Evaluation of Donor and Recipient Characteristics Involved in Descemet Stripping Automated Endothelial Keratoplasty Outcomes

Aims: To evaluate both donor and recipient features involved in visual acuity restoring and complication insurgence in eyes that have undergone Descemet stripping automated endothelial keratoplasty (DSAEK). Methods: In this retrospective study, charts of 111 eyes of 96 patients (mean age 70.25 ± 8.58 years) that underwent DSAEK were evaluated. Only Fuch's Distrophy (FD) or Bullous Keratopathy (BK) due to cataract surgery eyes were included. A complete ophthalmic check with endothelial cell density (ECD) and central corneal thickness (CCT) measurement was performed before surgery and at 1, 3, 6, and 12 months follow-up. Each DSAEK was performed by the same well-trained surgeon; only pre-cut lenticules, provided by same Eye Bank, were implanted. Results: A total of 48 (43%) complications have been observed (most of them were 22 partial graft detachments and 17 IOP spikes). At the last follow-up (mean: 8.58 ± 4.09 months), a significant increase (p < 0.05) of best corrected visual acuity (BCVA) was detected. Overall mean BCVA of the eyes evaluated was 0.40 ± 0.43 LogMAR with BK eyes showing a significantly higher improvement (p < 0.05) compared to FD eyes. The only factor showing a significant correlation (p < 0.05) with visual acuity enhancement was the implant of a lenticule thinner than 100 μm. Recipient features significantly (p < 0.05) associated with complications observed after surgery were glaucoma and diabetes mellitus. Conclusion: The use of a graft thinner than 100 μm can provide better visual acuity recovery while recipients affected by glaucoma or diabetes mellitus are more prone to develop complications after surgery

CD16-158-valine chimeric receptor T cells overcome the resistance of KRAS-mutated colorectal carcinoma cells to cetuximab

KRAS mutations hinder therapeutic efficacy of epidermal growth factor receptor (EGFR)-specific monoclonal antibodies cetuximab and panitumumab-based immunotherapy of EGFR+ cancers. Although cetuximab inhibits KRAS-mutated cancer cell growth in vitro by natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC), KRAS-mutated colorectal carcinoma (CRC) cells escape NK cell immunosurveillance in vivo. To overcome this limitation, we used cetuximab and panitumumab to redirect Fcγ chimeric receptor (CR) T cells against KRAS-mutated HCT116 colorectal cancer (CRC) cells. We compared four polymorphic Fcγ-CR constructs including CD16158F-CR, CD16158V-CR, CD32131H-CR, and CD32131R-CR transduced into T cells by retroviral vectors. Percentages of transduced T cells expressing CD32131H-CR (83.5 ± 9.5) and CD32131R-CR (77.7 ± 13.2) were significantly higher than those expressing with CD16158F-CR (30.3 ± 10.2) and CD16158V-CR (51.7 ± 13.7) (p < 0.003). CD32131R-CR T cells specifically bound soluble cetuximab and panitumumab. However, only CD16158V-CR T cells released high levels of interferon gamma (IFNγ = 1,145.5 pg/ml ±16.5 pg/ml, p < 0.001) and tumor necrosis factor alpha (TNFα = 614 pg/ml ± 21 pg/ml, p < 0.001) upon incubation with cetuximab-opsonized HCT116 cells. Moreover, only CD16158V-CR T cells combined with cetuximab killed HCT116 cells and A549 KRAS-mutated cells in vitro. CD16158V-CR T cells also effectively controlled subcutaneous growth of HCT116 cells in CB17-SCID mice in vivo. Thus, CD16158V-CR T cells combined with cetuximab represent useful reagents to develop innovative EGFR+KRAS-mutated CRC immunotherapies

In vitro elimination of epidermal growth factor receptor-overexpressing cancer cells by CD32A-chimeric receptor T cells in combination with cetuximab or panitumumab

Cetuximab and panitumumab bind the human epidermal growth factor receptor (EGFR). Although the chimeric cetuximab (IgG1) triggers antibody-dependent-cellular-cytotoxicity (ADCC) of EGFR positive target cells, panitumumab (a human IgG2) does not. The inability of panitumumab to trigger ADCC reflects the poor binding affinity of human IgG2 Fc for the FcγRIII (CD16) on natural killer (NK) cells. However, both human IgG1 and IgG2 bind the FcγRII (CD32A) to a similar extent. Our study compares the ability of T cells, engineered with a novel low-affinity CD32A131R-chimeric receptor (CR), and those engineered with the low-affinity CD16158F-CR T cells, in eliminating EGFR positive epithelial cancer cells (ECCs) in combination with cetuximab or panitumumab. After T-cell transduction, the percentage of CD32A131R-CR T cells was 74 ± 10%, whereas the percentage of CD16158F-CR T cells was 46 ± 15%. Only CD32A131R-CR T cells bound panitumumab. CD32A131R-CR T cells combined with the mAb 8.26 (anti-CD32) and CD16158F-CR T cells combined with the mAb 3g8 (anti-CD16) eliminated colorectal carcinoma (CRC), HCT116FcγR+ cells, in a reverse ADCC assay in vitro. Crosslinking of CD32A131R-CR on T cells by cetuximab or panitumumab and CD16158F-CR T cells by cetuximab induced elimination of triple negative breast cancer (TNBC) MDA-MB-468 cells, and the secretion of interferon gamma and tumor necrosis factor alpha. Neither cetuximab nor panitumumab induced Fcγ-CR T antitumor activity against Kirsten rat sarcoma (KRAS)-mutated HCT116, nonsmall-cell-lung-cancer, A549 and TNBC, MDA-MB-231 cells. The ADCC of Fcγ-CR T cells was associated with the overexpression of EGFR on ECCs. In conclusion, CD32A131R-CR T cells are efficiently redirected by cetuximab or panitumumab against breast cancer cells overexpressing EGFR

CAR-T cell. the long and winding road to solid tumors

Adoptive cell therapy of solid tumors with reprogrammed T cells can be considered the "next generation" of cancer hallmarks. CAR-T cells fail to be as effective as in liquid tumors for the inability to reach and survive in the microenvironment surrounding the neoplastic foci. The intricate net of cross-interactions occurring between tumor components, stromal and immune cells leads to an ineffective anergic status favoring the evasion from the host's defenses. Our goal is hereby to trace the road imposed by solid tumors to CAR-T cells, highlighting pitfalls and strategies to be developed and refined to possibly overcome these hurdles

Natural humoral immune response to ribosomal P0 protein in colorectal cancer patients

Tumor associated antigens are useful in colorectal cancer (CRC) management. The ribosomal P proteins (P0, P1, P2) play an important role in protein synthesis and tumor formation. The immunogenicity of the ribosomal P0 protein in head and neck, in breast and prostate cancer patients and the overexpression of the carboxyl-terminal P0 epitope (C-22 P0) in some tumors were reported

Improving accuracy of corneal power measurement with partial coherence interferometry after corneal refractive surgery using a multivariate polynomial approach

Background: To improve accuracy of IOLMaster (Carl Zeiss, Jena, Germany) in corneal power measurement after myopic excimer corneal refractive surgery (MECRS) using multivariate polynomial analysis (MPA). Methods: One eye of each of 403 patients (mean age 31.53 ± 8.47 years) was subjected to MECRS for a myopic defect, measured as spherical equivalent, ranging from - 9.50 to - 1 D (mean - 4.55 ± 2.20 D). Each patient underwent a complete eye examination and IOLMaster scan before surgery and at 1, 3 and 6 months follow up. Axial length (AL), flatter keratometry value (K1), steeper keratometry value (K2), mean keratometry value (KM) and anterior chamber depth measured from the corneal endothelium to the anterior surface of the lens (ACD) were used in a MPA to devise a method to improve accuracy of KM measurements. Results: Using AL, K1, K2 and ACD measured after surgery in polynomial degree 2 analysis, mean error of corneal power evaluation after MECRS was + 0.16 ± 0.19 D. Conclusions: MPA was found to be an effective tool in devising a method to improve precision in corneal power evaluation in eyes previously subjected to MECRS, according to our results.Background: To improve accuracy of IOLMaster (Carl Zeiss, Jena, Germany) in corneal power measurement after myopic excimer corneal refractive surgery (MECRS) using multivariate polynomial analysis (MPA). Methods: One eye of each of 403 patients (mean age 31.53 ± 8.47 years) was subjected to MECRS for a myopic defect, measured as spherical equivalent, ranging from - 9.50 to - 1 D (mean - 4.55 ± 2.20 D). Each patient underwent a complete eye examination and IOLMaster scan before surgery and at 1, 3 and 6 months follow up. Axial length (AL), flatter keratometry value (K1), steeper keratometry value (K2), mean keratometry value (KM) and anterior chamber depth measured from the corneal endothelium to the anterior surface of the lens (ACD) were used in a MPA to devise a method to improve accuracy of KM measurements. Results: Using AL, K1, K2 and ACD measured after surgery in polynomial degree 2 analysis, mean error of corneal power evaluation after MECRS was + 0.16 ± 0.19 D. Conclusions: MPA was found to be an effective tool in devising a method to improve precision in corneal power evaluation in eyes previously subjected to MECRS, according to our results