No abstract

Use of high dose post-transplant cyclophosphamide for graft versus host disease (GVHD) prophylaxis has expanded the use of un-manipulated haploidentical hematopoietic cell transplantation. The immediate post-transplant course in T-cell replete peripheral blood haploidentical hematopoietic cell transplantation (haplo-HCT) is often complicated by symptoms resembling the cytokine release syndrome (CRS) previously described in recipients of targeted cellular therapeutics. However, we know little about the incidence and impact of CRS on outcomes in these patients. To understand this syndrome in haplo-HCT patients, we reviewed data from 75 consecutive patients who received G-CSF mobilized T-cell replete peripheral blood haplo-HCT at a single center. Using CRS criteria described in recipients of chimeric antigen receptor T-cell therapies, we found 65/75 (87%) who met criteria for CRS though most of these were only mild (grade 1-2). However, nine patients (12%) experienced severe (grade 3-4) CRS. Median survival was 2.6 months (95% C.I. 0.43 – 5.8) in patients with severe CRS, compared with 13.1 months (95% CI. 8.1-Not Reached) in patients with mild CRS. Transplant related mortality (TRM) was worse in the severe CRS cohort with a hazard ratio of 4.59 (95% CI. 1.43-14.67) compared to mild CRS. Severe CRS patients had a significant delay in median time for neutrophil engraftment. Serum IL-6 levels were measured in ten haplo-HCT patients and were elevated in the early post-transplant setting. Seven patients with CRS were treated with tocilizumab resulting in a complete resolution of their CRS symptoms. Severe CRS represents a potential complication of peripheral blood haplo-HCT, is associated with worse outcomes, and anti-IL-6 Receptor (IL-6R) therapy is associated with rapid resolution of the CRS symptoms.

E-cadherin is a Ca(2+)-dependent intercellular adhesion molecule known to exert an invasion-suppressor function. In the present study, E-cadherin expression was immunohistochemically investigated in a retrospective series of 413 RO-resected gastric carcinomas using the monoclonal antibody (MAb) 5H9. Of these cases, 108 tumors revealed a preserved E-cadherin expression similar to that of normal gastric mucosa. In 95 tumors, E-cadherin expression was moderately reduced and in 86 tumors highly reduced. In 124 tumors, no or only a very weak dotted expression could be detected. There was a significant correlation between the degree of E-cadherin expression and the grade of tumor differentiation, as well as with histological type according to the Laurén and the WHO classifications. In contrast, no correlation could be demonstrated between E-cadherin expression and the prognostic parameters depth of invasion, lymph node involvement and vascular invasion. As shown by univariate Cox regression analysis, patients with E-cadherin-positive tumors had significantly better 3-and 5-year survival rates than patients with E-cadherin-negative tumors. This prognostic impact remained present in a multivariate Cox regression analysis, including the prognostic parameters pT category, pN category and vascular invasion.

As an emerging class of nanomaterial, nanoclusters hold great potential for biomedical applications due to their unique sizes and related properties. Herein, we prepared a 64Cu doped gold nanoclusters (64CuAuNCs, hydrodynamic size: 4.2 ± 0.5 nm) functionalized with AMD3100 or (Plerixafor) for targeted positron emission tomography (PET) imaging of CXCR4, an up-regulated receptor on primary tumor and lung metastasis in a mouse 4T1 orthotopic breast cancer model. We prepared a targeted 64CuAuNCs-AMD3100 (4.5 ± 0.4 nm) via one-step reaction with controlled conjugation of AMD3100 and specific activity, as well as improved colloid stability. In vivo pharmacokinetic evaluation showed favorable organ distribution and significant renal and fecal clearance within 48 h post injection. The expression of CXCR4 in tumors and metastasis was characterized by immunohistochemistry, western blot, and reverse transcription polymerase chain reaction analysis. PET imaging with 64CuAuNCs-AMD3100 demonstrated sensitive and accurate detection of CXCR4 in engineered tumors expressing various levels of the receptor while competitive receptor blocking studies confirmed targeting specificity of the nanoclusters. In contrast to non-targeted 64CuAuNCs and 64Cu-AMD3100 alone, the targeted 64CuAuNCs-AMD3100 detected up-regulated CXCR4 in early-stage tumors and pre-metastatic niche of lung earlier and with greater sensitivity. Taken together, we believe that 64CuAuNCs-AMD3100 could serve as a useful platform for early and accurate detection of breast cancer and metastasis providing an essential tool to guide the treatment.