Ultrastructural analysis reveals differences in the secretory activity among four regions of amniotic membrane

Human Amniotic Epithelial Cells (hAEC) from term placenta are a promising source of stem cells for regenerative medicine. In a previous study we observed histological heterogeneity, together with different expression of pluripotency markers and content in lipid granules among four regions of amniotic membrane (AM). To better investigate cell heterogeneity among different cell populations, we performed an ultrastructural study with Transmission Electron Microscopy. Term placentae from healthy women were collected after caesarean section and AM samples were freshly isolated from four regions: R1 (close to the umbilical cord); R2 (intermediate); R3 (peripheral to the placental disc); R4 (reflected amnion). Ultrastructural analysis revealed an epithelium of variable thickness, cellular shape, amount and type of vesicles in the four regions. The epithelium showed columnar hAEC with increased height in R1 and R3 and a multi-layered organization in R3, whereas it was a monolayer in the other regions. The highest amount of granules and vesicles was observed in R3, although R4 showed granules with a different density. Furthermore, in R1, R3 and R4 we noticed several vesicles of 100-150 nm in diameter, probably exosome-like structures, suggesting a consistent secretory activity. All along its length the epithelium was rich in microvilli both on the side facing the amniotic fluid and in lateral contacts (narrow desmosomal junctions) between cells. This in situ investigation shows for the first time differences in secretory activity and granules appearance along the AM as a proof of its heterogeneity. This could be relevant in clinical applications as the choice of the area could improve the effectiveness of AM/hAEC transplantation

The IMPACT study: early loss of skeletal muscle mass in advanced pancreatic cancer patients

Abstract Background Pancreatic cancer (PC) patients have multiple risk factors for sarcopenia and loss of skeletal muscle mass (LSMM), which may cause greater treatment toxicities, reduced response to cancer therapy, prolonged hospitalization, impaired quality of life, and worse prognosis. Methods This is a retrospective study on advanced PC patients treated at the Department of Oncology of Udine, Italy, from January 2012 to November 2017. Among 162 patients who received chemotherapy, 94 consecutive patients with an available computed tomography (CT) scan were retrospectively analyzed. The primary objective of our study was to explore if an early LSMM ≥ 10% (measured at first radiological evaluation and compared with baseline) and/or baseline sarcopenia may impact prognosis. Baseline sarcopenia was defined according to Prado's criteria. Skeletal muscle area was measured as cross‐sectional areas (cm2) using CT scan data through the Picture archiving and communication system (PACS) image system. Results In the whole cohort, 48% of patients were ≤70 years old, and 50% had metastatic disease. At baseline, 73% of patients had sarcopenia, and 16% presented a visceral fat area ≥ 44 cm2/m2. Overall, 21% experienced an early LSMM ≥ 10%. Approximately 33% of sarcopenic patients at baseline and ~35% of patients with early LSMM ≥ 10% had a body mass index > 25 kg/m2. Of note, 71% of patients were evaluated by a nutritionist, and 56% received a dietary supplementation (oral and/or parenteral). After a median follow‐up of 30.44 months, median overall survival (OS) was 11.28 months, whereas median progression‐free survival (PFS) was 5.72 months. By multivariate analysis, early LSMM ≥ 10% was significantly associated with worse OS [hazard ratio (HR): 2.16; 95% confidence interval (CI) 1.23–3.78; P = 0.007] and PFS (HR: 2.31; 95% CI 1.30–4.09; P = 0.004). Moreover, an exploratory analysis showed that inflammatory indexes, such as neutrophil–lymphocyte ratio variation, impact early LSMM ≥ 10% (odds ratio 1.31, 95% CI 1.06–1.61, P = 0.010). Conclusions Early LSMM ≥ 10% has a negative prognostic role in advanced PC patients. Further prospective investigations are needed to confirm these preliminary data

Immunotherapy for colorectal cancer: where are we heading?

Introduction: In the last few years, significant advances in molecular biology have provided new therapeutic options for colorectal cancer (CRC). The development of new drugs that target the immune response to cancer cells seems very promising and has already been established for other tumor types. In particular, the use of immune checkpoint inhibitors seems to be an encouraging immunotherapeutic strategy. Areas covered: In this review, the authors provide an update of the current evidence related to this topic, though most immunotherapies are still in early-phase clinical trials for CRC. To understand the key role of immunotherapy in CRC, the authors discuss the delicate balance between immune-stimulating and immune-suppressive networks that occur in the tumor microenvironment. Expert opinion: Modulation of the immune system through checkpoint inhibition is an emerging approach in CRC therapy. Nevertheless, selection criteria that could enable the identification of patients who may benefit from these agents are necessary. Furthermore, potential prognostic and predictive immune biomarkers based on immune and molecular classifications have been proposed. As expected, additional studies are required to develop biomarkers, effective therapeutic strategies and novel combinations to overcome immune escape resistance and enhance effector response

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

OUTCOME GRAVIDICO E TASSO DI RECIDIVA IN PAZIENTI SOTTOPOSTE A CONIZZAZIONE PER LESIONE INTRAEPITELIALE SQUAMOSA DI ALTO GRADO DELLA CERVICE UTERINA.

Il carcinoma della cervice uterina rappresenta in Europa e nel mondo, la quarta neoplasia per incidenza e per causa di morte, attestandosi come seconda, dopo il carcinoma della mammella, per incidenza e numero di decessi nella popolazione femminile. Il numero più consistente di decessi si verifica nei paesi di basso livello socio-economico. L’infezione da parte dei ceppi ad alto rischio oncogenico dell’HPV (Human Papillomavirus), costituisce la condizione necessaria per lo sviluppo delle lesione intraepiteliali, prima, e del carcinoma invasivo, poi. Sebbene nel corso della vita, più del 75% delle donne sessualmente attive contraggano il virus, nella maggior parte dei casi, esse non svilupperanno le sequele a cui l’infezione potrebbe condurre, in quanto, il sistema immunitario riesce a mettere in atto una clearance che si realizza, in più del 90% delle donne, entro i 24 mesi. Una relazione inversa lega prevalenza dell’infezione da HPV ed età, con un primo picco -più elevato - che interessa le donne di età sotto i 25 anni ed un secondo picco - meno accentuato - che si riferisce a donne adulte over 50. La sensibilizzazione verso i programmi di screening e l’aderenza ad essi, unitamente all’opportunità di effettuare prevenzione primaria, mediante vaccinazione, contribuiranno, in futuro, a ridurre l’impatto del carcinoma della cervice in maniera significativa. È proprio grazie allo screening che un crescente numero di lesioni intraepiteliali vengono precocemente individuate e trattate, scongiurando esiti infausti ma, talvolta, esponendo le pazienti al rischio di over-treatment. Il trattamento di elezione delle lesioni intraepiteliali di alto grado e del carcinoma microinvasivo è rappresentato dalla conizzazione, un presidio al tempo stesso diagnostico e terapeutico, che rientra nelle tecniche escissionali. Il termine comprende vari tipi di escissione, in blocco unico (da preferire) o sottoforma di prelievi multipli. Attualmente, la LEEP (Loop Electrosurgical Excision Procedure), consistente nella rimozione tissutale a radiofrequenza, è la tecnica più utilizzata per via dei vantaggi in termini di: ridotto sanguinamento, esecuzione in anestesia locale e riduzione delle complicanze stenotiche. Consente, inoltre, un migliore ripristino della neo giunzione squamo-colonnare, rendendo possibile una perfetta visualizzazione al follow-up cito-colposcopico. In quest’ottica, lo scopo della presente tesi è duplice: valutare gli eventi di recidiva ed indagare l’outcome ostetrico su un campione di 416 pazienti sottoposte a conizzazione nel periodo 2000-2014. Il fenomeno della recidiva è stato valutato mettendolo in relazione a diverse variabili: - età delle pazienti, - positività dei margini di resezione (esocervicali, endocervicali o positività di entrambi), - persistenza dell’infezione di HPV ad alto rischio singola o multipla a 3 e a 6 mesi dopo la conizzazione, - grading istologico, - profondità del cono rimosso, - presenza di espressione dell’ mRNA per le proteine virali E6/E7 , - dell’oncosoppressore p16. Soprattutto, l’interesse è stato rivolto alla stima della validità delle proteine E6 ed E7 e della p16, come indicatori di recidiva e di progressione. In secondo luogo, l’attenzione è stata posta sul trattamento delle lesioni pre-invasive della portio nelle donne in età fertile. È notevole, infatti, l’interesse clinico e scientifico suscitato dai possibili eventi gravidici avversi che la conizzazione potrebbe comportare. Questo lavoro mostra come, la rimozione di coni di profondità inferiore a 10 mm, non inferisca sull'esito delle gravidanze rispetto alla popolazione generale nè in termini di parti pretermine né di cesarei in travaglio, tantomeno in aborti

Identifying Optimal Irrigation Water Needs at District Scale by Using a Physically Based Agro-Hydrological Model

This paper mainly aims to illustrate an irrigation management tool to simulate scheduling of district-level water needs over the course of an irrigation season. The tool is mostly based on a daily model for simulating flow of water (and solutes) in heterogeneous agri-environmental systems (called FLOWS-HAGES). The model produces information on the daily evolution of: soil water contents and pressure potentials in the soil profile; water uptake and actual evapotranspiration; stress periods for each crop; return fluxes to the groundwater and their quality in terms of solute concentrations (e.g., nitrates). FLOWS-HAGES provides a daily list of hydrants to be operated according to water or crop-based criteria. The daily optimal sequence of hydrant use may thus be established by passing the volumes to be delivered on to the model for simulating the hydraulics of the irrigation network, in order to ensure that the discharges flowing inside the network of distribution pipes are delivered under optimal pressure head distribution in the system. All the above evaluations can be carried out in a stochastic framework to account for soil heterogeneity and climate changes. To illustrate the potential of FLOWS-HAGES, a case study was considered for a selected sector of the Irrigation District 10 in the “Sinistra Ofanto„ irrigation system (southern Italy, Apulia region). In a 139 ha area (Sector 6 of the Irrigation District), soil profiles were analyzed for characterization of hydraulic properties variability. Hydraulic properties were determined by a combination of field and laboratory measurements. Model simulations were validated by comparing soil water storage simulated and measured by a sensor based on electromagnetic induction technique. Irrigation water volumes and frequency calculated by the model were compared to the volumes actually supplied by the farmers. Compared to the farmers behavior, the model simulates more frequent irrigations with lower irrigation volumes. Finally, some indexes of irrigation performance were calculated for each farm under study. The resulting maps provide useful information on the spatial distribution of farmer behavior, indicating the abuse or underuse of water as well as the fraction of the water lost by drainage following the irrigation method applied