Impact of long-term elosulfase alfa treatment on respiratory function in patients with Morquio A syndrome

Objective

To present long-term respiratory function outcomes from an open-label, multi-center, phase 3 extension study (MOR-005) of elosulfase alfa enzyme replacement therapy (ERT) in patients with Morquio A syndrome.

Methods

In part 1 of MOR-005, patients initially randomized to ERT in the 24-week pivotal study (MOR-004) remained on their regimen (2.0 mg/kg/week or every other week); placebo patients were re-randomized to one of the two regimens. During part 2, all patients received elosulfase alfa 2.0 mg/kg/week. Respiratory function was one of the efficacy endpoints evaluated in MOR-005. Change from MOR-004 baseline to 120 weeks of treatment for the combined population was determined and compared with results from untreated patients from a Morquio A natural history study (MorCAP).

Results

Maximum voluntary ventilation (MVV) improved up to week 72 and then stabilized; forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV₁) increased continuously over 120 weeks. Mean increases in the modified per-protocol population was 9.2 % for FVC, 8.8 % for FEV₁, and 6.1 % for MVV after 120 weeks. All patients ≤14 years showed respiratory improvements, presumably in part related to growth; however, these were greater in treated patients. For those >14 years, treated patients showed improvements, while deterioration occurred in untreated. Altogether, the improvements were significantly greater (P?<?0.05) in treated patients.

Conclusions

Long-term ERT is associated with sustained improvements in respiratory function in Morquio A. In younger patients (≤14 years), some improvement may be ascribed to growth. In older patients, other mechanisms, e.g., decreased glycosaminoglycan storage, are likely involved.

     

Predictors of restenosis after treatment of bifurcational lesions with paclitaxel eluting stents: a multicenter prospective registry of 150 consecutive patients.

OBJECTIVES: The aim of the study was the assessment of the clinical, angiographic and procedural characteristics correlated with freedom from adverse events at 1 year in a real life setting of consecutive bifurcation lesions. BACKGROUND: Even if stent implantation has shown to be superior to conventional balloon angioplasty in most coronary lesions, bifurcation treatment with stent implantation both in main and in side branch (SB) still raises controversy. METHODS: We reviewed the results obtained in a prospective multicenter registry of 150 patients with 158 bifurcation lesions involving a SB of sufficient diameter to be treated, if necessary, with a polymer based paclitaxel eluting stent (PES, TAXUS). Two stents were used in 118 lesions (74.7%). Final kissing balloon inflation was performed in 87/118 lesions (73.7%) and in 30/40 lesions (75.0%) of the 2 and 1 stent group respectively. RESULTS: At 1-year clinical follow-up we observed 4 stent thromboses, all involving the SBs of the 2 stents group (2.7%). Unlike previous reports, revascularization involved the main vessel in the majority of patients (21/150, 14.0%). After an exploratory multivariable analysis the only parameter predictive of target lesion revascularization (TLR) (HR 0.52; CI 95% 0.11-0.86; p = 0.02) and target vessel revascularization (TVR) (HR 0.47; CI 95% 0.14-0.90; p = 0.03) was postprocedural main branch minimal lumen diameter (MB-MLD). CONCLUSIONS: In a real life setting of consecutive bifurcation lesions, thrombosis rate, concentrated in the SB and the 2-stents group, and need for target lesion revascularization remain higher than in less complex lesion subgroups treated with PES. No differences in immediate success and TLR were observed between 2 stents and 1 stent groups. The frequently observed suboptimal stent expansion and final MB-MLD predict 1 year revascularization.     

Weekly docetaxel versus CMF as adjuvant chemotherapy for elderly breast cancer patients: safety data from the multicentre phase 3 randomised ELDA trial

Within an ongoing multicentre phase 3 randomised trial (ELDA, cancertrials.gov ID: NCT00331097), early breast cancer patients, 65-79 years old, with average to high risk of recurrence, are randomly assigned to receive CMF (cyclophosphamide 600 mg/m2, methotrexate 40 mg/m2, fluorouracil 600 mg/m2, days 1-8) or docetaxel (35 mg/m2 days 1-8-15), every 4 weeks. Here we report an unplanned safety analysis prompted by an amendment introducing creatinine clearance as a tool to adjust methotrexate dose. Before such change, 101 patients with a median age of 70 were randomly assigned CMF (53 patients) or docetaxel (48 patients). At least one grades 3-4 toxic event of any type was reported in 40 (75.5%) and 19 (39.6%) patients with CMF and docetaxel, respectively (p=0.0002). Grades 3-4 hematological events were observed in 37 (69.8%) vs. 4 (8.3%) cases (p<0.0001) and grades 3-4 non-hematological toxicity in 12 (22.6%) vs. 15 (31.2%) patients (p=0.11), with CMF and docetaxel, respectively. A higher incidence of anemia, neutropenia, thrombocytopenia and febrile neutropenia was reported with CMF. Constipation, mucositis, nausea and vomiting were more common with CMF; diarrhoea, abdominal pain, dysgeusia, neuropathy and liver toxicity were more frequent with docetaxel. No significant interaction was found between the occurrence of severe toxicity and baseline variables, including creatinine clearance and geriatric activity scales. In conclusion, weekly docetaxel appears to be less toxic than CMF in terms of hematological toxicity.     

Effects of chronic administration of PPAR-gamma ligand rosiglitazone in Cushing's disease

OBJECTIVE: Rosiglitazone, a thiazolidinedione compound with peroxisome proliferator-activated receptor-gamma (PPAR-gamma)-binding affinity, is able to suppress adrenocorticotropic hormone (ACTH) secretion in treated mice and in AtT20 pituitary tumor cells. These observations suggested that thiazolidinediones may be effective as therapy for Cushing's disease (CD). PATIENTS AND METHODS: Rosiglitazone (8 mg/day) was administered to 14 patients with active CD (13 women, one man, 18-68 years). Plasma ACTH, serum cortisol (F) and urinary free cortisol (UFC) levels were measured before and then monthly during rosiglitazone administration. RESULTS: In six patients a reduction of ACTH and F levels and a normalization of UFC were observed 30-60 days after the beginning of rosiglitazone administration: there was a significant difference between basal and post-treatment values for UFC (1238+/-211 vs 154+/-40 nmol/24 h, P<0.03), but not for ACTH (15.9+/-3.7 vs 7.9+/-0.9 pmol/l) and F levels (531+/-73 vs 344+/-58 nmol/l). Two of six cases, followed up for 7 months, showed a mild clinical improvement. Eight patients were nonresponders after 30-60 days of rosiglitazone treatment: their ACTH, F and UFC levels did not differ before and during drug administration. Immunohistochemical analysis of pituitary tumors removed from two responder and two nonresponder patients showed a similar intense immunoreactivity for PPAR-gamma in about 50% of cells. CONCLUSIONS: The administration of rosiglitazone seems able to normalize cortisol secretion in some patients with CD, at least for short periods. Whether the activation of PPAR-gamma by rosiglitazone might be effective as chronic pharmacologic treatment of CD needs a more extensive investigation through a randomized and controlled study.     

Lymphocyte and immature dendritic cell infiltrates in differentiated, poorly differentiated, and undifferentiated thyroid carcinoma.

OBJECTIVE: Numerous studies indicate that papillary thyroid carcinomas (PTC) with lymphocytic infiltrates are associated with a less extensive disease at diagnosis and improved disease-free survival. The infiltration of lymphocytes and immature CD1a+ dendritic cells (DC) was characterized in papillary, poorly differentiated (PDC), and undifferentiated (UC) carcinomas to evaluate their association with immunological infiltrates. DESIGN: A series of 527 consecutive cases of thyroid carcinoma treated by total thyroidectomy were investigated by histopathological and immunohistochemical methods. The inflammatory infiltrate was quantified and typed in intratumoral and peritumoral tissues as well as in the controlateral lobe. MAIN OUTCOME: The intratumoral infiltrate was strongly reduced or absent in PDC and UC. Intense infiltrates were detected in the PTC tall cell variant. In all histotypes, the extent of the intratumoral and peritumoral infiltrates was comparable. Immature DC were detected in PTCs and markedly reduced in PDC and UC. CD1a+ DCs were detected in a small percentage of PDC and UC. CONCLUSIONS: Though a relationship between the extent of lymphocyte/DC infiltrates and the prognosis of PTCs could not be demonstrated, tumors with poor prognosis (PDCs, UCs) were characterized by markedly reduced lymphocyte/DC infiltrates. The study appears to confirm the protective role of DC and infiltrating lymphocytes against thyroid tumors.     

The metabolic cross‐talk between epithelial cancer cells and stromal fibroblasts in ovarian cancer progression: Autophagy plays a role

Cancer and stromal cells, which include (cancer‐associated) fibroblasts, adipocytes, and immune cells, constitute a mixed cellular ecosystem that dynamically influences the behavior of each component, creating conditions that ultimately favor the emergence of malignant clones. Ovarian cancer cells release cytokines that recruit and activate stromal fibroblasts and immune cells, so perpetuating a state of inflammation in the stroma that hampers the immune response and facilitates cancer survival and propagation. Further, the stroma vasculature impacts the metabolism of the cells by providing or limiting the availability of oxygen and nutrients. Autophagy, a lysosomal catabolic process with homeostatic and prosurvival functions, influences the behavior of cancer cells, affecting a variety of processes such as the survival in metabolic harsh conditions, the invasive growth, the development of immune and chemo resistance, the maintenance of stem‐like properties, and dormancy. Further, autophagy is involved in the secretion and the signaling of promigratory cytokines. Cancer‐associated fibroblasts can influence the actual level of autophagy in ovarian cancer cells through the secretion of pro‐inflammatory cytokines and the release of autophagy‐derived metabolites and substrates. Interrupting the metabolic cross‐talk between cancer cells and cancer‐associated fibroblasts could be an effective therapeutic strategy to arrest the progression and prevent the relapse of ovarian cancer.     

A randomized trial of ultrasound-guided anterior subcostal liver biopsy versus the conventional Menghini technique

An ultrasound-guided double pass biopsy technique using a large bore cutting needle via an anterior subcostal route (USAB) is described. The diagnostic adequacy of this biopsy procedure was evaluated in comparison with the traditional Menghini technique in 200 cases of suspected chronic liver disease randomly assigned to the two different procedures. Retrieval rate was better in the USAB group. The sample length was less than 15 mm in four cases in the USAB group and in 19 cases in the Menghini group. In three cases in the USAB group the second pass modified the diagnosis of the first specimen from chronic active hepatitis to active cirrhosis. In order to evaluate the safety and discomfort of the two procedures 340 patients assigned to the different techniques had liver ultrasound scans 6 and 24 h following percutaneous biopsy. USAB was associated with a reduced frequency of complications (one out of 170 patients vs. seven out of 170 patients who had the intercostal Menghini procedure). In our study, USAB seems to offer better sampling and size of individual samples, together with reduced frequency of major and minor complications.