BCG infection (BCGitis) following intravesical instillation for bladder cancer and time interval between treatment and presentation: A systematic review

Objective: Intravesical Bacillus Calmette-Guèrin (BCG) is an effective treatment in non––muscle-invasive bladder cancer, however, extravesical BCG infection may occur in remote organs as a potentially serious complication. Researchers aimed to assess whether a different timing of BCG infection after intravesical administration of BCG could be identified and estimated for each single involved organ. Methods: We performed a systematic literature review over systemic and genitourinary BCG infection case reports, including 271 published case reports for a total of 307 patients. Demographic data, clinical features, and timing of BCG infection development were collected and analyzed for each patient. Results: BCG infection developed with a different timing from last instillation, depending on the involved organ. Among the genitourinary complications, penile lesions occurred as early as 1 (1;3) weeks, while orchiepididymitis occurred as late as 56 (6.25;156) weeks. At the same time, granulomatous hepatitis and lungs involvement such as miliary pulmonary BCG infection occurred earlier, with a median time of 1 (1;4) and 1 (1;6) weeks respectively, whereas vascular, osteoarticular, and muscular complications developed with a median timing from last instillation of 52 (20;104), 68 (14;156), and 93 (29;156) weeks, respectively. The analysis detected a cluster between lungs, liver, and bone marrow complications on one side and muscular and osteoarticular or vascular complications on the other side was also observed. Conclusions: BCG infection after intravesical BCG for bladder cancer may develop even several months or years after the last instillation, depending on the involved organs. When BCG infection interests one or more organ, 2 main associative patterns are common: one involving lungs, liver, and bone marrow, with earlier occurrence but lower rates of microbiological diagnosis achievement, and one involving muscular and osteoarticular or vascular districts, with later occurrence but higher rates of microbiological evidence.     

Narrative review of prostate cancer grading systems: will the Gleason scores be replaced by the Grade Groups?

The Gleason grading system, proposed by Dr. Donald F. Gleason in 1966, is one of the most important prognostic factors in men with prostate cancer (PCa). At consensus conferences held in 2005 and 2014, organized by the International Society of Urological Pathology (ISUP), the system was modified to reflect the current diagnostic and therapeutic approaches. In particular, in the 2014 Conference, it was recognized that there were weaknesses with the original and the 2005 ISUP modified Gleason systems. Based on the results of a research conducted by Prof. JI Epstein and his group, a new grading system was proposed by the ISUP in order to address some of such deficiencies: i.e., the five distinct Grade Groups (GGs). Since 2014, results of studies have been published by different groups and societies, including the Genitourinary Pathology Society (GUPS), giving additional support to the prognostic role of the architectural Gleason patterns and, in particular, of the GGs. A revised GG system, taking into account the percentage of Gleason pattern (GP) 4, cribriform and intraductal carcinoma, tertiary GP 5, and reactive stroma grade, has shown to have some advantages, however not ready for adoption in the current practice. The aim of this contribution was to review the major updates and recommendations regarding the GPs and GSs, as well as the GGs, trying to give an answer to the following questions: “How has the grade group system been used in the routine?” and “will the Gleason scoring system be replace by the grade groups?” We also discussed the potential implementation in the future of molecular pathology and artificial intelligence in grading to further define risk groups in patients with PCa.     

Healthcare Workers’ (HCWs) attitudes towards mandatory influenza vaccination: A systematic review and meta-analysis

Influenza is a disease responsible for thousands of deaths every year. Although healthcare workers (HCWs) represent a way of contagion for patients, vaccination coverage among them is low. Mandatory vaccination has been proposed, but controversies remain. This systematic review and meta-analysis aimed to assess the acceptance of mandatory vaccination by HCWs, and to investigate associated characteristics. MEDLINE, Scopus, Embase, PsycInfo, CINAHL and Web of Science were used to search for studies assessing the topic. PRISMA statements were followed. Of the 13,457 univocal records found, 52 studies were included in the systematic review and 40 in the meta-analysis. The pooled proportion of HCWs accepting the policy was of 61% (95% CI: 53%- 68%) but with great heterogeneity between continents (from 54% in Europe to 69% in Asia) and in different professionals (from 40% in nurses to 80% in students). Vaccinated HCWs agreed more frequently with mandatory vaccination than non-vaccinated ones. More studies that consider mandatory vaccination acceptance as the main outcome are needed, but the results of this study confirm that in some settings the majority of HCWs favour mandatory vaccination. This, combined with effects that a flu epidemic could have if overlapped to pandemics with similar symptoms, requires renewed considerations on mandatory vaccination.     

Binge-eating disorder is associated with an unfavorable body mass composition in patients with non-alcoholic fatty liver disease

The interaction between eating disorders and non-alcoholic fatty liver disease (NAFLD) remains unexplored, especially with regards to binge-eating disorder (BED). Our team conducted a service evaluation project in order to assess risk factors for the presence of BED among patients with NAFLD and the impact of BED on body mass composition. The overall prevalence of patients screening positive to BED Screener-7 (BEDS-7) was 28.4%, while a previous diagnosis of depression and marital status (as single or separated) were independently associated with positive BED. Furthermore, patients with positive BEDS-7 had higher BMI, with greater visceral component and overall lower muscle mass. There was no difference in terms of liver disease severity as assessed by noninvasive markers of fibrosis. However, as body mass composition and sarcopenia have been shown to be associated to disease progression in patients with NAFLD, further studies are required to ascertain the long-term impact of BED in these patients. Moreover, further work is warranted to identify to implement multidisciplinary approach within clinical psychology for the management of patients with BED, who may be particularly challenging in terms of achieving lifestyle modifications. As a hepatology community, we should address NAFLD with a more holistic approach.     

Hydrophobic Bombyx mori Silk Fibroin: Routes to Functionalization with Alkyl Chains

Bombyx mori silk fibroin (SF) is a very versatile biopolymer due to its biocompatibility and exceptional mechanical properties which make possible its use as a functional material in several applications. SF can be modified with a large variety of chemical approaches which endow the material with tailored chemical–physical properties. Here, a systematic investigation of different routes is reported to graft long alkyl chains on SF based on both liquid- and solid-phase, aiming to modulate its hydrophobic behavior. The liquid phase method involves direct activation of SF tyrosine residues via diazo coupling and cycloaddition reactions, generating hydrophobic materials insoluble in any common solvent. The solid phase approach consists of the chemical modification of drop-casted SF films by esterification of hydroxyl groups of serine, threonine, and tyrosine SF residues with acyl chlorides of fatty acids. For the solid-state functionalization, a new class of hydrophobic pendant groups is synthesized, based on triple esters of gallic acid anhydrides, that are reacted with the biopolymer to further enhance its resulting hydrophobic features.     

Mesenteric cystic neoformations: Report of two cases

(Received for publication on Apr. 28, 1997; accepted on May 15, 1998)     

Soluble CD40 ligand plasma levels in lung cancer.

PURPOSE: Tumor-induced platelet activation may cause the release of various cytokines, including CD40 ligand (CD40L). Activation of the CD40/CD40L pathway in human tumors may result in thrombin generation, which is known to be involved in angiogenesis. Thus, we investigated whether soluble (s)CD40L levels are increased in patients with lung cancer as a result of platelet and/or coagulation activation. EXPERIMENTAL DESIGN: Citrated plasma samples were obtained from 120 patients with different stages and histotypes of lung cancer and 60 age- and sex-matched control subjects. sCD40L, sP-selectin (marker of platelet activation), prothrombin fragment 1 + 2, and thrombin-antithrombin III complex levels (both markers of coagulative activation) were measured in all samples. RESULTS: Patients with lung cancer had median sCD40L levels higher than in control subjects (0.46 versus 0.13 ng/ml; P < 0.0001), although correlation with the stage of disease was not evident. Nonetheless, sCD40L levels were significantly higher in squamous cancer compared with adenocarcinoma (0.75 versus 0.27 ng/ml; P < 0.05). Moreover, median sCD40L levels were higher in stage IV compared with nonmetastatic squamous lung cancer (1.02 versus 0.61 ng/ml; P < 0.05). sCD40L levels significantly correlated with sP-selectin (P < 0.001), prothrombin fragment 1 + 2 (P < 0.001), or thrombin-antithrombin III complex (P < 0.05) in squamous lung cancer, but only sP-selectin (P = 0.011) was independently related to sCD40L. CONCLUSIONS: These findings indicate that elevated sCD40L levels can be preferentially found in patients with advanced squamous cancer and provide evidence that increased levels of this cytokine are associated to the occurrence of in vivo platelet activation.     

Schedule-dependent cytotoxic interaction between epidoxorubicin and gemcitabine in human bladder cancer cells in vitro.

PURPOSE: The aim of the study was to evaluate the activity of epidoxorubicin (EPI) and gemcitabine (GEM) and to define the most effective schedule in human bladder cancer cells. EXPERIMENTAL DESIGN: The study was performed on HT1376 and MCR cell lines. Cells were exposed for 1 and 24 h to drugs used in different schemes. Cytotoxic activity was evaluated by the sulforhodamine B assay, potential clinical activity was estimated by relative antitumor activity, and the type of drug interaction was assessed using the method of Chou and Talalay. Cell cycle perturbations and apoptosis were assessed by flow cytometry; BAX, BCL-2, and P53 expression was evaluated by Western blot; and DNA damage was assessed using the alkaline Comet assay. RESULTS: EPI and GEM produced a cytotoxic effect in both cell lines, with 50% inhibitory concentration and relative antitumor activity values suggestive of a high clinical activity. Simultaneous treatment with EPI and GEM and the sequence GEM-->EPI caused an antagonistic interaction (combination index > 1) after both 1- and 24-h treatments. Conversely, the inverse sequence, EPI-->GEM, produced a synergistic interaction that was more pronounced in MCR cells than in HT1376 cells. The increase in DNA-damaged cells from 10% to 20% after single-drug exposure to 40-60% at the end of EPI-->GEM treatment may explain the synergistic interaction produced by the anthracycline-antimetabolite sequence. CONCLUSIONS: Our findings show that the efficacy of the EPI and GEM combination is highly schedule dependent and indicate that the most active scheme is EPI followed by GEM, which is currently being validated in an ongoing intravesical Phase I-II clinical protocol.     

Combined targeting of epidermal growth factor receptor and MDM2 by gefitinib and antisense MDM2 cooperatively inhibit hormone-independent prostate cancer.

PURPOSE: The epidermal growth factor receptor (EGFR) may play a relevant role in the progression, hormone therapy resistance, and prognosis of prostate cancer patients. Also MDM2, a negative p53 regulator that interacts with retinoblastoma (Rb), E2F, p19(arf) and the ras-mitogen-activated protein kinase(MAPK) cascade plays an important role in prostate cancer progression and prognosis. On the basis of the EGFR and MDM2 role in integrating signaling pathways critical for prostate cancer progression, we investigated whether their selective combined blockade may have a cooperative antitumor effect in prostate cancer. For this purpose, we have used the EGFR tyrosine kinase inhibitor gefitinib (ZD1839, Iressa) and a second generation hybrid oligonucleotide antisense MDM2 (AS-MDM2), respectively. EXPERIMENTAL DESIGN: Gefitinib and AS-MDM2 were administered to hormone-refractory and hormone-dependent human prostate cancer cells in vitro and to mice bearing tumor xenografts, evaluating the effects on growth, apoptosis, and protein expression, in vitro and in vivo. RESULTS: We demonstrated that the combination of gefitinib and AS-MDM2 synergistically inhibits the growth of hormone-independent prostate cancer cells in vitro. This effect is accompanied by the inhibition of MDM2, phosphorylated Akt (pAkt), phosphorylated MAPK (pMAPK), and vascular endothelial growth factor (VEGF) expression and by Rb hypophosphorylation. The combination of the two agents in nude mice bearing the same hormone-independent tumors caused a potent cooperative antitumor effect. Tumor samples analysis confirmed the inhibition of MDM2, pAkt, pMAPK, VEGF, and basic fibroblast growth factor expression. CONCLUSIONS: This study shows that EGFR and MDM2 play a critical role in the growth of prostate cancer, especially hormone-dependent, and that their combined blockade by gefitinib and AS-MDM2 causes a cooperative antitumor effect, supporting the clinical development of this therapeutic strategy.