Steroid-resistant intestinal aGVHD and refractory CMV and EBV infections complicated by haplo-HSCT were successfully rescued by FMT and CTL infusion

Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) produces similar survival outcomes as HLA-matched sibling donor allogeneic HCST in younger patients with acquired severe aplastic anemia (SAA). This study reported a 29-years-old man with SAA and intracranial hemorrhage who underwent haplo-HSCT with a modified BU/CY + ATG conditioning regimen. Neutrophil and platelet engraftment were both achieved on day 14 after HSCT. The patient developed grade IV acute graft-versus-host disease (aGVHD) on day 20 and acquired cytomegalovirus (CMV) and Epstein–Barr virus (EBV) infections on day 47. After the failure of methylprednisolone, basiliximab, ruxolitinib, and antiviral treatment, the patient was diagnosed with steroid-resistant grade IV aGVHD and refractory CMV and EBV infections. We performed fecal microbiota transplantation and infused CMV- and EBV-specific cytotoxic T lymphocytes. After that the stool volume and frequency gradually decreased, and viral DNA was undetectable on day 80. This report provides helpful clinical experience for treating steroid-resistant aGVHD and refractory viral infections.

The Efficacy of Transarterial Chemoembolization plus Apatinib or Sorafenib in the Treatment of Advanced Hepatocellular Carcinoma

Background. Transarterial chemoembolization (TACE) combined with sorafenib (TACE-S) or apatinib (TACE-A) is used in the treatment of hepatocellular carcinoma (HCC). However, to date, no study has compared the efficacy and safety of both treatments. The objective of this study was to compare the efficacy and safety of patients with advanced HCC who received either TACE-S or TACE-A. Methods. 193 patients with advanced HCC were included in the study between June 2015 and December 2019. Propensity score matching (PSM) analysis was used in the study to reduce selection bias. Results. Before PSM, the median overall survival (mOS) and median progression-free survival (mPFS) of patients treated with TACE-S were not significantly longer than in patients treated with TACE-A ( P = 0.703 , P = 0.514 ). TACE-A did not increase the mortality risk compared with TACE-S in the first 12 months (HR: 1.255, 95%CI: 0.796–1.978, P = 0.329 ) or after the 12-month mark (HR: 0.832, 95%CI: 0.482–1.436, p = 0.508 ). Similarly, TACE-A did not increase the tumor recurrence risk relative to TACE-S in the first 12 months (HR: 1.054, 95%CI: 0.744–1.493, P = 0.767 ) or after the 12-month mark (HR: 1.730, 95%CI: 0.592–5.049, P = 0.316 ). The subgroups analysis showed that TACE-A did not increase mortality risk or tumor recurrence risk relative to TACE-S. After PSM, similar results were presented. The III and IV stage adverse events in the TACE-A group were similar to those in the TACE-S group before PSM. Conclusions. Patients with advanced hepatocellular carcinoma could get similar survival benefits from treatment with either transarterial chemoembolization plus apatinib or transarterial chemoembolization plus sorafenib.

Progressive fibrosing interstitial lung disease: prevalence and clinical outcome

Background The progressive fibrosing (PF) phenotype of interstitial lung disease (ILD) is characterised by worsening respiratory symptoms, lung function, and extent of fibrosis on high-resolution computed tomography. We aimed to investigate the prevalence and clinical outcomes of PF-ILD in a real-world cohort and assess the prognostic significance of the PF-ILD diagnostic criteria. Methods Clinical data of patients with fibrosing ILD other than idiopathic pulmonary fibrosis (IPF) consecutively diagnosed at a single centre were retrospectively reviewed. A PF phenotype was defined based on the criteria used in the INBUILD trial. Results The median follow-up duration was 62.7 months. Of the total of 396 patients, the mean age was 58.1 years, 39.9% were men, and rheumatoid arthritis-ILD was the most common (42.4%). A PF phenotype was identified in 135 patients (34.1%). The PF-ILD group showed lower forced vital capacity and total lung capacity (TLC) than the non-PF-ILD group. The PF-ILD group also showed poorer survival (median survival, 91.2 months vs. not reached; P < 0.001) than the non-PF-ILD group. In multivariable Cox analysis adjusted for age, DLCO, HRCT pattern, and specific diagnosis, PF phenotype was independent prognostic factor (hazard ratio, 3.053; P < 0.001) in patients with fibrosing ILD. Each criterion of PF-ILD showed similar survival outcomes. Conclusions Our results showed that approximately 34% of patients with non-IPF fibrosing ILD showed a progressive phenotype and a poor outcome similar to that of IPF, regardless of the diagnostic criteria used.

Adenocarcinoma with Mixed Subtypes in the Early and Advanced Gastric Cancer

Objective. Adenocarcinoma with mixed subtypes (AM) is a histological classification based on the WHO classification. We aimed to compare the prognosis among AM, classic adenocarcinoma (CA), mucinous adenocarcinoma (MAC), and signet-ring cell carcinoma (SRCC) in early and advanced gastric cancer (EGC and AGC), respectively. Methods. The Surveillance, Epidemiology, and End Results (SEER) database was queried from 2001 to 2016. Univariate and multivariate Cox analyses were performed to compare prognosis between AM and histologic subtypes of CA, SRCC, and MAC in ECG and ACG. A nomogram was established to predict the cancer-specific survival (CSS) of gastric cancer (GC) patients with AM. C-index, calibration curves, and receiver operating characteristic (ROC) and decision curve analysis (DCA) curves were applied to examine the accuracy and clinical benefits. Results. In the prognosis among these four histological subtypes in EGC patients, there are no differences. For AGC patients, AM had a significantly poorer prognosis compared with CA and MAC ( P = 0.003 , 0.029) but similar prognosis to SRCC. A nomogram based on race, T stage, N stage, M stage, and surgical modalities was proposed to predict 1- and 3-year CSS for GC patients with AM (C-index: training cohort: 0.804, validation cohort: 0.748. 1- and 3-year CSS AUC: training cohort: 0.871 and 0.914, validation cohort: 0.810 and 0.798). 1- and 3-year CSS DCA curves showed good net benefits. Conclusions. EGC patients with AM had similar survival to those with CA, MAC, and SRCC. AM was an independent predictor of poor prognosis in AGC. A nomogram for predicting the prognosis of GC patients with AM was proposed to quantitatively assess the long-term survival.

T-Cell Large Granular Lymphocytic Leukemia with Atypical Immunophenotypes: A Single Center Retrospective Analysis of 17 Cases

Purpose T-cell large granular lymphocytic leukemia (T-LGLL) is characterized by expansion of cytotoxic T cells expressing αβ T cell receptor (TCR), CD2, surface CD3, CD8, CD57 as well as cytotoxic molecules. Atypical immunophenotypes of T-LGLL, including γδ TCR and CD4, reported in a small subset, remains to be well-defined. Methods We retrospectively analyzed immunophotypes and clinicopathologic features of 96 T-LGLL cases. Results We found a total of 17 cases with atypical immunophenotypes including 9 TCRγδ + cases and 8 CD4+ TCRαβ + cases. Pure red cell aplasia was less common in atypical immunophenotypes patients compared to that of typical immunophenotypes [0/17 (0%) vs. 26/79 (32.9%), p=0.005]. STAT3 mutations were also less frequent in atypical immunophenotypes cases, although accompanied with marginal significance (p=0.086). Conclusion Patients with atypical immunophenotypes showed a similar survival outcome to that of typical T-LGLL immunophenotypes. Additional efforts were needed to better understand the pathogenesis of these rare atypical immunophenotypes T-LGLL cases.

The EGFRvIII transcriptome in glioblastoma, a meta-omics analysis

Background EGFR is among the genes most frequently altered in glioblastoma, with exons 2-7 deletions (EGFRvIII) being amongst its most common genomic mutations. There are conflicting reports about its prognostic role and it remains unclear whether and how it differs in signalling compared with wildtype EGFR. Methods To better understand the oncogenic role of EGFRvIII, we leveraged four large datasets into one large glioblastoma transcriptome dataset (n=741) alongside 81 whole-genome samples from two datasets. Results The EGFRvIII/EGFR expression ratios differ strongly between tumours and ranges from 1% to 95%. Interestingly, the slope of relative EGFRvIII expression is near-linear, which argues against a more positive selection pressure than EGFR wildtype. An absence of selection pressure is also suggested by the similar survival between EGFRvIII positive and negative glioblastoma patients. EGFRvIII levels are inversely correlated with pan-EGFR (all wildtype and mutant variants) expression, which indicates that EGFRvIII has a higher potency in downstream pathway activation. EGFRvIII-positive glioblastomas have a lower CDK4 or MDM2 amplification incidence than EGFRvIII-negative (p=0.007), which may point towards crosstalk between these pathways. EGFRvIII-expressing tumours have an upregulation of ‘classical’ subtype genes compared to those with EGFR-amplification only (p=3.873e-6). Genomic breakpoints of the EGFRvIII deletions have a preference towards the 3’ end of the large intron-1. These preferred breakpoints preserve a cryptic exon resulting in a novel EGFRvIII variant and preserve an intronic enhancer. Conclusions These data provide deeper insights into the complex EGFRvIII biology and provide new insights for targeting EGFRvIII mutated tumours.

History and Perspective of Immunotherapy for Pythiosis

The fungus-like microorganism Pythium insidiosum causes pythiosis, a life-threatening infectious disease increasingly reported worldwide. Antimicrobial drugs are ineffective. Radical surgery is an essential treatment. Pythiosis can resume post-surgically. Immunotherapy using P. insidiosum antigens (PIA) has emerged as an alternative treatment. This review aims at providing up-to-date information of the immunotherapeutic PIA, with the focus on its history, preparation, clinical application, outcome, mechanism, and recent advances, in order to promote the proper use and future development of this treatment modality. P. insidiosum crude extract is the primary source of immunotherapeutic antigens. Based on 967 documented human and animal (mainly horses) pythiosis cases, PIA immunotherapy reduced disease morbidity and mortality. Concerning clinical outcomes, 19.4% of PIA-immunized human patients succumbed to vascular pythiosis instead of 41.0% in unimmunized cases. PIA immunotherapy may not provide an advantage in a local P. insidiosum infection of the eye. Both PIA-immunized and unimmunized horses with pythiosis showed a similar survival rate of ~70%; however, demands for surgical intervention were much lesser in the immunized cases (22.8% vs. 75.2%). The proposed PIA action involves switching the non-protective T-helper-2 to protective T-helper-1 mediated immunity. By exploring the available P. insidiosum genome data, synthetic peptides, recombinant proteins, and nucleic acids are potential sources of the immunotherapeutic antigens worth investigating. The PIA therapeutic property needs improvement for a better prognosis of pythiosis patients.