: Our review suggests increased risk of mortality and serious clinical events from COVID-19 infection in cancer patients. However, risk of adverse events does not seem to be increased by cancer therapies. True impact of COVID-19 on cancer patients will unravel over the next few months. We have also reviewed clinical features of COVID-19, recent recommendations from various medical, surgical, and radiation oncology societies for major solid tumor types like lung, breast, colorectal, and prostate cancer during the duration of this pandemic.

Subaxial Cervical Spine Injuries: Outcomes after Anterior Corpectomy and Instrumentation.

STUDY DESIGN: This is prospective study. PURPOSE: The purpose of this study is to assess the functional, neurological, and radiological outcomes of the patients of subaxial cervical spine injuries treated by anterior corpectomy and stabilization with anterior cervical locking plate and cage filled with bone. OVERVIEW OF THE LITERATURE: The principles in the treatment of unstable cervical spine injuries are reduction and stabilization of the injured segment, maintenance of cervical lordosis and decompression where indicated and ranges from nonoperative to combined anterior and posterior surgical fusion. There is, however, debate on the indications for anterior, posterior, or combined surgery. MATERIALS AND METHODS: The present study of 99 patients includes prospective patients of subaxial cervical spine injuries between February 2014 and February 2016 admitted and operated to Indira Gandhi Medical College, Shimla. Bony fusion, neurological recovery, Neck Disability Index and complication were studied in all patients. The mean follow-up period was 27 months (range 12-42 months). RESULTS: Of the 99 procedures, 77 (77.8%) involved a single vertebral level, 19 (19.2%) involved two levels, and 3 (3%) involved three levels corpectomy. The mean Neck Disability Index was 7.57 ± 5.42. Definitive Bridwell Grade 1 fusion was seen in 64.6% of the cases. No deterioration of neurological symptoms was seen. Dysphagia was the most common complication in 79 (79.8%) patients. One patient had minimal screw back out. CONCLUSIONS: Anterior cervical corpectomy and stabilization with cage filled with bone and cervical reflex locking plate are good method for subaxial cervical spine injuries with good fusion rates and probably procedure of choice for posttraumatic multiple disc prolapse with reduced hazards of multiple grafts.

Phase 1b trial of nintedanib in combination with bevacizumab in patients with advanced solid tumors.

PURPOSE: Vascular endothelial growth factor (VEGF) inhibitors have produced demonstrable but limited benefit for various cancers. One mechanism of resistance includes revascularization, secondary to upregulation of alternative pro-angiogenic platelet-derived growth factor receptor and fibroblast growth factor receptor pathways. Nintedanib is an oral, triple kinase inhibitor that blocks these pathways and may improve anti-tumor activity by overcoming resistance to anti-VEGF therapies. The primary objective of this first in-human study was to evaluate the safety and tolerability of nintedanib in combination with bevacizumab. METHODS: Patients were treated with escalating doses of nintedanib (150 mg or 200 mg oral twice daily) and bevacizumab (15 mg/kg once intravenously every 3 weeks) until disease progression or unacceptable toxicity using standard 3 + 3 phase 1 design. Plasma levels of angiogenic biomarkers were correlated with clinical outcomes. RESULTS: Eighteen patients with advanced tumors [lung (n = 9), colon (n = 8), and cervical (n = 1)] previously treated with at least two lines of chemotherapy including bevacizumab (n = 9, 50%) were enrolled. The highest dose of nintedanib was 200 mg twice a day with no observed dose-limiting toxicities (DLT). Common adverse events (AE) were fatigue (grade 1-3) and diarrhea (grade 1-2). Durable clinical response was observed in 55% patients pretreated with bevacizumab (1 complete and 4 stable response). Better disease control was correlated with higher than median baseline values for VEFGR2 and E-selectin, and lower levels for SDF-1α. CONCLUSION: Nintedanib was well-tolerated with bevacizumab with no DLT. Significant clinical activity was observed, including in bevacizumab-pretreated patients, suggesting nintedanib can overcome bevacizumab resistance.

Functional Outcomes of Subaxial Spine Injuries Managed With 2-Level Anterior Cervical Corpectomy and Fusion: A Prospective Study.

OBJECTIVE: To evaluate the results of operative management of subaxial spine injuries managed with 2-level anterior cervical corpectomy and fusion with a cervical locking plate and autologous bone-filled titanium mesh cage. METHODS: This study included 23 patients with a subaxial spine injury who matched the inclusion criteria, underwent 2-level anterior cervical corpectomy and fusion at our institution between 2013 and 2016, and were followed up for neurological recovery, axial pain, fusion, pseudarthrosis, and implant failure. RESULTS: According to Allen and Ferguson classification, there were 9 cases of distractive extension; 4 of compressive extension; 3 each of compressive flexion, vertical compression, and distractive flexion; and 1 of lateral flexion. Sixteen patients had a score of 6 on the Subaxial Injury Classification system, and the rest had a score of more than 6. The mean follow-up period was 19 months (range, 12-48 months). Neurological recovery was observed in most of the patients (78.21%). All patients experienced relief of axial pain. None of the patients received a blood transfusion. Twenty-one patients (91.3%) showed solid fusion and 2 (8.69%) showed possible pseudarthrosis, with no complications related to the cage or plate. CONCLUSION: Two-level anterior cervical corpectomy and fusion, along with stabilization with a cervical locking plate and autologous bone graft-filled titanium mesh cage, can be considered a feasible and safe method for treating specific subaxial spine injuries, with the benefits of high primary stability, anatomical reduction, and direct decompression of the spinal cord.

Prevalence of Measurable Disease in Metastatic Castration-resistant Prostate Cancer.

BACKGROUND: Because of the low historical prevalence of measurable disease in metastatic castration-resistant prostate cancer (mCRPC), phase II trials have used prostate-specific antigen (PSA) and bone scan changes as primary end points. Frequent whole-body imaging and improved computed tomography technology currently identify measurable disease more frequently, warranting consideration of objective response as a major end point. PATIENTS AND METHODS: Data from reported phase III trials of mCRPC were analyzed. The proportion of patients with measurable disease, setting (pre-docetaxel [D], D-based, post-D), year of starting accrual, PSA, and the requirement for symptoms were collected. The χ2 test was used to evaluate the association of variables with measurable disease rate. RESULTS: Twenty phase III trials totaling 19,276 men with mCRPC were evaluable. Three trials (n = 1289) started accruing before 2000 and 17 trials (n = 17,987) accrued after 2000. The proportion of measurable disease rate for all trials was 47.5%. The measurable disease rate was significantly higher (P < .001) in trials that accrued after 2000 versus before 2000 (48.7% vs. 31.1%; P < .001), D-based (51.8%) or post-D patients (48.9%) compared with pre-D patients (38.6%) and in trials allowing symptomatic versus asymptomatic/minimally symptomatic patients (50.1% vs. 40.0%). CONCLUSION: The proportion of men with measurable disease was significantly higher in phase III trials of mCRPC that accrued after 2000, in D-based or post-D patients and in trials that allowed symptomatic patients. Because of the association of objective measurable changes with survival, Response Evaluation Criteria in Solid Tumors changes might warrant consideration as a major end point in phase II trials to obtain a firm signal of efficacy before launching phase III trials.

Kinomic profiling identifies focal adhesion kinase 1 as a therapeutic target in advanced clear cell renal cell carcinoma.

The introduction of targeted therapies has caused a paradigm shift in the treatment of metastatic clear cell (cc)-renal cell carcinoma (RCC). We hypothesized that determining differential kinase activity between primary and metastatic tumor sites may identify critical drivers of progression and relevant therapeutic targets in metastatic disease. Kinomic profiling was performed on primary tumor and metastatic tumor deposits utilizing a peptide substrate microarray to detect relative tyrosine phosphorylation activity. Pharmacologic and genetic loss of function experiments were used to assess the biologic significance of the top scoring kinase on in vitro and in vivo tumor phenotypes. Kinomics identified 7 peptides with increased tyrosine phosphorylation in metastases that were significantly altered (p<0.005). Based on these peptides, bioinformatics analyses identified several candidate kinases activated in metastases compared to primary tumors. The highest ranked upstream kinase was Focal Adhesion Kinase 1 (FAK1). RCC lines demonstrate evidence of elevated FAK1 activation relative to non-transformed renal epithelial cells. Pharmacologic inhibition of FAK1 with GSK2256098 suppresses in vitro tumor phenotypes. In turn, FAK1 knockdown in RCC cells suppresses both in vitro phenotypes and in vivo tumor growth. Collectively, these data demonstrate functional activation of FAK1 in metastases and provide preclinical rationale for targeting this kinase in the setting of advanced ccRCC.

Functional outcome in unstable Hangman's fracture managed with anterior approach: A prospective study.

AIM: To study the functional outcome in unstable Hangman s fracture managed with anterior decompression and stabilization with cervical locking plate and tricortical bone graft. MATERIALS AND METHODS: Between 2010 and 2016, 44 patients (range: 19-75 years) with unstable Hangman's fracture underwent anterior decompression and stabilization with cervical locking plate and tricortical bone graft in our institution. RESULT: According to the Levine and Edwards classification, all patients were unstable with Type IA 6 (13.6), Type IIA 35 (79.5%), Type II (0), and Type III (6.8). The mean period of follow-up was 17 months (range: 6-48 months). Neurological recovery was observed in all nine patients. All patients were relieved from axial pain. None of the patients received blood transfusion. All patients showed solid fusion with no complication related to bone graft and plate. CONCLUSION: The anterior C2/C3 discectomy, fusion, and stabilization with cervical locking plate and tricortical bone graft are feasible and safe method in treating HangmanÊs fracture, with the benefit of high primary stability, anatomical reduction, and direct decompression of the spinal cord.

Phase II study of a novel taxane (Cabazitaxel-XRP 6258) in previously treated advanced non-small cell lung cancer (NSCLC) patients.

PURPOSE: Given the success of cabazitaxel in patients with prostate cancer who progressed after receiving prior chemotherapy, its preclinical efficacy in various cell lines and possible ability to cross blood-brain barrier, cabazitaxel was hypothesized to increase objective response rate (ORR) in second-line setting in non-small cell lung cancer (NSCLC). METHODS: This was a phase II 2-stage trial in 28 patients using two different treatment schedules (A: 20 mg/m(2) every 3 weeks intravenously and B: 8.4 mg/m(2) intravenously weekly) to determine the ORR of cabazitaxel with secondary end points including progression-free survival (PFS), safety, and overall survival (OS). RESULTS: There was one objective response in schedule B. PFS and OS of schedule A was 3 and 6 months, respectively. PFS and OS of schedule B was 3 and 13 months, respectively. The stable disease rate was higher in schedule A (SD = 69.23 %; 95 % CL 38.57, 90.90) as compared to schedule B (SD = 38.46 %; 95 % CL 13.86, 68.42), but this difference was not statistically significant (P value = 0.1156). There were two grade 5 toxicities from sepsis. Hematuria of any grade developed in greater percentage of patients (35%) as compared to previous cabazitaxel phase 3 trial and led to change in our protocol. CONCLUSIONS: Response to cabazitaxel in NSCLC was not as robust as seen in prostate cancer and not superior to currently used agents such as docetaxel, pemetrexed, and erlotinib. In absence of significant objective responses, the second stage of the study was not undertaken.

High Throughput Kinomic Profiling of Human Clear Cell Renal Cell Carcinoma Identifies Kinase Activity Dependent Molecular Subtypes.

Despite the widespread use of kinase-targeted agents in clear cell renal cell carcinoma (CC-RCC), comprehensive kinase activity evaluation (kinomic profiling) of these tumors is lacking. Thus, kinomic profiling of CC-RCC may assist in devising a classification system associated with clinical outcomes, and help identify potential therapeutic targets. Fresh frozen CC-RCC tumor lysates from 41 clinically annotated patients who had localized disease at diagnosis were kinomically profiled using the PamStation®12 high-content phospho-peptide substrate microarray system (PamGene International). Twelve of these patients also had matched normal kidneys available that were also profiled. Unsupervised hierarchical clustering and supervised comparisons based on tumor vs. normal kidney and clinical outcome (tumor recurrence) were performed and coupled with advanced network modeling and upstream kinase prediction methods. Unsupervised clustering analysis of localized CC-RCC tumors identified 3 major kinomic groups associated with inflammation (A), translation initiation (B), and immune response and cell adhesions (C) processes. Potential driver kinases implicated include PFTAIRE (PFTK1), PKG1, and SRC, which were identified in groups A, B, and C, respectively. Of the 9 patients who had tumor recurrence, only one was found in Group B. Supervised analysis showed decreased kinase activity of CDK1 and RSK1-4 substrates in those which progressed compared to others. Twelve tumors with matching normal renal tissue implicated increased PIM's and MAPKAPK's in tumors compared to adjacent normal renal tissue. As such, comprehensive kinase profiling of CC-RCC tumors could provide a functional classification strategy for patients with localized disease and identify potential therapeutic targets.