Prophylaxis of radiation-associated mucositis in conventionally treated patients with head and neck cancer: a double-blind, phase III, randomized, controlled trial evaluating the clinical efficacy of an antimicrobial lozenge using a validated mucositis scoring system.

PURPOSE: Mucositis occurs in almost all patients treated with radiotherapy for head and neck cancer. The aim of this multicenter, double-blind, prospective, randomized trial was to evaluate the clinical efficacy of an economically viable antimicrobial lozenge (bacitracin, clotrimazole, and gentamicin [BcoG]) in the alleviation of radiation-induced mucositis in patients with head and neck cancer. PATIENTS AND METHODS: One hundred thirty-seven eligible patients were randomized to treatment with either antimicrobial lozenge (69 patients) or placebo lozenge (68 patients). The primary end point of the study was the time to development of severe mucositis from the start of radiotherapy. Secondary end points included severity and duration of mucositis, pain measurement, radiation therapy interruption, and quality of life. Mucositis was scored using a validated mucositis scoring system. RESULTS: Toxicity profiles were similar between the two arms of the study. The median time to development of severe mucositis from the start of radiotherapy was 3.61 weeks on BCoG and 3.96 weeks on placebo (P =.61). There were no statistically significant differences between the arms in the extent of severe mucositis as measured by physician, in oral toxicities as recorded by patients, or in radiotherapy delays. CONCLUSION: This study was conducted on the basis of a pilot study that demonstrated the BCoG lozenge to be tolerable and microbiologically efficacious. A validated mucositis scoring system was used. However, in this group of patients treated with conventional radiotherapy, the lozenge did not impact significantly on the severity of mucositis. Whether such a lozenge would be beneficial in treatment situations where rate of severe mucositis is higher (ie, in patients treated with unconventional fractionation or with concomitant chemotherapy) is unknown.     

Understanding organization structures of the college, university, high school, clinical, and professional settings

Athletes participate at many different levels of competition--from amateur to professional, from backyard sandlot to Yankee Stadium. There are as many different organized structures involved in providing medical care to athletes as there are types of athletes themselves. Although the organizational structures involved in providing medical care for a little league team in a small town are different from those involved in providing care for a professional baseball team, the mission is the same-caring for athletes. This is the central theme of this article. Though there are different organizational structures, there are more common threads than differences in the mission of those who provide medical care for athletes at any level.     

Costimulatory receptors in jawed vertebrates: conserved CD28, odd CTLA4 and multiple BTLAs

CD28 family of costimulatory receptors is comprised of molecules with a single V-type extracellular Ig domain, a transmembrane and an intracytoplasmic region with signaling motifs. CD28 and cytotoxic T lymphocyte antigen-4 (CTLA4) homologs have been recently identified in rainbow trout. Other sequences similar to mammalian CD28 family members have now been identified using teleost, Xenopus and chicken databases. CD28- and CTLA4 homologs were found in all vertebrate classes whereas inducible costimulatory signal (ICOS) was restricted to tetrapods, and programmed cell death-1 (PD1) was limited to mammals and chicken. Multiple B and T Lymphocyte Attenuator (BTLA) sequences were found in teleosts, but not in Xenopus or in avian genomes. The intron/exon structure of btlas was different from that of cd28 and other members of the family. The Ig domain encoded in all the btla genes has features of the C-type structure, which suggests that BTLA does not belong to the CD28 family. The genomic localization of these genes in vertebrate genomes supports the split between the BTLA and CD28 families.     

Acute adverse effects of radiation therapy and local recurrence in relation to dietary and plasma beta carotene and alpha tocopherol in head and neck cancer patients

There is a debate concerning the effects of antioxidant vitamins during radiation therapy: Can they reduce the adverse effects of therapy without reducing treatment efficacy? We examined whether dietary and plasma beta carotene and alpha tocopherol were related to severe acute adverse effects of radiation therapy and to cancer local recurrence. We conducted a prospective study of 540 head and neck cancer patients treated by radiation therapy. Dietary intakes of beta carotene and alpha tocopherol were measured by a validated food frequency questionnaire and plasma levels were determined. Acute adverse effects of radiation therapy and local recurrence were documented. A higher beta carotene dietary intake was associated with fewer severe acute adverse effects: odds ratio (OR) = 0.61 [95% confidence interval (CI) = 0.40-0.93]. There was a tendency for a similar effect for plasma beta carotene: OR = 0.73 (95% CI = 0.48-1.11). Participants with higher plasma beta carotene had a significantly lower rate of local recurrence (hazard ratio = 0.67; 95% CI = 0.45-0.99). Alpha tocopherol was not related to severe adverse effects or to cancer recurrence. This study suggests that a higher usual dietary beta carotene intake can reduce the occurrence of severe adverse effects of radiation therapy and decrease local cancer recurrence.     

CaxP and Ca/P in the parenteral feeding of preterm infants

Preterm infants requiring prolonged intravenous feeding frequently develop pathologic fractures and rickets. Infants who receive large amounts of calcium have fewer fractures. This observation led us to determine the maximal amounts of calcium and phosphate that can be added to parenteral nutrition solutions without the precipitation of calcium phosphate and to determine the optimal ratio of calcium to phosphate in these solutions. Clinical observations and in vitro experiments indicate that the product of calcium x phosphate (CaxP) in the dextrose-amino acid solution should not exceed 75 square millimolar (square millimole per square liter) to prevent calcium phosphate precipitation in barium-impregnated silicone rubber catheters and should not exceed 100 square millimolar in solutions administered through peripheral veins. Seven intake and output studies were performed in preterm infants to determine the ratio of calcium to phosphate (Ca/P) in the total parenteral nutrition solutions that minimized urinary losses. A Ca/P ratio of 5.0 minimized the sum of the calcium plus phosphate losses in the urine. However, experience with long-term total parenteral nutrition in preterm infants, awareness of the acute and life-threatening effects of body phosphate depletion, and an unmeasured endogenous enteric calcium secretion all suggest that a Ca/P ratio of approximately 3.0 provides a safer compromise between the acute and serious complications of phosphate deficiency and the chronic problems of fractures and rickets due to calcium deficiency.     

Dual Redox/pH-Sensitive Micelles Self-Assembled From Star-Like Amphiphilic Copolymers Based On Sucrose For Controlled Doxorubicin Delivery

Novel dual redox/pH-sensitive star-like amphiphilic sucrose-oligo(butyl fumarate) (thioglycolic acid conjugate)–SS–poly(ethylene glycol) (Suc-OBF(TGA)–SS–PEG) copolymers and their self-assembled micelles were prepared and utilized for intracellular doxorubicin delivery. Importance of changing the hydrophobic chain length on micelles properties was investigated. Results showed that the micelles with longer hydrophobic chain exhibited smaller size and were more stable in aqueous solution. The redox and pH sensitivity of the micelles was confirmed by the change of micelle diameter/diameter distribution measured by dynamic light scattering and the change of micellar morphology observed by scanning electron microscope. The micelles display a decent doxorubicin loading capacity. In vitro release studies showed that only 14.3% doxorubicin was released from doxorubicin-loaded micelles under physiological conditions in 30 h. The release of doxorubicin was accelerated at pH 5.5 or in the presence of 10 mM glutathione at pH 7.4 (46.9% and 76.9% of doxorubicin was released, respectively, in 30 h). The doxorubicin release was further expedited under pH 5.5 and 10 mM GSH conditions (91.4%). Suc-OBF(TGA)–SS–PEG micelles displayed no cytotoxicity toward HDF cells. MTT assays indicated that doxorubicin-loaded micelles had good cytotoxicity against MCF-7 cells. This work suggested that star-like amphiphilic Suc-OBF(TGA)–SS–PEG copolymer micelles may provide a promising platform for delivering doxorubicin and other hydrophobic anticancer drugs.     

Safety and feasibility of motexafin gadolinium administration with whole brain radiation therapy and stereotactic radiosurgery boost in the treatment of ??6 brain metastases: a multi-institutional phase II trial

To determine the safety, tolerability, and report on secondary efficacy endpoints of motexafin gadolinium (MGd) in combination with whole-brain radiotherapy (WBRT) and stereotactic radiosurgery (SRS) for patients with ≤ 6 brain metastases. We conducted an international study of WBRT (37.5 Gy in 15 fractions) and SRS (15-21 Gy) with the addition of MGd (5 mg/kg preceding each fraction beginning week 2). The primary endpoint was to evaluate the rate of irreversible grade 3 or any grade ≥ 4 neurotoxicity and establish feasibility in preparation for a phase III trial. Sixty-five patients were enrolled from 14 institutions, of which 45 (69%) received SRS with MGd as intended and were available for evaluation. Grade ≥ 3 neurotoxicity attributable to radiation therapy within 3 months of SRS was seen in 2 patients (4.4%), including generalized weakness and radionecrosis requiring surgical management. Immediately following the course of MGd plus WBRT, new brain metastases were detected in 11 patients (24.4%) at the time of the SRS treatment planning MRI. The actuarial incidence of neurologic progression at 6 months and 1 year was 17 and 20%, respectively. The median investigator-determined neurologic progression free survival and overall survival times were 8 (95% CI: 5-14) and 9 months (95% CI: 6-not reached), respectively. We observed a low rate of neurotoxicity, demonstrating that the addition of MGd does not increase the incidence or severity of neurologic complications from WBRT with SRS boost.     

Comparison of toxicity associated with early morning versus late afternoon radiotherapy in patients with head-and-neck cancer: a prospective randomized trial of the National Cancer Institute of Canada Clinical Trials Group (HN3)

PURPOSE: Based on our demonstration of a circadian rhythm in the human oral mucosa cell cycle, with most cells in the G(1) phase in the morning and M phase at night, we hypothesized that morning radiotherapy (RT) would lead to less oral mucositis than afternoon RT. METHODS AND MATERIALS: A total of 216 patients were randomized to morning (8-10 AM) vs. afternoon (4-6 PM) RT and stratified by radiation dose, smoking status, and center. Patients receiving primary or postoperative RT alone were eligible. Oral mucositis was scored using the Radiation Therapy Oncology Group (RTOG) criteria and a validated scoring system. RESULTS: Of 205 evaluable patients, 52.9% vs. 62.4% developed RTOG Grade 3 or greater mucositis after morning vs. afternoon RT, respectively (p = 0.17). Morning RT was also associated with significantly less weight loss after 5 months (p = 0.024). In a subgroup of 111 patients treated to a dose of 66-70 Gy in 33-35 fractions, exploratory analyses revealed a significant reduction in Grade 3 or greater mucositis with morning RT (44.6% vs. 67.3%, p = 0.022) and a longer interval to the development of Grade 3 or greater mucositis (median, >7.9 vs. 5.6 weeks, p = 0.033). In 53 patients, who smoked during therapy, a significant reduction was found in Grade 3 or greater mucositis with morning RT (42.9% vs. 76%, p = 0.025). CONCLUSION: In this proof of principle study, morning RT was associated with significantly less weight loss after 5 months and an apparent reduction in oral mucositis in a subset of patients receiving >/=66 Gy and in patients who smoked during therapy.