Autologous fat as a rectal–prostate spacer for prostate brachytherapy: Results at 6 months

PurposeImplanted rectal spacers (IRS) have been developed to increase the distance between the prostate and the rectum, thus optimizing dose escalation. Cost is a disadvantage and there are still uncertainties as to their durability. We have developed an autologous fat transfer (AFT) technique to use as an IRS. We aim to present the feasibility and durability at 6 months of AFT placed immediately after the implant of the seeds in low-dose-rate brachytherapy (BT).Methods and MaterialsThirty-five patients underwent AFT (12 were treated with primary BT, 7 with a combined primary treatment of external beam radiotherapy + BT, 16 with salvage BT). The isodose used for primary BT was 14400 cGy, 11,000 cGy after 4600 cGy of external beam radiotherapy in the combined group, and 14400 cGy for the salvage group. Patients underwent a CT scan at 1, 3, and 6 months to measure the distance between the rectum and the prostate.ResultsAn average of 32.7 cc (20–40) of fat was transferred successfully in 100% of cases. The mean distance to the rectum at the level of the base, middle, and apex at 1 and 6 months were 11.2, 9.7, and 7.6 mm; 8.3, 8.1, and 5.9 mm, respectively. No rectal toxicity or major complications were reported.ConclusionsThe use of fat as an IRS seems to be a valid alternative to reduce rectal toxicity after BT, achieving equivalent distances to synthetic IRS. It is feasible, safe, and the loss of distance at 6 months is small. Cost is lower than other alternatives.     

Perineal burn care: French working group recommendations

Objectives

Burns to the perineum are frequently exposed to faeces. Diverting colostomy is often described to prevent faecal soiling. Because this technique is invasive with frequent complications, use of non-surgical devices including specifically designed faecal management systems has been reported in perineal burns.

Methods

In order to standardise the faecal management strategy in patients with perineal burns, a group of French experts was assembled. This group first evaluated the ongoing practice in France by analysing a questionnaire sent to every French burn centre. Based on the results of this study and on literature data, the experts proposed recommendations on the management of perineal burns in adults.

Results

Specifically designed faecal management systems are the first-line method to divert faeces in perineal burns. The working group proposed recommendations and an algorithm to assist in decisions in the management of perineal burns in four categories of patients, depending on total burn skin area, depth and extent of the perineal burn.

Conclusion

In France, non-surgical devices are the leading means of faecal diversion in perineal burns. The proposed algorithm may assist in decisions in the management of perineal burns. The expert group emphasises that large clinical studies are needed to better evaluate these devices.     

Assessment of the genotoxic and carcinogenic potentials of 3‐aminothiophene derivatives using in vitro and in silico methodologies

Thiophene derivatives, a class of compounds widely used in products such as pharmaceuticals, agrochemicals or dyestuffs, represent chemicals of concern. Indeed, the thiophene ring is often considered as a structural moiety that may be involved in toxic effects in humans. We primarily focus on the genotoxic/mutagenic and carcinogenic potentials of the methyl 3‐amino‐4‐methylthiophene‐2‐carboxylate (1), a precursor of the articaine local anesthetic (4) which falls within the scope of the European REACH (Registration, Evaluation, Authorisation and restriction of CHemicals) legislation. To discern some structure–toxicity relationships, we also studied two related compounds, namely the 3‐amino 4‐methylthiophene (2) and the 2‐acetyl 4‐chlorothiophene (3). Techniques employed to assess mutagenic and DNA‐damaging effects involved the Salmonella mutagenicity assay (or Ames test) and the single‐cell gel electrophoresis assay (or Comet assay). In the range of tested doses, none of these derivatives led to a positive response in the Ames tests and DNA damage was only observed in the Comet assay after high concentration exposure of 2. The study of their carcinogenic potential using the in vitro SHE (Syrian Hamster Embryo) cell transformation assay (CTA) highlighted the activity of compound 2. A combination of experimental data with in silico predictions of the reactivity of thiophene derivatives towards cytochrome P450 (CYP450), enabled us to hypothesize possible pathways leading to these toxicological profiles. Copyright © 2013 John Wiley & Sons, Ltd.     

Rituximab (anti-CD20 monoclonal antibody) as single first-line therapy for patients with follicular lymphoma with a low tumor burden: clinical and molecular evaluation

The clinical activity of rituximab, a chimeric monoclonal antibodywhich binds to the CD20 antigen, was evaluated as a single first-linetherapy for patients with follicular non-Hodgkin lymphoma (NHL). Fiftypatients with follicular CD20⁺ NHL and a low tumor burdenwere analyzed for clinical and molecular responses. They received 4 weekly infusions of rituximab at a dose of 375 mg/m². Theresponse rate a month after treatment (day 50) was 36 of 49 (73%),with 10 patients in complete remission, 3 patients in completeremission/unconfirmed, and 23 patients in partial remission. Tenpatients had stable disease, and the disease progressed in 3 patients. One of 13 (8%) patients in complete remission, 9 of 23 (39%) patients in partial remission, and 5 of 10 (50%) patients withstable disease exhibited disease progression during the first year.Within the study population, 32 patients were initially informative forpolymerase chain reaction (PCR) data on bcl-2-J_H rearrangement. On day 50, 17 of 30 patients (57%) were negative forbcl-2-J_H rearrangement in peripheral blood, and 9 of 29 (31%) were negative in bone marrow; a significant association wasobserved between molecular and clinical responses(P < .0001). At month 12, 16 of 26 patients (62%) werePCR negative in peripheral blood. These results indicate that earlymolecular responses can be sustained for up to 12 months and that thisresponse is highly correlated with progression-free survival. Rituximabhas a high clinical activity and a low toxicity and induces a highcomplete molecular response rate in patients with follicular lymphomaand a low tumor burden.     

Fulminant hepatitis due to human adenovirus

Purpose

To describe the demographics, clinical manifestations, treatment and outcomes of patients with human adenovirus (HAdV) hepatitis.

Methods

A case of fulminant HAdV hepatitis in a patient with chronic lymphocytic leukemia receiving rituximab and fludarabine is described. We conducted a comprehensive review of the English-language literature through May, 2012 in search of definite cases of HAdV hepatitis.

Results

Eighty-nine cases were reviewed. Forty-three (48 %) were liver transplant recipients, 19 (21 %) were bone marrow transplant recipients, 11 (12 %) had received chemotherapy, five (6 %) had severe combined immunodeficiency, four (4 %) were HIV infected, two had heart transplantation, and two were kidney transplant recipients. Ninety percent (46/51) of patients presented within 6 months following transplantation. Fever was the most common initial symptom. Abdominal CT scan revealed hypodense lesions in eight of nine patients. Diagnosis was made by liver biopsy in 43 (48 %), and on autopsy in 46 (52 %). The HAdV was isolated at other sites in 54 cases. Only 24 of 89 patients (27 %) survived: 16 whose immunosuppression was reduced, six with liver re-transplantation, and two who received cidofovir and intravenous immunoglobulin.

Conclusion

HAdV hepatitis can manifest as a fulminant illness in immunocompromised hosts. Definitive diagnosis requires liver biopsy. Early consideration of a viral etiology, reduction in immunosuppression, and liver transplantation can be potentially life-saving.     

HRAS germline mutations impair LKB1/AMPK signaling and mitochondrial homeostasis in Costello syndrome models

Germline mutations that activate genes in the canonical RAS/MAPK signaling pathway are responsible for rare human developmental disorders known as RASopathies. Here, we analyzed the molecular determinants of Costello syndrome (CS) using a mouse model expressing HRAS p.G12S, patient skin fibroblasts, hiPSC-derived human cardiomyocytes, a HRAS p.G12V zebrafish model, and human fibroblasts expressing lentiviral constructs carrying HRAS p.G12S or HRAS p.G12A mutations. The findings revealed alteration of mitochondrial proteostasis and defective oxidative phosphorylation in the heart and skeletal muscle of CS mice that were also found in the cell models of the disease. The underpinning mechanisms involved the inhibition of the AMPK signaling pathway by mutant forms of HRAS, leading to alteration of mitochondrial proteostasis and bioenergetics. Pharmacological activation of mitochondrial bioenergetics and quality control restored organelle function in HRAS p.G12A and p.G12S cell models, reduced left ventricle hypertrophy in CS mice, and diminished the occurrence of developmental defects in the CS zebrafish model. Collectively, these findings highlight the importance of mitochondrial proteostasis and bioenergetics in the pathophysiology of RASopathies and suggest that patients with CS may benefit from treatment with mitochondrial modulators.