Prospective screening increases the detection of potentially curable hepatocellular carcinoma: results in 8900 high-risk patients

Objectives

Historically, only 10% of patients with hepatocellular carcinoma (HCC) are diagnosed with early-stage, potentially curable disease. In this study, chronic hepatitis virus-infected patients were prospectively screened to determine: (i) the proportion of patients diagnosed with potentially curable HCC, and (ii) survival following curative therapy.

Methods

The study included 8900 chronic hepatitis virus-infected patients enrolled in a prospective screening programme, of whom 1335 (15.0%) were infected with hepatitis B virus (HBV), 7120 (80.0%) with hepatitis C virus (HCV), and 445 (5.0%) with both HBV and HCV. Screening was conducted every 6 months and included serum alpha-fetoprotein (AFP) measurement and ultrasonography. Curative treatments included liver transplantation, resection, radiofrequency ablation and/or ethanol injection.

Results

Hepatocellular carcinoma was diagnosed in 765 (8.6%) patients. Of 1602 patients with cirrhosis, 758 (47.3%) developed HCC. Curative treatment was possible in 523 (68.4%) of the 765 HCC patients. Two- and 5-year rates of overall survival in the curative treatment group were 65% and 28%, respectively, compared with 10% and 0% in the advanced disease group (P < 0.001).

Conclusions

Prospective screening of patients at high risk for the development of HCC increases the proportion of patients diagnosed with potentially curable disease. This may result in an increase in the number of longterm survivors. Screening strategies should focus on patients with chronic HBV or HCV infection who have progressed to cirrhosis because more than 40% of these patients will develop HCC.     

Osteonecrosis of the jaws in patients assuming oral bisphosphonates for osteoporosis: A retrospective multi-hospital-based study of 87 Italian cases

BackgroundBisphosphonates (BPs) are currently the chief drugs for the prevention/treatment of osteoporosis; one of their adverse effects is the osteonecrosis of the jaw (BRONJ). The primary endpoints of this multi-center cross-sectional study are: i) an observation of the clinical features of BRONJ in 87 osteoporotic, non-cancer patients; and ii) an evaluation of their demographic variables and comorbidities.Methods87 BRONJ patients in therapy for osteoporosis with BPs from 8 participating clinical Italian centers were consecutively identified and studied. After BRONJ diagnosis and staging, comorbidities and data relating to local and drug-related risk factors for BRONJ were collected.Results77/87 (88.5%) patients in our sample used alendronate as a BP type; the duration of bisphosphonate therapy ranged from 2 to 200 months, and 51.7% of patients were in treatment for ≤ 38 months (median value). No comorbidities or local risk factors were observed in 17 (19.5%) patients, indicating the absence of cases belonging to BRONJ forms triggered by surgery. BRONJ localization was significantly associated with age: an increased risk of mandible localization (p = 0.002; OR = 6.36, 95%CI = [1.89; 21.54]) was observed for those over 72 yrs. At multivariate analysis, the increased risk of BRONJ in the mandible for people over 72 yrs (OR′ = 6.87, 95%CI = [2.13; 2.21]) was confirmed for a BP administration > 56 months (OR′ = 4.82, 95%CI = [2.13; 22.21]).ConclusionOur study confirms the fundamental necessity of applying protocols of prevention in order to reduce the incidence of BRONJ in osteoporotic, non-cancer patients in the presence of comorbidities and/or local risk factor as well as, less frequently, in their absence.     

From the Cover: The steady-state mosaic of disturbance and succession across an old-growth Central Amazon forest landscape

Old-growth forest ecosystems comprise a mosaic of patches in different successional stages, with the fraction of the landscape in any particular state relatively constant over large temporal and spatial scales. The size distribution and return frequency of disturbance events, and subsequent recovery processes, determine to a large extent the spatial scale over which this old-growth steady state develops. Here, we characterize this mosaic for a Central Amazon forest by integrating field plot data, remote sensing disturbance probability distribution functions, and individual-based simulation modeling. Results demonstrate that a steady state of patches of varying successional age occurs over a relatively large spatial scale, with important implications for detecting temporal trends on plots that sample a small fraction of the landscape. Long highly significant stochastic runs averaging 1.0 Mg biomass⋅ha⁻¹⋅y⁻¹ were often punctuated by episodic disturbance events, resulting in a sawtooth time series of hectare-scale tree biomass. To maximize the detection of temporal trends for this Central Amazon site (e.g., driven by CO₂ fertilization), plots larger than 10 ha would provide the greatest sensitivity. A model-based analysis of fractional mortality across all gap sizes demonstrated that 9.1–16.9% of tree mortality was missing from plot-based approaches, underscoring the need to combine plot and remote-sensing methods for estimating net landscape carbon balance. Old-growth tropical forests can exhibit complex large-scale structure driven by disturbance and recovery cycles, with ecosystem and community attributes of hectare-scale plots exhibiting continuous dynamic departures from a steady-state condition.     

Osteonecrosis of jaw beyond antiresorptive (bone-targeted) agents: new horizons in oncology

ABSTRACT

Introduction: Osteonecrosis of the jaw (ONJ) is a clinically important, potentially painful and debilitating condition, which can affect the quality of life of cancer patients. Since 2003, ONJ appeared as a Bisphosphonate(BP)-related class effect, and the term Bisphosphonate-Related Osteonecrosis of the Jaw (BRONJ) was widespread.

Areas Covered: Under discussion in this review is the fact that ONJ cases have been reported after treatment including antiangiogenic agents and other “targeted therapy”, with and without BPs. Consequently, the comprehensive term Medication-Related Osteonecrosis of the Jaw (MRONJ) has been introduced. The clinical aspects and the prognosis of ONJ associated with these new drugs are still less reported, but basing on their pharmacodynamics, they could be different from the well-known BRONJ. Accordingly, recommendations largely in use for BRONJ should be extended to these new forms, but critically applied and with respect to the individual risk assessment.

Expert Opinion: There is a high risk of underdiagnoses for ONJ due to a lack of awareness, and too much restrictive or incomplete diagnostic criteria; at the same time, with regard to ONJ associated to the new non –antiresorptive agents, described here, we observe the strong need to improve the defining of any distinguished feature in their diagnosis, prevention and therapy.     

Exhaled nitric oxide levels in systemic sclerosis with and without pulmonary involvement

BACKGROUND: Systemic sclerosis (SSc) is a connective tissue disorder of unknown etiology that is often complicated by pulmonary involvement, with pulmonary hypertension (PH) and interstitial lung disease (ILD) being the major causes of death. It has been suggested that the amount of nitric oxide (NO) in exhaled air may predict the onset of complications. The aim of the study was to measure exhaled NO in SSc patients and investigate its relationship with pulmonary involvement with and without PH. METHODS: Fifty patients (5 men and 45 women; mean age, 59.1 +/- 11.7 years [+/- SD]) with a diagnosis of SSc based on the preliminary criteria of the American Rheumatism Association, and 40 healthy control subjects (5 men and 35 women; mean age, 58.3 +/- 12.2 years) underwent exhaled NO measurements by means of a chemiluminescence analyzer, pulmonary function tests, high-resolution thorax CT, and Doppler echocardiography. RESULTS: Exhaled NO concentrations were significantly higher in SSc patients than control subjects (p = 0.02), and significantly lower in the patients with ILD and/or PH than in those without PH (p < 0.01). There was a significant inverse correlation between pulmonary artery systolic pressure and exhaled NO concentration in all of the studied patients (r = - 0.5, p < 0.001). CONCLUSIONS: Our results indicate that exhaled air NO concentrations are lower in SSc patients with lung involvement than in those without, and that SSc patients without ILD or PH have higher exhaled NO values than healthy subjects.     

Mucinous Rectal Adenocarcinoma Can Be Associated to Tumor Downstaging after Preoperative Chemoradiotherapy

Purpose The aim of this study was to evaluate downstaging as primary end point, and progression-free survival and overall survival as secondary end points, in rectal adenocarcinoma patients treated with preoperative chemoradiation. Methods One hundred and thirty-six extraperitoneal adenocarcinoma patients (33 low rectum T2, 74 T3, 29 T4 [without sacral invasion], 25 with mucinous subtype) were treated with posterior pelvis preoperative radiotherapy (5040 cGy total dose, 180 cGy/fr, 5 fr/w, 10–15 MV linac X-rays) and concomitant 5-fluorouracil-based chemotherapy. After 6 to 8 weeks patients underwent surgery and prechemoradiation clinical stage was compared with pathologic stage to evaluate downstaging in each patient. Seventy-four patients received adjuvant chemotherapy. Median follow-up was 39 months (4–84). Results Forty-four patients had macroscopic complete response, 52 patients had partial response, 37 patients showed no change and 3 patients had progression. At multivariate analysis only histotype showed correlation with downstaging (hazard ratio = 0.350 and 0.138 – 0.885 95 percent confidence interval) because of the evidence for poor downstaging in mucinous subtype. There were no significant differences in overall survival and progression-free survival between adenocarcinoma and mucinous subtype. Conclusions The main finding is that mucinous histology is associated with poor downstaging after preoperative chemoradiation but this poor response was not associated with worse outcome in this small study. The good outcome for mucinous histology is at odds with other reports in the literature and requires further study.     

The new tumor-suppressor gene inhibitor of growth family member 4 (ING4) regulates the production of proangiogenic molecules by myeloma cells and suppresses hypoxia-inducible factor-1 alpha (HIF-1alpha) activity: involvement in myeloma-induced angiogenesis

Angiogenesis has a critical role in the pathophysiology of multiple myeloma (MM); however, the molecular mechanisms underlying this process are not completely elucidated. The new tumor-suppressor gene inhibitor of growth family member 4 (ING4) has been recently implicated in solid tumors as a repressor of angiogenesis. In this study, we found that ING4 expression in MM cells was correlated with the expression of the proangiogenic molecules interleukin-8 (IL-8) and osteopontin (OPN). Moreover, we demonstrate that ING4 suppression in MM cells up-regulated IL-8 and OPN, increasing the hypoxia inducible factor-1alpha (HIF-1alpha) activity and its target gene NIP-3 expression in hypoxic condition. In turn, we show that the inhibition of HIF-1alpha by siRNA suppressed IL-8 and OPN production by MM cells under hypoxia. A direct interaction between ING4 and the HIF prolyl hydroxylase 2 (HPH-2) was also demonstrated. Finally, we show that ING4 suppression in MM cells significantly increased vessel formation in vitro, blunted by blocking IL-8 or OPN. These in vitro observations were confirmed in vivo by finding that MM patients with high IL-8 production and microvascular density (MVD) have significantly lower ING4 levels compared with those with low IL-8 and MVD. Our data indicate that ING4 exerts an inhibitory effect on the production of proangiogenic molecules and consequently on MM-induced angiogenesis.