Resistance to Imatinib Mesylate-induced apoptosis in acute lymphoblastic leukemia is associated with PTEN down-regulation due to promoter hypermethylation

The aim of our study was to determine the potential mechanism(s) implicated in Imatinib resistance in patients with Ph+ ALL. Resistance of Ph+ ALL cells to Imatinib-induced apoptosis was associated with lack of inhibition of Akt phosphorylation. Addition of the PI3K inhibitor LY294002 to Imatinib significantly increased apoptosis of Ph+ ALL cells. Interestingly, expression of PTEN was reduced in Ph+ ALL cells which was due to PTEN promoter hypermethylation. Treatment of Ph+ ALL cells with 5-Aza-2'-deoxycytidine was associated with an increased expression of PTEN and an increase in cell apoptosis. These results suggest that Imatinib resistance in patients with ALL may be dependent at least in part to PTEN down-regulation due to the abnormal promoter hypermethylation and support the potential role of de-methylating agents for the treatment of patients with Ph+ ALL.     

Pure white cell aplasia an exceptional condition in the immunological conundrum of thymomas: Responses to immunosuppression and literature review

Thymomas are tumours frequently associated with autoimmune manifestations or immunodeficiencies like Good syndrome. In rare cases, pure white cells aplasia (PWCA) has been described in association with thymomas. PWCA is characterized by agranulocytosis of autoimmune background primary refractory to granulocyte colony‐stimulating factor (G‐CSF). It is necessary the use of immunosuppressor to allow granulocyte recovery. Without treatment, it could be fatal.     

MicroRNA expression profiling in Imatinib-resistant Chronic Myeloid Leukemia patients without clinically significant ABL1-mutations

The development of Imatinib Mesylate (IM), the first specific inhibitor of BCR-ABL1, has had a major impact in patients with Chronic Myeloid Leukemia (CML), establishing IM as the standard therapy for CML. Despite the clinical success obtained with the use of IM, primary resistance to IM and molecular evidence of persistent disease has been observed in 20-25% of IM treated patients. The existence of second generation TK inhibitors, which are effective in patients with IM resistance, makes identification of predictors of resistance to IM an important goal in CML. In this study, we have identified a group of 19 miRNAs that may predict clinical resistance to IM in patients with newly diagnosed CML.     

Onset of Graves’ disease during pregnancy in a woman with established hypothyroidism

Background: Pregnancy strongly influences the thyroid gland and its function. Thyroid guidelines recommend a 30 to 50% increase of the preconceptional levothyroxine dose in women with hypothyroidism, when pregnancy is diagnosed.

Case: A 33 year-old, 8-week pregnant woman with hypothyroidism, presents with a 2-week history of palpitations, sweating, nervousness and fatigue. Physical examination shows tachycardia (108 bpm), distal tremors and diffuse goiter. After biochemical confirmation of hyperthyroidism, her levothyroxine dose is reduced and finally interrupted. Propylthiouracil is started and maintained until after the delivery of a healthy baby at week 40. Two weeks postpartum, hyperthyroidism worsens and propylthiouracil is replaced by methimazole. Eighteen months after delivery 7.5?mCi 131Iodine was given. Two months later, hypothyroidism developed and levothyroxine was initiated.

Conclusion: Although conversion of Hashimoto's hypothyroidism into Graves' disease is exceptional in pregnancy, pregnant women with autoimmune hypothyroidism should ideally have their TSH concentrations measured before empirically increasing their levothyroxine dose.     

Neoadjuvant immunotherapy in non-small-cell lung cancer: Times are changing—and fast

Recent data from a phase 3 trial have shown that the addition of immunotherapy to neoadjuvant chemotherapy improves event-free survival in patients with non-small-cell lung cancer (NSCLC). This is the first positive phase 3 trial in this setting, although several phase 3 trials are currently investigating the efficacy of neoadjuvant and adjuvant immunotherapy in resectable NSCLC.     

Laparoscopic Cholecystectomy: Its Effect on the Prognosis of Patients with Gallbladder Cancer

Numerous reports suggest more recurrences and a worse prognosis after laparoscopic cholecystectomy (LC) than after open cholecystectomy (OC). The objective of this study was to compare the survival rate of patients undergoing a laparoscopic procedure versus those undergoing an open operation. A series of 24 patients with gallbladder cancer detected after LC were compared with 40 consecutive patients with gallbladder cancer detected after OC. Patients were matched by wall invasion, age, and whether they underwent a reoperation or only cholecystectomy. The series included 2 patients with in situ tumors, 2 with mucosal tumors, 1 with muscular invasion, 13 with subserosal invasion, and 6 with serosal invasion. Recurrences were observed in 4 of the 10 patients with subserosal compromise who underwent reoperation. In contrast, in the OC group of 26 patients with subserosal invasion, 20 of whom were reoperated, only 2 had a recurrence. Of the six patients with serosal infiltration, three in the LC underwent reoperation, all of whom had recurrences that precluded resection. Of the 12 patients in the OC group who presented with serosal invasion, 6 were reoperated and 4 had a recurrence. Overall survival curves did not show differences when patients were compared according to the type of procedure performed. Similarly, the analysis of patients according to the level of wall invasion indicated that there was no significant difference in survival. Although multiple reports have shown a worse prognosis for patients with gallbladder cancer undergoing LC, this study did not show a significant survival difference between the two methods. Although there is a higher but insignificant recurrence rate among the patients who underwent LC, this is not translated into survival.     

Effects of potassium apigenin and verbena extract on the wound healing process of SKH‐1 mouse skin

Tissue repair is a complex process, which may be favoured or inhibited by different factors. Potassium apigenin (AP) and other flavonoids present in verbena extract (PLX^®) possess powerful anti‐inflammatory properties. The aim of this study was to evaluate the effects of topical treatment with AP and PLX gels on wounds inflicted on SKH‐1/CRL mice. Forty‐eight SKH‐1 mice were used (4 groups with 12 animals each), which were subjected to wound excision with a round scalpel, 4 mm in diameter, on the dorsal skin. The animals were divided into four groups: Group I received topical applications of apigenin gel; Group II received PLX gel; Group III received vehicle gel; Group IV acted as control. Wound contraction, reepithelialisation, inflammation and neovascularisation (by means of immunohistochemical staining with anti‐laminin) were recorded at study periods established at 2, 7 and 14 days. Reepithelialisation was faster in Groups I and II at 7 days (56·25% grade 3 and 43·75% grade 4) compared with the other groups. The degree of inflammation showed improvement with a tendency towards statistical significance in Groups I and II at 2 and 7 days. Anti‐laminin staining was more intense in the group treated with PLX at the 2‐ and 7‐day periods. Topical treatment with PLX gel improved the degree of reepithelialisation and inflammation, and favoured neo‐vascularisation of the wounds at 2 and 7 days following surgery.