Faculty Bibliography

BACKGROUND: We aimed to improve the outcomes for locoregionally advanced nasopharyngeal carcinoma by testing the feasibility and safety of the addition of bevacizumab to chemoradiotherapy. METHODS: We enrolled patients older than 18 years with stage IIB-IVB nasopharyngeal carcinoma from 19 centres in North America and Hong Kong. Treatment consisted of three cycles of bevacizumab (15 mg/kg) and cisplatin (100 mg/m(2)) both given on days 1, 22, and 43 of radiation (70 Gy) with intensity-modulated radiation therapy delivered over 33 days on a daily basis, Monday through Friday. Patients then received three cycles of bevacizumab (15 mg/kg) and cisplatin (80 mg/m(2)), both given on days 64, 85, and 106 after radiation, and three cycles of fluorouracil (1000 mg/m(2) per day), given on days 64-67, 85-88, and 106-109 after radiation. The primary endpoint was the occurrence of treatment-related grade 4 haemorrhage or any grade 5 adverse event in the first year. Analyses were done with all eligible patients who started protocol treatment. The trial is registered at ClinicalTrials.gov, number NCT00408694. FINDINGS: From Dec 13, 2006, to Feb 5, 2009, we enrolled 46 patients, of whom 44 were eligible for analysis. We recorded no grade 3-4 haemorrhages or grade 5 adverse events; nine patients (20%) had a treatment-related grade 1-2 haemorrhage. Nine patients had one or more grade 4 blood or bone marrow-related complication (grade 4 leucopenia was noted in six patients, grade 4 lymphopenia in five, grade 4 neutrophils in five, and grade 4 anaemia in one). One patient had two grade 4 infections with grade 3-4 neutrophils. One patient reported grade 4 tinnitus, one patient reported grade 4 thrombosis, one reported grade 4 radiation mucositis, and two reported grade 4 pharyngolaryngeal pain. With a median follow-up of 2.5 years (IQR 2.1-2.9), the estimated 2 year locoregional progression-free interval was 83.7% (95% CI 72.6-94.9), the 2 year distant metastasis-free interval was 90.8% (82.2-99.5), the 2 year progression-free survival was 74.7% (61.8-87.6), and 2 year overall survival was 90.9% (82.3-99.4). INTERPRETATION: The addition of bevacizumab to standard chemoradiation treatment for patients with nasopharyngeal carcinoma is feasible, and might delay the progression of subclinical distant disease. FUNDING: National Cancer Institute, USA.

BACKGROUND: Patients with small, low-/intermediate-risk parotid cancers, treated with surgery, and who have the single prognostic factor of close and/or positive margins, constitute an unusual subset. This study evaluates local control and morbidity associated with postoperative radiation therapy for low/intermediate grade parotid cancer in these patients. METHODS: Between 1999 and 2006, 17 patients underwent postoperative radiation therapy at Beth Israel Medical Center for acinic cell carcinoma or low-intermediate-grade mucoepidermoid carcinoma of the parotid with close/positive margins. Pathology, treatment, and follow-up data were retrospectively analyzed for morbidity and local control. Two- and 5-year estimates of survival outcomes were performed followed by an analysis of complications. RESULTS: There were no local failures and no significant long-term complications. CONCLUSIONS: Patients with small, low-risk cancer of the parotid gland have excellent local control and low treatment-related morbidity when receiving postoperative radiation therapy for positive or close margins of resection.

European and North American strains of the parasite Toxoplasma gondii belong to three distinct clonal lineages, type I, type II, and type III, which differ in virulence. Understanding the basis of Toxoplasma strain differences and how secreted effectors work to achieve chronic infection is a major goal of current research. Here we show that type I and III infected macrophages, a cell type required for host immunity to Toxoplasma, are alternatively activated, while type II infected macrophages are classically activated. The Toxoplasma rhoptry kinase ROP16, which activates STAT6, is responsible for alternative activation. The Toxoplasma dense granule protein GRA15, which activates NF-kappaB, promotes classical activation by type II parasites. These effectors antagonistically regulate many of the same genes, and mice infected with type II parasites expressing type I ROP16 are protected against Toxoplasma-induced ileitis. Thus, polymorphisms in determinants that modulate macrophage activation influence the ability of Toxoplasma to establish a chronic infection.

Osteoradionecrosis (ORN) of the mandible is a significant complication of radiation therapy for head and neck cancer. In this condition, bone within the radiation field becomes devitalized and exposed through the overlying skin or mucosa, persisting as a non-healing wound for three months or more. In 1926, Ewing first recognized the bone changes associated with radiation therapy and described them as "radiation osteitis". In 1983, Marx proposed the first staging system for ORN that also served as a treatment protocol. This protocol advocated that patients whose disease progressed following conservative therapy (hyperbaric oxygen (HBO), local wound care, debridement) were advanced to a radical resection with a staged reconstruction utilizing a non-vascularized bone graft. Since the introduction of Marx's protocol, there have been advances in surgical techniques (i.e. microvascular surgery), as well as in imaging techniques, which have significantly impacted on the diagnosis and management of ORN. High resolution CT scans and orthopantamograms have become a key component in evaluating and staging ORN, prior to formulating a treatment plan. Patients can now be stratified based on imaging and clinical findings, and treatment can be determined based on the stage of disease, rather than determining the stage of disease based on a patient's response to a standardized treatment protocol. Reconstructions are now routinely performed immediately after resection of the diseased tissue rather than in a staged fashion. Furthermore, the transfer of well-vascularized hard and soft tissue using microvascular surgery have brought the utility of HBO treatment in advanced ORN into question.

BACKGROUND: Radiation is a known risk factor for poor wound healing. Patients undergoing intraoperative radiation therapy (IORT) typically receive higher cumulative doses to their wound beds than patients treated with conventional radiation therapy. We review our experience with IORT in patients undergoing resection of head and neck cancer and flap reconstruction. Logistics of delivery and outcomes are discussed. METHODS: A retrospective chart review was performed on all patients at Beth Israel Medical Center who underwent IORT for head and neck cancer between 2000 and 2007. Twenty-one patients receiving 22 treatments involving flap reconstruction were identified. The results of these reconstructions were evaluated for complications and functional outcome. RESULTS: All patients had complex surgical wounds of the face, upper aerodigestive tract, or neck who received IORT in conjunction with pedicled or free flap closure. Twenty-five flaps in 21 patients were performed in the setting of IORT. All patients received between 10 and 15 Gy of IORT administered directly to the wound bed. There were no perioperative mortalities. Wound breakdown occurred in three cases, all of which were treated successfully by operative revision. Functionally, most patients did well and performed similarly to historic controls for their type of reconstruction. CONCLUSIONS: Reconstruction using flaps in the context of IORT can be achieved with expectation of good wound healing in the majority of cases despite heavy cumulative doses of radiation to recipient wound beds.

PURPOSE: To establish the safety and toxicity profile of daily gefitinib with radiation alone or with concurrent chemoradiotherapy in previously untreated patients with locally advanced squamous cell head and neck cancer (LAHNC). PATIENTS AND METHODS: Patients with intermediate-stage LAHNC were treated with concomitant boost radiation (RT) alone with escalating doses of daily gefitinib (250 or 500 mg; cohort I). Once a safety profile was determined with RT alone, patients with high-risk disease were then treated with daily gefitinib (250 or 500 mg), weekly cisplatin (CDDP; 30 mg/m2), and once-daily RT (cohort II). Patients also received post-RT gefitinib at 250 mg daily for a period of up to 2 years. RESULTS: Twenty-three patients were enrolled and assessable for toxicity. No dose-limiting toxicities (DLTs) were observed in patients treated in cohort I at either 250 or 500 mg of gefitinib daily with concomitant boost RT to 72 Gy. In patients receiving chemoradiotherapy and gefitinib (cohort II), DLTs included one grade 4 diarrhea and one grade 4 neutropenic fever. Fifteen patients started maintenance gefitinib, and eight (53%) experienced grade 1 to 2 acne-like skin rash and diarrhea, but no grade 3 or 4 toxicity occurred. CONCLUSION: Gefitinib (250 or 500 mg daily) was well tolerated with concomitant boost RT or concurrent chemoradiotherapy with weekly CDDP. Protracted administration of gefitinib for up to 2 years at 250 mg daily was also tolerated well.