Abstract Malignant pleural mesothelioma is a highly aggressive cancer with a very poor prognosis. Although the mechanism of carcinogenesis is not fully understood, approximately 80% of malignant ...pleural mesothelioma can be attributed to asbestos fiber exposure. This disease is largely unresponsive to conventional chemotherapy or radiotherapy, and most patients die within 10–17 months of their first symptoms. Currently, malignant pleural mesothelioma therapy is guided by clinical stage and patient characteristics rather than by the histological or molecular features of the tumor. Several molecular pathways involved in malignant pleural mesothelioma have been identified; these include cell cycle regulation, apoptosis, growth factor pathways, and angiogenesis. Unfortunately, several agents targeting these processes, including erlotinib, gefitinib, and imatinib, have proven ineffective in clinical trials. A greater understanding of the molecular pathways involved in malignant pleural mesothelioma is needed to develop better diagnostics, therapeutics, and preventative measures. Moreover, understanding the biological basis of mesothelioma progression may facilitate personalized treatment approaches, and early identification of poor prognostic indicators may help reduce the heterogeneity of the clinical response. This paper reviews advances in the molecular biology of malignant pleural mesothelioma in terms of pathogenesis, the major molecular pathways and the associated therapeutic strategies, and the roles of biomarkers.
Phosphate metabolism is crucial in the pathophysiology of secondary hyperparathyroidism and vascular calcification. High phosphate levels have been consistently associated with unfavorable outcomes ...in dialysis patients, but several limitations are still hampering a resolutive definition of the optimal targets of phosphate serum levels to be achieved in this cohort. Nonetheless, hyperphosphatemia is a late marker of phosphate overload in humans. Clinical nephrologists routinely counteract the positive phosphate balance in dialysis patients through nutritional counseling, stronger phosphate removal by dialysis and prescription of phosphate binders. However, the superiority against placebo of phosphate control by diet, dialysis or binders in terms of survival has never been tested in dedicated randomized controlled trials. The present review discusses this conundrum with particular emphasis on the rationale supporting the value of a simultaneous intervention against phosphate overload in dialysis patients via the improvement of dietary intakes, dialysis efficiency and an individualized choice of phosphate binders.
Introduction
Recently major efforts have been made to define the oligometastatic setting, but for head and neck cancer (HNC) limited data are available. We aimed to evaluate outcome of ...oligometastatic HNC treated with Stereotactic body radiotherapy (SBRT) as metastasis-directed therapy.
Materials and methods
We analyzed patients treated with SBRT on a maximum of five oligometastases from HNC, in up to two organs. Concomitant treatment was allowed. End points were toxicity, local control of treated metastases (LC), progression-free survival (PFS) and overall survival (OS).
Results
48 consecutive patients and 71 lesions were treated. With a follow-up of 20.2 months, most common primary tumors were larynx (29.2%) and salivary glands (29.2%), while common site of metastases was lung (59.1%). Median dose was 48 Gy (21–75) in 3–8 fractions. Treatment was well tolerated, with two patients reporting mild pain and nausea. LC rates at 1 and 2 years were 83.1% and 70.2%. Previous local therapy (HR 4.97;
p
= 0.002), oligoprogression (HR 4.07;
p
= 0.031) and untreated metastases (HR 4.19;
p
= 0.027) were associated with worse LC. PFS at 1 and 2 years were 42.2% and 20.0%. Increasing age (HR 1.03;
p
= 0.010), non-adenoid cystic carcinoma (HR 2.57;
p
= 0.034) and non-lung metastases (HR 2.20;
p
= 0.025) were associated with worse PFS. One- and 2-years OS were 81.0% and 67.1%. Worse performance status (HR 2.91;
p
= 0.049), non-salivary primary (HR 19.9;
p
= 0.005), non-lung metastases (HR 2.96;
p
= 0.040) were correlated with inferior OS.
Conclusions
SBRT can be considered a safe metastasis-directed therapy in oligometastatic HNC.
Efficacy of the treatment seems to be higher when administered upfront in the management of metastatic disease; however, selection of patients need to be improved due to the relevant risk of appearance of new metastatic site after SBRT.
Studies indicate that adjuvant 5-fluorouracil (5-FU) with folinic acid (FA) in colorectal cancer patients with completely resectable liver-limited metastases (LMCRC) offers clinical benefit over ...surgery alone. This phase III trial compared FOLFIRI with simplified 5-FU/FA in this setting.
LMCRC patients were randomized to receive every 14 days, FA, 400 mg/m2 infused over 2 h, followed by 5-FU as a 400 mg/m2 i.v. bolus, followed by continuous 5-FU infusion, 2400 mg/m2 over 46 h (LV5FUs) with or without irinotecan: 180 mg/m2 infusion (FOLFIRI). The primary end point was disease-free survival (DFS); secondary end points included overall survival (OS) and safety.
Treated patients (n = 306) were balanced for critical prognostic factors in each arm. Median DFS in patients receiving LV5FUs was 21.6 versus 24.7 months for FOLFIRI hazard ratio (HR) 0.89, log-rank P = 0.44. No significant differences were found in OS. A trend was observed for improved DFS in patients receiving FOLFIRI within 42 days of surgery (HR 0.75, P = 0.17). Grade 3/4 toxic effects were more common in patients treated with FOLFIRI versus LV5FUs (47% versus 30%) with neutropenia being most common (23% versus 7%).
FOLFIRI in the adjuvant treatment of LMCRC showed no significant improvement in DFS compared with LV5FUs.
Background
Recently, a platform of T‐cell replete haploidentical hematopoietic stem cell transplantation (haplo‐HSCT) using post‐transplant cyclophosphamide (Cy) has shown high reproducibility and ...acceptable safety profile.
Method
This prospective cohort analysis allowed us to collect data on infections among 70 consecutive recipients of haplo‐HSCT affected by various hematologic malignancies.
Results
After a median follow‐up of 23 months, cumulative incidence of viral infections was 70% (95% confidence interval CI 59–81) at 100 days and 77% (95% CI 67–87) at 1 year; 35 of 65 patients at risk had CMV reactivation (54%) and the rate of polyomavirus‐virus‐associated cystitis was 19% (13/70). Cumulative incidence of bacterial and fungal infections at 1 year were 63% (95% CI 51–75) and 12% (95% CI 4–19), respectively. Of note, only 1 invasive fungal infection occurred beyond 1 year after transplant (day +739).
Conclusion
In conclusion, despite a high rate of viral infections in the early period, present data suggest a satisfactory infectious profile after T‐cell replete haplo‐HSCT using post‐transplant Cy. These results may help clinicians to improve both prophylactic and therapeutic antimicrobial strategies in this emerging haploidentical setting.
Low-flow low-gradient aortic stenosis (LFLG AS) with reduced left ventricle ejection fraction (LVEF) is still a diagnostic and therapeutic challenge. The aim of this paper is to review the latest ...evidences about the assessment of the valvular disease, usually difficult because of the low-flow status, and the therapeutic options. Special emphasis is given to the available diagnostic tools for the characterization of LFLG AS without functional reserve at stress echocardiography and to the factors that clinicians should evaluate to choose between surgical aortic valve repair, transcatheter aortic valve implantation, or medical therapy.
The osteogenic transcription factor, Runx2, is abnormally expressed in prostate cancer (PCa) and associated with metastatic disease. During bone development, Runx2 is activated by signals known to be ...hyperactive in PCa including the RAS/MAP kinase pathway, which phosphorylates Runx2 on multiple serine residues including S301 and S319 (equivalent to S294 and S312 in human Runx2). This study examines the role of these phosphorylation sites in PCa. Runx2 was preferentially expressed in more invasive PCa cell lines (PC3>C4-2B>LNCaP). Furthermore, analysis using a P-S319-Runx2-specific antibody revealed that the ratio of P-S319-Runx2/total Runx2 as well as P-ERK/total ERK was highest in PC3 followed by C4-2B and LNCaP cells. These results were confirmed by immunofluorescence confocal microscopy, which showed a higher percentage of PC3 cells staining positive for P-S319-Runx2 relative to C4-2B and LNCaP cells. Phosphorylated Runx2 had an exclusively nuclear localization. When expressed in prostate cell lines, wild-type Runx2 increased metastasis-associated gene expression, in vitro migratory and invasive activity as well as in vivo growth of tumor cell xenografts. In contrast, S301A/S319A phosphorylation site mutations greatly attenuated these Runx2 responses. Analysis of tissue microarrays from 129 patients revealed strong nuclear staining with the P-S319-Runx2 antibody in primary PCas and metastases. P-S319-Runx2 staining was positively correlated with Gleason score and occurrence of lymph node metastases while little or no Runx2 phosphorylation was seen in normal prostate, benign prostate hyperplasia or prostatitis indicating that Runx2 S319 phosphorylation is closely associated with PCa induction and progression towards an aggressive phenotype. These studies establish the importance of Runx2 phosphorylation in prostate tumor growth and highlight its value as a potential diagnostic marker and therapeutic target.
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