Time-course of arm lymphedema and potential risk factors for progression of lymphedema after breast conservation treatment for early stage breast cancer.

The objective of this study was to describe the progression of arm lymphedema (ALE) after the initial presentation among patients receiving breast conservation therapy for early stage breast cancer and to identify potential risk factors contributing to ALE progression. The study sample was the 266 stage I or II breast cancer patients with documented ALE who underwent breast conservation therapy that included lumpectomy, axillary staging followed by radiation therapy. ALE were graded according to a difference of 0.5-2 cm (mild), 2.1-3 cm (moderate), and >3 cm (severe) in the circumference between the upper extremities for the treated and untreated sides. ALE at presentation was scored as mild, moderate, and severe in 109 (41%), 125 (47%), and 32 (12%) patients, respectively. One third of patients with ALE progressed to a more severe grade of lymphedema at 5 years of follow-up. Age older than 65 years at the time of breast cancer treatment was associated with higher risk of ALE progression when compared 65 year age or younger (p = 0.04). The patients who had regional lymph node irradiation including posterior axillary boost were at higher risk of lymphedema progression than the patients treated with whole breast irradiation only (p = 0.001). Progression of ALE is a common occurrence. The current study provides support for the utility of routine arm measurements after breast cancer treatment to facilitate timely diagnosis and treatment of ALE.

Lack of compliance with national vaccination guidelines in oncology patients receiving radiation therapy.

Cancer patients are at increased risk for potentially life-threatening infections. Patient safety goals recently issued by the Joint Commission on the Accreditation of Healthcare Organizations (JCAHO) and current Centers for Disease Control and Prevention (CDC) guidelines recommend vaccinations for all cancer patients over the age of 65 (for Pneumococcus) and 50 years of age (annually, for Influenza). The authors investigated vaccination practices in patients over a season of risk at a university-based outpatient cancer treatment clinic. Of 204 patients recruited, 196 (93%) completed the survey. Overall, 30% of patients reported never receiving the Influenza vaccine (33% of patients >50 years old), and 56% reported never receiving the Pneumococcal vaccine (30% of patients >65 years old). Only 7% of patients reported being asked or informed about vaccination by their oncologists. Substantial proportions of patients undergoing cancer treatment have not received vaccinations as recommended by national guidelines. The reasons cited for lack of compliance seem correctable, and doing so would potentially prevent mortality and morbidity, thereby improving the care of cancer patients. Recommended vaccinations may now include that for the Influenza A virus (H1N1).

Cellular responses to EGFR inhibitors and their relevance to cancer therapy.

EGFR is a trans-membrane receptor tyrosine kinase that belongs to the HER family of receptors. The EGFR family plays an essential role in normal organ development by mediating morphogenesis and differentiation. Unlike normal cells that have tight regulatory mechanisms controlling EGFR pathways, tumor cells often have dysregulated EGFR signaling through receptor overexpression and/or mutation. This leads to proliferation under adverse conditions, invasion of surrounding tissues, and increased angiogenesis as well as resistance to radiation and chemotherapy. Therefore, EGFR is a legitimate therapeutic target. Numerous EGFR inhibitors are under development, but to date only four of them are FDA-approved, including two that inhibit the receptor's intracellular tyrosine kinase activity (gefitinib and erlotinib) and two that block extracellular ligand binding (cetuximab, and most recently panitumumab). In this review, we focus on how these different inhibitors affect EGFR signaling and the mechanisms by which they potentiate the effects of chemotherapy and radiation therapy. Numerous clinical trials have been conducted with these agents either as monotherapy, in combination with chemotherapy, or concurrently with radiation. Unfortunately, many of the clinical trials reported so far have shown at best limited gains; therefore, understanding the actions of these agents is essential to improving their efficacy in the treatment of cancers.

Role of Gabapentin in Managing Mucositis Pain in Patients Undergoing Radiation Therapy to the Head and Neck.

BACKGROUND: Oral mucositis (OM) is a painful and debilitating side effect that affects 80%-100% of patients undergoing radiation therapy for head and neck cancer. This dose-limiting side effect may potentially lead to pain, dehydration, malnutrition, infection, and treatment breaks. Treatment breaks can lead to decreased disease control and suboptimal patient outcomes. No primary prevention exists for OM, and management is focused on pain control. Compelling evidence exists that OM pain has somatic and neuropathic components. OBJECTIVES: This article reviews the existing literature on the use of gabapentin (Neurontin®) as a co-analgesic in treating the neuropathic pain in OM. METHODS: A literature search was performed using CINAHL® and PubMed with the search terms gabapentin and oral mucositis. The selected articles were briefly screened for relevance, and three were included in this review. FINDINGS: No systematic reviews exist on the role of gabapentin for neuropathic pain in radiation-induced OM. Two retrospective studies concluded that gabapentin reduced escalation of opioid doses and unplanned treatment breaks. One retrospective study demonstrated favorable swallowing outcomes. Pain and OM are nursing-sensitive outcomes that can be significantly affected by evidence-based nursing interventions.

Postoperative PET/CT and target delineation before adjuvant radiotherapy in patients with oral cavity squamous cell carcinoma.

BACKGROUND: The purpose of this study was for us to present our evaluation of the effectiveness of positron emission tomography (PET)/CT imaging in postoperative patients with oral cavity squamous cell carcinoma (SCC) before initiating adjuvant radiation therapy. METHODS: Treatment planning PET/CT scans were obtained in 44 patients with oral cavity SCC receiving adjuvant radiation. We identified target areas harboring macroscopic disease requiring higher radiation doses or additional surgery. RESULTS: Fourteen PET/CT scans were abnormal. Thirteen patients underwent surgery and/or biopsy, increased radiation dose, and/or addition of chemotherapy. Eleven patients received higher radiation doses. Patients undergoing imaging >8 weeks were more likely to have abnormal results (p = .01). One-year distant metastases-free survival was significantly worse in patients with positive PET/CT scans (61.5% vs 92.7%; p = .01). The estimated positive predictive value (PPV) was 38% for postoperative PET/CT scanning. CONCLUSION: We demonstrated that 32% of patients have abnormal PET/CT scans resulting in management changes. Patients may benefit from postoperative PET/CT imaging to optimize adjuvant radiation treatment planning. © 2015 Wiley Periodicals, Inc. Head Neck 38: E1285-E1293, 2016.

Repeat gamma knife radiosurgery for refractory or recurrent trigeminal neuralgia: treatment outcomes and quality-of-life assessment.

PURPOSE: Stereotactic radiosurgery (SRS) has become a minimally invasive treatment modality for patients with refractory trigeminal neuralgia. It is unclear, however, how best to treat patients with pain that is refractory or recurrent after initial SRS. We report on treatment outcomes and quality of life for patients treated with repeated SRS for refractory or recurrent trigeminal neuralgia. METHODS AND MATERIALS: Between June 1996 and June 2001, 112 patients with trigeminal neuralgia were treated with SRS at the University of Maryland Medical Center. Eighteen patients underwent repeat SRS 3-42 months (median, 8 months) after initial radiosurgery because of unsatisfactory or unsustained pain relief. Patients received a median prescription dose of 75 and 70 Gy, respectively, for the first and second treatments. Self-reports of pain control were assessed with a standard questionnaire containing the complete Barrow Neurologic Institute Pain Scale. RESULTS: The median follow-up was 37.5 months (range, 12-68 months) after initial SRS and 24.5 months (range, 6-65 months) after repeat SRS. For the 18 patients in this series, the percentage of patients reporting excellent, good, fair, and poor responses after the initial and repeat SRS was 50%, 28%, 6%, and 16% and 45%, 33%, 0%, and 22%, respectively. None of the 3 patients with pain refractory to initial SRS responded to repeat SRS. Among those with recurrent pain after initial SRS, 14 patients (93%) achieved excellent or good pain outcomes after repeat SRS. The actuarial analysis revealed a 1-year recurrence rate of 22%, with no patients reporting recurrent pain after 9 months of follow-up. Two patients (11%) reported new or increased facial numbness after retreatment, which was described as bothersome by one. Repeat SRS resulted in a median 60% improvement in quality of life, and 56% of patients believed that the procedure was successful. CONCLUSION: Despite a modest dose reduction, repeat SRS provided similar rates of complete pain control as the initial procedure, but was not effective for patients with no response to initial treatment. Repeat SRS was more efficacious for those patients who experienced longer periods of pain relief after the initial SRS. The incidence of complications was not significantly different from that observed for initial SRS. In this series, most patients had significant improvements in quality of life.

Constraining the brachial plexus does not compromise regional control in oropharyngeal carcinoma.

BACKGROUND: Accumulating evidence suggests that brachial plexopathy following head and neck cancer radiotherapy may be underreported and that this toxicity is associated with a dose-response. Our purpose was to determine whether the dose to the brachial plexus (BP) can be constrained, without compromising regional control. METHODS: The radiation plans of 324 patients with oropharyngeal carcinoma (OPC) treated with intensity-modulated radiation therapy (IMRT) were reviewed. We identified 42 patients (13%) with gross nodal disease <1 cm from the BP. Normal tissue constraints included a maximum dose of 66 Gy and a D05 of 60 Gy for the BP. These criteria took precedence over planning target volume (PTV) coverage of nodal disease near the BP. RESULTS: There was only one regional failure in the vicinity of the BP, salvaged with neck dissection (ND) and regional re-irradiation. There have been no reported episodes of brachial plexopathy to date. CONCLUSIONS: In combined-modality therapy, including ND as salvage, regional control did not appear to be compromised by constraining the dose to the BP. This approach may improve the therapeutic ratio by reducing the long-term risk of brachial plexopathy.

Larynx-sparing techniques using intensity-modulated radiation therapy for oropharyngeal cancer.

The purpose of the current study was to explore whether the laryngeal dose can be reduced by using 2 intensity-modulated radiation therapy (IMRT) techniques: whole-neck field IMRT technique (WF-IMRT) vs. junctioned IMRT (J-IMRT). The effect on planning target volumes (PTVs) coverage and laryngeal sparing was evaluated. WF-IMRT technique consisted of a single IMRT plan, including the primary tumor and the superior and inferior neck to the level of the clavicular heads. The larynx was defined as an organ at risk extending superiorly to cover the arytenoid cartilages and inferiorly to include the cricoid cartilage. The J-IMRT technique consisted of an IMRT plan for the primary tumor and the superior neck, matched to conventional antero-posterior opposing lower neck fields at the level of the thyroid notch. A central block was used for the anterior lower neck field at the level of the larynx to restrict the dose to the larynx. Ten oropharyngeal cancer cases were analyzed. Both the primary site and bilateral regional lymphatics were included in the radiotherapy targets. The averaged V95 for the PTV57.6 was 99.2% for the WF-IMRT technique compared with 97.4% (p = 0.02) for J-IMRT. The averaged V95 for the PTV64 was 99.9% for the WF-IMRT technique compared with 98.9% (p = 0.02) for J-IMRT and the averaged V95 for the PT70 was 100.0% for WF-IMRT technique compared with 99.5% (p = 0.04) for J-IMRT. The averaged mean laryngeal dose was 18 Gy with both techniques. The averaged mean doses within the matchline volumes were 69.3 Gy for WF-MRT and 66.2 Gy for J-IMRT (p = 0.03). The WF-IMRT technique appears to offer an optimal coverage of the target volumes and a mean dose to the larynx similar with J-IMRT and should be further evaluated in clinical trials.

Gabapentin for the treatment of pain syndrome related to radiation-induced mucositis in patients with head and neck cancer treated with concurrent chemoradiotherapy.

BACKGROUND: This retrospective study evaluated the efficacy of gabapentin for the treatment of pain syndromes related to radiation-induced mucositis in patients with head and neck cancers treated with concurrent chemoradiation. METHODS: Data from 42 patients with head and neck malignancies treated with concurrent chemoradiotherapy using an intensity-modulated radiotherapy technique were analyzed. Gabapentin was initiated in the second week of radiotherapy. Opiates were prescribed in addition to gabapentin as clinically indicated to obtain adequate pain control. RESULTS: At a median dose of 2700 mg/day of gabapentin, only 33% and 55% of patients required additional low-dose narcotic medications for pain control during the third and fourth week of treatment, respectively, despite exhibiting a grade 2 or higher mucositis in 71% and 86% of the patients, respectively. Furthermore, during the last weeks of treatment, 71% of the patients required additional low-dose opiates for adequate pain control, despite the presence of grade 2 or higher mucositis in 95% and 100% of patients at Weeks 5 and 6, respectively. Only 1 patient had a treatment-related interruption of >3 days during chemoradiotherapy. CONCLUSIONS: Gabapentin appears to be promising in reducing the need for high total doses of opioids and avoiding unplanned treatment interruptions for patients with head and neck malignancies treated with concurrent chemoradiotherapy and should be further evaluated prospectively in controlled clinical trials.

Gabapentin for the treatment of pain related to radiation-induced mucositis in patients with head and neck tumors treated with intensity-modulated radiation therapy.

BACKGROUND: This retrospective study evaluates the efficacy of gabapentin for the treatment of pain syndrome related to radiation-induced mucositis in patients with head and neck tumors. METHODS: Thirty cases of head and neck malignancies treated with radiotherapy were analyzed. RESULTS: By using a median dose of 2700 mg/day of gabapentin, only 10% of patients required additional narcotic pain medications for adequate pain relief during the third and fourth week of treatment, despite grade 2 or higher mucositis present in 56% and 73% of the patients, respectively. Likewise, during the last weeks of intensity-modulated radiation therapy (IMRT), only 35% of patients required additional narcotics for pain control, despite the presence of grade 2 or higher mucositis in 80% of cases. CONCLUSIONS: Gabapentin appears promising in reducing the need for narcotic pain medication for patients with head and neck malignancies treated with IMRT and should be further evaluated prospectively in controlled clinical trials.

Intracellular expression of the plasmid-encoded toxin from enteroaggregative Escherichia coli.

The plasmid-encoded toxin (Pet) from enteroaggregative Escherichia coli is a serine protease autotransporter that acts as an enterotoxin and cytotoxin. When applied to epithelial cells in culture, purified toxin induces cell elongation and rounding, followed by exfoliation of cells from the substratum. These effects are accompanied by loss of actin stress fibers and electrophysiologic changes. Although it has been hypothesized that Pet has an intracellular site of action, evidence for this is indirect. In addition, Pet has recently been shown to cleave spectrin in vitro and in vivo. If Pet requires intracellular localization to execute its toxic effects, then intracellular expression of the protein could induce cytopathic effects similar to those observed when the toxin is applied to the cell surface. To test this hypothesis, we expressed the mature Pet toxin (comprising only the passenger domain of the Pet precursor) in the cytoplasm of HEp-2 cells by using mammalian expression vectors. Separately, we expressed the Pet passenger domain mutated at the catalytic serine (PetS260A), a construct that has been reported to lack toxic effects. Forty-eight hours after transient transfection of pcDNA3.1-pet in HEp-2 cells, we observed cell elongation and other morphological changes similar to those induced by applied toxin. Cells transfected with pcDNA3.1 vector alone appeared normal, while cells expressing the PetS260A mutant displayed similar (though less pronounced) changes compared with those in cells expressing pcDNA3.1-pet. Notably, intracellular expression of Pet was accompanied by condensation of the spectrin cytoskeleton. These studies corroborate an intracellular site of action for the Pet toxin, further implicate a role for spectrin in Pet intoxication, and provide a powerful tool for Pet structure and function analyses.

Structure-function analysis of the enteroaggregative Escherichia coli plasmid-encoded toxin autotransporter using scanning linker mutagenesis.

The plasmid-encoded toxin (Pet) from enteroaggregative Escherichia coli is a cytopathic serine protease, which is prototypical of a large family of bacterial autotransporter toxins. To further elucidate the structure-function relationships of this toxin, we employed transposon-based scanning linker mutagenesis. A subset of insertions throughout the Pet mature toxin (passenger) domain reduced secretion to the extracellular space. Many of these mutants were undetectable, but secretion of a subset of mutants with insertions in the N-terminal half of the toxin could be restored to wild type secretion levels if cultured in the presence of 0.1% Triton X-100. Secretion of two mutants with insertions at the extreme C terminus was partially restored when co-expressed with a minimal clone of EspP, a related autotransporter protein. Several well secreted mutants with insertions in the N-terminal third of the molecule reduced protease activity over 20-fold, suggesting that the protease domain is located within this N-terminal region of Pet. We have also identified two insertional mutants in the middle of the passenger domain that were proteolytic but no longer cytopathic; these mutants displayed decreased binding and internalization upon incubation with HEp-2 cells. Our data suggest the existence of separate functional domains mediating Pet proteolysis, secretion, and cell interaction.

Functional comparison of serine protease autotransporters of enterobacteriaceae.

The plasmid-encoded toxin (Pet) of enteroaggregative Escherichia coli (EAEC) belongs to a family of high-molecular-weight serine protease autotransporters of Enterobacteriaceae (SPATEs) which also includes Pic from EAEC and Shigella flexneri, EspC from enteropathogenic E. coli, EspP from enterohemorrhagic E. coli, Sat from uropathogenic E. coli, Tsh from avian pathogenic E. coli, and SepA from S. flexneri. Phylogenetic analysis shows the SPATE proteins to represent a distinct subfamily of autotransporters with amino acid identities ranging from 35 to 55%, providing a powerful resource to direct structure-function studies. In this study, we show that these related proteins are proteases with divergent substrate specificities, suggesting different functions. The cleavage profile of oligopeptides was found to be unique for each SPATE protein. The SPATEs showed proteolytic activity for several substrates, namely mucin, pepsin, human coagulation factor V, and erythroid spectrin. The cleavage of spectrin has been hypothesized as the mechanism through which Pet induces cytopathic effects. However, whereas Pet, Sat, and EspC cleaved spectrin, only Pet and Sat elicited cytopathic effects; the remaining SPATEs did not cause any morphological changes to HEp-2 cell monolayers. EspC and Pet exhibited acid-dissociable binding to HEp-2 cells. However, Pet was more efficient at entering HEp-2 cells, suggesting a basis for the different abilities of these two proteases to damage cells. Our data suggest that, despite the homologies observed among these proteins, the SPATEs have different pathogenetic functions only partly dependent on their substrate specificities.