Large granular lymphocytic leukaemia after solid organ and haematopoietic stem cell transplantation

T-cell large granular lymphocytic leukaemia (T-LGLL) is a chronic clonal lymphoproliferative disorder of cytotoxic T lymphocytes which commonly occurs in older patients and is often associated with autoimmune diseases. Among 246 patients with T-LGLL seen at our institution over the last 10 years, we encountered 15 cases following solid organ or haematopoietic stem cell transplantation. Here, we studied the clinical characterization of these cases and compared them to de novo T-LGLL. This experience represented a clear picture of the intricate nature of the disease manifestation and the complexities of several immune mechanisms triggering the clonal expansion.     

Extended experience with a non-cytotoxic DNMT1-targeting regimen of decitabine to treat myeloid malignancies

The nucleoside analogue decitabine can deplete the epigenetic regulator DNA methyltransferase 1 (DNMT1), an effect that occurs, and is saturated at, low concentrations/doses. A reason to pursue this molecular-targeted effect instead of the DNA damage/cytotoxicity produced with high concentrations/doses, is that non-cytotoxic DNMT1-depletion can cytoreduce even p53-null myeloid malignancies while sparing normal haematopoiesis. We thus identified minimum doses of decitabine (0·1–0·2 mg/kg) that deplete DNMT1 without off-target anti-metabolite effects/cytotoxicity, and then administered these well-tolerated doses frequently 1–2X/week to increase S-phase dependent DNMT1-depletion, and used a Myeloid Malignancy Registry to evaluate long-term outcomes in 69 patients treated this way. Consistent with the scientific rationale, treatment was well-tolerated and durable responses were produced (~40%) in genetically heterogeneous disease and the very elderly.     

High-dose chemotherapy and stem cell transplantation for patients with stage IV breast cancer without clinically evident disease: correlation of CD34+ selection to clinical outcome

Forty-five patients with metastatic breast cancer without clinically evident disease were treated with thiotepa 750 mg/m2, mitoxantrone 40 mg/m2 and carboplatin 1000 mg/m2 followed by stem cell transplantation to determine the safety and efficacy of CD34+ selection of peripheral blood stem cells. Of these, 15 patients' (group I) stem cells were processed through Baxter Isolex 300 device for CD34+ selection, whereas 30 patients (group II) received unmanipulated stem cells. Toxicity, progression-free survival and survival were compared between these two groups. There was no difference in transfusion requirements, white cell count and platelet recovery and non-hematologic toxicity between the two groups. The survival of patients in group I was 27 months compared to 38 months in group II (P = 0.8). The progression-free survival was 12 months and 13.5 months for group I and group II patients, respectively (P = 0.6). Our results indicate that while there is no adverse effect, there is also no significant advantage of CD34+ selection in terms of progression-free survival and survival in patients with metastatic breast cancer without clinically evident disease. Bone Marrow Transplantation (2000).     

Effect of weight loss after weight loss surgery on plasma N-terminal pro-B-type natriuretic peptide levels

Natriuretic peptides have multiple beneficial cardiovascular effects. Previous cross-sectional studies have indicated that obese subjects have lower natriuretic peptide concentrations than those of normal weight. It is not known whether this relative natriuretic peptide deficiency is reversible with weight loss. We studied 132 obese subjects undergoing weight loss surgery with serial measurement of plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations at preoperative, early (1 to 2 months), and late postoperative (6 months) points. In addition, 20 subjects also underwent echocardiography at baseline and 6 months after surgery. Significant weight loss was observed after surgery (median body mass index 45.1, 41.0, and 32.9 kg/m(2) for the 3 corresponding points, analysis of variance p <0.001). The median NT-proBNP levels increased substantially (31.6, 66.9, and 84.9 pg/ml; p <0.001). The average intrasubject increase in NT-proBNP at the 2 postoperative points was 3.4 and 5.0 times the preoperative level (p <0.001 for both points vs preoperatively). In the multivariate regression models adjusted for clinical characteristics and insulin resistance, the strongest predictor of the change in NT-proBNP level 6 months after weight loss surgery was the change in weight (p = 0.03). Echocardiography showed a mean intrasubject reduction in left ventricular mass index of 18% (p <0.001) and mild improvements in diastolic function, with no change in ejection fraction. In conclusion, we have demonstrated that weight loss is associated with early and sustained increases in NT-proBNP concentrations, despite evidence of preserved systolic and improved diastolic function. These findings suggest a direct, reversible relation between obesity and reduced natriuretic peptide levels.     

A comparison of the presence of Theileria ovis by PCR amplification of their SSU rRNA gene in small ruminants from two provinces of Pakistan

ObjectiveTo compare the presence of Theileria ovis in small ruminants from two provinces of Pakistan and to determine the risk factors associated with the spread of theileriosis.MethodsIn present study, a total of 210 blood samples were collected from sheep (n=99) and goats (n=111) from 5 sampling sites in Punjab (Dera Ghazi Khan, Layyah, Multan and Rahim Yar Khan districts) and Khyber Pukhtoon Khwa (district Kohat) provinces, in Pakistan, from randomly selected herds. Data on the characteristics of the animals (species, gender, age, tick presence or absence, prior treatment for babesiosis) and the herd (location, size, species of animals, dogs associated with the herds, tick burden of dogs associated with the herds) was collected through questionnaires.ResultsTwelve blood samples (6% of total), 11 from district Kohat, produced the 520 base pairs DNA fragment specific for small subunit ribosomal RNA (ssu rRNA) gene of Theileria ovis, by PCR amplification, of which 11 were sheep and 1 was goat indicating that sheep are more significantly (P=0.001) prone to this parasite. On the other hand parasite was detected only in 2 out of 210 samples (1%) by blood smear screening confirming PCR as the reliable detection tool.ConclusionsPCR is more sensitive and reliable diagnostic tool for detection of Theileria sp. as compared to blood smear screening. Incidence of Theileria ovis is very high in Khyber Pukhtoon Khwa as compared to Punjab province. It was also observed that presence of ticks on animals was the only significant risk factor associated with the theileriosis in small ruminants.     

Investigations into Pulsed High-Intensity Focused Ultrasound–Enhanced Delivery: Preliminary Evidence for a Novel Mechanism

Pulsed high-intensity focused ultrasound (HIFU) exposures without ultrasound contrast agents have been used for noninvasively enhancing the delivery of various agents to improve their therapeutic efficacy in a variety of tissue models in a nondestructive manner. Despite the versatility of these exposures, little is known about the mechanisms by which their effects are produced. In this study, pulsed-HIFU exposures were given in the calf muscle of mice, followed by the administration of a variety of fluorophores, both soluble and particulate, by local or systemic injection. In vivo imaging (whole animal and microscopic) was used to quantify observations of increased extravasation and interstitial transport of the fluorophores as a result of the exposures. Histological analysis indicated that the exposures caused some structural alterations such as enlarged gaps between muscle fiber bundles. These effects were consistent with increasing the permeability of the tissues; however, they were found to be transient and reversed themselves gradually within 72 h. Simulations of radiation force–induced displacements and the resulting local shear strain they produced were carried out to potentially explain the manner by which these effects occurred. A better understanding of the mechanisms involved with pulsed HIFU exposures for noninvasively enhancing delivery will facilitate the process for optimizing their use. (E-mail: vfrenkel@cc.nih.gov)     

1 Versus 2-cm Excision Margins for pT2-pT4 Primary Cutaneous Melanoma (MelMarT): A Feasibility Study

Background

There is a lack of consensus regarding optimal surgical excision margins for primary cutaneous melanoma?>?1 mm in Breslow thickness (BT). A narrower surgical margin is expected to be associated with lower morbidity, improved quality of life (QoL), and reduced cost. We report the results of a pilot international study (MelMarT) comparing a 1 versus 2-cm surgical margin for patients with primary melanoma?>?1 mm in BT.

Methods

This phase III, multicentre trial [NCT02385214] administered by the Australia & New Zealand Medical Trials Group (ANZMTG 03.12) randomised patients with a primary cutaneous melanoma?>?1 mm in BT to a 1 versus 2-cm wide excision margin to be performed with sentinel lymph node biopsy. Surgical closure technique was at the discretion of the treating surgeon. Patients’ QoL was measured (FACT-M questionnaire) at baseline, 3, 6, and 12 months after randomisation.

Results

Between January 2015 and June 2016, 400 patients were randomised from 17 centres in 5 countries. A total of 377 patients were available for analysis. Primary melanomas were located on the trunk (56.9%), extremities (35.6%), and head and neck (7.4%). More patients in the 2-cm margin group required reconstruction (34.9 vs. 13.6%; p?<?0.0001). There was an increased wound necrosis rate in the 2-cm arm (0.5 vs. 3.6%; p?=?0.036). After 12 months’ follow-up, no differences were noted in QoL between groups.

Discussion

This pilot study demonstrates the feasibility of a large international RCT to provide a definitive answer to the optimal excision margin for patients with intermediate- to high-risk primary cutaneous melanoma.