Beneficial effects of combining nilotinib and imatinib in preclinical models of BCR-ABL+ leukemias

Drug resistance resulting from emergence of imatinib-resistant BCR-ABL point mutations is a significant problem in advanced-stage chronic myelogenous leukemia (CML). The BCR-ABL inhibitor, nilotinib (AMN107), is significantly more potent against BCR-ABL than imatinib, and is active against many imatinib-resistant BCR-ABL mutants. Phase 1/2 clinical trials show that nilotinib can induce remissions in patients who have previously failed imatinib, indicating that sequential therapy with these 2 agents has clinical value. However, simultaneous, rather than sequential, administration of 2 BCR-ABL kinase inhibitors is attractive for many reasons, including the theoretical possibility that this could reduce emergence of drug-resistant clones. Here, we show that exposure of a variety of BCR-ABL+ cell lines to imatinib and nilotinib results in additive or synergistic cytotoxicity, including testing of a large panel of cells expressing BCR-ABL point mutations causing resistance to imatinib in patients. Further, using a highly quantifiable bioluminescent in vivo model, drug combinations were at least additive in antileukemic activity, compared with each drug alone. These results suggest that despite binding to the same site in the same target kinase, the combination of imatinib and nilotinib is highly efficacious in these models, indicating that clinical testing of combinations of BCR-ABL kinase inhibitors is warranted.     

Effect of hemoglobin levels on cardiovascular outcomes in patients with isolated systolic hypertension and left ventricular hypertrophy (from the LIFE study)

The optimal hemoglobin level in patients with hypertension or heart failure is not yet defined. The aim of the present investigation was to examine the relation of hemoglobin with cardiovascular outcomes in high-risk patients with isolated systolic hypertension (ISH) and left ventricular hypertrophy (LVH). In 1,326 patients with ISH in the Losartan Intervention For Endpoint Reduction in Hypertension (LIFE) study, hemoglobin and cardiovascular outcomes were examined using Cox proportional hazard models. Baseline hemoglobin was negatively related to rate of cardiovascular death (hazard ratio 0.81 per 1 g/dl, 95% confidence interval [CI] 0.67 to 0.98, p = 0.032) after adjusting for baseline Framingham risk score, LVH, treatment, and estimated glomerular filtration rate. Hemoglobin decreased slightly during the study and the decrease was more pronounced in the losartan group (13.9 +/- 1.3 to 13.6 +/- 1.4 g/dl) than in the atenolol group (13.9 +/- 1.2 to 13.8 +/- 1.4 g/dl). Hemoglobin as a time-varying covariate was negatively associated with rate of cardiovascular death (hazard ratio 0.75, 95% CI 0.63 to 0.90, p <0.001) and stroke (hazard ratio 0.84, 95% CI 0.72 to 0.99, p = 0.040) after adjusting for baseline Framingham risk score, LVH, treatment, and estimated glomerular filtration rate. In conclusion, in this high-risk population with ISH and LVH, lower hemoglobin at baseline was associated with higher probability of cardiovascular death, and decrease in hemoglobin over time was associated with higher probability of cardiovascular death or stroke; this effect was attenuated by treatment with losartan.     

Identification of BCR-ABL point mutations conferring resistance to the Abl kinase inhibitor AMN107 (nilotinib) by a random mutagenesis study

Patients with advanced stages of chronic myeloid leukemia (CML) often manifest imatinib mesylate resistance associated with point mutations in BCR-ABL. AMN107 is a new higher-potency inhibitor of BCR-ABL. To identify mutations in BCR-ABL that could result in resistance to AMN107, a cDNA library of BCR-ABL mutants was introduced into Ba/F3 cells followed by selection in AMN107 (0.125-0.5 microM). A total of 86 individual, drug-resistant colonies were recovered, and the SH3, SH2, and kinase domains of BCR-ABL were sequenced. A total of 46 colonies had single point mutations in BCR-ABL, with a total of 17 different mutations, all within the kinase domain. The other 40 colonies had multiple point mutations and were not analyzed further. Each of the 17 single point mutants were reconstructed by site-directed mutagenesis of native BCR-ABL and found to be approximately 2.5- to 800-fold more resistant to AMN107 than native BCR-ABL. The mutations included 6 known imatinib mesylate-resistant mutations, including T315I, which showed complete resistance to AMN107. Interestingly, most AMN107-resistant mutants were also resistant to imatinib mesylate. These results may predict some of the resistance mutations that will be detected in clinical trials with this kinase inhibitor.     

Syringocystadenoma papilliferum: A case series and review of the literature in Indian context

Syringocystadenoma papilliferum (SCAP) is a rare benign skin adnexal tumour commonly (50%) found in infants and children and less commonly (15–30 %) found at puberty and in adolescents. It usually presents as irregular papule or smooth hairless plaque on the scalp and forehead, however, nodular or verrucous transformation is reported at puberty. Microscopically it is characterized by ducts connecting to the surface, containing papillary processes and lined with two epithelial layers. Head and neck is the commonest (75%) and lower extremity is the rarest reported location. Here we report a case series of SCAP at five different locations throughout the body. The clinical and histological features and the differential diagnoses are also discussed.     

Multimodality approach: A revolutionary concept in the management of diabetic limb ulcers

Aim

The aim of the study is to evaluate the results of the multimodality approach to diabetic limb ulcers.

Background

Management of diabetic limb ulcers requires a multisystem approach that addresses the component problems of the nervous, vascular, skeletal, immune and integumentary system.

Materials and Method

The study period was from January 2012 to September 2013, and involved 60 patients with both type 1 and type 2 diabetes that also had limb ulcers.

Results

Mean duration of healing in controls was 23.1564 ± 6.7859 weeks and in cases 15.6723 ± 4.0084 weeks. Ulcers converted from grade 2 to grade 1 in 18 cases, from grade 3 to grade 1 in five cases, and from grade 3 to grade 2 in three cases. Five controls and two cases had to undergo amputation.

Discussion

Diabetes is the prime cause of non-traumatic amputations in the United States accounting for 54,000 to 55,000 limbs lost every year [5]. Hunt T K et al found that PDGF gel healed a greater percentage of patients after 10 weeks of application [19]. Edmonds M E et al (1986) observed that the recurrence rate of ulceration was 26% among those with special footwear and 83% among those who returned to using their regular footwear [23].

Conclusion

Although limb problems in diabetics cannot be completely eradicated, it is evident that a number of hospitalizations and health costs directly attributable to such problems can be reduced by adopting a multimodality approach.     

Using a tightRope? to treat a complex fracture of the trapezium

We present the case of a 23-year-old man with a combined scaphoid fracture and comminuted trapezium fracture, treated surgically with percutaneous fixation of the scaphoid fracture and concomitant Arthrex Mini TightRope^® stabilisation of base of thumb metacarpal to base of index finger metacarpal. The patient made a good functional recovery, returning to usual activities within six weeks. We suggest that this technique could be used to treat complex trapezium fractures that cannot be reconstructed with surgery.