Citations

Abstract: Calciphylaxis is a rare, painful, and life-threatening condition with a high mortality rate. Although the etiology of calciphylaxis is not well understood, it has been proposed that calcium deposition within and around subcutaneous vessels restricts blood flow chronically, thereby predisposing the patient to acute pannicular and dermal thrombosis. Given increasing recognition of the role of hypercoagulability in calciphylaxis, this retrospective cohort study sought to evaluate the presence of thromboses and dermal angioplasia in calciphylaxis. Moreover, we aimed to validate previous observations about the histopathology of calciphylaxis compared with skin biopsies from patients with end-stage renal disease but without calciphylaxis. After a meticulous clinical chart review, we assessed the corresponding skin biopsies for the presence of vessel calcification, thromboses, and dermal angioplasia in skin biopsies from patients with calciphylaxis (n = 57) and compared with those from patients with end-stage renal disease but without calciphylaxis (n = 26). Histopathologic findings were correlated with clinical features such as chronic kidney disease, diabetes, or associated malignancy. Our results validated a prior observation that calciphylaxis was significantly more likely to show calcification of dermal vessels and diffuse dermal thrombi. This study reports the frequent finding of dermal angioplasia, a potential marker of chronic low-grade ischemia, as another frequent microscopic finding in calciphylaxis. Among cases of calciphylaxis, histopathologic changes in patients with chronic kidney disease were indistinguishable from those in patients without chronic kidney disease, thereby implying a final common pathogenic pathway in both uremic and nonuremic calciphylaxis. In future, larger, prospective studies may be useful in validating these findings.

Objectives/HypothesisDesign and test a novel biomaterial for injection laryngoplasty aimed to increase the duration of effectiveness of micronized acellular dermis.Study DesignAnimal model.MethodsInjection laryngoplasty was performed in three groups (n = 5) of New Zealand White rabbits. Acellular dermis was either used alone as a control (group 1), was combined with undifferentiated stem cells (group 2), or with predifferentiated chondrocytic cells (group 3). Groups 2 and 3 were supplemented with growth factors. Animals were sacrificed 4 and 12 weeks after laryngoplasty and histologic analysis was completed. The major outcome measure was volume of tissue remaining.ResultsAfter 4 weeks, the mean volume of tissue remaining was 341 ± 89 mm3, 295 ± 102 mm3, and 133 ± 15 mm3, for groups 1 to 3, respectively. At the 12‐week time point, volumes were 62 ± 62 mm3, 235 ± 35 mm3, and 107 ± 99 mm3. After 12 weeks, there was a significantly higher volume in group 2 compared to group 1 or 3 (P = .01, P = .04). Volumes between week 4 and week 12 were significantly lower in group 1 (P = .02), but not significantly different for groups 2 and 3 (P = .38, P = .74). Histologic evaluation revealed a robust lymphocytic infiltration in all cases as well as morphologic and immunophenotypic features suggestive of chondrogenic differentiation in a single animal.ConclusionsMicronized acellular dermis combined with stem cells and growth factors showed significantly less resorption 12 weeks after injection laryngoplasty compared to micronized acellular dermis alone. Groups using novel tissue‐engineered biomaterial showed a lower resorption rate over time compared with acellular dermis alone.Level of EvidenceNA. Laryngoscope, 128:160–167, 2018

Human papillomavirus (HPV)–related multiphenotypic sinonasal carcinoma (HMSC), originally known as HPV-related carcinoma with adenoid cystic carcinoma-like features, is a peculiar neoplasm that is restricted to the sinonasal tract, exhibits features of both a surface-derived and salivary gland carcinoma (particularly adenoid cystic carcinoma), and is associated with high-risk HPV. Given the limited number of published cases, the full clinicopathologic spectrum of this neoplasm is unclear. Here, we present an updated experience of 49 cases. All cases of HMSC were obtained from the authors’ files. Immunohistochemistry for p16, c-kit, and myoepithelial cell markers (S100, actin, calponin, p63, and/or p40) was performed along with RNA in situ hybridization for HPV (type 33-specific as well as a high-risk cocktail). Fluorescence in situ hybridization studies for fusions ofMYB,NFIB, andMYBL1was performed on a subset of cases. Clinical follow-up was obtained from medical records. A total of 49 cases of HMSC were collected. Twenty-eight (57%) were from women and 18 (43%) from men, ranging in age from 28 to 90 years (mean, 54 y). Of 40 cases with detailed staging information, 43% of HMSCs presented with a high T-stage (T3 or T4). Histologically, most grew predominantly as solid nests of basaloid cells exhibiting high mitotic rates and frequent necrosis, with histologic and immunohistochemical evidence of myoepithelial differentiation. Most cases also demonstrated foci of cribriform and/or tubular growth, along with an inconspicuous population of ducts. Thirty-four (69%) cases demonstrated an unusual pattern of surface involvement where markedly atypical squamous cells colonized tracts of the sinonasal mucosa. Less consistent histologic features included squamous differentiation within the invasive tumor (n=6), sarcomatoid transformation (n=5) including overt chondroid differentiation (n=3), and prominent epithelial-myoepithelial carcinoma-like growth (n=3). All cases were positive for p16 by immunostaining and HPV by RNA in situ hybridization. Thirty-three (67%) were positive for HPV 33. No cases tested forMYB,MYBL1, orNFIBgene fusions were positive. In the 38 cases with follow-up data, (mean follow-up, 42 mo) 14 recurred locally and 2 metastasized (lung, finger). There were no regional lymph node metastases, and no tumor-related deaths. HMSC is a distinct sinonasal neoplasm characterized by myoepithelial differentiation, frequent surface epithelial involvement, and the presence of high-risk HPV (especially type 33). Although it classically exhibits a cribriforming pattern that closely resembles adenoid cystic carcinoma, our expanded series highlights a histologic spectrum that is much broader than previously recognized, warranting a change in terminology. HMSC usually presents as a large and destructive sinonasal mass with high-grade histologic features, but it paradoxically behaves in a relatively indolent manner, underscoring the importance of distinguishing HMSC from true adenoid cystic carcinoma, squamous cell carcinoma, and other histologic mimickers.

Bone atrophy and its related fragility fractures are frequent, late side effects of radiotherapy in cancer survivors and have a detrimental impact on their quality of life. In another study, we showed that parathyroid hormone 1‐34 and anti‐sclerostin antibody attenuates radiation‐induced bone damage by accelerating DNA repair in osteoblasts. DNA damage responses are partially regulated by the ubiquitin proteasome pathway. In the current study, we examined whether proteasome inhibitors have similar bone‐protective effects against radiation damage. MG132 treatment greatly reduced radiation‐induced apoptosis in cultured osteoblastic cells. This survival effect was owing to accelerated DNA repair as revealed by γH2AX foci and comet assays and to the up‐regulation of Ku70 and DNA‐dependent protein kinase, catalytic subunit, essential DNA repair proteins in the nonhomologous end‐ joining pathway. Administration of bortezomib (Bzb) reversed the loss of trabecular bone structure and strength in mice at 4 wk after focal radiation. Histomorphometry revealed that Bzb significantly increased the number of osteoblasts and activity in the irradiated area and suppressed the number and activity of osteoclasts, regardless of irradiation. Two weeks of Bzb treatment accelerated DNA repair in bone‐lining osteoblasts and thus promoted their survival. Meanwhile, it also inhibited bone marrow adiposity. Taken together, we demonstrate a novel role of proteasome inhibitors in treating radiation‐induced osteoporosis.—Chandra, A., Wang, L., Young, T., Zhong, L., Tseng, W.‐J., Levine, M. A., Cengel, K., Liu, X. S., Zhang, Y., Pignolo, R. J., Qin, L. Proteasome inhibitor bortezomib is a novel therapeutic agent for focal radiation‐induced osteoporosis. FASEB J. 32, 52‐62 (2018). www.fasebj.org

Hypermobility may be associated with decreased lower extremity proprioception, which in turn may increase injury risk. The prevalence of hypermobility in dancers varies across studies, but joint hypermobility appears to be more common in dancers than in the general population. The purpose of this study was to determine how hypermobility affects eyes-closed single-limb balance as an indirect measure of proprioception in dancers. The secondary aim was to compare hypermobility and balance across dancer affiliation groups. Data were collected from 45 professional dancers, 11 collegiate modern dancers, 227 student dancers, and 15 pre-professional dancers during routine dance screens. Dancer hypermobility status was assessed via an eight-point Beighton-Horan Laxity test. Single-limb balance time, in seconds, was assessed in parallel position with the eyes closed. Hypermobile (HM) and non-hy-permobile (NHM) dancers showed very similar balance times (HM median: 36.5 seconds; NHM median: 33.0 seconds; p = 0.982). Hypermobility was not significantly different between dancer affiliation groups (p = 0.154): 47% in ballet academy students, 27% in collegiate modern dancers, 62% in pre-professional dancers, and 36% in professional dancers. The student, pre-professional, and professional ballet dancers all demonstrated longer balance times than the collegiate modern dancers; however, this difference was only significant between the professional ballet dancers and collegiate modern dancers (p = 0.026). Dancers demonstrated a higher prevalence of hypermobility than what has been reported for the general population. Joint hypermobility did not affect eyes-closed single-limb balance time. Future studies are needed to determine if joint hypermobility affects more sensitive measures of proprioception and risk of injury.

391 Background: Prior economic analysis of a 12-gene assay (Oncotype DX), compared with patterns of care reported in the NCCN database of patients with stage II, T3, DNA mismatch repair proficient (MMR-P) colon cancer, predicted that the assay would save medical costs and improve patient well-being (Hornberger et al., Value Health, 2012). This study assessed the validity of those findings with actual adjuvant chemotherapy (aCT) recommendations. Methods: Outcomes and costs were estimated for patients with stage II, T3, MMR-P colon cancer using a Markov model. A study of 141 patients from 17 sites in the Mayo Clinic Cancer Research Consortium collected data on aCT recommended before and after knowledge of the 12-gene assay results (Srivastava et al. abstract). Quality-adjusted life years (QALY) and medical resource use after recurrence were computed using guideline-validated state-transition probability estimation methods. Risk of progression and incidence of adverse events with different aCT regimens were based on published literature. Drug and administration costs for aCT were obtained from 2012 Medicare fee schedules. One-way sensitivity analyses were conducted to evaluate parameter influence on economic impact. Results: After receiving the 12-gene assay results, physician recommendations in favor of aCT decreased 22% (95% CI 11%-32%; McNemar test p<0.001) from 73 (52%) to 42 (30%) patients. Oxaliplatin aCT and 5-FU monotherapy recommendations each declined 11%. Average aCT costs decreased $5,738 for drugs, $668 for administration, and $3,268 for adverse events management. Overall, average total direct medical costs decreased $4,203. The net effect on average patient well-being was a gain of 0.083 QALYs. Total medical costs are most influenced by change in aCT recommendations, 5-FU monotherapy efficacy, and oxaliplatin drug acquisition cost. Savings are expected to persist even if the cost of oxaliplatin dropped by >75% due to generic substitution. Conclusions: The 12-gene assayhas been shown to alter aCT recommendations for patients with stage II, T3, MMR-P colon cancer. This study provides real-world confirmation that these changes in aCT reduce direct medical costs and improve patient well-being.

49 Background: Predicting nodal positivity can guide surgical planning in breast cancer. Memorial Sloan-Kettering Cancer Center (MSKCC) and MD Anderson Cancer Center (MDACC) have established nomograms to predict sentinel node positivity. We propose that addition of distance of tumor from the nipple (DFN) can improve their performance. Methods: With IRB approval clinical T1/T2 tumors with pre-biopsy ultrasound were reviewed. MSKCC and MDACC nomogram predictions and the AUC-ROC were calculated. The addition of DFN was examined using multiple logistic regression and comparison of AUC-ROC values. Results: 401 breast cancers with clinical T1 (85%) or T2 (15%) tumors in 395 patients were included; of which 79/401 (19.7%) were node positive. Tumors were significantly closer to the nipple in those with positive nodes. 17/33 (51.5%) tumors within 2 cm of the nipple were node-positive versus 62/368 (16.8%) tumors > 2 cm from the nipple (p<0.0001). The MSKCC and MDACC nomograms each demonstrated good discrimination between node positive and negative patients with AUC-ROC values of 0.71 (95% CI: 0.64-0.77) and 0.74 (95% CI: 0.68-0.81), respectively. When added to the MSKCC nomogram, DFN ≤2 cm contributed significantly (OR 4.78, p=0.0001) to prediction of node positivity and improved the AUC-ROC to 0.73 (95% CI: 0.67-0.80). Similarly, DFN ≤2 cm was significant (OR 4.73, p=0.0002) when added to the MDACC nomogram and improved the AUC to 0.76 (95% CI: 0.70-0.82). Within nomogram probability categories, the proportion with positive nodes was consistently higher with DFN ≤2 cm. Conclusions: Tumor distance from nipple is associated with nodal positivity. When added to nomograms it improves prediction of node positivity. DFN should be considered when considering likelihood of nodal positivity for treatment planning. [Table: see text]