Colorectal Cancer Stage at Diagnosis Before vs During the COVID-19 Pandemic in Italy

IMPORTANCE Delays in screening programs and the reluctance of patients to seek medical attention because of the outbreak of SARS-CoV-2 could be associated with the risk of more advanced colorectal cancers at diagnosis. OBJECTIVE To evaluate whether the SARS-CoV-2 pandemic was associated with more advanced oncologic stage and change in clinical presentation for patients with colorectal cancer. DESIGN, SETTING, AND PARTICIPANTS This retrospective, multicenter cohort study included all 17 938 adult patients who underwent surgery for colorectal cancer from March 1, 2020, to December 31, 2021 (pandemic period), and from January 1, 2018, to February 29, 2020 (prepandemic period), in 81 participating centers in Italy, including tertiary centers and community hospitals. Follow-up was 30 days from surgery. EXPOSURES Any type of surgical procedure for colorectal cancer, including explorative surgery, palliative procedures, and atypical or segmental resections. MAIN OUTCOMES AND MEASURES The primary outcome was advanced stage of colorectal cancer at diagnosis. Secondary outcomes were distant metastasis, T4 stage, aggressive biology (defined as cancer with at least 1 of the following characteristics: signet ring cells, mucinous tumor, budding, lymphovascular invasion, perineural invasion, and lymphangitis), stenotic lesion, emergency surgery, and palliative surgery. The independent association between the pandemic period and the outcomes was assessed using multivariate random-effects logistic regression, with hospital as the cluster variable. RESULTS A total of 17 938 patients (10 007 men [55.8%]; mean [SD] age, 70.6 [12.2] years) underwent surgery for colorectal cancer: 7796 (43.5%) during the pandemic period and 10 142 (56.5%) during the prepandemic period. Logistic regression indicated that the pandemic period was significantly associated with an increased rate of advanced-stage colorectal cancer (odds ratio [OR], 1.07; 95%CI, 1.01-1.13; P = .03), aggressive biology (OR, 1.32; 95%CI, 1.15-1.53; P < .001), and stenotic lesions (OR, 1.15; 95%CI, 1.01-1.31; P = .03). CONCLUSIONS AND RELEVANCE This cohort study suggests a significant association between the SARS-CoV-2 pandemic and the risk of a more advanced oncologic stage at diagnosis among patients undergoing surgery for colorectal cancer and might indicate a potential reduction of survival for these patients

Corneal Bioengineering

The cornea is the main structure of the ocular surface and enables the transmission of light entering the eye. The cornea is covered by a nonkeratinized stratified epithelium, which is renewed by stem cells located in the basal layer of the limbus. Injury and disease, such as chemical and thermal burns, can destroy the limbus leading to a limbal stem cell deficiency (LSCD) with consequent visual loss. In 1997, Pellegrini et al. firstly described the use of ex vivo cultured limbal epithelial stem cell to treat LSCD. Since then, several reports describing alternative methods of the clinical use of this technology have been published but the retention of stem cells, which is the essential property of the graft, has not been investigated. The definition of a graftable limbal culture in light of the clinical performance must follow specific quality criteria, here discussed, which are relevant for the future use of any cultured cell type for clinical application

Characterization of the gene expression profile of human hippocampus in mesial temporal lobe epilepsy with hippocampal sclerosis

One of the main putative causes of therapy refractory epilepsy in mesial temporal lobe epilepsy (MTLE) with hippocampal sclerosis is the overexpression of multidrug transporters (MDTs) at the blood-brain barrier (BBB). It steps up the removal of antiepileptic drugs (AEDs) out of the brain cells across the BBB resulting in a low concentration of AEDs within the target cells. Some of the mechanisms of AED resistance are most likely to be genetically determined. To obtain more information about the underlying pathophysiology of intractability in epilepsy, we compared the global gene expression profile of human hippocampus and hippocampal-derived microvascular endothelial cells from MTLE with HS patients and controls. At the level of MDT, a significant up-regulation was found for ABCB1 (P-gp), ABCB2, ABCB3, and ABCB4, which was mainly related to endothelial cells. The data on the MDT were validated and extended by quantitative RT-PCR. Surprisingly, inflammatory factors such as interleukins (IL-1α, IL-1β, IL-6, and IL-18) and cytokines (TNF-α and TGF-β1) were found to be up-regulated in hippocampal parenchyma. The overexpression of P-gp, IL-1β, and IL-6 was also confirmed by immunohistochemistry (IHC). Our results suggest that complex expression changes of ABC-transporters may play a decisive role in pharmacoresistance in MTLE. Further studies on the new and unexpected overexpression of inflammatory cytokines may unlock hitherto undiscovered pathways of the underlying pathophysiology of human MTLE

Leukemogenesis induced by wild-type and STI571-resistant BCR/ABL is potently suppressed by C/EBPα

Chronic phase–to–blast crisis transition in chronic myelogenous leukemia (CML) is associated with differentiation arrest and down-regulation of C/EBPα, a transcription factor essential for granulocyte differentiation. Patients with CML in blast crisis (CML-BC) became rapidly resistant to therapy with the breakpoint cluster region–Abelson murine leukemia (BCR/ABL) kinase inhibitor imatinib (STI571) because of mutations in the kinase domain that interfere with drug binding. We show here that the restoration of C/EBPα activity in STI571-sensitive or -resistant 32D-BCR/ABL cells induced granulocyte differentiation, inhibited proliferation in vitro and in mice, and suppressed leukemogenesis. Moreover, activation of C/EBPα eradicated leukemia in 4 of 10 and in 6 of 7 mice injected with STI571-sensitive or -resistant 32D-BCR/ABL cells, respectively. Differentiation induction and proliferation inhibition were required for optimal suppression of leukemogenesis, as indicated by the effects of p42 C/EBPα, which were more potent than those of K298E C/EBPα, a mutant defective in DNA binding and transcription activation that failed to induce granulocyte differentiation. Activation of C/EBPα in blast cells from 4 patients with CML-BC, including one resistant to STI571 and BMS-354825 and carrying the T315I Abl kinase domain mutation, also induced granulocyte differentiation. Thus, these data indicate that C/EBPα has potent antileukemia effects even in cells resistant to ATP-binding competitive tyrosine kinase inhibitors, and they portend the development of anti-leukemia therapies that rely on C/EBPα activation

KLK3 and steroid 5-alpha reductase type II (SRD5A2) gene polymorphisms might affect clinical reliability of serum PSA measurement.

Background. Serum levels of fPSA, tPSA and of their ratio are used for prostate cancer (PC) screening. PSA synthesis depends on pathology, but also on KLK3 gene polymorphisms and on androgen transcriptional effects. The V89 isoform of Steroid 5-\u3b1 reductase type II (SRD5A2) by enhancing diihydrotestosterone, might also enhance PSA. Methods. we ascertained whether -5429T>G, -5412T>C, -4643A>G KLK3 SNPs and their haplotypes, and V89L polymorphisms of SRD5A2 gene might affect the serum levels of fPSA, tPSA and f/tPSA. We studied 711 men consecutively subjected to prostate biopsy: 291 PC, 351 benign prostatic hyperplasia (BPH), 69 controls. Results. six KLK3 haplotypes were derived by Arlequin software; nine genotypes were inferred, with an overall frequency of: TTA/ TTA (62,03%), GCG/TTA (28.56%), GCA/TTA (3.37%), GCG/GCG (2.95%), TTA/TTG (1.55%), GCA/GCG (0.56%), GCG/TTG (0.42%), GTA/TTA (0.42%), TCA/TTA (0.14%). Among BPH patients, not PC or controls, fPSA (p=0.08) and tPSA (p<0.05) were decreased in TTA/TTA with respect to GCG/GCG and GCG/TTA (chi-square for trend: p=0.02 and p=0.01). Among PC, not BPH or controls, fPSA (p=0.03) and tPSA (p=0.01) were increased in SRD5A2 V/V homozygotes (chi-square for trend: p=0.01 and p=0.005). The NPV of tPSA 2.5 <= 10 ug/L and f/tPSA <=10% was higher among GCG/TTA (75%) than among TTA/TTA (64%). Conclusions. when evaluating serum fPSA and tPSA to obtain a differential diagnosis between PC and BPH, individual genetic background might affect serum levels and reduce diagnostic reliability of the test result

Comparative assessment of cultures from oral and urethral stem cells for urethral regeneration

Urethral reconstruction has received much attention in recent years, due to pathologies such as recurrence of urethral strictures after treatments. Various surgical techniques have been developed to obtain the best risk-benefit ratio, such as autologous grafts taken from the oral cavity. Tissue engineering and stem cells, growing tissue from a small biopsies, can further improve surgery, reducing invasiveness and morbidity. To determine whether urethra or other epithelia can be equally useful for urethra engineering, a comparison of clonogenic ability, proliferative potential and stem cell markers should be obtained. In this study, 19 biopsies from urethra, and 21 from oral mucosa were obtained from patients, during reconstructive surgery. Urethral and oral tissues were removed from the same donor, to develop primary cultures and cell characterization. The long term regenerative properties of both tissues was investigated in vitro by life span, clonal analysis and markers of different clonal types. Results revealed the same high proliferative potential for urethra and oral mucosa cultures, but maintenance of specific markers. Karyotype and growth factor dependence confirmed the normal phenotype of cultured cells. Clonal analysis of the proliferative compartment highlighted a very different proportion of stem and transient amplifying cells, characterised by dissimilar cell size profile and marker expression. In conclusion, both tissues can be cultured and preserve their stem cells in vitro. Few differences appeared in oral mucosa vs urethra, suggesting that they can be equally useful for tissue engineering of the urethral tract

Validation of the 2009 TNM Version in a Large Multi-Institutional Cohort of Patients Treated for Renal Cell Carcinoma: Are Further Improvements Needed?

Background: A new edition of the TNM was recently released that includes modifications for the staging system of kidney cancers. Specifically, T2 cancers were subclassified into T2a and T2b (10 cm vs >10 cm), tumors with renal vein involvement or perinephric fat involvement were classified as T3a cancers, and those with adrenal involvement were classified as T4 cancers. Objective: Our aim was to validate the recently released edition of the TNM staging system for primary tumor classification in kidney cancer. Design, setting, and participants: Our multicenter retrospective study consisted of 5339 patients treated in 16 academic Italian centers. Intervention: Patients underwent either radical or partial nephrectomy. Measurements: Univariable and multivariable Cox regression models addressed cancer-specific survival (CSS) after surgery. Results and limitations: In the study, 1897 patients (35.5%) were classified as pT1a, 1453 (27%) as pT1b, 437 (8%) as pT2a, 153 (3%) as pT2b, 1059 (20%) as pT3a, 117 (2%) as pT3b, 26 (0.5%) as pT3c, and 197 (4%) as pT4. At a median follow-up of 42 mo, 786 (15%) had died of disease. In univariable analysis, patients with pT2b and pT3a tumors had similar CSS, as did patients with pT3c and pT4 tumors. Moreover, both pT3a and pT3b stages included patients with heterogeneous outcomes. In multivariable analysis, the novel classification of the primary tumor was a powerful independent predictor of CSS ( p for trend <0.0001). However, the substratification of pT1 tumors did not retain an independent predictive role. The major limitations of the study are retrospective design, lack of central pathologic review, and the small number of patients included in some substages. Conclusions: The recently released seventh edition of the primary tumor staging system for kidney tumors is a powerful predictor of CSS. However, some of the substages identified by the classification have overlapping prognoses, and other substages include patients with heterogeneous outcomes. The few modifications included in this edition may have not resolved the most critical issues in the previous version