Combination of proteasome inhibitors bortezomib and NPI-0052 trigger in vivo synergistic cytotoxicity in multiple myeloma

Our recent study demonstrated that a novel proteasome inhibitor NPI-0052 triggers apoptosis in multiple myeloma (MM) cells, and importantly, that is distinct from bortezomib (Velcade) in its chemical structure, effects on proteasome activities, and mechanisms of action. Here, we demonstrate that combining NPI-0052 and bortezomb induces synergistic anti-MM activity both in vitro using MM cell lines or patient CD138(+) MM cells and in vivo in a human plasmacytoma xenograft mouse model. NPI-0052 plus bortezomib-induced synergistic apoptosis is associated with: (1) activation of caspase-8, caspase-9, caspase-3, and PARP; (2) induction of endoplasmic reticulum (ER) stress response and JNK; (3) inhibition of migration of MM cells and angiogenesis; (4) suppression of chymotrypsin-like (CT-L), caspase-like (C-L), and trypsin-like (T-L) proteolytic activities; and (5) blockade of NF-kappaB signaling. Studies in a xenograft model show that low dose combination of NPI-0052 and bortezomib is well tolerated and triggers synergistic inhibition of tumor growth and CT-L, C-L, and T-L proteasome activities in tumor cells. Immununostaining of MM tumors from NPI-0052 plus bortezomib-treated mice showed growth inhibition, apoptosis, and a decrease in associated angiogenesis. Taken together, our study provides the preclinical rationale for clinical protocols evaluating bortezomib together with NPI-0052 to improve patient outcome in MM.     

Medullary and papillary tumors are frequently associated in the same thyroid gland without evidence of reciprocal influence in their biologic behavior.

Papillary thyroid microcarcinoma (mPTC), is a very frequent incidental finding with a frequency varying from a few percent to 35% at postmortem histopathologic examinations. However, the presence of mPTC in patients undergoing thyroidectomy for multinodular goiter (MNG) and for Graves' disease (GD) has been found to be lower. Patients with medullary thyroid carcinoma (MTC) and papillary thyroid carcinoma (PTC) association have been published as anecdotal case reports, as well as kindred with familial MTC or multiple endocrine neoplasia (MEN) 2A with some members simultaneously affected by MTC and PTC. We studied the prevalence and the biological behavior of MTC associated with PTC, with particular attention to those cases in which a mPTC was incidentally found. Twenty-seven of 196 (13.8%) MTC cases showed an association with PTC and in particular 21 of 190 (11.05%) with an incidental mPTC. This percentage is higher than that reported in the literature on the association of mPTC with GD (2.8%-4.5%) and MNG (3%). Also the percentage of the more general association of MTC/PTC, not restricted to mPTC, found in our series (13.8%) is higher than that reported in studies that analyzed the prevalence of PTC (any size) in patients treated for MNG (7.5%). A similarly high percentage of MTC/PTC had not been reported before and in particular there are no reports on large series of MTC/PTC. We also analyzed the epidemiologic, clinical, and pathologic features of MTC associated and not associated with PTC without finding any difference. In particular the outcome of the MTC did not appear to be influenced by the presence of the PTC and the specific radioiodine treatments. Moreover, although we cannot completely exclude a shared pathogenic event as the cause of both MTC and PTC, the molecular analysis of RET gene alterations did not show any common mutation.     

Interobserver reproducibility of the controlled attenuation parameter (CAP) for quantifying liver steatosis

Purpose

This study was conducted to prospectively investigate the interobserver reproducibility of controlled attenuation parameter (CAP) measurements and the relationship among the CAP and body mass index (BMI), gender and age.

Methods

Consecutive subjects were studied using the M+ probe of the FibroScan device (Echosens, Paris, France). Measurements were performed by two raters (rater1 and rater2). Interobserver agreement was assessed by using the concordance correlation coefficient (CCC). The Pearson r coefficient was used to test correlation between two study variables, and linear regression was used for the multivariate model.

Results

Three hundred fifty-one subjects (227 males and 124 females) were prospectively studied. The CCC was 0.82 (95 % CI 0.78–0.85) overall, 0.80 (95 % CI 0.75–0.85) for BMI <25 kg/m², 0.76 (95 % CI 0.69–0.84) for BMI 25–29 kg/m² and 0.65 (95 % CI 0.41–0.88) for BMI ≥30 kg/m². The CCC was 0.44 (95 % CI 0.31–0.56) for CAP values ≤240 dB/m and 0.72 (95 % CI 0.65–0.79) for CAP values >240 dB/m. In univariate analysis, age and BMI by gender were correlated with the CAP. Multiple regression analysis confirmed the relationship of the CAP with age and BMI, but not with gender.

Conclusions

The results of this study show that the interreader agreement in CAP measurement is good. In healthy volunteers, the CAP is strongly correlated with age and BMI.     

Cicatricial iatrogenic lower eyelid malposition in skin cancer surgery: results of a combined approach

PurposeMalposition of the lower lid, including rounding of the lateral canthal angle, lower eyelid retraction with inferior scleral show, and ectropion, is a relatively frequent complication in the surgical treatment of skin cancer of the cheek and zygomatic areas. The tarsal strip technique, in association with a vertical vector cheek lift, is a reliable method for correcting lower lid malposition.Materials and patientsFrom January 2008 to January 2010, we treated 19 patients with lower eyelid malposition after skin cancer surgery of the cheek and zygomatic areas. To correct lower eyelid malposition, we used the tarsal strip technique and a vertical vector cheek lift in all patients.ResultsEleven patients had scleral show and eight patients had ectropion. Sixteen patients obtained satisfactory correction of the eyelid malposition in a single surgical procedure, while three patients required a second surgical step to correct the remaining scleral show. Good esthetic and functional results were achieved in all cases.ConclusionsThe surgical treatment of skin cancer of the cheek and zygomatic areas has the potential for postoperative sequelae. The tarsal strip technique, in association with a vertical vector cheek lift, is a relatively simple technique for correcting scleral show and ectropion.