High-grade Malignancy Research Articles

Diagnosis of Low-Grade Urothelial Neoplasm in the Era of the Second Edition of the Paris System for Reporting Urinary Cytology.

The Paris System for Reporting Urinary Cytology (TPS) is considered the gold standard when it comes to diagnostic classifications of urine specimens. Its second edition brought some important changes, including the abolition of the diagnostic category of "low-grade urothelial neoplasm (LGUN)", acknowledging the inability of cytology to reliably discern low-grade urothelial lesions. In this retrospective study, we assessed the validity of this change, studying the cytological diagnoses of histologically diagnosed low-grade urothelial carcinomas during a three-year period. Moreover, we correlated the sum of the urinary cytology diagnoses of this period with the histological diagnoses, whenever available. Although all the cytological diagnoses of LGUN were concordant with the histological diagnoses, most low-grade urothelial carcinomas were misdiagnosed cytologically. Subsequently, the positive predictive value (PPV) of urinary cytology for the diagnosis of LGUN was 100%, while the sensitivity was only 21.7%. Following the cyto-histopathological correlation of the sum of the urinary cytology cases, the sensitivity of urinary cytology for the diagnosis of high-grade urothelial carcinoma (HGUC) was demonstrated to be 90.1%, the specificity 70.8%, the positive predictive value (PPV) 60.3%, the negative predictive value (NPV) 93.6% and the overall accuracy 77.2%, while for LGUN, the values were 21.7%, 97.2%, 87.5%, 58.6% and 61.9%, respectively. Risk of high-grade malignancy was 0% for the non-diagnostic (ND), 4.8% for the non-high-grade urothelial carcinoma (NHGUC), 33.3% for the atypical urothelial cells (AUCs), 65% for the suspicious for high-grade urothelial carcinoma (SHGUC), 100% for the HGUC and 12.5% for the LGUN diagnostic categories. This study validates the incorporation of the LGUN in the NHGUC diagnostic category in the second edition of TPS. Moreover, it proves the ability of urinary cytology to safely diagnose HGUC and stresses the pivotal role of its diagnosis.

Induction Chemotherapy for Locoregionally Advanced Sinonasal Squamous Cell Carcinoma and Sinonasal Undifferentiated Carcinoma: A Comprehensive Review.

Sinonasal squamous cell carcinoma (SNSCC) and sinonasal undifferentiated carcinoma (SNUC) are two of the most common, high-grade malignancies of the sinonasal cavity. The standard of care for resectable lesions per the National Comprehensive Cancer Network (NCCN) guidelines includes surgical resection with negative margins plus adjuvant radiation therapy. However, surgery for locally advanced disease with both orbital and intracranial involvement is associated with significant morbidity and poor overall survival. Over the last decade, induction chemotherapy (IC) has emerged as part of a multimodal treatment strategy to optimize locoregional disease control and minimize substantial surgical morbidity such as orbital exenteration without compromising rates of overall survival. The response to IC both guides additional therapy and helps prognosticate a patient's disease. This narrative review examines the data surrounding the management of patients with SNSCC and SNUC. The pros and cons of upfront surgical management plus adjuvant therapy will be explored, and the case for IC will be presented. The IC-specific regimens and treatment paradigms for SNSCC and SNUC will each be explored in detail. Organ preservation, treatment morbidity, and survival data will be presented, and evidence-based recommendations will be presented for the management of these patients.

High expression of IL4I1 is correlated with poor prognosis and immune infiltration in thyroid cancer

BackgroundThyroid cancer-related deaths mostly result from metastasis. It was reported that the immunometabolism associated enzyme interleukin-4-induced-1 (IL4I1) was related to tumor metastasis. The present study was intended to investigate the effects of IL4I1 on thyroid cancer metastasis and its relationship with the prognosis.MethodsData from Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) were analyzed to find out the different mRNA expressions of IL4I1 between thyroid cancer and normal tissues. And Human Protein Atlas (HPA) was used to assess IL4I1 protein expression. To further differentiate thyroid cancer from normal tissues and estimate the impact of IL4I1 on the prognosis, the receiver operating characteristic curve (ROC) and Kaplan–Meier (KM) method was performed. The protein–protein interaction (PPI) network was established using STRING, and functional enrichment analyses were conducted by “clusterProfiler” package. Then, we assayed the correlation between IL4I1 and some related molecules. The relationship between IL4I1 and immune infiltration was performed using “Gene Set Variation Analysis (GSVA)” package in TCGA and tumor-immune system interaction database (TISIDB). Finally, we did in vitro experiments in order to further prove the bioeffects of IL4I1 on metastasis.ResultsThe expression of IL4I1 mRNA and IL4I1 protein was significantly upregulated in thyroid cancer tissues. The increment of IL4I1 mRNA expression was related to high-grade malignancy, lymph node metastases and extrathyroidal extension. The ROC curve displayed the cutoff value of 0.782, with the sensitivity of 77.5% and the specificity of 77.8%. KM survival analysis showed that there was a worse PFS in patients with high IL4I1 expression than those with low IL4I1 expression (p = 0.013). Further study indicated that IL4I1 was associated with lactate, body fluid secretion, positive regulation of T cell differentiation, and cellular response to nutrients in Gene Ontology (GO) analysis. Moreover, IL4I1 was found correlated with immune infiltration. Finally, the in vitro experiments revealed the promotion of IL4I1 on cancer cell proliferation, migration and invasion.ConclusionsThe increased IL4I1 expression is markedly correlated with the immune imbalance in the tumor microenvironment (TME) and predicts poor survival in thyroid cancer. This study reveals the potential clinical biomarker of poor prognosis and the target of immune therapy in thyroid cancer.

Neutrophil-, Monocyte- and Platelet-to-Lymphocyte Ratios, and Absolute Lymphocyte Count for Diagnosis of Malignant Soft-tissue Tumors.

Soft-tissue tumors are difficult to differentiate as benign or malignant. Immune markers, such as the neutrophil-lymphocyte ratio (NLR), monocyte-lymphocyte ratio (MLR), platelet-lymphocyte ratio (PLR), and absolute lymphocyte count (ALC) in serum, have been reported to be useful in the diagnosis and predicting prognosis of several malignancies. We investigated the diagnostic value of these immune markers in differentiating soft-tissue tumors. A total of 692 patients who underwent biopsy or surgery of soft-tissue tumors were included and divided into benign tumor, low-grade malignancy, or high-grade malignancy groups. Immune markers were calculated from the preoperative blood tests and compared between the groups. A receiver operating curve (ROC) analysis was conducted between the benign disease group and a combination of the groups with malignancy to determine which immune marker had the most diagnostic value. NLR and MLR were significantly different between the three groups with benign disease having the lowest value and high-grade malignancies the highest. Benign disease was also associated with lower PLR and higher ALC. There was no difference between the low- and high-grade malignancies in PLR and ALC. From the ROC analysis, NLR had the highest area under the curve (AUC) value of 0.773 out of the four markers. When limited to small tumors (≤30 mm), NLR had the highest AUC value of 0.729. The NLR showed the highest diagnostic value, although the diagnostic ability was not adequately high to differentiate benign and malignant soft-tissue tumors alone. NLR may serve as diagnostic support in combination with clinical history, physical findings, and tumor-imaging results.

Esophageal Neuroendocrine Carcinoma Presenting After Definitive Chemoradiation of Squamous Cell Carcinoma in the Same Location

ABSTRACT Esophageal neuroendocrine carcinoma is very rare and highly aggressive. An 85-year-old man with a history of esophageal squamous cell carcinoma in remission presented 4 years after definitive chemoradiation with new-onset dysphagia. Endoscopy with biopsy revealed high-grade malignancy consistent with neuroendocrine carcinoma. Treatment options were limited to chemotherapy because of his metastatic disease, and he unfortunately died 14 months after diagnosis. The occurrence of esophageal neuroendocrine carcinoma in a site of prior squamous cell carcinoma is very uncommon, and this likely represents a case of radiation-induced malignancy. Therefore, when undergoing radiotherapy, patients and providers should discuss the possibility of this life-threatening complication.

Primary cardiac angiosarcoma initially diagnosed on pericardial fluid cytology with histology and autopsy correlation.

Primary cardiac angiosarcoma is an exceedingly rare high-grade malignancy of the heart originating from endothelial cells, with a predilection for the right atrium in male. Clinical diagnosis is extremely challenging because of the nonspecific symptoms and radiological findings. Although almost always presenting with massive recurrent pericardial effusions, cardiac angiosarcoma diagnosed based on pericardial fluid has rarely been reported, either due to the paucity of malignant cells or misdiagnosis due to low familiarity/suspicion and lack of proper workup. Unfortunately, patients with this disease often receive definitive diagnosis post-mortem. We report a case of primary cardiac angiosarcoma initially diagnosed on pericardial fluid. The cytomorphology and immunophenotype of angiosarcoma in fluid, as well as the challenges and practical recommendations in using pericardial fluid cytology for early diagnosis of this deadly disease are discussed.

Atypical urothelial cells classified according to the Paris System for Reporting Urinary Cytology: A 2-year experience with histological correlation from a Finnish tertiary care center-low rate and high risk of malignancy.

The Paris System for Reporting Urinary Cytology (TPS) was issued to shift the focus of urine cytology to high-grade lesions to increase the diagnostic accuracy of urine cytology. The aim of this study was to evaluate the power of TPS in the atypical urothelial cells (AUC) category with histological correlation and follow-up. The data cohort consisted of 3741 voided urine samples collected during a 2-year period between January 2017 and December 2018. All samples were prospectively classified using TPS. This study focuses on the subset of 205 samples (5.5%) classified as AUC. All cytological and histological follow-up data were analyzed until 2019, and the time between each sampling was documented. Of the 205 AUC cases, cytohistological correlation was possible in 97 (47.3%) cases. Of these, 36 (12.7%) were benign in histology, 27 (13.2%) were low-grade urothelial carcinomas, and 34 (16.6%) were high-grade urothelial carcinomas. Overall, the risk of malignancy was 29.8% for all cases in the AUC category, and 62.9% in the histologically confirmed cases. The risk of high-grade malignancy was 16.6% in all the AUC category samples and 35.1% in the histological follow-up group. The performance of 5.5% AUC cases is considered good and within the limits proposed by TPS. TPS is widely accepted by cytotechnologists, cytopathologists, and clinicians; it improves communication and patient management.

TRIM4 Expression Related to Malignant Progression and Cisplatin Resistance in Osteosarcoma.

Osteosarcoma (OS) is a high-grade intraosseous malignancy. Twenty to thirty percent of OS patients react poorly to standard therapy with a combination of surgical resection and chemotherapy. It is necessary to find molecules that play an important role in this. This study explored the role of TRIM4 in OS chemotherapy sensitivity and malignant progression. The expression of TRIM4 in OS tissues and cells was examined by RT-qPCR, immunohistochemical staining, and western blot. Specific siRNA was transfected into U2-OS and SAOS2 cells to target TRIM4. Cell biological behavior was examined by CCK-8, Transwell, and flow cytometry experiments. Cisplatin-resistant SAOS2 (SAOS2-Cis-R) cells were established, and the effect of TRIM4 expression on the cisplatin response of SAOS2 cells was tested. Knockdown of TRIM4 significantly inhibited the proliferation, migration, and invasion of U2-OS and SAOS2 cells and induced apoptosis. TRIM4 expression was significantly higher in chemotherapy-resistant OS tissues compared to chemotherapy-sensitive OS tissues. Furthermore, the expression of TRIM4 in SAOS2-Cis-R cells was significantly increased compared to parental SAOS2 cells. Moreover, overexpression of TRIM4 enhanced cisplatin resistance in parental SAOS2 cells, while the downregulation of TRIM4 expression enhanced cisplatin sensitivity of SAOS2-Cis-R cells. High TRIM4 expression might be associated with malignant progression and poor response to chemotherapy response of OS. Targeting TRIM4 may be beneficial for OS treatment or combination therapy.

Topology-based radiomic features for prediction of parotid gland cancer malignancy grade in magnetic resonance images.

The malignancy grades of parotid gland cancer (PGC) have been assessed for a decision of treatment policies. Therefore, we have investigated the feasibility of topology-based radiomic features for the prediction of parotid gland cancer (PGC) malignancy grade in magnetic resonance (MR) images. Two-dimensional T1- and T2-weighted MR images of 39 patients with PGC were selected for this study. Imaging properties of PGC can be quantified using the topology, which could be useful for assessing the number ofthe k-dimensional holes or heterogeneity in PGC regions using invariants of the Betti numbers. Radiomic signatures were constructed from 41,472 features obtained after a harmonization using an elastic net model. PGC patients were stratified using a logistic classification into low/intermediate- and high-grade malignancy groups. The training data were increased by four times to avoid the overfitting problem using a synthetic minority oversampling technique. The proposed approach was assessed using a 4-fold cross-validation test. The highest accuracy of the proposed approach was 0.975 for the validation cases, whereas that of the conventional approach was 0.694. This study indicated that topology-based radiomic features could be feasible for the noninvasive prediction of the malignancy grade of PGCs.

Malignant phyllodes tumors of the breast: the malignancy grading and associations with prognosis

This study aimed to correlate clinicopathological parameters with survival outcomes in a cohort of patients diagnosed with malignant phyllodes tumors (MPTs). We also analyzed the malignancy grade of MPTs and investigated the prognostic significance of the malignancy grading system. Clinicopathological parameters, malignancy grades, and clinical follow-up data of 188 women diagnosed with MPTs in a single-institution were analyzed. MPTs of the breast were grouped according to stromal atypia, stromal overgrowth, mitotic count, tumor differentiation, and necrosis. A Fleiss' kappa statistic was calculated to test the agreement between the pathologists for the grading of MPTs. Disease-free survival (DFS), distant metastasis-free survival (DMFS) and overall survival (OS) were estimated using the Kaplan-Meier method and compared between groups using the log-rank test. Cox regression was carried out to identify factors predictive of locoregional recurrence (LRR), distant metastasis (DM) and death. A total of 188 MPTs were classified according to the malignancy grading system: 88 (46.8%) as low grade, 77 (41%) as an intermediate grade, and 23 (12.2%) as high grade. Excellent agreement between pathologists for the grading of MPTs (Fleiss' kappa 0.807). In our study population, the occurrence of DM and death were associated with the malignancy grade of MPTs (P < 0.001). Based on the DFS curves, the presence of heterologous elements (P = 0.025) and younger age (P = 0.014) were independent prognostic indicators. Additionally, the malignancy grade retained independent prognostic significance for predicting DMFS and OS (P < 0.001 and P = 0.009). Higher malignancy grade, presence of heterologous elements, younger age, larger tumor size, and recent rapid tumor growth are poor prognostic factors for MPTs of the breast. The malignancy grading system may be generalized in the future.

P2X1 and P2X7 Receptor Overexpression Is a Negative Predictor of Survival in Muscle-Invasive Bladder Cancer.

Bladder cancer is amongst the most common causes of cancer death worldwide. Muscle-invasive bladder cancer (MIBC) bears a particularly poor prognosis. Overexpression of purinergic P2X receptors (P2XRs) has been associated with worse outcome in several malignant tumors. Here, we investigated the role of P2XRs in bladder cancer cell proliferation in vitro and the prognostic value of P2XR expression in MIBC patients. Cell culture experiments with T24, RT4, and non-transformed TRT-HU-1 cells revealed a link between high ATP concentrations in the cell culture supernatants of bladder cell lines and a higher grade of malignancy. Furthermore, proliferation of highly malignant T24 bladder cancer cells depended on autocrine signaling through P2X receptors. P2X1R, P2X4R, and P2X7R expression was immunohistochemically analyzed in tumor specimens from 173 patients with MIBC. High P2X1R expression was associated with pathological parameters of disease progression and reduced survival time. High combined expression of P2X1R and P2X7R increased the risk of distant metastasis and was an independent negative predictor of overall and tumor-specific survival in multivariate analyses. Our results suggest that P2X1R/P2X7R expression scores are powerful negative prognostic markers in MIBC patients and that P2XR-mediated pathways are potential targets for novel therapeutic strategies in bladder cancer.

Clinicopathologic Significance of Anterior Prostate Cancer: Comparison With Posterior Prostate Cancer in the Era of Multiparametric Magnetic Resonance Imaging.

Anterior prostate cancer (APC) has been considered an indolent tumor, most commonly arising in the transition zone (TZ). More recently, detection of APC has been facilitated through multiparametric magnetic resonance imaging and improved biopsy techniques, enabling earlier detection. The pathologic features and clinical significance of pure APC in a large contemporary series of well-characterized tumors have, to date, not been elucidated. Cases with APC defined as cancer present anterior to the urethra only were identified from 1761 consecutive radical prostatectomy specimens accessioned between January 2015 and August 2016. The clinicopathologic features of these cases were compared with those of pure posterior prostate cancer (PPC) and the features of anterior peripheral zone (APZ) cancers were compared with those of TZ cancers. In addition, the tumor series from 2015 to 2016 was compared with a cohort of 1054 patients accessioned before the utilization of multiparametric magnetic resonance imaging in the routine workup of patients with prostate cancer. In the 2015-2016 series, there were 188 (10.7%) patients with APC compared with 5.4% in the series from the pre-multiparametric magnetic resonance imaging era. No difference was observed between APC and PPC with regards to patient age or mean serum prostate-specific antigen at presentation. Mean tumor volume and positive surgical margin (PSM) rates were significantly higher in APC. In contrast, PPC was more commonly high grade with more frequent extraprostatic extension (EPE). None of the cases of APC had infiltration of the seminal vesicle or lymph node involvement, in contrast to PPC, with almost 14% of cases in each category. The 3- and 5-year biochemical recurrence-free survival was significantly higher in APC when compared with PPC, although this was not retained on multivariable analysis which included tumor location. On division of APCs according to anatomic zone of origin, 45% were APZ cancer and 37% TZ cancer. On comparison of APZ and TZ cancers, there were no significant differences in mean age and serum prostate-specific antigen at presentation as well as tumor volume, Gleason score, and PSM rate. High-grade malignancy (Gleason score >3 + 4=7) was seen in 26% of TZ cancers which compared with 44% of APZ cancers and 56% of PPC cancers. The rate of EPE was significantly higher in APZ when compared with TZ cancer ( P< 0.0005); however, the biochemical recurrence rate was not significantly different between the groups. The prevalence of APC in radical prostatectomy specimens has increased in recent times, in association with earlier detection at a stage amenable to curative surgical treatment. APC, when compared with PPC, is less commonly high grade with less frequent EPE, despite the APC group having larger tumors and a higher PSM rate at presentation. However, not all anterior cancers are indolent. Anterior cancers are more commonly seen in the APZ than the TZ and APZ cancers appear more locally aggressive than TZ cancers.

The Role of Surgery in Primary Chest Wall Tumors: Over 20 Years' Experience in Resection and Reconstruction.

Primary chest wall tumors comprise a heterogeneous group of neoplasms arising from soft tissues and bones. While surgical excision is the standard of care for benign tumors, the management of malignant tumors requires multimodal treatment. We conducted a predictive analysis of outcome, recurrence-free and overall survival. We retrospectively reviewed the clinical and pathological records of all patients treated in our center between 1998 and 2020. 53 patients (15-85 years) were treated in our department. The average tumor diameter was 65 ± 35 mm (10-160 mm). Negative margins were obtained in 48 patients (90.6%), whereas in the remaining 5, R1 resection was accomplished. Median overall survival was 63,03 months (1-282 months). Overall survival was 90% at 1 year, 78% at 2 years, and 61% at 5 years. Our analysis identified tumor diameter, postoperative complications, and high grade of malignancy as factors that can influence prognosis. The treatment of primary chest wall tumors remains a very challenging process. Different histological types preclude definition of an unequivocal approach. Complete resection with healthy margins remains a definitive cornerstone in the treatment of these cancers as part of a more comprehensive approach.

Abstract 2052: High-plex spatial multiomics of pediatric and adult diffuse midline glioma, H3 K27-altered

Abstract Background: Diffuse midline glioma (DMG), H3 K27-altered are highly aggressive malignancies of the central nervous system that affect both pediatric and adult populations. The immune layout and genetic changes within the tumor microenvironment associated with these high-grade malignancies are thought to play an integral role in the phenotypic differences in tumor presentation and clinical course between both populations. Comparative landscapes between pediatric and adult DMGs is not known. Methods: The NanoString GeoMxTM Digital Spatial Profiler platform was used to determine the immune marker and genetic layout in a cohort of both pediatric and adult DMG, H3 K27-altered tissue samples. Three fluorescently labeled antibodies targeting immune cells (CD45), epithelial cells (PanCK), tumor cells (H3 K27M) and a nucleic acid stain (SYTO-13) were used to identify and separate out the various components within the tumor tissues from selected regions of interest. The resultant information was then pooled into libraries that were run through the Illumina sequencing platform to assess transcriptomic and proteomic data for both cohorts of samples. Results: Our data revealed the immune and genetic expression seen within both populations across multiple regions of interest within the samples. Differences were seen specific to each population that may have clinical significance and warrant further exploration including a significant increase in genes associated with RTK pathways in the pediatric samples. Conclusion: The digital spatial analysis of pediatric and adult DMG, H3 K27-altered shows differences within the molecular landscape which may contribute to the clinical differences between both populations. These observed differences may play a role in future treatments and further research is needed to explore this. Citation Format: Sudarshawn Damodharan, Alyssa Rosenbloom, Mahua Dey. High-plex spatial multiomics of pediatric and adult diffuse midline glioma, H3 K27-altered [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2052.

Extranasal T/NK lymphoma with a fatal outcome: A case report

Extranodal T/NK lymphoma (LTNKEN) is a rare and aggressive form of non-Hodgkin lymphoma of high-grade malignancy. A distinction is made between the nasal forms, characterized by primary involvement of the nasal cavity, and the extranasal forms. Primary skin involvement is highly rare. Diagnosis is based on immunohistochemical studies. Treatment includes chemotherapy and radiotherapy. This type of lymphoma has a poor prognosis even with treatment. Herein, we report a Moroccan case of cutaneous T/NK lymphoma in a young patient with a primary cutaneous localization of fatal evolution. Key words: Lymphoma; Extranodal lymphoma; T/NK lymphoma; Non-hodgkin lymphoma

Awake craniotomy for low-grade gliomas

Aim: The aim of this study was to evaluate the efficacy of awake brain surgery for benign glial brain tumours in the Department of Neurosurgery of the Military Institute of Medicine in Warsaw. Materials and methods: Between 2020 and 2021, 9 out of 17 patients with a radiological diagnosis of a low-grade glioma located within or in the vicinity of eloquent brain areas were operated on under awake conditions. The average preoperative tumour volume was 29.6 cm3. Preoperative management included a repeat magnetic resonance imaging supplemented with functional magnetic resonance imaging and tractography, as well as neuropsychological assessment. The cortex and subcortical structures were stimulated intraoperatively at 1.5–4 mA. The intraoperative assessment covered: motor functions, speech, and, additionally in two patients, visual field width and contralateral neglect. Results: Based on magnetic resonance imaging on the first postoperative day, complete removal of the tumour was confirmed in 7 patients. In 2 patients, resection was subtotal due to the fact that part of the tumour that infiltrated eloquent structures was left. In 6 patients, transient neurological deterioration was observed in the early perioperative period, which resolved within 2 months after surgery. In 3 patients, histopathological examination revealed a tumour with a higher grade of malignancy than expected. Conclusions: Our experience confirms that surgical treatment of benign glial tumours using direct electrical stimulation in awake patients is an effective and safe method allowing effective tumour resection with a minimised risk of adverse neurological sequelae.

Deciphering the role of QPCTL in glioma progression and cancer immunotherapy.

Glioma is the most lethal and most aggressive brain cancer, and currently there is no effective treatment. Cancer immunotherapy is an advanced therapy by manipulating immune cells to attack cancer cells and it has been studied a lot in glioma treatment. Targeting the immune checkpoint CD47 or blocking the CD47-SIRPα axis can effectively eliminate glioma cancer cells but also brings side effects such as anemia. Glutaminyl-peptide cyclotransferase-like protein (QPCTL) catalyzes the pyroglutamylation of CD47 and is crucial for the binding between CD47 and SIRPα. Further study found that loss of intracellular QPCTL limits chemokine function and reshapes myeloid infiltration to augment tumor immunity. However, the role of QPCTL in glioma and the relationship between its expression and clinical outcomes remains unclear. Deciphering the role of QPCTL in glioma will provide a promising therapy for glioma cancer immunotherapy. QPCTL expression in glioma tissues and normal adjacent tissues was primarily analyzed in The Cancer Genome Atlas (TCGA) database, and further validated in another independent cohort from the Gene Expression Omnibus (GEO) database, Chinese Glioma Genome Atlas (CGGA), and Human Protein Atlas (HPA). The relationships between QPCTL expression and clinicopathologic parameters and overall survival (OS) were assessed using multivariate methods and Kaplan-Meier survival curves. And the proteins network with which QPCTL interacted was built using the online STRING website. Meanwhile, we use Tumor Immune Estimation Resource (TIMER) and Gene Expression Profiling Interactive Analysis (GEPIA) databases to investigate the relationships between QPCTL expression and infiltrated immune cells and their corresponding gene marker sets. We analyzed the Differentially Expressed Genes (DEGs) including GO/KEGG and Gene Set Enrichment Analysis (GSEA) based on QPCTL-high and -low expression tumors. In contrast to normal tissue, QPCTL expression was higher in glioma tumor tissue (p < 0.05). Higher QPCTL expression was closely associated with high-grade malignancy and advanced tumor stage. Univariate and multivariate analysis indicated the overall survival of glioma patients with higher QPCTL expression is shorter than those with lower QPCTL expression (p < 0.05). Glioma with QPCTL deficiency presented the paucity of infiltrated immune cells and their matching marker sets. Moreover, QPCTL is essential for glioma cell proliferation and tumor growth and is a positive correlation with glioma cell stemness. High QPCTL expression predicts high grades of gliomas and poor prognosis with impaired infiltration of adaptive immune cells in the tumor microenvironment as well as higher cancer stemness. Moreover, targeting QPCTL will be a promising immunotherapy in glioma cancer treatment.

Sarcomatoid urothelial carcinoma of the renal pelvis treated with immunotherapy

BackgroundSarcomatoid carcinoma is a rare, high-grade malignancy with epithelial and mesenchymal components. It may be a good candidate for immunotherapy because it is associated with overexpression of programmed cell death ligand 1. Sarcomatoid urothelial carcinoma (UC) of the upper urinary tract is extremely rare. Here we report the first case of sarcomatoid UC of the renal pelvis that responded to immunotherapy.Case presentationA 79-year-old man was referred to our hospital complaining of various symptoms, including anorexia and abdominal pain. A computed tomography scan revealed a right atrial tumor, a 9 cm left renal mass with a renal vein tumor thrombus, para-aortic lymphadenopathy, and multiple small lung nodules. The patient underwent resection of the right atrial tumor. Pathological analysis of the tumor did not lead to an accurate diagnosis even after several rounds of immunohistochemistry. He underwent a needle biopsy of the left kidney and was initially diagnosed with collecting duct carcinoma, a rare subtype of renal cell carcinoma (RCC). Following the initial diagnosis, immunotherapy with nivolumab and ipilimumab commenced. Thereafter, almost all lesions, including the left renal tumor, were reduced in size. However, he underwent a left nephrectomy approximately a year after beginning immunotherapy due to repeated left renal bleeding. Histological examination of the nephrectomy specimen revealed two forms of cancer—sarcomatoid UC and conventional high-grade UC. Two months after surgery, the patient was found to have new lung metastases. He underwent chemotherapy with gemcitabine and cisplatin, followed by immunotherapy with pembrolizumab. However, both treatments were ineffective. The patient died of cancer 19 months after his first admission.ConclusionsThe presented case of sarcomatoid UC of the renal pelvis that partially responded to immunotherapy suggests that immunotherapy can be a promising treatment for sarcomatoid UC.

Therapeutic implication of chimeric antigen receptor T-cell therapy for head and neck squamous cell carcinoma.

Therapeutic implication of chimeric antigen receptor T-cell therapy for head and neck squamous cell carcinoma.

Nivolumab With or Without Ipilimumab in Pediatric Patients With High-Grade CNS Malignancies: Safety, Efficacy, Biomarker, and Pharmacokinetics: CheckMate 908.

Therapeutic options are limited in pediatric CNS malignancies. CheckMate 908 (NCT03130959) is an open-label, sequential-arm, phase 1b/2 study investigating nivolumab (NIVO) and NIVO+ipilimumab (IPI) in pediatric patients with high-grade CNS malignancies. Patients (N=166) in 5 cohorts received NIVO 3mg/kg every 2 weeks (Q2W) or NIVO 3mg/kg+IPI 1mg/kg every 3 weeks (4 doses) followed by NIVO 3mg/kg Q2W. Primary endpoints included overall survival (OS; newly diagnosed diffuse intrinsic pontine glioma [DIPG]) and progression-free survival (PFS; other recurrent/progressive or relapsed/resistant CNS cohorts). Secondary endpoints included other efficacy metrics and safety. Exploratory endpoints included pharmacokinetics and biomarker analyses. As of January 13, 2021, median OS (80% CI) was 11.7 (10.3-16.5) and 10.8 (9.1-15.8) months with NIVO and NIVO+IPI, respectively, in newly diagnosed DIPG. Median PFS (80% CI) with NIVO and NIVO+IPI was 1.7 (1.4-2.7) and 1.3 (1.2-1.5) months, respectively, in recurrent/progressive high-grade glioma; 1.4 (1.2-1.4) and 2.8 (1.5-4.5) months in relapsed/resistant medulloblastoma; and 1.4 (1.4-2.6) and 4.6 (1.4-5.4) months in relapsed/resistant ependymoma. In patients with other recurrent/progressive CNS tumors, median PFS (95% CI) was 1.2 (1.1-1.3) and 1.6 (1.3-3.5) months, respectively. Grade 3/4 treatment-related adverse-event rates were 14.1% (NIVO) and 27.2% (NIVO+IPI). NIVO and IPI first-dose trough concentrations were lower in youngest and lowest-weight patients. Baseline tumor programmed death ligand 1 expression was not associated with survival. NIVO±IPI did not demonstrate clinical benefit relative to historical data. The overall safety profiles were manageable with no new safety signals.