BRAFV600E mutation as a predictor of thyroid malignancy in indeterminate nodules: A systematic review and meta-analysis.

BACKGROUND: Thyroid nodules are usually diagnosed using fine-needle aspiration (FNA). The sensitivity limitations of FNA result in 10-30% of nodules being classified as "indeterminate". The BRAFV600E mutation is associated with papillary thyroid carcinoma (PTC). We conducted a systemic review and meta-analysis to evaluate the diagnostic utility of the BRAFV600E mutation in indeterminate nodules. METHOD: PUBMED and EMBASE were searched for studies testing for the BRAFV600E involving indeterminate nodules (Thy3a, Thy3f, Thy4) and containing information on final surgical histopathology. Thirty two studies involving 3150 indeterminate nodules were included in the analysis. RESULTS: The overall sensitivity and specificity for BRAFV600E for the diagnosis of thyroid malignancy was 0.40 (95% CI: 0.32-0.48) and 1.00 (95% CI: 0.98-1.00) respectively. The diagnostic odds ratio (DOR) was 205.4 (95% CI: 40.1-1052). With a Fagan plot, the post-test probability of thyroid cancer, given a negative mutation was 6%, but this rose to 92% with a positive result. On subgroup analysis, for Thy3a nodules, the pooled sensitivity and specificity for thyroid malignancy was 0.21 (95% CI: 0.13-0.34) and 1.00 (95% CI: 0.98-1.00). For Thy3f nodules, the pooled sensitivity and specificity was 0.09 (95% CI: 0.03-0.20) and 1.00 (95% CI: 0.05-1.00) respectively. For Thy4 nodules, the corresponding sensitivity and specificity was 0.58 (95% CI: 0.5-0.64) and 0.99 (95% CI: 0.95-1.00) respectively. CONCLUSIONS: Despite a high specificity for thyroid cancer, BRAFV600E mutation has a low overall sensitivity and therefore has a limited diagnostic value as a single screening test.

Anti-thymocyte globulin for conditioning in matched unrelated donor hematopoietic cell transplantation provides comparable outcomes to matched related donor recipients.

Rabbit anti-thymocyte globulin (ATG) is used as prophylaxis against GVHD following allogeneic hematopoietic cell transplantation (HCT). At our institution, ATG is exclusively used in the conditioning of matched unrelated donor (URD) transplant recipients. A total of 50 URD HCT recipients who received ATG (ATG group) were retrospectively compared with 48 matched related donor (MRD) HCT recipients who did not receive ATG (no ATG group). There were no significant differences between the groups in rates of day 100 mortality, acute GVHD or relapse. Chronic GVHD incidence was significantly lower in the ATG group (P = 0.007). At a median follow-up of 36 months in the entire cohort, 50% patients are alive in the ATG group and 63% of the patients are alive in the no ATG group (P = 0.13). We conclude that the administration of ATG to patients undergoing URD HCT preserves the anti-leukemia benefit of the transplant, while reducing the risk of developing GVHD, resulting in OS rates that are comparable to MRD HCT recipients.

Posaconazole salvage therapy allows successful allogeneic hematopoietic stem cell transplantation in patients with refractory invasive mold infections.

We describe the clinical courses of 3 patients with hematologic malignancies (2 with acute myelogenous leukemia and 1 with multiple myeloma) who developed invasive fungal infections due to uncommon molds (Alternaria spp., Paecilomyces lilacinus, and Zygomycetes). Breakthrough invasive fungal infections of the sinus (n=1), lung (n=3), and pericardium (n=1) developed despite fluconazole prophylaxis and failed to respond to treatment with other licensed antifungal therapies, including amphotericin B (n=3), caspofungin (n=2), and voriconazole (n=3), and surgical intervention (n=2). Salvage therapy with posaconazole oral suspension resulted in successful outcomes in all 3 patients, who subsequently underwent allogeneic hematopoietic stem cell transplantation (HSCT) while on continued posaconazole therapy. The median duration of posaconazole treatment before HSCT was 5 months (range: 1.5-6 months). Posaconazole salvage therapy allowed successful allogeneic HSCT in 3 patients with refractory invasive mold infections.

Second allografts for relapsed hematologic malignancies: feasibility of using a different donor.

A second allogeneic hematopoietic stem cell transplant (HSCT) for relapsed hematologic malignancies is an option in select patients after an initial allograft has failed. If the original donor is not available, a different donor may have to be considered. We report our experience of performing a second allogeneic HSCT using a different donor in patients with relapsed leukemia and lymphoma. In a 5-year period, six patients underwent a second allograft with myeloablative conditioning using a different donor. Four of these were retransplanted using a matched-unrelated donor. Four of the patients (67%) remain progression-free at a median follow-up of 32 months (range 3-72). There were no cases of transplant-related mortality. We conclude that a second allogeneic HSCT using a different donor is a viable option for selected patients relapsing after an allograft if the original donor is not available.

Acquired factor VII deficiency in hematopoietic stem cell transplant recipients.

Acquired factor VII (FVII) deficiency in the absence of vitamin K deficiency, oral anticoagulant therapy, synthetic liver dysfunction, or DIC is rare, with only a handful of cases thus far reported. In the period from 1990 to 1996 we identified eight patients with acquired FVII deficiency, all of whom presented with prolongation of the prothrombin time (PT) in the first 2 weeks following stem cell transplantation (SCT). The mean plasma FVII clotting activity (FVII:c) was 22% (range 8-35%) with an approximately equivalent reduction in FVII antigen (FVII:Ag) level. Mean plasma levels of fibrinogen and factors II, V, IX, and X were normal. Protein C activity was significantly depressed in only one of the three patients in whom it was measured. Several patients experienced bleeding complications, and hemorrhage directly accounted for death in two cases. Veno-occlusive disease of the liver developed in three patients. We conclude that FVII deficiency should be considered in the differential diagnosis of prolonged PT in patients who have recently undergone SCT. The mechanism of this acquired deficiency state remains to be defined.

T-cell factor-1 expression during human natural killer cell development and in circulating CD56(+) bright natural killer cells.

Transcription factors are essential to govern differentiation along the lymphoid lineage from uncommitted hematopoietic stem cells. Although many of these transcription factors have putative roles based on murine knockout experiments, their function in human lymphoid development is less known and was studied further. Transcription factor expression in fresh and cultured adult human bone marrow and umbilical cord blood progenitors was evaluated. We found that fresh CD34(+)Lin(-) cells that are human leukocyte antigen (HLA)-DR(-) or CD38(-) constitutively express GATA-3 but not T-cell factor-1 (TCF-1) or Id-3. Culture with the murine fetal liver cell line AFT024 and defined cytokines was capable of inducing TCF-1 mRNA. However, no T-cell receptor gene rearrangement was identified in cultured progeny. Id-3, a basic helix loop helix factor with dominant negative function for T-cell differentiation transcription factors, also was upregulated and may explain unsuccessful T-cell maturation. To better understand the developmental link between natural killer (NK) cells derived from progenitors, we studied NK cell subsets circulating in blood. CD56(+bright), but not CD56(+dim), NK cells constitutively express TCF-1 by reverse transcriptase polymerase chain reaction and Western blot analysis. The TCF-1 isoform found in CD56(+bright) cells, which express lectin but not immunoglobulin class I recognizing inhibitory receptors, was identical to that induced in NK cell differentiation culture and was distinctly different from isoforms in T cells. These results suggest that TCF-1 does not target human killer immunoglobulin receptor genes, TCF-1 is uniquely expressed in circulating CD56(+bright) NK cells, and specific TCF-1 isoforms may play an important role in regulating NK differentiation from a common NK/T-cell progenitor.

Infections during mobilizing chemotherapy and following autologous stem cell transplantation.

Autologous peripheral blood stem cells (PBSC), for transplantation following high-dose chemotherapy, are collected using regimens containing cytokines with or without chemotherapy. The added period of neutropenia prior to stem cell transplantation (SCT) in patients receiving chemotherapy mobilization may increase the risk of infections following transplantation. We studied the incidence of culture-positive infections in 107 consecutive patients who were divided into three groups, according to whether they experienced extended neutropenia during chemotherapy for stem cell mobilization as well as post autotransplant. All the patients received antibiotic prophylaxis and hematopoietic growth factors during neutropenia. The total duration of pre-transplant neutropenia differed among the three mobilization schemes (growth factors alone; one cycle; or two cycles of chemotherapy plus growth factor for mobilization) at 0, 6 and 18 days, respectively (median). However the post-autograft time to myeloid engraftment was similar at 10 days (median). The incidence of culture-proven infections in all three groups was similar. Using fluconazole for yeast prophylaxis, 40% patients developed gastrointestinal colonization with yeast, and the majority of speciated isolates were Candida glabrata. Bacteremia developed in 22% and 9% of patients with S. epidermidis and Gram-negative organisms, respectively, while 11% developed C. difficile-associated diarrhea. In conclusion, treatment using none, one or two cycles of mobilizing chemotherapy pre-transplant does not influence the overall incidence of infections among autologous SCT recipients. However, although post-transplant neutropenia is brief, infections remain a significant cause of morbidity.

Bleeding risk and platelet transfusion refractoriness in patients with acute myelogenous leukemia who undergo autologous stem cell transplantation.

Therapy for acute myelogenous leukemia can be complicated by alloimmunization to histocompatibility antigens (HLA), with resultant refractoriness to platelet transfusions. Autologous peripheral blood or bone marrow stem cell transplantation (referred here collectively as 'autoBMT') is emerging as a standard consolidative strategy in acute myelogenous leukemia (AML). We had noted life-threatening bleeding associated with platelet transfusion refractoriness following autoBMT; we therefore retrospectively analyzed 39 AML patients for this complication following BMT. All patients received high-dose chemoradiotherapy, followed by infusion of allogeneic sibling donor (n = 12, alloBMT) or autologous (n = 27, autoBMT) stem cells. HLA alloimmunization was assessed if patients were suspected of immune refractoriness to random donor platelet transfusions. Within 100 days of stem cell infusion, one of three alloBMT and six of 12 autoBMT recipients tested were HLA alloimmunized (not statistically significant, NS). Five of six HLA alloimmunized autoBMT patients experienced delayed bleeding, which contributed to their demise while still in remission (P < 0.001). Increased platelet requirements in HLA alloimmunized autoBMT recipients were observed between days 61 and 100 post-BMT, at a median of 211 platelet transfusions vs 0 in non-alloimmunized autoBMT patients (P < 0.01) and 17 in alloBMT patients. Our data suggest that platelet transfusion refractoriness, when associated with HLA alloimmunization, is a risk factor for increased platelet transfusion requirements, delayed bleeding, and poor outcome following autoBMT for AML.