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Background: Several strategies have been investigated to improve the 4% survival advantage of adjuvant chemotherapy in early-stage non-small-cell lung cancer (NSCLC). In this investigator-initiated study we aimed to evaluate the predictive utility of the messenger RNA (mRNA) expression levels of excision repair cross complementation group 1 (ERCC1) and thymidylate synthase (TS) as assessed in resected tumor., Patients and Methods: Seven hundred and seventy-three completely resected stage II-III NSCLC patients were enrolled and randomly assigned in each of the four genomic subgroups to investigator's choice of platinum-based chemotherapy (C, n = 389) or tailored chemotherapy (T, n = 384). All anticancer drugs were administered according to standard doses and schedules. Stratification factors included stage and smoking status. The primary endpoint of the study was overall survival (OS)., Results: Six hundred and ninety patients were included in the primary analysis. At a median follow-up of 45.9 months, 85 (24.6%) and 70 (20.3%) patients died in arms C and T, respectively. Five-year survival for patients in arms C and T was of 65.4% (95% CI (confidence interval): 58.5% to 71.4%) and 72.9% (95% CI: 66.5% to 78.3%), respectively. The estimated hazard ratio (HR) was 0.77 (95% CI: 0.56-1.06, P value: 0.109) for arm T versus arm C. HR for recurrence-free survival was 0.89 (95% CI: 0.69-1.14, P value: 0.341) for arm T versus arm C. Grade 3-5 toxicities were more frequently reported in arm C than in arm T., Conclusion: In completely resected stage II-III NSCLC tailoring adjuvant chemotherapy conferred a non-statistically significant trend for OS favoring the T arm. In terms of safety, the T arm was associated with better efficacy/toxicity ratio related to the different therapeutic choices in the experimental arm., Competing Interests: Disclosure GVS received honoraria from AstraZeneca, Eli Lilly, MSD, Pfizer, Roche, Johnson & Johnson, Takeda; consulting or advisory role for Eli Lilly, BeiGene and AstraZeneca, received institutional research funding from Eli Lilly and MSD and received travel, accommodations from Bayer. SN received honoraria or consulted for Eli Lilly, Amgen, BeiGene, AstraZeneca, Bristol Myers Squibb, Abbvie, Boehringer Ingelheim, MSD, Roche, Pfizer and Takeda. All other authors have declared no conflicts of interest., (Copyright © 2021. Published by Elsevier Ltd.)

Purpose: This report analyzed the outcomes of patients undergoing surgery for oral squamous cell carcinoma (OSCC) to identify the value of prognostic factors., Material and Methods: A total of 525 patients were studied who had undergone surgery for oral squamous cell carcinoma (OSCC) between 2000 and 2011, of whom 222 had received postoperative radiation-therapy (PORT) and or chemoradiation-therapy (PORTC). For each patient, personal data, histological findings, treatment and outcome were recorded and analyzed statistically. Survival curves were calculated using the Kaplan-Meier algorithm, and the difference in survival among subgroups was examined., Results: The overall survival (OS) and disease-specific survival (DSS) 5-year survival rate in the 525 patients were respectively 71.38% and 73.18%. The differences in the overall survival and disease-specific 5-year survival were significant (p < 0.05) for age < 40 years, site of origin, N status, staging, grading, osseous medullar infiltration, and perineural invasion. In patients undergoing radiation therapy, only perineural invasion negatively influenced the survival prognosis. In 150 pT1 cases of tongue and floor-of-mouth cancer, an infiltration depth (ID) > 4 mm was statistically correlated with poorer prognosis., Conclusions: The results demonstrate an improvement in the 5-year OS and DSS rates during the past decade compared with the previous decade. Univariate analysis revealed that age, tumor staging, and lymph node involvement, extracapsular spread, grading, perineurial invasion, infiltration depth, and osseus medullary invasion were associated significantly with overall survival and disease-specific survival., (Copyright © 2016 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.)

Background: The nucleotide excision repair pathway is crucial for cellular DNA integrity and the ERCC1 helicase is also potentially involved in resistance to platinum-based chemotherapy, and high levels of ERCC1 mRNA in tumours have been associated with cisplatin resistance in different human cancers. The aim of this work was to investigate the correlation between DNA repair gene expression levels in tumour tissue, normal tissue and peripheral blood samples from patients with two common human cancers, non-small cell lung cancer (NSCLC) and squamous cell carcinoma of the head and neck (HNSCC), to test if blood gene expression could be a proxy for tumour tissue gene expression to predict response to platinum-based chemotherapy., Methods: Using RT-qPCR we determined ERCC1, ERCC2, ERCC4, XPA, XPC, XRCC1, XRCC3, APEX, OGG1, MGMT mRNA levels in fresh NSCLC, normal lung and HNSCC tissue, as well as blood, from NSCLC and HNSCC patients who were treated surgically., Results: Target gene expression in NSCLC and HNSCC tissue was higher than in blood. A statistically significant correlation (p<0.05) was found between target gene mRNA expression in tumour tissue and blood, in particular ERCC1, MGMT, XPC, XRCC1 and XRCC3 in NSCLC and APEX, ERCC1, ERCC2, ERCC4, XRCC1 and XRCC3 in HNSCC., Conclusions: The existence of a significant correlation between blood and tumour tissue expression of some genes of clinical interest, such as ERCC1 in NSCLC and HNSCC, could allow the introduction in clinical practice of a simple test that would measure mRNA levels of DNA repair genes in peripheral blood samples instead of tissue samples to determine prognostic and predictive factors in NSCLC and HNSCC patients., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Introduction: This report analysed the outcome of patients undergoing surgery for oral squamous cell carcinoma in order to identify the prognostic value of several factors., Patients: A total of 245 patients were studied who had undergone surgery for oral squamous cell carcinoma between 1989 and 2002, of whom 109 had received postoperative radiation therapy., Methods: For each patient, personal data, alcohol and tobacco consumption, symptoms, histological findings, treatment, and outcome were recorded and analysed statistically. Survival curves were calculated using the Kaplan-Meier algorithm, and the difference in survival among subgroups was examined., Results: The overall 5-year survival rate in the 245 patients was 63% (72.5% at 3 years). The differences in the 5-year survival were significant (p<0.05) for the site of origin, N and pN status, TNM stage, grading, status of the resection margins, osseous infiltration, and perineural invasion. Vascular involvement as a discriminator was not statistically significant. In patients undergoing radiation therapy, only perineural invasion negatively influenced the 5-year survival prognosis (p<0.01)., Conclusion: The overall survival rate was within the (previously) reported range. The prognostic value of many parameters is widely recognized; the combined evaluation of 'composite factors' is promising.

The CD69 glycoprotein is an early activation antigen of T and B lymphocytes but it expression is induced in vitro on cells of most hematopoietic lineages, including neutrophils after stimulation with PMA or fMLP. In this study, we investigated whether CD69 expression on human neutrophils could be modulated by inflammatory or anti-inflammatory cytokines (IL-1beta, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-18, G-CSF, GM-CSF, TNF-alpha, TGF-beta, IFN-alpha, IFN-gamma). Resting neutrophils from healthy subjects did not express CD69 on the cell surface; moreover, a preformed intracellular pool of CD69 was not evident in these cells. CD69 was barely detectable on these cells after overnight incubation in medium while overnight incubation with GM-CSF, IFN-gamma or IFN-alpha significantly induced CD69 expression on neutrophils with GM-CSF appearing to be the most potent inducer. This induction was dependent on a new protein synthesis as it was significantly inhibited by cycloheximide (about 50% inhibition). CD69 cross-linking on GM-CSF-primed neutrophils sinergized with LPS and increased TNF-alpha production and secretion suggesting a role for CD69-positive neutrophils in the pathogenesis and maintenance of different inflammatory diseases.

Background: This study was undertaken to investigate the relations between whole body oxygen consumption (VO2), oxygen delivery (DO2), and hemodynamic variables during cardiopulmonary bypass., Methods: One hundred one patients were studied during cooling, hypothermia, and rewarming. Oxygen consumption, DO2, hemodynamics, and DO2crit were measured at these times., Results: There was a direct linear relation between DO2 and VO2 during all three times. No relation between VO2 and hemodynamics was detected during cooling; during hypothermia, an inverse linear relation with peripheral arterial resistance was found. Finally, during rewarming, there was a direct relation with pump flow rate, and an inverse relation with arterial pressure and arterial resistance. The same relations among the variables were found at delivery levels above or below DO2crit., Conclusions: During cardiopulmonary bypass there is a direct linear relation between DO2 and VO2; the relations with hemodynamic variables depend on the phases of cardiopulmonary bypass. This suggests that increasing delivery levels may recruit and perfuse more vascular beds, and higher delivery levels are advisable during perfusion. During rewarming and hypothermia, lower arterial resistances are also desirable to optimize VO2.

The effects of acute right ventricular (RV) pressure and volume overloads on left ventricular (LV) filling are well known, while the significance of chronic RV pressure overload on LV function has been less studied. To evaluate the LV impairment, 30 patients with chronic cor pulmonale and pulmonary arterial hypertension secondary to chronic obstructive lung diseases (COLDs) were studied. All patients underwent respiratory tests and arterial blood gas assessment. An echo-Doppler examination was made to measure LV ejection fraction (EF), RV and LV end-diastolic and end-systolic diameters and areas, RV/LV area indexes, LV diastolic and systolic eccentricity indexes, mitral and tricuspid flow patterns, and mitral flow velocity in late and early diastole (A/E) indexes. A right heart catheterization was carried out to determine the resting mean pulmonary arterial pressure (mPAP). The data showed a marked enlargement of RV, compressing the left through a leftward shift of interventricular septum. A linear regression analysis detected a significant correlation between mPAP and the following parameters: RV/LV diastolic and systolic area indexes (r=0.75, p<0.0001; r=0.84, p<0.000, respectively), mitral A/E index (r=0.61, p<0.0005), and LV diastolic and systolic eccentricity indexes (r=0.93, p<0.0001; and r=0.83, p<0.0001). No correlations were found between echo-Doppler data and functional respiratory parameters. From these results, we conclude that chronic RV pressure overload induces LV filling impairment despite a normal systolic phase, due to septal leftward shift. In fact, chronic RV pressure overload distorts early diastolic LV geometry delaying LV filling phase, and the functional diastolic impairment of the LV is closely correlated to pulmonary hypertension levels.

The bcl-2 gene is translocated into the Ig loci in about 80% of human follicular lymphomas and in 10% of B-type chronic lymphocytic leukemias (B-CLL), resulting in a high level of expression. We have compared the expression of bcl-2 transcripts and protein in B-CLL cells in their normal equivalent CD5+ B cells and in normal B-cell populations representative of different in vivo and in vitro stages of activation and proliferation. We report here that bcl-2 was expressed in 11 of 11 cases of CD5+ B-CLL clones, contrasting with the absent expression in normal CD5+ B cells. Activation of 173 and 183 B-CLL cells by phorbol esters (12-O-tetradecanoylphorbol-13-acetate [TPA]) to IgM secretion without concomitant DNA synthesis resulted in a rapid but transient downregulation of bcl-2 expression. In contrast, the reduction of bcl-2 at both the messenger RNA and protein levels was sustained after mitogenic stimulation, suggesting that bcl-2 expression and proliferation are inversely related in these cells. This notion was further supported by immunocytochemical analysis showing that bcl-2 was primarily expressed in small resting lymphocytes and in cells differentiating to the plasma cell stage, but less expressed in Ki67-positive proliferating B blasts. Moreover, it was also supported by the low level of bcl-2 in exponentially growing Epstein-Barr virus-carrying lymphoblastoid and B-CLL cell lines. The regulation of bcl-2 expression in B-CLL resembled that of normal tonsillar follicular B cells, in which a high level of expression was found in resting mantle zone B cells but not in the proliferating germinal center B cells. Based on these findings and the role of bcl-2 in maintaining B-cell memory, we propose that the phenotype of B-CLL cells corresponds to a mantle zone memory-type B cell.

We have verified the hypothesis that multiple myeloma (MM) may be disseminated by circulating clonogenic cells that selectively home to the bone marrow (BM) to receive the signal(s) leading to proliferation, terminal differentiation, and production of the osteoclast activating factors. Long-term cultures of stromal cells have been developed from the BM of nine patients with MM. These cells were mostly fibroblast-like elements, interspersed with a proportion of scattered macrophages and rare osteoclasts. BM stromal cells were CD54+, produced high levels of interleukin-6 (IL-6) and measurable amounts of IL-1 beta, and were used as feeder layers for autologous peripheral blood mononuclear cells (PBMC). After 3 weeks of cocultures, monoclonal B lymphocytes and plasma cells, derived from PBMC, developed and the number of osteoclasts significantly increased. Both populations grew tightly adherent to the stromal cell layer and their expansion was matched by a sharp increase of IL-6 and by the appearance of IL-3 in the culture supernatant. These data attribute to BM stromal cells a critical role in supporting the growth of B lymphocytes, plasma cells, and osteoclasts and the in vivo dissemination of MM.

The translocated c-myc oncogene in Burkitt's lymphoma (BL) and murine plasmacytoma (MPC) has been proposed to be expressed at a stage of differentiation at which the gene is normally silent, resulting in a continuous proliferation and an inhibited terminal differentiation. To determine whether c-myc is differently expressed at the various stages of the differentiation pathway, we used B-type chronic lymphocytic leukemia (B-CLL) cells, representing resting B lymphocytes, inducible to proliferation and/or differentiation in vitro. The c-myc protein, and Ig lambda-light chain and PCA-1 antigen as markers of B-cell maturation, were analyzed in single, morphologically defined cells by immunocytochemical double-staining. The proliferation of individual cells was determined by 3H-thymidine incorporation and by analysis of Ki-67 antigen expression. The results show that the level of c-myc expression correlates to the stage of differentiation and to the proliferative activity. Uninduced resting cells did not express c-myc. The c-myc protein was observed in the highest amount at the proliferative B-lymphoblast stage of maturation and was reduced in plasmablasts and undetectable in plasma cells. The results suggest that maturation of B cells into nonproliferative, terminally differentiated plasma cells is associated with a downregulated c-myc expression and thus support the view that the deregulated c-myc gene in BL and MPC is expressed at an inappropriate stage of maturation and thereby inhibits terminal differentiation.

A significant proportion of cord blood CD5+ B cells express the activation molecules CD23, CD25, and transferrin receptor; react with the cell-cycle-associated monoclonal antibody (MoAb) Ki67; can be induced to enter the S phase of cell cycle by interleukin-2 (IL-2), IL-4, or low-molecular-weight B-cell growth factor (Imw-BCGF) and, exposed to IL-1 and IL-2, acquire the features (sIgD-, CD5-, CD10+, CD38+) of B blasts proliferating in the germinal centers of secondary follicles. These findings indicate that CD5+ B cells are preactivated and, in the proper microenvironment, may give rise to CD5- B cells.

The microanatomy of the dot-shaped, close-contact sites called podosomes and the mechanism of their formation have been investigated in vitro in the malignant lymphocytes of B chronic lymphocytic leukemia (B-CLL). In this paper the authors demonstrate that in B-CLL podosomes: (1) vinculin, talin, and beta 2 integrin (CD18) rings surround an F-actin core; (2) the beta 1 integrin is localized within the F-actin core; (3) the beta 3 integrin is not present. This distribution and organization of adhesion-related molecules appears to be unique to B-CLL lymphocytes, since it has not been observed in normal B cells. B-CLL adhesion and podosome formation are inhibited by the synthetic peptide GRGDSP that contains the Arg-Gly-Asp (RGD) sequence.