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Aim: Doxorubicin/Cyclophosphamide (AC) is one of the standard adjuvant anthracycline-containing regimens that is still in use for breast cancer treatment. Cancer cell resistance and AC-induced side effects make treatment suboptimal and worsen patients' quality of life. This study aimed to improve trans-ferulic acid's (TFA) efficiency via loading into folate-receptor-targeted-poly lactic-co-glycolic acid nanoparticles (FA-PLGA-TFA NPs). Also, investigating both the antitumor efficacy of Doxorubicin (Dox)/FA-PLGA-TFA NPs combination against dimethylbenz[a]anthracene (DMBA)-induced breast cancer and its safety profile., Methods: FA-PLGA-TFA NPs were optimally fabricated and characterized. Levels of Notch1, Hes1, Wnt-3a, β-catenin, MMP-9, cyclin D1, Permeability-Glycoprotein (P-gp), ERα, PR, and HER2 were assessed as a measure of the antitumor efficacy of different treatment protocols. Histopathological examination of heart and bone, levels of ALT, AST, ALP, CK-MB, and WBCs count were evaluated to ensure the combination's safety profile., Key Findings: Dox/FA-PLGA-TFA NPs not only inhibited Notch signaling but also suppressed Notch synergy with Wnt, estrogen, progesterone, and HER2 pathways. Interestingly, Dox/FA-PLGA-TFA NPs decreased P-gp level and preserved heart, bone, and liver health as well as WBCs count., Significance: Dox/FA-PLGA-TFA NPs reduced the side-effects of each single drug, and at the same time exerted excellent antitumor activity that surpass the AC regimen in evading cancer cell resistance and having a superior safety profile., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

In recent decades, the fabrication of composite membranes using nanoparticles has played a vital role in membrane distillation (MD) technique. It could make available membranes with superior characteristics as excellent candidates for MD technique. The most well-known obstacles regarding the MD method are the low productivity and high cost. Thus, fabricating membranes with superior properties is a significant challenge. In the current study, a composite membrane has been fabricated using 0.25, 0.5, and 0.75 weight percent (wt.%) of graphene nanoparticles (GNPs) with polystyrene (PS) as a base polymer and characterized using SEM, FTIR, and contact angle. The characterization results prove the successful fabrication using electrospinning and the validity of the fabricated membranes to be applied to direct contact membrane distillation (DCMD). In addition, a DCMD experimental setup has been designed to examine the performance of the fabricated membranes and compare the performance of blank PS with composite PS/GNPs membranes. The results show that all fabricated membranes produced an approximately similar average flux of about 10 kg/m 2 h, while the highest GNPs wt.% showed the highest salt rejection. Accordingly, this composite membrane has been examined at different operating parameters and showed stable performance. Moreover, feed temperature and the rate of flow have a positive impact on the overall performance of the DCMD.

Membrane distillation is an active technique that provides pure water with very good rejection and could be applied to water of extremely high salinity. The low productivity of membrane distillation needs intensive efforts to be competitive with other desalination techniques. In this current study, a composite (PS/GNP) membrane, which is composed of polystyrene (PS) based and 0.25% weight percent graphene nanoplates (GNP) has been fabricated via electrospinning and compared with the blank PS membrane. SEM, FTIR, contact angle and porosity characterization have been performed, and the results show that the validity of the predefined conditions, and the contact angle of the composite membrane, which is found to be 91.68°, proved the hydrophobic nature of the composite membrane. A numerical simulation using Ansys 2020 software has been introduced to study the performance of the fabricated composite membrane when used in direct contact membrane distillation (DCMD). The numerical model has been validated with experimental work from the literature and showed an excellent match. The blank PS and composite PS/GNP membranes have been investigated and compared at different operating conditions, i.e., hot water supply temperature and system flow rate. The results show that the composite PS/GNP membrane outperforms the blank PS membrane at all studied operating conditions.

Objective: To comprehensively examine the prognostic significance of extranodal extension (ENE) in human papillomavirus-positive oropharyngeal squamous cell carcinoma (HPV-positive OPSCC)., Methods: Retrospective cohort of cases diagnosed with HPV-positive OPSCC from 2010 to 2015 in the National Cancer Database. Inclusion of all OPSCC HPV-positive cases with appropriate International Classification of Diseases-0-3 codes that received surgery with a neck dissection. Univariate and multivariable analyses were conducted. Hazard ratios (HR) for the independent effects of ENE and N stage on overall survival were estimated by Cox proportional hazards regression., Results: Cases that were ENE-negative had the highest 5-year survival (92.6%; 95% confidence interval [CI]: 90.5%-94.7%). ENE-positive cases had the lowest 5-year survival (84.0%; 95% CI: 80.7%-87.4%). After adjusting for confounding variables, ENE-positivity was associated with almost twice the hazard of death (HR = 1.90; 95% CI: 1.35-2.67) compared to ENE-negative cases. Nodal (N) category 1, ENE-positive status was associated with an increased risk of death (HR = 1.88; 95% CI: 1.26-2.80) compared with N1, ENE-negative status. Compared to N1/ENE-negative cases, N2/ENE-positive cases had the poorest survival (HR: 2.93; 95% CI: 1.94-4.43). Both microscopic and macroscopic ENE were associated with worse outcomes compared to node-positive/ENE-negative status., Conclusion: The implementation of the American Joint Committee on Cancer 8th edition staging system provides a much-improved framework to develop and discuss treatment plans for HPV-positive OPSCC. We feel that careful consideration should be given to the importance of ENE in patients with HPV-positive OPSCC., Level of Evidence: 4 Laryngoscope, 130:939-945, 2020., (© 2019 The American Laryngological, Rhinological and Otological Society, Inc.)

Distant metastases are relatively common in breast cancer, but spread to the head and neck region is uncommon and can be diagnostically challenging. Pathology databases of two academic hospitals were searched for patients. The diagnoses were by morphologic comparison with the primary breast specimen (when available) or through the use of immunohistochemical stains characteristic of breast carcinoma (cytokeratin 7, mammaglobin, GCDFP15, and/or GATA3 positive-excluding new primary tumors at the respective head and neck sites). Of the 25 patients identified, only 22 (88.0 %) had a known history of breast carcinoma. Time from primary diagnosis to head and neck metastasis was highly variable, ranging from 1 to 33 years (mean = 10.9 years). The most common locations were neck lymph nodes (8 cases), orbital soft tissue (5), oral cavity (3), skull base (3), mastoid sinus (2), nasal cavity (1), palatine tonsil (1), and facial skin (1). Clinical presentations were highly variable, ranging from cranial nerve palsies without a mass lesion to oral cavity erythema and swelling to bone pain. Histologically, two cases showed mucosal (or skin)-based mass lesions with associated pagetoid spread in the adjacent epithelium, a feature normally associated with primary carcinomas. Three tumors were misdiagnosed pathologically as new head and neck primary tumors. This series demonstrates the extreme variability in clinical and pathologic features of breast cancer metastatic to the head and neck, including long time intervals to metastasis.

The BRAF mutation occurs commonly in papillary thyroid carcinoma (PTC). Previous investigations of its utility to predict recurrence-free survival (RFS) and disease-specific survival (DSS) have reported conflicting results and its role remains unclear. The purpose of this retrospective study was to determine the incidence of the BRAF mutation and analyze its relationship to clinicopathologic risk factors and long-term outcomes in the largest, single-institution American cohort to date. BRAF mutational status was determined in 508 PTC patients using RFLP analysis. The relationships between BRAF mutation status, patient and tumor characteristics, RFS, and DSS were analyzed. The BRAF mutation was present in 67% of patients. On multivariate analysis, presence of the mutation predicted only for capsular invasion (HR, 1.7; 95% CI, 1.1-2.6), cervical lymph node involvement (HR, 1.7; 95% CI, 1.1-2.7), and classic papillary histology (HR, 1.8; 95% CI 1.1-2.9). There was no significant relationship between the BRAF mutation and RFS or DSS, an observation that was consistent across univariate, multivariate, and Kaplan-Meier analyses. This is the most extensive study to date in the United States to demonstrate that BRAF mutation is of no predictive value for recurrence or survival in PTC. We found correlations of BRAF status and several clinicopathologic characteristics of high-risk disease, but limited evidence that the mutation correlates with more extensive or aggressive disease. This analysis suggests that BRAF is minimally prognostic in PTC. However, prevalence of the BRAF mutation is 70% in the general population, providing the opportunity for targeted therapy., (© 2015 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Sarcomatoid carcinomas are rare malignancies which represent poorly differentiated epithelial tumors that may be difficult to recognize as such. While some cases may have obvious epithelial areas, the sarcomatoid areas are poorly distinguishable from true sarcoma at the light microscopic level and, by immunohistochemistry, often show only limited staining for traditional epithelial markers such as cytokeratin or epithelial membrane antigen. This can be particularly problematic for diagnosis on small biopsy specimens. We sought to assess the diagnostic utility of several immunohistochemical markers of epithelial differentiation including p63, MOC-31, and thyroid transcription factor-1 on sarcomatoid carcinomas of the head and neck (19 cases; 'spindle cell carcinomas'), lung (19 cases), and urinary bladder (11 cases). These results were compared to immunohistochemistry for the traditional epithelial markers pan-cytokeratin and epithelial membrane antigen. Staining for p63 showed the greatest diagnostic utility, positive in 63, 50, and 36% of head and neck, lung, and urinary bladder sarcomatoid carcinomas, respectively. p63 stains were positive in many cases where immunohistochemistry was negative for both pan-cytokeratin and epithelial membrane antigen. All three alternative markers were quite specific for epithelial differentiation, each staining less than 10% of the control group of 73 various primary and metastatic sarcomas, melanomas, and benign spindle cell lesions. In conclusion, immunostaining beyond traditional pan-cytokeratin and epithelial membrane antigen may have diagnostic utility in this context., (Modern Pathology (2005) 18, 1471-1481. doi:10.1038/modpathol.3800451; published online 10 June 2005.)

The term juvenile ossifying fibroma is used in the literature in naming 2 microscopically distinct fibro-osseous lesions of the craniofacial skeleton. One is characterized by small uniform spherical ossicles resembling psammoma bodies (psammomatoid juvenile ossifying fibroma). The other is distinguished by trabeculae of fibrillary osteoid and woven bone (trabecular juvenile ossifying fibroma). Three new cases of each type are reported, and the literature is extensively reviewed for published cases of these 2 entities.Psammomatoid juvenile ossifying fibroma is reported more commonly than trabecular juvenile ossifying fibroma. It affects patients from a wider age range (3 months to 72 years) and an older mean age range (16-33 years) as compared with 2 to 12 years and 8(1/2) to 12 years, respectively, for trabecular juvenile ossifying fibroma. In both types there is a slight male predominance and the lesions are unencapsulated and tend to infiltrate adjacent bone. A significant difference between the 2 tumors is their site of occurrence. Although psammomatoid juvenile ossifying fibroma occurs predominantly in the sinonasal and orbital bones, trabecular juvenile ossifying fibroma predominantly affects the jaws. Aggressive growth occurs in some-but not all-cases of both types. Such behavior may be related to younger patient age and the concurrent development of aneurysmal bone cysts, which is seen more frequently in psammomatoid juvenile ossifying fibroma. This study demonstrates that not only histologic but also demographic and clinical differences between psammomatoid juvenile ossifying fibroma and trabecular juvenile ossifying fibroma warrant their classification as 2 distinct clinicopathologic entities.

Objective: To determine the impact of delayed regional metastases, distant metastases, and second primary tumors on the therapeutic outcomes in squamous cell carcinomas of the larynx and hypopharynx., Study Design: Chart review and statistical analysis., Methods: A retrospective tumor registry analysis was made of patients with squamous cell carcinomas of the larynx and hypopharynx who were treated with curative intent in the Department of Otolaryngology-Head and Neck Surgery and the Radiation Oncology Center of the Washington University School of Medicine (St. Louis, MO) between January 1971 and December 1991 and developed delayed regional metastases (2 y after treatment), distant metastases, and second primary malignancies., Results: In 2550 patients, the mean age (59.8 y), sex (8.5 male patients and 1 female patient), and tumor differentiation did not affect the incidence of delayed distant, regional, or second primary malignancies. The overall incidence of delayed regional metastases was 12.4% (317/2550 patients); distant metastases, 8.5% (217/2550); and second primary tumors, 8.9% (228/2550), with a 5-year disease-specific survival of 41%, 6.4%, and 35%, respectively. Second primary malignancies were not statistically related to the origin of the primary tumor, tumor staging, or delayed regional and distant metastases (P =.98). Delayed regional metastases and distant metastases were related to advanced primary disease (T4 stage), lymph node metastases (node positive [N+]), tumor location (hypopharynx), and locoregional tumor recurrence (P < or =.028). Advanced regional metastases at initial diagnosis (N2 and N3 disease) increased the incidence of delayed and distant metastases threefold (P =.017). These two metastatic parameters were significantly greater in hypopharyngeal tumors than in laryngeal tumors (P =.037). The incidences of delayed regional metastases by anatomical location of the primary tumor were as follows: glottic, 4.4%; supraglottic, 16%; subglottic, 11.5%; aryepiglottic fold, 21.9%; pyriform sinus, 31.1%; and posterior hypopharyngeal wall, 18.5%. The incidences of distant metastases were as follows: glottic, 4%; supraglottic, 3.7%; subglottic, 14%; aryepiglottic fold, 16%; pyriform fossa, 17.2%; and posterior hypopharyngeal wall, 17.6%. Seventeen hypopharyngeal tumors (2%) presented with M1 disease. Delayed regional metastases to the ipsilateral treated neck had a significantly worse survival prognosis than delayed metastases to the contralateral nontreated neck (P =.001)., Conclusions: Conclusions are as follows: 1) The incidence of second primary tumors is independent from the primary tumor staging and distant and delayed regional metastases. The highest incidence occurred in patient groups with the highest disease-free survival rates (P =.0378). 2) Highest incidence of delayed and distant metastases occurred in hypopharyngeal tumors and was three times greater than in laryngeal cancers (P =.028). 3) Salvage therapeutic rates were poor for delayed metastases to the ipsilateral treated nodes and distant metastases as compared with contralateral neck metastases and second primary tumors (P =.001). 4) Delayed and distant lymph node metastases were significantly higher in advanced primary disease (T4 stage), locoregional recurrences, and regional disease (N2 and N3) (P =.028) in both the larynx and hypopharynx. 5) The higher incidence of delayed and distant metastatic disease was related to more advanced initial tumor presentation in hypopharyngeal cancer as compared with laryngeal cancer (P =.039). 6) Incidence of distant metastases was greatest between 1.5 and 6 years after initial treatment with a mean incidence being less than or equal to 3.2 years.

Several regions of chromosome arm 8p are frequently deleted in a variety of human malignancies including those of the prostate, head and neck, lung, and colon, suggesting that there is more than one tumor suppressor gene on this chromosome arm. Both laryngeal and oral squamous cell carcinomas exhibit three distinct and nonoverlapping regions of deletion on 8p. We have further refined the localization of the putative suppressor in 8p23 by using eight microsatellite loci to create a high resolution deletion map of 150 squamous cell carcinomas of the larynx and oral cavity. These new data demonstrate that there are two distinct classes of deletion within this relatively small region of the chromosome and suggest two possible locations for the gene within the D8S264 to D8S1788 interval. We also determined that there is little difference between the allelic loss frequencies of microsatellites mapping near the telomeric ends of other chromosome arms and loci mapping to more centromere proximal regions of the same arm. These data suggest that the high allelic loss frequencies seen at 8p23 loci are not the result of a generalized instability of chromosome ends and are instead consistent with the activation of a specific suppressor gene.

Polymorphous low-grade adenocarcinoma is a recently recognized salivary gland carcinoma arising primarily within the oral cavity. Most of these tumors are readily diagnosed; occasionally, however, they may be confused histologically with cellular mixed tumors. The difficulty stems from the bland cytologic nature of cellular mixed tumors and their organizational diversity, together with the irregular pushing growth at their interface with adjacent soft tissues, on histologic examination. Because of this diagnostic problem, we evaluated the use of glial fibrillary acidic protein localization in the differential diagnosis of polymorphous low-grade adenocarcinoma and cellular mixed tumor. Twelve oral polymorphous low-grade adenocarcinomas (polymorphous low-grade adenocarcinoma) and twelve cellular mixed tumors were selected and stained for glial fibrillary acidic protein (glial fibrillary acidic protein) using a strept-avidin-biotin system and examined independently by each investigator. In addition, five tumors with limited material (three cellular mixed tumors and two polymorphous low-grade adenocarcinoma) from the consultation service of one author were evaluated using the same techniques. Two polymorphous low-grade adenocarcinoma stained positive in very focal areas and only in the epithelial component; staining did not occur in the stroma. Fourteen of fifteen mixed tumors focally to diffusely expressed glial fibrillary acidic protein. Only one tumor did not express glial fibrillary acidic protein. In mixed tumors with only focal staining, the most helpful differential diagnostic feature was positive staining of the mesenchyme-like cells adjacent to epithelial nests. We did not find this latter staining pattern in any of the polymorphous low-grade adenocarcinoma.

A case of primary intrathyroidal paraganglioma is reported, and the light microscopic and immunohistochemical findings are described. Primary paragangliomas of the thyroid region are extremely uncommon and are therefore often confused clinically and histopathologically with more common intrathyroidal mass lesions. The diagnostic difficulties are underscored by the present case, which was misdiagnosed twice, firstly as a medullary thyroid carcinoma and secondly as a follicular thyroid carcinoma. Immunohistochemistry may be very helpful in arriving at the correct diagnosis. The case was further complicated by a second neck mass contralateral to the original thyroid nodule, which was interpreted as consistent with metastasis. The second lesions was proved angiographically and histologically to be a carotid body paraganglioma.

Primary epithelial neoplasms of the salivary gland in children are uncommon but are well recognized and occur principally in the major salivary glands. The purpose of this report is to document our experience with an adenocarcinoma of the buccal submucosa (one of several sites of minor salivary gland tissue) that metastasized to multiple bones as the initial sites of distant disease after a local recurrence. The clinical history, imaging studies, and microscopic sections including immunoperoxidase studies were evaluated from the primary tumor, local recurrence, and a metastatic lesion from the femur. The histopathologic features and immunohistochemical phenotype of the adenocarcinoma in the buccal submucosa supported its salivary gland origin. This case of adenocarcinoma of the intraoral buccal tissues independent of the parotid gland in a 12-year-old female is an unusual clinical presentation of a salivary gland neoplasm in childhood, and its ability to metastasize to distant skeletal sites is also remarkable in terms of a primary salivary gland carcinoma regardless of age at diagnosis.

The advantages of using a laser to cut a hole in the ossicular chain include increased precision, decreased likelihood of disarticulation, and elimination of noise-induced threshold shift associated with conventional drills. This study was designed to determine optimal energy settings and cooling technique to minimize tissue injury. Laser ablated holes were cut in rabbit femurs with different endostat fibers at power settings of 1.6 to 5.0 watts. Comparable burr holes were cut by a high-speed drill and the animals were sacrificed at different time intervals. Specimens were evaluated microscopically for tissue injury by the amount of cell necrosis of the surrounding osteocytes, bone marrow changes, and denaturation of bone matrix. Changes in healing were assessed by the production and ossification of the granulation tissue. Laser ablated holes created with 1.6 to 2.0 watts at 2 to 7 days demonstrated thermal damage comparable to conventionally drilled holes. At 14 to 28 days these holes demonstrated advanced healing and integrated lamellar bone. In contrast, higher power (> 3.5 watts) at 2 to 7 days demonstrated Significantly more osteocyte loss, marked bone marrow fibrosis, and bone matrix denaturation. At 14 to 28 days these holes showed evidence of delayed healing and osseous plugs not integrated with the surrounding bone.

The soft tissue profile adaptation to anterior maxillary intrusion was evaluated by comparing preoperative and 6-month postoperative cephalograms of ten adult patients. Holdaway's soft tissue analysis was the method utilized for profile evaluation. Lip protrusion and interlabial gap were decreased significantly and acceptable lip competency was provided postoperatively. Other factors also played a role in controlling the final soft tissue appearance.

Single crystal sapphire implants are commercially prepared ceramics of aluminum oxide. These endosseous implants have been placed in patients at Washington University since 1978. The course of patients has been followed closely with periodic clinical and radiographic evaluations. Sapphire is well tolerated by hard and soft tissue and provides excellent abutments for fixed partial dentures.

A case of calcifying odontogenic cyst is presented. An analysis of the previously reported cases indicates the variable clinical, radiographic and histopathologic features of the lesion.

Cephalometric studies of eighteen cases of ankylosis of the temporomandibular joint, treated surgically, were undertaken. Arthroplasty tended to correct the characteristic facial deviation of patients with ankylosis and approximate the facial features of these patients to those of a normal person. These changes were found to occur in a larger percentage of the patients and to a greater magnitude 6 months postoperatively than 1 week following surgery. These findings support the concept that the mandible grows in response to functional stimulation and emphasize the importance of early surgical treatment of ankylosis of the temporomandibular joint.

Pellets of powdered DMBA were implanted in the parotid glands of inbred male Fischer rats, and all experimental animals in which the carcinogen was implanted for 8, 10, 12, and 14 weeks developed well-differentiated squamous-cell carcinomas. When the carcinogen was implanted for longer periods of time, tumors developed in a smaller percentage of the experimental animals. Also, the weight of the parotid glands continued to increase with time following implantation of DMBA, reaching its highest level after 10 weeks, and then gradually decreasing with time. Different possible explanations for the regression of the induced parotid tumors are offered.