Sequential second free fibula flap for the reconstruction of metachronous osteoradionecrosis of the mandible

Osteoradionecrosis (ORN) of the mandible is a potentially catastrophic complication of external beam radiation therapy for head and neck malignancies. A 55-year-old man treated with chemoradiation for base-of-tongue cancer presented with a necrotic left mandibular body and underwent left mandibulectomy with right free fibula osteocutaneous flap reconstruction. Two and a half years later, he presented with right mandibular body ORN and underwent a second mandibular resection and subsequent reconstruction with a left fibula osteocutaneous free flap fixed in the midline to the previously placed contralateral fibula. He recovered well from all procedures. To the best of our knowledge, we report the first case of a patient with metachronous ORN of the mandible requiring resection and subsequent reconstruction with sequential free fibula flaps. Even in the presence of prior microvascular reconstructions, patients can successfully undergo additional reconstructive procedures to restore their function, appearance, and quality of life.     

Innovation in anterior mandibular alveolar distraction osteogenesis: Introduction of a new bone-borne distraction device and first clinical results

Segmental distraction osteogenesis of the anterior mandibular alveolar process (frontblock) is a sufficient method to avoid extractions in patients with dental crowding and to decompensate retroalveolism. Up to now dental-borne devices were used, but limitate the indications for front-block distraction.A new bone-borne distraction device for mandibular alveolar front-block movement is introduced in this study. The distractor allows sufficient segmental transport without loading on the teeth. Clinical evaluations of 7 patients have been performed including the feasibility and predictability of the distraction, postoperative pain and patients’ discomfort. The results indicate that this technique is a promising strategy in the correction of dental crowding, correcting the curve of Spee and to decompensate mandibular retroalveolism even in patients with impaired periodontal health and a thin mandibular symphysis.     

Recurrent disseminated intravascular coagulation caused by intermittent dosing of rifampin

Daily rifampin therapy is associated with minimal adverse effects, but administration on an intermittent or interrupted basis has been associated with severe immunoallergic reactions such as hemolytic anemia, acute renal failure, and disseminated intravascular coagulation. We describe a patient with Mycobacterium leprae infection who experienced recurrent episodes of disseminated intravascular coagulation after intermittent exposures to rifampin, and review eight previously reported cases of rifampin-associated disseminated intravascular coagulation. In six (75%) cases, previous exposure to rifampin was reported and seven (87.5%) patients were receiving the medication on an intermittent or interrupted basis. Clinical features of rifampin-associated disseminated intravascular coagulation included fever, hypotension, abdominal pain, and vomiting within hours of ingestion. Average time to reaction was 3-6 doses if rifampin was being administered on a monthly schedule. Three (37.5%) of eight reported cases were fatal. A complete history of previous exposure to rifampin is recommended before intermittent therapy with this medication.     

Ofatumumab monotherapy in rituximab-refractory follicular lymphoma: results from a multicenter study

New treatments are required for rituximab-refractory follicular lymphoma (FL). In the present study, patients with rituximab-refractory FL received 8 weekly infusions of ofatumumab (CD20 mAb; dose 1, 300 mg and doses 2-8, 500 or 1000 mg; N = 116). The median age of these patients was 61 years, 47% had high-risk Follicular Lymphoma International Prognostic Index scores, 65% were chemotherapy-refractory, and the median number of prior therapies was 4. The overall response rate was 13% and 10% for the 500-mg and 1000-mg arms, respectively. Among 27 patients refractory to rituximab monotherapy, the overall response rate was 22%. The median progression-free survival was 5.8 months. Forty-six percent of patients demonstrated tumor reduction 3 months after therapy initiation, and the median progression-free survival for these patients was 9.1 months. The most common adverse events included infections, rash, urticaria, fatigue, and pruritus. Three patients experienced grade 3 infusion-related reactions, none of which were considered serious events. Grade 3-4 neutropenia, leukopenia, anemia, and thrombocytopenia occurred in a subset of patients. Ofatumumab was well tolerated and modestly active in this heavily pretreated, rituximab-refractory population and is therefore now being studied in less refractory FL and in combination with other agents in various B-cell neoplasms. The present study was registered at www.clinicaltrials.gov as NCT00394836.     

Rac2-MRC-cIII-generated ROS cause genomic instability in chronic myeloid leukemia stem cells and primitive progenitors

Chronic myeloid leukemia in chronic phase (CML-CP) is induced by BCR-ABL1 oncogenic tyrosine kinase. Tyrosine kinase inhibitors eliminate the bulk of CML-CP cells, but fail to eradicate leukemia stem cells (LSCs) and leukemia progenitor cells (LPCs) displaying innate and acquired resistance, respectively. These cells may accumulate genomic instability, leading to disease relapse and/or malignant progression to a fatal blast phase. In the present study, we show that Rac2 GTPase alters mitochondrial membrane potential and electron flow through the mitochondrial respiratory chain complex III (MRC-cIII), thereby generating high levels of reactive oxygen species (ROS) in CML-CP LSCs and primitive LPCs. MRC-cIII-generated ROS promote oxidative DNA damage to trigger genomic instability, resulting in an accumulation of chromosomal aberrations and tyrosine kinase inhibitor-resistant BCR-ABL1 mutants. JAK2(V617F) and FLT3(ITD)-positive polycythemia vera cells and acute myeloid leukemia cells also produce ROS via MRC-cIII. In the present study, inhibition of Rac2 by genetic deletion or a small-molecule inhibitor and down-regulation of mitochondrial ROS by disruption of MRC-cIII, expression of mitochondria-targeted catalase, or addition of ROS-scavenging mitochondria-targeted peptide aptamer reduced genomic instability. We postulate that the Rac2-MRC-cIII pathway triggers ROS-mediated genomic instability in LSCs and primitive LPCs, which could be targeted to prevent the relapse and malignant progression of CML.