Emerging radiation techniques for early-stage breast cancer after breast-conserving surgery.

Standard whole-breast irradiation consisting of a dose of 45-50 Gy over 5 weeks with or without the addition of a boost to the tumor bed has equivalent survival to mastectomy and is considered to be the standard of care for most patients with early-stage breast cancer. Newer techniques have been developed to shorten the course of radiation or limit normal tissue exposure in an attempt to increase accessibility to and tolerance of radiation therapy. This article will review some of the newer regimens and techniques for treating early-stage breast cancer after breast-conserving surgery.

Adenovirally delivered tumor necrosis factor-alpha improves the antiglioma efficacy of concomitant radiation and temozolomide therapy.

PURPOSE: Treatment of malignant glioma involves concomitant temozolomide and ionizing radiation (IR). Nevertheless, overall patient survival remains poor. This study was designed to evaluate if addition of Ad.Egr-tumor necrosis factor (TNF), a replication defective adenovector encoding a cDNA for TNF-alpha, to temozolomide and IR can improve overall antiglioma effect. EXPERIMENTAL DESIGN: The efficacy of combination treatment with Ad.Egr-TNF, IR, and temozolomide was assessed in two glioma xenograft models. Animal toxicity and brain histopathology after treatment were also examined. In addition, in an attempt to explain the antitumor interaction between these treatments, the activation status of the transcription factor nuclear factor-kappaB was examined. RESULTS: Triple therapy (Ad.Egr-TNF, IR, and temozolomide) leads to significantly increased survival in mice bearing glioma xenografts compared with dual treatment. Fifty percent of animals treated with the triple regimen survive for >130 days. Pathologic examination shows that triple therapy leads to a complete response with formation of a collagenous scar. No significant change in myelination pattern is noted after triple therapy, compared with any double treatment. Treatment of intracranial glioma bearing mice with Ad.Egr-TNF and IR leads to cachexia and poor feeding that does not improve, whereas triple therapy results in less toxicity, which improves over 21 days. Both Ad.Egr-TNF and IR activate nuclear factor-kappaB, and temozolomide inhibits this activity in an inhibitor of kappaBalpha (IkappaBalpha)-independent manner. CONCLUSION: This work shows that the addition of adenoviral TNF-alpha gene delivery to temozolomide and IR significantly improves antiglioma efficacy and illustrates a potential new treatment regimen for use in patients with malignant glioma.

Phase II study of bevacizumab in combination with docetaxel and radiation in locally advanced squamous cell carcinoma of the head and neck.

BACKGROUND: The purpose of this study was to establish the efficacy and toxicities of concurrent bevacizumab and docetaxel with radiation for locally advanced head and neck squamous cell carcinoma (HNSCC). METHODS: Patients with previously untreated HNSCC received standard daily radiotherapy (RT) with concurrent weekly docetaxel (20 mg/m(2) ) and biweekly bevacizumab (5 mg/kg). Biweekly bevacizumab was then continued for up to 1 year after RT. The primary objective was progression-free survival (PFS). Secondary objectives included overall survival (OS), patterns of failure, and toxicities of treatment. RESULTS: Thirty patients were recruited. With median follow-up of 38 months, the 3-year PFS, OS, locoregional recurrence-free survival, and distant metastasis-free survival was 61.7%, 68.2%, 84.5%, and 80.5%, respectively. The most common local toxicities were mucositis and dermatitis. Two patients developed hemorrhage. There was no grade 5 toxicity. CONCLUSION: The combination of bevacizumab, docetaxel, and RT is tolerable and effective in HNSCC. This regimen is worthy of further study in appropriate subset of patients receiving chemoradiation therapy.

ACR Appropriateness Criteria(®) non-spine bone metastases.

Bone metastases are a common clinical problem, affecting many types of cancer patients. The presence of tumor in bone can cause significant morbidity including pain, neurological dysfunction, hypercalcemia, and pathological fracture leading to functional loss. The optimal treatment of a patient with bone metastases depends on many factors, including evaluation of the patient's goals of care, performance status, mechanical stability of the affected bone, life expectancy, and overall extent of disease. Treatment options may include radiotherapy, systemic therapies, surgical stabilization, medical pain management, and radiopharmaceuticals. Ideal management of bone metastases requires a coordinated multidisciplinary approach among diagnostic radiologists, radiation oncologists, medical oncologists, orthopedic surgeons, pain specialists, physiatrists, and palliative care specialists. The American College of Radiology Appropriateness Criteria(®) are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guidelines development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

ACR Appropriateness Criteria® Metastatic Epidural Spinal Cord Compression and Recurrent Spinal Metastasis.

Metastatic epidural spinal cord compression (MESCC) is an oncologic emergency and if left untreated, permanent paralysis will ensue. The treatment of MESCC is governed by disease, patient, and treatment factors. Patient's preferences and goals of care are to be weighed into the treatment plan. Ideally, a patient with MESCC is evaluated by an interdisciplinary team promptly to determine the urgency of the clinical scenario. Treatment recommendations must take into consideration the risk-benefit profiles of surgical intervention and radiotherapy for the particular individual's circumstance, including neurologic status, performance status, extent of epidural disease, stability of the spine, extra-spinal disease status, and life expectancy. In patients with high spinal instability neoplastic score (SINS) or retropulsion of bone fragments in the spinal canal, surgical intervention should be strongly considered. The rate of development of motor deficits from spinal cord compression may be a prognostic factor for ultimate functional outcome, and should be taken into account when a treatment recommendation is made. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every three years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

ACR Appropriateness Criteria ® spinal bone metastases.

Abstract The spine is a common site of involvement in patients with bone metastases. Apart from pain, hypercalcemia, and pathologic fracture, progressive tumor can result in neurologic deterioration caused by spinal cord compression or cauda equina involvement. The treatment of spinal bone metastases depends on histology, site of disease, extent of epidural disease, extent of metastases elsewhere, and neurologic status. Treatment recommendations must weigh the risk-benefit profile of external beam radiation therapy (EBRT) for the particular individual's circumstance, including neurologic status, performance status, extent of spinal disease, stability of the spine, extra-spinal disease status, and life expectancy. Patients with spinal instability should be evaluated for surgical intervention. Research studies are needed that evaluate the combination or sequencing of localized therapies with systemic therapies including chemotherapy, hormonal therapy (HT), osteoclast inhibitors (OI), and radiopharmaceuticals. The roles of stereotactic body radiation therapy (SBRT) in the management of spinal oligometastasis, radioresistant spinal metastasis, and previously irradiated but progressive spinal metastasis are emerging, but more research is needed to validate the findings from retrospective studies. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 2 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

ACR Appropriateness Criteria® non-spine bone metastases.

Bone is one of the most common sites of metastatic spread of malignancy, with possible deleterious effects including pain, hypercalcemia, and pathologic fracture. External beam radiotherapy (EBRT) remains the mainstay for treatment of painful bone metastases. EBRT may be combined with other local therapies like surgery or with systemic treatments like chemotherapy, hormonal therapy, osteoclast inhibitors, or radiopharmaceuticals. EBRT is not commonly recommended for patients with asymptomatic bone metastases unless they are associated with a risk of pathologic fracture. For those who do receive EBRT, appropriate fractionation schemes include 30 Gy in 10 fractions, 24 Gy in 6 fractions, 20 Gy in 5 fractions, or a single 8 Gy fraction. Single fraction treatment maximizes convenience, while fractionated treatment courses are associated with a lower incidence of retreatment. The appropriate postoperative dose fractionation following surgical stabilization is uncertain. Reirradiation with EBRT may be safe and provide pain relief, though retreatment might create side effect risks which warrant its use as part of a clinical trial. All patients with bone metastases should be considered for concurrent management by a palliative care team, with patients whose life expectancy is less than six months appropriate for hospice evaluation. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every two years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

The ttsA gene is required for low-calcium-induced type III secretion of Yop proteins and virulence of Yersinia enterocolitica W22703.

Pathogenic Yersinia species use a virulence-plasmid encoded type III secretion pathway to escape the innate immune response and to establish infections in lymphoid tissues. At least 22 secretion machinery components are required for type III transport of 14 different Yop proteins, and 10 regulatory factors are responsible for activating this pathway in response to environmental signals. Although the genes for these products are located on the 70-kb virulence plasmid of Yersinia, this extrachromosomal element does not appear to harbor genes that provide for the sensing of environmental signals, such as calcium-, glutamate-, or serum-sensing proteins. To identify such genes, we screened transposon insertion mutants of Y. enterocolitica W22703 for defects in type III secretion and identified ttsA, a chromosomal gene encoding a polytopic membrane protein. ttsA mutant yersiniae synthesize reduced amounts of Yops and display a defect in low-calcium-induced type III secretion of Yop proteins. ttsA mutants are also severely impaired in bacterial motility, a phenotype which is likely due to the reduced expression of flagellar genes. All of these defects were restored by complementation with plasmid-encoded wild-type ttsA. LcrG is a repressor of the Yersinia type III pathway that is activated by an environmental calcium signal. Mutation of the lcrG gene in a ttsA mutant strain restored the type III secretion of Yop proteins, although the double mutant strain secreted Yops in the presence and absence of calcium, similar to the case for mutants that are defective in lcrG gene function alone. To examine the role of ttsA in the establishment of infection, we measured the bacterial dose required to produce an acute lethal disease following intraperitoneal infection of mice. The ttsA insertion caused a greater-than-3-log-unit reduction in virulence compared to that of the parental strain.