Real-World Use of Isavuconazole as Primary Therapy for Invasive Fungal Infections in High-Risk Patients with Hematologic Malignancy or Stem Cell Transplant

(1) Introduction: Invasive fungal infections (IFIs) are a major cause of morbidity and mortality among immunocompromised patients with hematologic malignancies (HM) and stem cell transplants (SCT). Isavuconazole was approved by FDA as a primary therapy for Invasive Aspergillosis (IA) and Mucormycosis. The aim of this study is to look at the real-world use of Isavuconazole in patients with HM and evaluate their clinical outcomes and safety. (2) Methods: We conducted a retrospective study of HM patients at MD Anderson Cancer Center who had definite, probable or possible mold infections between 1 April 2016 and 31 January 2020 and were treated with Isavuconazole for a period of at least 7 days. Clinical and radiological findings were assessed at baseline and at 6 and 12 weeks of follow up. (3) Results: We included 200 HM patients with IFIs that were classified as definite (11), probable (63) and possible (126). Aspergillus spp was the most commonly isolated pathogen. The majority of patients (59%) received prophylaxis with anti-mold therapy and Isavuconazole was used as a primary therapy in 43% of patients, and as salvage therapy in 58%. The switch to Isavuconazole was driven by the failure of the primary therapy in 66% of the cases and by adverse effects in 29%. Isavuconazole was used as monotherapy in 30% of the cases and in combination in 70%. Adverse events possibly related to Isavuconazole were reported in eight patients (4%) leading to drug discontinuation. Moreover, a favorable response with Isavuconazole was observed in 40% at 6 weeks and in 60% at 12 weeks. There was no significant difference between isavuconazole monotherapy and combination therapy (p = 0.16 at 6 weeks and p = 0.06 at 12 weeks). Finally, there was no significant difference in outcome when Isavuconazole was used after failure of other anti-mold prophylaxis or treatment versus when used de novo as an anti-mold therapy (p = 0.68 at 6 weeks and p = 0.25 at 12 weeks). (4) Conclusions: Whether used as first-line therapy or after the failure of other azole and non-azole prophylaxis or therapies, isavuconazole seems to have a promising clinical response and a good safety profile as an antifungal therapy in high-risk cancer patients with hematologic malignancies. Moreover, combination therapy did not improve the outcome compared to Isavuconazole therapy.

Sinonasal Neuroendocrine Carcinoma: 15 Years of Experience at a Single Institution

Objectives Sinonasal neuroendocrine carcinomas (SNECs) are among the rarest paranasal sinus cancers. Consensus guidelines for therapy are difficult to develop due to limited data regarding the natural history and successful treatment of these tumors. This study presents 15 years of experience treating SNEC at a single institution and a review of the literature. Design Retrospective review. Setting Academic medical center in the United States. Participants Patients diagnosed with primary SNEC. Main Outcome Measures Overall survival. Results Thirteen patients were identified and included. Overall estimated survival was 74.6% at 5 years. Ten of 13 (76.9%) patients were diagnosed with high-grade neuroendocrine carcinoma and three (23.1%) with intermediate or low grade. All three patients with low- or intermediate-grade cancer survived more than 10 years from their initial diagnosis (median survival: 11.6 years) and are currently alive. The four patients who died had high-grade carcinoma, and estimated overall 5-year survival for all patients with high-grade carcinomas was 65.6%. Five patients, all with high-grade carcinoma, of seven who completed primary chemoradiation therapy (CRT) required salvage resection, and 60% are alive without disease. Conclusion This cohort has a higher overall rate of survival than many recent case series and reviews. There is consensus that multimodal therapy is preferred over monotherapy, but approaches to treatment vary widely. Our approach of surgical resection as primary therapy for low-grade tumors and primary CRT for high-grade SNEC has been successful, and could indicate hope for improved survival among these patients.

GRAP2 is a Prognostic Biomarker and Correlated with Immune Infiltration in Lung Adenocarcinoma

Background: GRAP2 is an adaptor protein involved in leukocyte-specific protein-tyrosine kinase signaling; however, the prognostic value of GRAP2 and its correlation with immune cell infiltration in lung adenocarcinoma (LUAD) remain unclear.Methods: All original data were downloaded from the TCGA database and integrated via R 3.2.2. GRAP2 expression was explored with the TCGA and TIMER databases. We evaluated the influence of GRAP2 on clinical prognosis using the Kaplan-Meier plotter, Gene Expression Omnibus (GEO) database and GEPIA database. Correlations between GRAP2 and cancer immune characteristics were analyzed via TIMER and TISIDB databases. Finally, we confirmed the expression of GRAP2 in LUAD by immunohistochemistry staining.Results: Transcription levels of GRAP2 were significantly lower in several human cancers, including LUAD, than in adjacent normal tissues. We also found that tumor tissues have lower protein expression levels of GRAP2 compared with adjacent normal tissues in LUAD by immunohistochemistry staining. The down-regulated GRAP2 was associated with poorer overall survival, pathologic stage, T stage, N stage and primary therapy outcome in LUAD. Mechanically, we identified a hub gene that included a total of 91 GRAP2 co-expressed genes, which were tightly associated with immune response in LUAD. GRAP2 expression was positively correlated with infiltrating levels of B cells, CD8+ T cells, dendritic cells, eosinophils, macrophages, mast cells, Th2 cells, Th1 cells, Th17 cells, NK cells and neutrophils. GRAP2 expression level also affected the cumulative survival time of B cells and dendritic cells. GRAP2 expression is positively correlated with multiple immune markers, chemokines, chemokine receptors and MHC molecules of LUAD.Conclusions: These findings suggest that GRAP2 is a tumor suppressor gene and can be used as a prognostic biomarker for determining prognosis and immune infiltration in LUAD.

Complete Response of a Mutated BRCA2 Metastatic Clear Cell Endometrial Adenocarcinoma to the Poly (ADP ribose) Polymerase (PARP) Inhibitor Olaparib

Background: Cancer of the endometrium is the most common gynecologic malignancy in developed countries and the second most common in developing countries. Endometrioid tumors tend to have a favorable prognosis and typically present at an early stage with abnormal uterine bleeding. Clear cell carcinoma as well as serous endometrial carcinoma are associated with a poorer prognosis. Patients with metastatic endometrial cancer are treated with systemic therapy either following surgery or as primary therapy. As far as second-line chemotherapy is concerned, there are no general agreements on the chemotherapy to be used. Furthermore, to the best of knowledge, there are no studies on the use of poly (ADP ribose) polymerase (PARP) inhibitors in endometrial cancer even in BRCA mutated tumors. Case Report: We here present the case report of an 81-year-old woman with a mutated BRCA2 metastatic clear cell endometrial adenocarcinoma that showed an excellent clinical and radiological response to the PARP inhibitor olaparib. Conclusion: Olaparib could be successfully used in this patient setting.

lncRNA PCAT14 Is a Diagnostic Marker for Prostate Cancer and Is Associated with Immune Cell Infiltration

Objective. To investigate the relationship between the long noncoding RNA (lncRNA) Prostate cancer-associated transcription factors 14 (PCAT14) and the clinical characteristics of prostate cancer and immune cell infiltration. Methods. The relationship between PCAT14 expression and the clinicopathological characteristics of prostate cancer was analyzed based on The Cancer Genome Atlas (TCGA) database. Receiver operating characteristic (ROC) curves were used to evaluate the value of PCAT14 as a diagnostic marker for prostate cancer. The relationship between PCAT14 and immune cell infiltration was analyzed to explore the effect of PCAT14 on the immune-related functions of prostate cancer. Results. The ROC curve showed that PCAT14 had a significant diagnostic ability ( area under curve = 0.818 ) for prostate cancer. A reduced expression of PCAT14 in prostate cancer was related to T stage, N stage, primary therapy outcome, residual tumor, Gleason score, and age. The expression of PCAT14 was independently associated with the progression-free interval in prostate cancer patients. The infiltration of immune cells in prostate cancer showed a significant negative correlation between the expression of PCAT14 and plasmacytoid dendritic cells, activated dendritic cells, regulatory T cells, and neutrophils. Conclusions. PCAT14 is highly expressed in prostate cancer and is expected to be a diagnostic marker. PCAT14 might promote the development of prostate cancer through chemokines, antimicrobials, and cytokines that affect the infiltration of immune cells.

High Expression of H2BC12 Predicts Poor Survival Outcome of Low-Grade Gliomas: A Study Based on TCGA Data

Purpose Low-grade gliomas (LGG) have highly variable clinical behaviors, with a high incidence of disease progression as 70% within ten years. Regardless of treatment combining surgery and radiotherapy or chemotherapy, LGG is still associated with adverse survival outcomes. Therefore, our study was performed to satisfy the increasing demand of novel sensitive biomarkers and therapeutic targets in treatment and diagnosis of LGG. Methods The TCGA data set was used to examine the relationship between H2BC12 expression and clinical pathologic characteristics. The significance of H2BC12 expression in prognosis was also investigated. In addition, H2BC12 expression-related pathways were enriched by gene set enrichment analysis (GSEA). Association analysis of H2BC12 gene expression and immune infiltration was performed by single sample gene set enrichment analysis (ssGSEA). Results Significantly up-regulated expression of H2BC12 mRNA was found in LGG tissue when compared to normal tissue and was proven to be diagnostic (have diagnostic significance) for LGG. In the meantime, high H2BC12 levels were associated with WHO grade, IDH status, 1p/19q codeletion, primary therapy outcome and histological type of LGG, and additionally, prognostic for adverse survival outcomes. In the multivariate analysis, high H2BC12 levels were identified to be an independent predictor for poor survival outcomes of LGG patients. Pathways in cancer, signaling by Wnt or PI3K-AKT signaling pathway, DNA repair, cellular senescence and DNA double strand break repair were differentially activated in the phenotype that positively associated with H2BC12. Conclusion H2BC12 is a promising biomarker for the diagnosis and prognosis of LGG.

Radiation Therapy for Adenoid Cystic Carcinoma of the Head and Neck

Adenoid cystic carcinoma of the head and neck is an uncommon malignancy that can arise in the major or minor salivary glands. Perineural invasion (PNI) is an extremely frequent finding in cases of adenoid cystic carcinoma (ACC) that can be associated with significant patient morbidity and poor prognosis. By contrast, ACC rarely demonstrates lymphovascular space invasion thereby making PNI the major avenue for metastasis and a driver of treatment rationale and design. Radiotherapy is often utilized post-operatively to improve locoregional control or as a primary therapy in unresectable disease. Here we aim to review the role of radiotherapy in the management of this malignancy with a focus on target delineation and treatment regimens in the definitive, recurrent, and metastatic settings.

On the black slope: analysis of the course of a blunt renal trauma collective in a winter sports region

Purpose The aim of this study was to analyze the injury patterns and clinical course of a winter sport dominated by blunt renal trauma collective. Methods Blunt renal trauma cases (N = 106) treated in a Level 1 Trauma Center in Austria were analyzed. Results We encountered 12.3% grade 1, 10.4% grade 2, 32.1% grade 3, 38.7% grade 4 and 6.6% grade 5 renal traumata classified according to the American Association for the Surgery of Trauma (AAST). The mechanisms of injury (MOI) did not have an influence on the frequency of HG trauma (i.e., grade 4 and 5). No concomitant injuries (CIs) were found in 57.9% of patients. The number of patients without CIs was significantly higher in the sports associated trauma group compared to other MOIs (p < 0.01). In 94.3% the primary treatment was a non-operative management (NOM) including 56.6% conservative, 34.0% endourological, and 3.8% interventional therapies. A follow-up computed tomography (FU-CT) was performed in 81.1%, 3.3 days after trauma. After FU-CT, the primary therapy was changed in 11.4% of cases (grade ≥ 3). Comparing the Hb loss between the patients with grade 3 and 4 kidney trauma with and without revision surgery, we find a significantly increased Hb loss within the first 96 h after the trauma in the group with a needed change of therapy (p < 0.0001). The overall rate of nephrectomy (primary or secondary) was 9.4%. Independent predictors of nephrectomy were HG trauma (p < 0.01), age (p < 0.05), and sex (p < 0.05). The probability of nephrectomy was lower with (winter) sports-associated trauma (p < 0.1). Conclusions Sports-associated blunt renal trauma is more likely to occur isolated, and has a lower risk of severe outcomes, compared to other trauma mechanisms. NOM can successfully be performed in over 90% of all trauma grades.

Polish Multi-Institutional Study of Children with Ependymoma—Clinical Practice Outcomes in the Light of Prospective Trials

We performed a multi-institutional analysis of 74 children with ependymoma to evaluate to what extent the clinical outcome of prospective trials could be reproduced in routine practice. The evaluation of factors that correlated with outcome was performed with a log rank test and a Cox proportional-hazard model. Survival was estimated with the Kaplan–Meier method. The majority of patients had brain tumours (89%). All had surgery as primary treatment, with adjuvant radiotherapy (RTH) and chemotherapy (CTH) applied in 78% and 57%, respectively. Median follow-up was 80 months and 18 patients died. Five- and 10-year overall survival (OS) was 83% and 73%. Progression was observed in 32 patients, with local recurrence in 28 cases. The presence of metastases was a negative prognostic factor for OS. Five- and 10-year progression-free survival (PFS) was 55% and 40%, respectively. The best outcome in patients with non-disseminated brain tumours was observed when surgery was followed by RTH (+/−CTH afterwards; p = 0.0001). Children under 3 years old who received RTH in primary therapy had better PFS (p = 0.010). The best outcome of children with ependymoma is observed in patients who received radical surgery followed by RTH, and irradiation should not be omitted in younger patients. The role of CTH remains debatable.

GPI Is a Prognostic Biomarker and Correlates With Immune Infiltrates in Lung Adenocarcinoma

BackgroundGlucose-6-phosphate isomerase (GPI) plays an important role in glycolysis and gluconeogenesis. However, the role of GPI in lung adenocarcinoma (LUAD) remains unclear.MethodsAll original data were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases and integrated via R 3.2.2. GPI expression was explored with TCGA, GEO, and Oncomine databases. Immunohistochemistry staining was used to analyze GPI expression in clinical specimens. The correlations between GPI and cancer immune characteristics were analyzed via the TIMER and TISIDB databases. GPI-specific siRNAs were used to verify the role of GPI expression on cell proliferation and cell cycle distribution.ResultsIn general, GPI is predominantly overexpressed and has reference value in the diagnosis and prognostic estimation of LUAD. Upregulated GPI was associated with poorer overall survival, clinical stage, N stage, and primary therapy outcome in LUAD. Mechanistically, we identified a hub gene that included a total of 56 GPI-related genes, which were tightly associated with the cell cycle pathway in LUAD patients. Knockdown of GPI induced cell proliferation inhibition and cell cycle arrest. GPI expression was positively correlated with infiltrating levels of Th2 cells and regulatory T cells (Tregs); in contrast, GPI expression was negatively correlated with infiltrating levels of CD8+ T cells, central memory T cells, dendritic cells, macrophages, mast cells, and eosinophils. GPI was negatively correlated with the expression of immunostimulators, such as CD40L, IL6R, and TMEM173, in LUAD.ConclusionGPI may play an important role in the cell cycle and can be used as a prognostic biomarker for determining the prognosis and immune infiltration in LUAD.