Abstract Many of the cellular abnormalities present in solid tumors are structural in nature and involve the proteins of the extracellular matrix (ECM). Periostin is a protein produced and secreted ...by the fibroblasts as a component of the ECM where it is involved in regulating intercellular adhesion. The expression of periostin has an important physiological role during embryogenesis and growth, namely at the level of bone, dental, and cardiac tissues. Many studies indicate that periostin plays an important role for tumor progression in various types of cancer, such as colon, lung, head and neck, breast, ovarian, and prostate. To the best of our knowledge, a limited number of studies have investigated periostin expression in urogenital cancer, such as prostate, bladder, penile, and renal cancer, and no studies were performed in testis cancer. In this review article, we summarize the most recent knowledge of periostin, its genetic and protein structure, and the role of the different isoforms identified and sequenced so far. In particular, we focus our attention on the role of this protein in genitourinary tumors, trying to emphasize the role not only as a possible prognostic marker, but also as a possible target for the development of future anticancer therapies.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Congenital pulmonary lymphangiectasia (PL) is a rare developmental disorder involving the lung, and characterized by pulmonary subpleural, interlobar, perivascular and peribronchial lymphatic ...dilatation. The prevalence is unknown. PL presents at birth with severe respiratory distress, tachypnea and cyanosis, with a very high mortality rate at or within a few hours of birth. Most reported cases are sporadic and the etiology is not completely understood. It has been suggested that PL lymphatic channels of the fetal lung do not undergo the normal regression process at 20 weeks of gestation. Secondary PL may be caused by a cardiac lesion. The diagnostic approach includes complete family and obstetric history, conventional radiologic studies, ultrasound and magnetic resonance studies, lymphoscintigraphy, lung functionality tests, lung biopsy, bronchoscopy, and pleural effusion examination. During the prenatal period, all causes leading to hydrops fetalis should be considered in the diagnosis of PL. Fetal ultrasound evaluation plays a key role in the antenatal diagnosis of PL. At birth, mechanical ventilation and pleural drainage are nearly always necessary to obtain a favorable outcome of respiratory distress. Home supplemental oxygen therapy and symptomatic treatment of recurrent cough and wheeze are often necessary during childhood, sometimes associated with prolonged pleural drainage. Recent advances in intensive neonatal care have changed the previously nearly fatal outcome of PL at birth. Patients affected by PL who survive infancy, present medical problems which are characteristic of chronic lung disease.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Prostate cancer (PCa), the second most common cancer affecting men worldwide, shows a broad spectrum of biological and clinical behaviour representing the epiphenomenon of an extreme heterogeneity. ...Androgen deprivation therapy is the mainstay of treatment for advanced forms but after few years the majority of patients progress to castration-resistant prostate cancer (CRPC), a lethal form that poses considerable therapeutic challenges.
Western blotting, immunocytochemistry, invasion and reporter assays, and in vivo studies were performed to characterize androgen resistant sublines phenotype in comparison to the parental cell line LNCaP. RNA microarray, mass spectrometry, integrative transcriptomic and proteomic differential analysis coupled with GeneOntology and multivariate analyses were applied to identify deregulated genes and proteins involved in CRPC evolution.
Treating the androgen-responsive LNCaP cell line for over a year with 10 μM bicalutamide both in the presence and absence of 0.1 nM 5-α-dihydrotestosterone (DHT) we obtained two cell sublines, designated PDB and MDB respectively, presenting several analogies with CRPC. Molecular and functional analyses of PDB and MDB, compared to the parental cell line, showed that both resistant cell lines were PSA low/negative with comparable levels of nuclear androgen receptor devoid of activity due to altered phosphorylation; cell growth and survival were dependent on AKT and p38MAPK activation and PARP-1 overexpression; their malignant phenotype increased both in vitro and in vivo. Performing bioinformatic analyses we highlighted biological processes related to environmental and stress adaptation supporting cell survival and growth. We identified 15 proteins that could direct androgen-resistance acquisition. Eleven out of these 15 proteins were closely related to biological processes involved in PCa progression.
Our models suggest that environmental factors and epigenetic modulation can activate processes of phenotypic adaptation driving drug-resistance. The identified key proteins of these adaptive phenotypes could be eligible targets for innovative therapies as well as molecules of prognostic and predictive value.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Lower limb lymphedema (LLL) is the most disabling adverse effect of surgical treatment of vulvar cancer. This study describes the use of microsurgical lymphatic venous anastomosis (LVA) to prevent ...LLL in patients with vulvar cancer undergoing inguinofemoral lymph node dissection (ILND).
The study included 8 patients with invasive carcinoma of the vulva who underwent unilateral or bilateral ILND. Before incision of the skin in the inguinal region, blue dye was injected in the thigh muscles to identify the lymphatic vessels draining the leg. Lymphatic venous anastomosis was performed by inserting the blue lymphatics coming from the lower limb into one of the collateral branches of the femoral vein (telescopic end-to-end anastomosis). An historical control group of 7 patients, which underwent ILND without LVA, was used as comparison. After 1 month from the surgery, all patients underwent a lymphoscintigraphy.
In the study group, 4 patients underwent bilateral ILND, and 4 patients underwent unilateral ILND. Blue-dyed lymphatics and nodes were identified in all patients. It was possible to perform LVA in all the patients. The mean (SD) time required to perform a monolateral LVA was 23.1 (3.6) minutes (range, 17-32 minutes). The mean (SD) follow-up was 16.7 (6.2) months; there was only 1 case of grade 1 lymphedema of the right leg. Lymphoscintigraphic results showed a total mean transport index were 9.08 and 14.54 in the study and the control groups, respectively (P = 0.092).
This study shows for the first time the feasibility of LVA in patients with vulvar cancer undergoing ILND. Future studies including larger series of patients should clarify whether this microsurgical technique reduces the incidence of LLL after ILND.
PN is a secreted cell adhesion protein critical for carcinogenesis. Elevated serum levels of PN have been implicated as playing an important role in different types of cancer, and a few reports ...suggest a potential role as a prognostic marker. We evaluated the prognostic significance of preoperative serum PN concentration in patients with BCa receiving curative surgery. Enzyme-Linked Immunosorbent Assay (ELISA) was performed to determine the preoperative serum PN level in 182 patients. The correlations between serum PN concentration with clinical pathological features and PN expression in primary tumor samples were analyzed. The prognostic impact of serum PN levels with all-cause and BCa-specific mortality was also investigated. Appropriate statistics were used. Elevated serum PN levels were significantly associated with patient age (p = 0.005), adjuvant systemic therapy (p = 0.04) and progesterone receptor (PgR) status (p = 0.02). No correlation between PN preoperative serum levels and other clinical-pathological parameters, including either the epithelial or the stromal PN expression of primary tumor or the combination of the two, was found. Similarly, no association between serum PN levels and either all-cause or BCa-specific mortality was found. However, subgroup analysis revealed a correlation between higher PN serum levels and all-cause mortality in patients with node-negative disease (p = 0.05) and in those with a low PgR expression (p = 0.03). Higher levels of serum PN were also found to correlate with BCa-specific mortality in the subgroup of patients who did not receive any adjuvant systemic therapy (p = 0.04). Our findings suggest that PN was detectable in the serum of early BCa patients before surgery and increased base-line serum levels predicted worse long-term survival outcomes in specific subgroups of patients.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
In 2016, Rosenberg and colleagues published the results of this programmed death ligand 1 (PD-L1) inhibitor in patients who had previously received platinum-based chemotherapy.1 Atezolizumab showed ...good tolerability and durable responses, which were associated with increased levels of PD-L1. ...absence of predictive biomarkers is a tricky issue and proper patient selection is the actual challenge to be faced in bladder cancer. Alfred Pasieka/Science Photo Library Submissions should be made via our electronic submission system at http://ees.elsevier.com/thelancet/ We declare no competing interests. 1 JE Rosenberg, J Hoffman-Censits, T Powles, Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial, Lancet, Vol. 387, 2016, 1909-1920 2 AV Balar, MD Galsky, JE Rosenberg, Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial, Lancet, Vol. 389, 2017, 67-76 3 T Powles, I Durán, MS van der Heijden, Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial, Lancet, 2017, published online Dec 18.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
The recently published phase II prospective SWITCH trial evaluated whether patients with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone acetate could benefit from a ...‘steroid switch’ from prednisone to dexamethasone. A total of 26 patients, both chemonaïve (14 patients) or pretreated with docetaxel (12 patients), with biochemical and/or limited radiological progression, were enrolled in this trial. Primary endpoint was prostate specific antigen (PSA) 30 defined as the proportion of patients with a PSA level decline 30% or more after 6 weeks of treatment with abiraterone acetate + dexamethasone. Secondary endpoints were: a PSA50 rate (defined as the proportion of patients with PSA decline of 50% or more after 12 weeks on abiraterone acetate + dexamethasone), biochemical and radiological progression-free survival (bPFS and rPFS, respectively), benefit from subsequent treatment and identification of biomarkers of response. Primary endpoint was reached in 46.2% of patients (12 patients), and two patients had an objective partial response on computed tomography scan. Median bPFS and rPFS were 5.3 months and 11.8 months. We present a case series of 11 patients who were consecutively treated with a steroid switch at our institution from January 2016 to August 2018 to investigate if this strategy could be used in a ‘real-life’ setting. We observed a PSA30 response in two patients (18%), median bPFS was 4.77 months (95% confidence interval CI 2.5–14.6) and median rPFS was 7.2 months (95% CI 3.8–15.5). Seven patients had a radiological stable disease as best response to steroid switch. Three patients were being still treated with abiraterone acetate + dexamethasone at data cut-off time. Our case series confirms that switching from prednisone to dexamethasone during abiraterone acetate treatment produces biochemical and radiological responses in both a predocetaxel and a postdocetaxel setting, providing a clinical benefit in mCRPC patients. However, to date, there is no clear indication as to which patient could benefit most from this kind of strategy.
...data showing modest activity of lenalidomide as a single agent in patients with chemotherapy-naive castration-resistant prostate cancer were available only in 2014,5 and the evidence about the ...therapeutic activity of the combination of lenalidomide with docetaxel and prednisone comes from just two phase 1 studies.6,7 In both studies, the activity of this combination was not particularly encouraging as it did not seem to differ much from data reported in the docetaxel and predisone group of the TAX327 trial.8 Because castration-resistant prostate cancer is a notoriously heterogeneous disease and assessment of tumour response is difficult, a formal phase 2 trial should have been the logical subsequent step. Randomisation and the selection of appropriate response endpoints (eg, radiological progression-free survival or prostate-specific antigen progression) would have been preferred logical step in phase 2 development and would probably have helped to increase confidence about the assumed superiority of the combination, which was probably overestimated before initiation of the MAINSAIL trial, and its toxic effects, which were probably underestimated.
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