Safety and Feasibility of Rehabilitation Interventions in Children Undergoing Hematopoietic Stem Cell Transplant With Thrombocytopenia.

OBJECTIVE: To analyze the relation between platelet counts, intensities of physical therapy (PT) and occupational therapy (OT) services received, and frequencies of bleeding complications in children undergoing hematopoietic stem cell transplant (HSCT) during a period of severe thrombocytopenia. DESIGN: Retrospective review study. SETTING: Tertiary care hospital. PARTICIPANTS: Children (N=63; age, <18y) hospitalized for HSCT in 2010 and 2011 who received PT and OT services while markedly thrombocytopenic (platelet count, ≤50K/mcL). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Intensities of PT and OT interventions, patients' platelet counts on specific therapy days, and any bleeding events (minor or major) that occurred during or shortly after rehabilitation interventions. RESULTS: Sixty-two patients (accounting for 63 HSCTs) met the criteria for analysis. Fifty-six of these patients (57 HSCTs) underwent PT and/or OT while markedly thrombocytopenic. There was no correlation between platelet counts and intensities of rehabilitation interventions. There were no major bleeding events. There was no association between minor bleeding events and intensities of PT or OT interventions and no association between minor bleeding events and platelet counts. Only 5 minor bleeding events occurred during or after moderate or intensive therapy out of 346 PT and OT sessions (1.5%). CONCLUSIONS: The results of our study suggest that bleeding complications during or after mobilization and supervised exercise during PT and OT in children with severe thrombocytopenia undergoing HSCT are minor and relatively rare. These are encouraging results for both patients and rehabilitation specialists treating this population who is at high risk of developing immobility-related complications.

Peripheral nervous system injury after high-dose single-fraction image-guided stereotactic radiosurgery for spine tumors.

OBJECTIVE The object of this study was to determine the percentage of high-dose (1800-2600 cGy) single-fraction stereotactic radiosurgery (SF-SRS) treatments to the spine that result in peripheral nervous system (PNS) injury. METHODS All patients treated with SF-SRS for primary or metastatic spine tumors between January 2004 and May 2013 and referred to the Rehabilitation Medicine Service for evaluation and treatment of neuromuscular, musculoskeletal, or functional impairments or pain were retrospectively identified. RESULTS Five hundred fifty-seven SF-SRS treatments in 447 patients resulted in 14 PNS injuries in 13 patients. All injures resulted from SF-SRS delivered to the cervical or lumbosacral spine at 2400 cGy. The overall percentage of SF-SRS treatments resulting in PNS injury was 2.5%, increasing to 4.5% when the thoracic spine was excluded from analysis. The median time to symptom onset following SF-SRS was 10 months (range 4-32 months). The plexus (cervical, brachial, and/or lumbosacral) was affected clinically and/or electrophysiologically in 12 (86%) of 14 cases, the nerve root in 2 (14%) of 14, and both in 6 (43%) of 14 cases. All patients experienced pain and most (93%) developed weakness. Peripheral nervous system injuries were CTCAE Grade 1 in 14% of cases, 2 in 64%, and 3 in 21%. No dose relationship between SF-SRS dose and PNS injury was detected. CONCLUSIONS Single-fraction SRS to the spine can result in PNS injury with major implications for function and quality of life.

Revision Distal Femoral Arthroplasty With the Compress(®) Prosthesis Has a Low Rate of Mechanical Failure at 10 Years.

BACKGROUND: Patients with failed distal femoral megaprostheses often have bone loss that limits reconstructive options and contributes to the high failure rate of revision surgery. The Compress(®) Compliant Pre-stress (CPS) implant can reconstruct the femur even when there is little remaining bone. It differs from traditional stemmed prostheses because it requires only 4 to 8 cm of residual bone for fixation. Given the poor long-term results of stemmed revision constructs, we sought to determine the failure rate and functional outcomes of the CPS implant in revision surgery. QUESTIONS/PURPOSES: (1) What is the cumulative incidence of mechanical and other types of implant failure when used to revise failed distal femoral arthroplasties placed after oncologic resection? (2) What complications are characteristic of this prosthesis? (3) What function do patients achieve after receiving this prosthesis? METHODS: We retrospectively reviewed 27 patients who experienced failure of a distal femoral prosthesis and were revised to a CPS implant from April 2000 to February 2013. Indications for use included a minimum 2.5 mm cortical thickness of the remaining proximal femur, no prior radiation, life expectancy > 10 years, and compliance with protected weightbearing for 3 months. The cumulative incidence of failure was calculated for both mechanical (loss of compression between the implant anchor plug and spindle) and other failure modes using a competing risk analysis. Failure was defined as removal of the CPS implant. Followup was a minimum of 2 years or until implant removal. Median followup for patients with successful revision arthroplasty was 90 months (range, 24-181 months). Functional outcomes were measured with the Musculoskeletal Tumor Society (MSTS) functional assessment score. RESULTS: The cumulative incidence of mechanical failure was 11% (95% confidence interval [CI], 4%-33%) at both 5 and 10 years. These failures occurred early at a median of 5 months. The cumulative incidence of other failures was 18% (95% CI, 7%-45%) at 5 and 10 years, all of which were deep infection. Three patients required secondary operations for cortical insufficiency proximal to the anchor plug in bone not spanned by the CPS implant and unrelated to the prosthesis. Median MSTS score was 27 (range, 24-30). CONCLUSIONS: Revision distal femoral replacement arthroplasty after a failed megaprosthesis is often difficult as a result of a lack of adequate bone. Reconstruction with the CPS implant has an 11% failure rate at 10 years. Our results are promising and demonstrate the durable fixation provided by the CPS implant. Further studies to compare the CPS prosthesis and other reconstruction options with respect to survival and functional outcomes are warranted. LEVEL OF EVIDENCE: Level IV, therapeutic study.

Carpal tunnel syndrome in breast cancer survivors with upper extremity lymphedema.

INTRODUCTION: Lymphedema has long been considered a risk factor for median nerve compression at the wrist and carpal tunnel syndrome (CTS). This association is based on limited and poor quality data. We analyzed the association between lymphedema and CTS. METHODS: Breast cancer survivors with upper extremity lymphedema and electrophysiologically confirmed CTS were assessed retrospectively. The severity of lymphedema was graded using the National Institutes of Health Common Terminology Criteria for Adverse Events (CTCAE) v4.03. The severity of CTS was graded in accordance with accepted criteria. RESULTS: Nineteen patients (38 sides) met the criteria for analysis. There was no association between presence of lymphedema and CTS (P = 0.66) or between lymphedema severity and CTS severity (P = 0.79). There were no cases of infection or worsening lymphedema as a result of needle EMG. CONCLUSIONS: These findings do not support lymphedema as an etiologic factor in the pathogenesis of CTS.

Carbon fiber intramedullary nails reduce artifact in postoperative advanced imaging.

OBJECTIVE: This study assessed whether radiolucent carbon fiber reinforced-polyetheretherketone (CFR-PEEK) intramedullary nails decreased hardware artifact on magnetic resonance imaging (MRI) and computed tomography (CT) in vitro and in an oncologic patient population. MATERIALS AND METHODS: In vitro and clinical evaluations were done. A qualitative assessment of metal artifact was performed using CFR-PEEK and titanium nail MRI phantoms. Eight patients with a femoral or tibial prophylactic CFR-PEEK nail were retrospectively identified. All patients had postoperative surveillance imaging by MRI, CT, and were followed for a median 20 months (range, 12-28 months). CFR-PEEK images were compared to images from a comparative group of patients with titanium femoral intramedullary nails who had a postoperative MRI or CT. A musculoskeletal-trained radiologist graded visualization of the cortex, corticomedullary junction, and bone-muscle interface, on T1-weighted (T1W), STIR, and contrast-enhanced T1-weighted fat-saturated (T1W FS) sequences of both groups with a five-point scale, performing independent reviews 4 months apart. Statistical analysis used the Wilcoxon rank-sum test and a weighted kappa. RESULTS: Substantially less MRI signal loss occurred in the CFR-PEEK phantom than in the titanium phantom simulation, particularly as the angle increased with respect to direction of the static magnetic field. CFR-PEEK nails had less MRI artifact than titanium nails on scored T1W, STIR, and contrast-enhanced T1W FS MRI sequences (p ≤ 0.03). The mean weighted kappa was 0.64, showing excellent intraobserver reliability between readings. CONCLUSIONS: CFR-PEEK intramedullary nail fixation is a superior alternative to minimize implant artifact on MRI or CT imaging for patients requiring long bone fixation.

Neither FDG-PET Nor CT can distinguish between a pathological complete response and an incomplete response after neoadjuvant chemoradiation in locally advanced rectal cancer: a prospective study.

OBJECTIVE: To prospectively compare the ability of flourodeoxyglucose-positron emission tomography (FDG-PET) and computed tomography (CT) to identify a pathological complete response (pCR) in patients with rectal cancer treated by chemoradiation. BACKGROUND: A major obstacle in pursuing nonoperative management in patients with rectal cancer after chemoradiation is the inability to identify a pCR preoperatively. METHODS: A total of 121 patients with rectal cancer were prospectively enrolled. FDG-PET scans and helical CT scans were obtained before and after neoadjuvant chemoradiation. Consensus readings of PET and CT scans were used to classify certainty of disease (5-point confidence rating scale). The ability of PET and CT scans to accurately distinguish a pCR (ypT0) from an incomplete response (ypT1-4) was estimated using the area under the receiver operating characteristic curve (AUC). RESULTS: Of the 121 patients, 26 (21%) had a pCR. PET and CT scans were equally inadequate at distinguishing a pCR from an incomplete response (AUC = 0.64 for both, P = 0.97). Among the 26 patients with a pCR, 14 (54%) and 5 (19%) were classified as complete responders on PET and CT scans, respectively. Among the 95 patients with an incomplete pathological response, 63 (66%) and 90 (95%) were classified as incomplete responders on PET and CT scans, respectively. None of the individual PET parameters, including visual response score, mean standard uptake value (SUVmean), maximum SUV (SUVmax), and total lesion glycolysis, accurately distinguished a pCR (AUCs = 0.57-0.73). CONCLUSIONS: Neither PET nor CT scans have adequate predictive value to be clinically useful in distinguishing a pCR from an incomplete response and, therefore, should not be obtained for the purpose of attempting to predict a pCR after neoadjuvant chemoradiation for rectal cancer.

Successful Rearing of Nutritionally Supplemented Rotifers (Brachionus plicatilis) at Reduced Salinity for Zebrafish (Danio rerio) Polyculture.

Rotifers, Brachionus plicatilis, are a valuable first exogenous feed for zebrafish because they can provide continuous nutrition for growing zebrafish larvae when used in a rotifer-zebrafish polyculture. Typically cultured at high salinities (>10 ppt), B. plicatilis are temporarily immobilized when moved to lower salinities (5 ppt) used for polycultures, decreasing their accessibility and attractiveness to the larvae. The nutritional value of rotifers varies based on their diet, typically live algae, which has limited nutritional value and may pose biosecurity risks. After confirming that rotifers consume and can reproduce when fed an irradiated, processed larval fish diet (PD), they were reared at 5 or 15 ppt, and fed various combinations of an algae mix and/or PD. Population densities and percentages of egg-bearing rotifers were quantified daily until the population density plateaued, and then their nutritional value was assessed. Results indicated that rotifers thrived at both salinities. Those fed PD were successfully maintained at >500 rotifers per mL and contained a greater ω-6/ω-3 fatty acid ratio. Our findings indicate that enriching rotifers with PD raised at 5 ppt can potentially eliminate rotifer immobilization in polyculture, while providing a nutritious, attractive diet for zebrafish larvae and decreasing biosecurity risks.

Hypoxia-related proteins in patients with rectal cancer undergoing neoadjuvant combined modality therapy.

BACKGROUND: We have previously demonstrated the prognostic significance of rectal cancer pathologic response to neoadjuvant chemoradiation. Recent studies in other cancers have reported that hypoxia influences response to neoadjuvant chemoradiation. OBJECTIVE: This study aimed to 1) characterize hypoxia-related protein expression in locally advanced rectal cancer before neoadjuvant chemoradiation, 2) determine the comodulation of hypoxia-related protein expression, and 3) evaluate the relationship between hypoxia-related protein expression and overall survival, time to recurrence, and tumor regression grade. DESIGN: Immunohistochemical analysis of 4 hypoxia-related proteins (HIF-1α, CA-IX, VEGF, and GLUT-1) was performed on archival pretreatment rectal cancer biopsies. PATIENTS: : Eighty-five patients with locally advanced rectal cancer treated with neoadjuvant radiation and 5-fluorouracil-based chemotherapy were included. MAIN OUTCOME MEASURES: The impact of hypoxia-related protein expression on outcome was evaluated by use of Cox proportional hazards model. Hypoxia-related protein expression was correlated with tumor regression grade by use of Spearman correlation coefficients. RESULTS: Median follow-up was 54 months. CA-IX expression was associated with overall survival (p = 0.01). HIF-1α expression was weakly correlated with VEGF (r = 0.26, p = 0.02) and GLUT-1 (r = 0.35, p = 0.001). Hypoxia-related protein expression was not associated with time to recurrence or Mandard tumor regression grade. CONCLUSIONS: Elevated CA-IX expression may be associated with poorer overall survival in locally advanced rectal cancer treated by neoadjuvant chemoradiation and resection. The expression of the hypoxia-related proteins HIF-1α, VEGF, and GLUT-1 may be comodulated in locally advanced rectal cancer. Further studies are needed to evaluate the mechanisms governing hypoxia regulation and the role of hypoxia in rectal cancer response to neoadjuvant chemoradiation.

FDG-PET assessment of rectal cancer response to neoadjuvant chemoradiotherapy is not associated with long-term prognosis: a prospective evaluation.

BACKGROUND: At present there is no defined role for routine FDG-PET in the preoperative evaluation of nonmetastatic rectal cancer. OBJECTIVE: The primary objective of this study was to evaluate the ability of FDG-PET to predict long-term prognosis based on the response to neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer. DESIGN: This was a prospective study. SETTINGS: This study was performed at an academic, tertiary care, comprehensive cancer center. PATIENTS: One hundred twenty-seven patients with locally advanced rectal cancer were enrolled between September 1999 and December 2005. INTERVENTIONS: All patients underwent FDG-PET scans before and after neoadjuvant chemoradiotherapy. MAIN OUTCOME MEASURES: FDG-PET parameters were evaluated by at least 2 study board-certified nuclear medicine physicians, and included mean standard uptake value, maximum standard uptake value, total lesion glycolysis, and visual response score. The main outcome measures were time to recurrence and disease-specific survival. RESULTS: Of 127 patients, 82 (65%) were men, the median age was 60 years (range, 27-82), 110 patients had stage II/III disease, and 17 patients had stage IV disease. Median follow-up among survivors was 77 months (range, 1-115 months). Nine patients had unresectable metastatic disease and were excluded from the time-to-recurrence analysis. At 5 years, 74% (95% CI = 66%-81%) of patients had not had recurrences (locally and/or distantly). The 5-year disease-specific survival was 89% (95% CI = 81%-93%). On univariate analysis, visual response score and time to recurrence came closest to having an association (HR = 0.83, 95% CI = 0.68-1.01, p = 0.06). On multivariate analysis, the visual response score was not significant (p = 0.85). No FDG-PET parameter was associated with disease-specific survival. CONCLUSIONS: Assessment of rectal cancer response to neoadjuvant chemoradiotherapy by FDG-PET provides no prognostic information. Therefore, serial FDG-PET before and after neoadjuvant chemoradiotherapy should not be performed for this purpose.

Morbidity of sentinel node biopsy: relationship between number of excised lymph nodes and patient perceptions of lymphedema.

BACKGROUND: Sentinel lymph node biopsy (SLNB) is associated with reduced morbidity, although lymphedema remains a significant complication. Previously, we found no association between number of excised lymph nodes (LNs) and measured lymphedema in SLNB patients. In this analysis, we examined the relationship between number of LNs excised during SLNB and patient-perceived lymphedema. METHODS: A total of 600 women who underwent SLNB for breast cancer were prospectively studied. Measured lymphedema was evaluated by circumferential bilateral upper-extremity measurements taken preoperatively and 3-8 years postoperatively. Patient-perceived lymphedema was evaluated by interview at follow-up. The relationship between lymphedema, total LNs excised, and clinicopathologic variables was assessed with Fisher's exact test, Wilcoxon rank-sum test, kappa statistic, and McNemar's test. RESULTS: At a median of 5 years, 18 (3%) patients reported perceived lymphedema. More LNs were excised in patients with perceived lymphedema compared with those without (median, 5.5 vs. 3; p = 0.01). Only 6 of 18 women with perceived lymphedema had objectively measured lymphedema (kappa = 0.22). Patients with numbness more likely reported perceived lymphedema (p = 0.03) and had more LNs excised (p = 0.02). Women with surgery on the nondominant axilla were less likely to perceive arm swelling, regardless of the presence of measured lymphedema. CONCLUSIONS: After SLNB alone, patient-perceived lymphedema is uncommon, but its prevalence increases with more LNs excised. There is poor agreement between patient perceptions and objective measures. Our data suggest that factors other than limb enlargement, such as sensory nerve injury resulting from retrieval of more LNs and laterality of surgery, may play a significant role in patient perception of lymphedema after SLNB.

Tissue expander breast reconstruction is not associated with an increased risk of lymphedema.

BACKGROUND: Recent reports have demonstrated that lymphedema can occur after even minor pertubation of the axillary region such as sentinel lymph node biopsy (SLNB). The impact of breast reconstruction on the development of lymphedema, however, remains unknown. Therefore, the purpose of this study was to determine the impact of immediate tissue expander breast reconstruction on the risk of developing lymphedema. MATERIALS AND METHODS: We identified patients who had undergone mastectomy with SLNB or SLNB and axillary lymph node dissection (ALND) with or without breast reconstruction using our prospectively maintained lymphedema and breast reconstruction databases. The development of lymphedema was evaluated prospectively using arm measurements and a validated questionnaire. Associations between variables were examined. Logistic regression was used to examine the association of reconstruction on prevalence of lymphedema while adjusting individually for BMI, age, and weight gain after surgery. RESULTS: Characteristics of patients with or without reconstruction were similar except for age, BMI, and weight gain since surgery. Median follow-up was 5 years. Among patients treated with mastectomy with SLNB or SLNB/ALND, those undergoing reconstruction had a lower rate of measured lymphedema than those who did not (5% vs. 18%, P < .0004). The reconstructed group also had fewer patients with both measured and self-reported lymphedema (3% vs. 12%, P < .002). Differences in the rates of measured lymphedema between groups persisted following univariate logistical regression for differences in age, BMI, and weight gain. CONCLUSIONS: Tissue expander breast reconstruction in patients undergoing SLNB or SLNB/ALND does not increase the risk of developing measured or perceived lymphedema.

Morbidity of sentinel node biopsy in breast cancer: the relationship between the number of excised lymph nodes and lymphedema.

BACKGROUND: Despite the reduced morbidity associated with sentinel lymph node biopsy (SLNB), lymphedema remains a clinically relevant complication. We hypothesized that a higher number of lymph nodes (LNs) removed during SLNB is associated with a higher risk of lymphedema. METHODS: Six hundred patients with clinically node-negative breast cancer who underwent SLNB were prospectively studied. Circumferential bilateral upper extremity measurements were performed preoperatively and at 3-8 years after surgery. Association of lymphedema with total number of LNs excised and other clinicopathologic variables was analyzed by the Spearman rank correlation coefficient, Fisher's exact test, Wilcoxon rank sum test, and logistic regression. RESULTS: At a median follow-up of 5 years, 5% of patients had developed lymphedema. Factors associated with lymphedema included weight and body mass index. There was no association between the number of LNs removed and the change in upper extremity measurements or in the incidence of lymphedema. Among patients with lymphedema (n = 31) compared to those without, the mean (3.9 vs. 4.2), median (4 vs. 3), and range (1-9 vs. 1-17) of number of LNs removed were similar (P = 0.93). Among the 33 women with ≥ 10 LNs removed, none developed lymphedema. CONCLUSIONS: In this population of 600 women who underwent SLNB, there is no correlation between number of LNs removed and change in upper extremity circumference or incidence of lymphedema. These data suggest that other factors, such as the global disruption of the lymphatic channels during axillary lymph node dissection, play a larger role in development of lymphedema than does the number of LNs removed.

A preliminary report on the efficacy of a dynamic jaw opening device (dynasplint trismus system) as part of the multimodal treatment of trismus in patients with head and neck cancer.

OBJECTIVE: To examine the effectiveness of a dynamic jaw opening device as part of a multimodal treatment strategy for trismus in patients with head and neck cancer. DESIGN: Retrospective cohort study. SETTING: Tertiary care cancer center. PARTICIPANTS: Patients with head and neck cancer and trismus (N=20). INTERVENTION: All patients underwent assessment by a board-certified physiatrist and were referred to physical therapy for delivery of the DTS and instructed to progress use of the DTS to 30 minutes 3 times a day. Additional modalities for the treatment of trismus including pain medications and botulinum toxin injections were prescribed as clinically indicated. MAIN OUTCOME MEASURES: Change in maximal interincisal distance (MID) as documented in the medical record. RESULTS: The use of the DTS as part of multimodal therapy including physical therapy, pain medications, and botulinum toxin injections as deemed clinically appropriate resulted in an overall improvement of the MID from 16.5mm to 23.5mm (P<.001). Patients who could comply with the treatment recommendations for DTS treatment did better than those who could not, with an improvement of the MID from 16 mm to 27 mm (P<.001) versus 17 mm to 22 mm (P=.88). CONCLUSIONS: The DTS is a safe and effective component of a multimodal strategy for improving trismus associated with head and neck cancer and its treatment. Further investigation is needed to determine the relative efficacy of the treatment modalities available for trismus including physical therapy and other jaw stretching devices.

Impact of Pronase, Sodium Thiosulfate, and Methylene Blue Combinations on Development and Survival of Sodium Hypochlorite Surface-Disinfected Zebrafish (Danio rerio) Embryos.

Embryo surface disinfection is utilized in aquaculture to decrease the risk of pathogen introduction into established colonies. Zebrafish embryos are commonly disinfected with unbuffered sodium hypochlorite at 25-50 ppm for 10 min with or without concurrent treatment with chemicals, including pronase (Pron), sodium thiosulfate, and/or methylene blue; however, the impact of these chemicals on embryo survival and development has not been evaluated. In this study, AB and casper embryos were exposed to disinfection protocols that used Pron, sodium thiosulfate, and/or methylene blue (given alone, in various combinations, or all three combined) with 50 and 100 ppm sodium hypochlorite performed 6 and 24 h postfertilization (HPF). All groups were evaluated for survival, hatching, and malformations at 5 days postfertilization. Maximal survival (69%-97%) and hatching rates (66%-94%) were generally observed with sodium hypochlorite disinfection followed by exposure to both Pron and sodium thiosulfate and maintenance in standard embryo medium without methylene blue. Methylene blue had variable effects on survival and hatching. Higher survival and hatching rates were seen in AB embryos disinfected at 6 HPF and casper embryos disinfected at 24 HPF. Susceptibility to sodium hypochlorite toxicity differed by strain, emphasizing the need to test disinfection protocols on small embryo cohorts.

Definitive maxillary obturator prosthesis: Timelines for fabrication and follow-up.

INTRODUCTION: A definitive maxillary obturator prosthesis can be used to rehabilitate a maxillary defect with the aim of improving speech, deglutition, and elimination of oronasal regurgitation. The aims of this study were (1) to determine the time required to fabricate a definitive maxillary obturator prosthesis and (2) to compare the fabrication and follow-up times between a patient's first and second definitive maxillary obturator prosthesis. MATERIALS AND METHODS: A retrospective review was completed of patients that had maxillary definitive obturators fabricated following head and neck surgery from 2002 to 2018 (n = 173). Demographics, clinical data, date of surgery, start date of fabrication, follow-up dates, and prosthesis follow-up data were collected. RESULTS: The median time to delivery of the patient's first definitive maxillary obturator prosthesis from the date of surgery was 7.7 months for nonradiated patients and 9.6 months for radiated patients (P ≤ .05). Additionally, there was a significant difference in the median number of appointments to fabricate the 1st definitive maxillary obturator prosthesis as compared to the 2nd prosthesis (6 vs 5; P ≤ .05). CONCLUSION: Fabrication timelines differed based on history of radiotherapy and patient experience. This data is helpful to set expectations for patients and practitioners regarding the process for prosthesis fabrication and follow-up.

Frequency and distinctive spectrum of KRAS mutations in never smokers with lung adenocarcinoma.

PURPOSE: KRAS mutations are found in approximately 25% of lung adenocarcinomas in Western countries and, as a group, have been strongly associated with cigarette smoking. These mutations are predictive of poor prognosis in resected disease as well as resistance to treatment with erlotinib or gefitinib. EXPERIMENTAL DESIGN: We determined the frequency and type of KRAS codon 12 and 13 mutations and characterized their association with cigarette smoking history in patients with lung adenocarcinomas. RESULTS: KRAS mutational analysis was done on 482 lung adenocarcinomas, 81 (17%) of which were obtained from patients who had never smoked cigarettes. KRAS mutations were found in 15% (12 of 81; 95% confidence intervals, 8-24%) of tumors from never smokers. Similarly, 22% (69 of 316; 95% confidence intervals, 17-27%) of tumors from former smokers, and 25% (21 of 85; 95% confidence intervals, 16-35%) of tumors from current smokers had KRAS mutations. The frequency of KRAS mutation was not associated with age, gender, or smoking history. The number of pack years of cigarette smoking did not predict an increased likelihood of KRAS mutations. Never smokers were significantly more likely than former or current smokers to have a transition mutation (G-->A) rather than the transversion mutations known to be smoking-related (G-->T or G-->C; P < 0.0001). CONCLUSIONS: Based on our data, KRAS mutations are not rare among never smokers with lung adenocarcinoma and such patients have a distinct KRAS mutation profile. The etiologic and biological heterogeneity of KRAS mutant lung adenocarcinomas is worthy of further study.

Osteonecrosis of the maxilla and mandible in patients with advanced cancer treated with bisphosphonate therapy.

Cases of osteonecrosis of the jaw (ONJ) have been reported with an increasing frequency over the past 5 years. ONJ is most often identified in patients with cancer who are receiving intravenous bisphosphonate (IVBP) therapy, but it has also been diagnosed in patients receiving oral bisphosphonates for nonmalignant conditions. To further categorize risk factors associated with ONJ and potential clinical outcomes of this condition, we performed a retrospective study of patients with metastatic bone disease treated with intravenous bisphosphonates who have been evaluated by the Memorial Sloan-Kettering Cancer Center Dental Service between January 1, 1996 and January 31, 2006. We identified 310 patients who met these criteria. Twenty-eight patients were identified as having ONJ at presentation to the Dental Service and an additional 7 patients were subsequently diagnosed with ONJ. Statistically significant factors associated with increased likelihood of ONJ included type of cancer, duration of bisphosphonate therapy, sequential IVBP treatment with pamidronate followed by zoledronic acid, comorbid osteoarthritis or rheumatoid arthritis, and benign hematologic conditions. Our data do not support corticosteroid use or oral health as a predictor of risk for ONJ. Clinical outcomes of patients with ONJ were variable with 11 patients demonstrating improvement or healing with conservative management. Our ONJ experience is presented here.

Transmission of Pseudoloma neurophilia in Laboratory Zebrafish (Danio rerio) When Using Mass Spawning Chambers and Recommendations for Chamber Disinfection.

Pseudoloma neurophilia, a microsporidium that primarily infects neural tissues, is a common pathogen in laboratory zebrafish. The risk of parasite transmission with different spawning apparatuses and the effectiveness of disinfection are unknown. In this study, we spawned uninfected zebrafish with P. neurophilia-infected zebrafish in either 50 L mass spawning chambers (MSCs) or 1 L standard breeding tanks (BTs). Fish were spawned once or thrice, with and without chamber disinfection between uses, to evaluate risk of vertical and horizontal transmission. Six disinfection protocols were tested to determine which effectively eliminated residual spores. We demonstrated that three consecutive uses of an MSC significantly increased the risk of transmission to other fish when compared to the use of BTs or only one spawning event in an MSC (both p < 0.0001). Vertical transmission was not detected with any method. Disinfection with ∼100 ppm bleach soak (pH ∼7.0), 75 ppm Wescodyne® soak, and 175 ppm Wescodyne Plus spray was 100% effective in eliminating spores from the MSCs. Disinfection of MSCs before spawning did not decrease P. neurophilia transmission when infected fish remained present in the breeding population. Researchers should avoid using endemically infected fish in MSCs to minimize transmission of pathogens within their colonies.

Ivermectin-compounded Feed Compared with Topical Moxidectin-Imidacloprid for Eradication of Demodex musculi in Laboratory Mice.

Demodex musculi is a prostigmatid follicular mite that has rarely been reported in laboratory mice. Although prevalence of this species has not been assessed formally, we have found that many imported mouse strains from noncommercial sources harbor Demodex mites. To assess whether an acaricide can be used to eradicate this mite, infested immunocompromised mice were provided ivermectin-compounded (12 ppm) feed without restriction for 8 wk (n = 10), were treated topically with moxidectin and imidacloprid (MI; 3 and 13 mg/kg, respectively) weekly for 8 wk (n = 10), or remained untreated (n = 10). Mice were confirmed to be mite-infested before treatment and were tested after treatment by using fur plucks (FP), deep skin scrapes (DSS), and PCR analysis of fur swabs. In addition, the presence of mites was confirmed through skin biopsies at 2 study endpoints (1 wk [n = 5] and 12 wk [ n = 5] after treatment). Samples collected before treatment and from untreated mice were positive for D. musculi at all time points and by all test modalities. After treatment, all ivermectin-treated animals remained infested, whereas mice treated with MI were repeatedly negative by all test modalities. An additional shortened treatment trial revealed that 4 wk of MI (n = 7) was insufficient to eradicate mites. Neither treatment produced any evidence of adverse effects according to hematology, serum chemistry parameters, behavior, body weight, and histopathology. Of the 70 PCR assays performed in treated mice, 14 were positive when FP+DSS was negative. In 6 cases where PCR results were negative, 5 were positive by FP+DSS and a single sample was positive on skin biopsy. Although PCR analysis has a high detection rate for D. musculi, FP+DSS can further enhance the detection rate. In conclusion, topical MI administered for 8 consecutive weeks can safely eradicate D. musculi from an immunocompromised mouse strain.