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Comments on a research which analyzed the implications of frequent loss of Rb2/p130 in human ovarian carcinoma. Role of the protein levels of the retinoblastoma gene in the development of ovarian cancer; Lack of medical detection systems which would contribute to the early detection of the disease; Importance of the research to the development of treatments for the disease.

Focuses on a medical study about the role of p27 in the pathogenesis and prognostic characterization of endometrial cancer. Definition of p27; Method used in the study to determine the expression status of p27; Reasons for the deregulated cellular proliferation; Clinical function of the kinase inhibitor protein.

Anti-melanoma differentiation-associated gene 5 antibody (anti-MDA-5 Ab) is associated with amyopathic dermatomyositis (DM). These patients are particularly at high-risk for developing acute and rapidly progressive interstitial lung disease (ILD). Given the lack of muscle-related symptoms, along with its sudden onset and rapid clinical progression, the diagnosis of anti-MDA-5 Ab + ILD represents a challenge for clinicians. Even after the diagnosis is established, prognosis remains dismal owing to a hyperinflammatory state, mimicking cytokine storm, commonly refractory to potent immunosuppressive therapy. Hence, we present an elderly African American man who developed acute and rapidly progressive ILD in the setting of positive anti-MDA5 Ab, in whom lung histopathology was consistent with organizing phase of diffuse alveolar damage. Despite receiving combined immunosuppression with corticosteroids, cyclosporine, and cyclophosphamide, he developed irreversible lung injury within a month and was eventually referred for lung transplant evaluation., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

A tonsillar mass in a young patient with no medical issues routinely presents as an infectious process. Practitioners must maintain a broad differential if diagnostic testing does not support an infection. Neoplasm must be excluded. Otolaryngologists must consider malignancies other than squamous cell carcinoma, the most common oropharyngeal malignancy, and lymphoma. Rare tumors, such as sarcomas, must also be considered. Otolaryngologists must be familiar with the proper management of rare oropharyngeal malignancies., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

A woman in her 40s presented with a 3-month history of lower abdominal pain and intermenstrual bleeding. Ultrasound of the pelvis disclosed a 4 cm left adnexal mass. An MRI of the pelvis revealed a 2.2×3.6×2.4 cm solid, enhancing left ovarian mass. Due to high suspicion for malignancy, she underwent laparoscopic left salpingo-oophorectomy and resection of the tumour. Histopathology revealed papillary thyroid carcinoma in the background of struma ovarii as confirmed by thyroglobulin and thyroid transcription factor-1 positivity on immunohistochemistry. BRAF mutation analysis was negative. An ultrasound of the thyroid gland showed two low-risk nodules. An iodine-123 whole-body scan showed normal uptake in the thyroid gland. Thyroid-stimulating hormone (TSH) was 1.070 mcIU/mL (0.450-4.500), and thyroglobulin was 6.8 ng/mL (1.5-38.5). We risk-stratified this patient as low risk for recurrence. Risk stratification of malignant struma ovarii is essential to determine suitable thyroid targeting adjuvant therapy and reduce the risk of recurrence., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Beta-catenin is involved in intercellular adhesion and participates in the Wnt signaling pathway. This study evaluated the expression pattern and prognostic value of β-catenin in a series of endometrial carcinoma patients. Immunohistochemical analyses were used to assess the expression and subcellular localization of β-catenin from tissue sections of 74 patients with endometrial carcinoma. No correlation was found between beta-catenin expression and clinicopathological parameters. Patients expressing nuclear β-catenin ( n = 13; 16%) showed a more favorable prognosis than patients expressing membranous β-catenin; the 5-year disease-related survival rate was 100% for cases expressing nuclear β-catenin, compared with 73.8% (SE 0.08) of cases expressing membranous β-catenin ( p = 0.04). Although statistical significance was not reached ( p = 0.15), cases expressing nuclear β-catenin showed a 5-year disease-free survival rate of 90.9% (SE 0.08) compared with 67.4% (SE 0.08) of cases expressing membranous β-catenin. Univariate Cox analysis revealed that membranous β-catenin expression was found to be associated with a relative risk of death of 33.9 ( p = 0.04). The stage of disease ( p = 0.0006), histology ( p = 0.003), and grading ( p = 0.008) were also significantly correlated with disease-free survival according to univariate Cox analyses. Determining β-catenin expression and localization patterns may predict survival in patients with endometrial cancer and, therefore, should be considered a potential prognostic marker of disease.

Calciphylaxis is a rare disease characterized by calcification of small- to medium-sized blood vessels in the dermis and subcutaneous fat, resulting in cutaneous necrosis. Although most commonly shown in patients with end-stage kidney disease, it has also been reported in patients with other diseases, including alcoholic cirrhosis and malignancies. Here, we report an unusual case of calciphylaxis in an orthotopic liver transplant recipient with acute kidney injury. The patient, a 43-year-old white female with a history of type 2 diabetes mellitus, alcoholic cirrhosis, and normal kidney function, presented with decompensated liver disease and hepatorenal syndrome; she no longer responded to medical treatment and required treatment with dialysis. Ten days after admission, she underwent liver transplant, resulting in improved liver function tests. She had acute tubular necrosis (creatinine peak: 325 μmol/L) from sustained hypotension during and after surgery, which required 4 sessions of dialysis over 2weeks. Six weeks after her transplant, she developed painful, nonulcerating, erythematous plaques over her shins and thighs. Skin biopsy of the lesions showed calciphylaxis, calcium deposits, and thrombotic vasculopathy. She also developed severe hypercalcemia (calcium level of 2.75 mmol/L) from immobility, which required treatment with a bisphosphonate and hemodialysis. The lesions improved 6 weeks later, and her renal function returned to normal. Calciphylaxis diagnosed in an orthotopic liver transplant recipient with acute kidney injury has not been previously reported. We hypothesize that her chronic inflammatory state caused down-regulation and low levels of fetuin A and protein C. She also had other risk factors, including hypoalbuminemia, obesity, systemic glucocorticoids, and alcoholic liver disease. Calciphylaxis can occur in patients with alcoholic cirrhosis and acute renal failure even after liver transplant. Further studies into the pathogenesis of this disease may help us understand why it develops in these patients and not others with the same risk factors.

Objective: Traumatic brain injury (TBI) is characterized by damage to the blood-brain barrier, inflammation, and edema formation. In this pilot study, we aimed to investigate the effects of a complement inhibitor, C1-esterase inhibitor (C1 INH), on brain edema and inflammation in a rat model of mild TBI., Methods: Thirty-six male Sprague Dawley rats were randomly assigned to control, TBI, or TBI plus C1 INH groups. TBI and TBI plus C1 INH rats received an injection of saline or 25 IU/kg C1 INH, respectively, with TBI using a weight drop model. Control rats received saline only. Rats were subsequently euthanized and their brain tissue harvested for analysis. The primary outcome was the extent of edema as assessed by the brain's water content. Secondary outcomes included enzyme-linked immunosorbent assays to determine levels of pro-inflammatory mediators., Results: Tumor necrosis factor-α levels were significantly greater in TBI rats than control rats, indicating that inflammation was generated by the weight drop impact. Brain water content following TBI was significantly different between TBI rats treated with C1-INH (78.7%±0.12), untreated TBI rats (79.3%±0.12), and control rats (78.6%±0.15, P=0.001). There was a significant decrease in C3a and interleukin 2 levels among C1 INH-treated rats compared with untreated TBI rats, but no change in levels of tumor necrosis factor-α and S100β., Conclusion: C1-INH inhibited the complement pathway, suggesting that C1-INH may have a therapeutic benefit in TBI. Further studies are needed to investigate the effect of C1-INH on clinical outcomes.

Placement of vancomycin powder into the surgical wound prior to closure has been shown to reduce postoperative infections in spine surgery. This study examines the effect of vancomycin powder on formation of epidural fibrosis (EF). Twenty-two rats underwent a two-level lumbar laminectomy. A control group, a low-dose and a high dose vancomycin powder (applied prior to closure) group was formed. Rats were sacrificed at 30 days and a blinded fellowshiptrained pathologist evaluated the laminectomy segments for EF. 50% of the samples in the high-dose vancomycin group were EF grade 3, compared to 20% of the low-dose and 16.7% of control samples. The average fibrosis grade for the high dose, low dose and control groups were 2.4, 1.4 and 1.8, respectively. There were more grade 3 EF specimens in the high dose vancomycin group. While the average EF grade was also higher in this group, there was not a statistical difference compared with the other groups., Competing Interests: Conflict of interest: the authors declare no conflict of interest.

Background: Venous thromboembolism prophylaxis in the general trauma population is well established. However, risk of increased intracranial hemorrhage in traumatic brain injury (TBI) population is of concern. The aim for this study is to identify a reproducible model of mild traumatic brain injury (mTBI), evaluated by clinical and histological markers and test the hypothesis that enoxaparin increases the risk of spontaneous brain hemorrhage., Methods: 40 male Sprague Dawley rats were randomly assigned to 5 groups: group 1 (sham) with no TBI along with 4 groups comparing mTBI with and without pharmacological intervention using enoxaparin at 24 h and 72 h respectively. Mild traumatic brain injury was induced using a weight drop apparatus, with a clinical endpoint of time to right (TTR), along with histological and spectrophotometer analysis for qualitative hemorrhage., Results: There is a statistically significant difference between group 1 (sham) and all other groups with a mean longer time to right of 64 s (p = 0.005) in the mTBI groups. There was a statistically significant difference between group 1 (sham) and all other groups with an increase of 6 g/dL hemoglobin (p < 0.001) in the mTBI groups with no difference in hemorrhage between groups that were treated with enoxaparin., Conclusion: The weight drop apparatus is a reproducible model for mTBI that has correlations with clinical and qualitative data. This model was able to produce clinical signs of concussion, as reflected by longer TTR and increased hemoglobin in the mTBI groups. Upon further analysis, there wasno increase in hemorrhage in the pharmacological intervention groups with enoxaparin., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Introduction: Molecular thyroid testing is increasingly being used to further stratify risk of malignancy in cytologically indeterminate thyroid nodules. We report our experience using three commercially available tests in a community hospital setting., Materials and Methods: All molecular test reports (Afirma, ThyroSeqV2, and ThyGENX/ThyraMIR) on thyroid nodules from Einstein Medical Center, Philadelphia, between April 2014 to March 2017 were compared with follow-up surgical results as part of a quality assurance exercise. Slides and records of disparities were reviewed., Results: Ninety-five thyroid nodules with molecular testing were identified with surgical follow up available on 19. No benign Afirma results had surgical follow-up. All 7 suspicious Afirma results had surgery, with 3 being benign on follow-up. Ten ThyroseqV2 tested nodules had follow-up surgery and included 2 papillary carcinomas following a completely negative result and another papillary carcinoma following over expression of the NIS gene reported as likely benign. One case with a TP53 mutation was benign on follow-up total thyroidectomy. Follow-up on 1 NRAS point mutation by ThyGenX/ThyraMIR was confirmed malignant although the microRNA portion of the test was negative., Conclusions: Quality assurance review refined our utilization practices as we better appreciated the limitations of molecular testing and use relative to other factors in managing indeterminate thyroid nodules., (Copyright © 2017 American Society of Cytopathology. Published by Elsevier Inc. All rights reserved.)

Soft tissue sarcomas typically present as soft, painless masses on an extremity. Here, we present a patient with metastatic soft tissue sarcomas at his dialysis access site. This association with dialysis access has not been documented previously. A 62-year-old man presented with a nonhealing wound on his left upper extremity after excision of a pseudoaneurysmal arteriovenous fistula. The patient had received a second kidney transplant that was functioning well. Immunosuppression included tacrolimus, mycophenolate mofetil, and prednisone. He was induced with thymoglobulin twice. A biopsy was performed showing a high-grade pleomorphic sarcoma. A magnetic resonance image of his left upper extremity showed an 11 × 5.5 × 3 cm mass abutting the biceps and brachialis muscles. Also, we discovered several lesions in the axilla and the left side of the neck, which were suspicious for metastases. A positron emission tomography-computed tomography scan confirmed a left upper extremity soft tissue mass, with marked fluorodeoxyglucose uptake, in abnormally enlarged axillary, and supraclavicular lymph nodes of the left thorax, consistent with metastases. The patient underwent chemotherapy and radiation therapy. Soft tissue sarcomas are rare. A high index of suspicion is needed to make a diagnosis. This is the first reported case of a soft tissue sarcoma discovered at a dialysis access site. As with all malignancies, early diagnosis is key to patient survival. Thorough physical examinations and increased vigilance by physicians caring for immunosuppressed patients is invaluable.

Background: Fine needle aspiration cytology represents the most important tool in the diagnosis of thyroid nodules, mostly in discriminating malignant from benign lesions. The diagnosis of medullary thyroid carcinoma (MTC) may present some problems related to its deceptive morphologic picture. This diagnosis may be supported by immunocytochemistry (ICC), which may be difficult to carry out on the conventional smears., Design: The diagnostic efficacy of ICC for the diagnosis of MTC with respect to other thyroid neoplasms on slides processed by thin-layer cytology (TLC) is evaluated., Patients: In the period between January 2002 and December 2005, 8,200 FNAB were processed. ICC on TLC slides was required in 33 cases. Conventional smears were fixed in ethanol, whereas TLC slides were processed with the Thin Prep 2000 method. All slides were then stained with Papanicolaou. In all cases where MTC was morphologically suspected, ICC for calcitonin, monoclonal carcinoembryonic antigen, and thyroglobulin was carried out only on TLC slides., Results: Thirty-three thyroid cytologic cases had ICC on the TLC slides, including 22 follicular proliferations and 11 malignant lesions. The application of ICC on TLC was conclusive in 32 cases and inconclusive in 1 case. Twenty cases underwent surgery. No false-positive and false-negative cases were found. Sensitivity and specificity were 100%, and the overall diagnostic accuracy was 100%., Conclusions: ICC can be successfully applied on TLC slides. The combined results of morphology and a small immunopanel including thyroglobulin, calcitonin, and carcinoembryonic antigen yields a 100% diagnostic efficacy for MTC., Condensed Abstract: Fine needle aspiration cytology is an excellent technique for diagnosing malignant neoplasms of the thyroid, especially those derived from the follicular cells. A correct preoperative diagnosis of C-cell-derived tumors (MTC), which is essential for both the surgical approach to the primary tumor and the management of the patient, should rely not only on the morphologic picture but also on the immunocytochemical yielding using an immunopanel, which is particularly satisfactory on the TLC slides.

Objective: To demonstrate the unique morphologic and phenotypic features observed in cases of T-cell lymphomas presenting as effusions., Study Design: Cytologic slides and flow cytometric histograms of 8 cases of body fluids with T-cell lymphoma were retrospectively reviewed. Morphologic features, flow cytometric histograms and immunophenotypes of the cells were evaluated., Results: Three of the 8 cases showed 1 or more of the following: intermediate-to-large cells with an increased nuclear-cytoplasmic ratio, finely granular or vacuolated cytoplasm and round or convoluted vesicular nuclei with a prominent single or multiple nucleoli. Flow cytometric studies of these 3 cases showed an abnormal scatter pattern in the myelomonocytic region of the histograms. Phenotypic analysis revealed variable expression of a T-cell phenotype. The remaining cases showed the conventional morphologic and flow cytometric features of a T-cell lymphoma., Conclusion: Morphologic alterations of neoplastic T-cells in body fluids can result in a variety of potentially incorrect diagnoses. The unusual flow cytometric histogram can serve as a useful clue for the diagnosis of T-cell lymphoma in body fluids but could be a potential pitfall for a false negative. Detailed cytologic evaluation combined with flow cytometric study can improve diagnostic accuracy.

We have evaluated if ultrasound imaging (US) and various commercially available contrast microbubbles can serve as a non-invasive systemically administered delivery vehicle for site-specific adenoviral-mediated gene transfer in vitro and in vivo. The contrast agents were tested for their ability to enclose and to protect an adenoviral vector carrying the GFP marker gene (Ad-GFP) into the microbubbles. We have also evaluated the ability of the innate immune system to inactivate free adenoviruses as well as unenclosed viruses adsorbed on the surface of the contrast agents and in turn the ability of the microbubbles to enclose and to protect the viral vectors from such agents. In vitro as well as in vivo, innate components of the immune system were able to serve as inactivating agents to clear free viral particles and unenclosed adenoviruses adsorbed on the microbubbles' surface. Systemic delivery of Ad-GFP enclosed into microbubbles in the tail vein of nude mice resulted in specific targeting of the GFP transgene. Both fluorescence microscopy and GFP immunohistochemistry demonstrated US guided specific transduction in the targeted cells only, with no uptake in either heart, lungs or liver using complement-pretreated Ad-GFP microbubbles. This approach enhances target specificity of US microbubble destruction as a delivery vehicle for viral-mediated gene transfer., (Copyright 2006 Wiley-Liss, Inc.)

Control of the G1/S-phase transition as well as angiogenic switch are two of the most studied mechanisms in cancer. The current study examined the correlation between the immunohistochemical expression of pRb2/p130, VEGF, EZH2, p53, p16, p21waf-1, p27, and PCNA in Barrett's esophagus (BE). Overall, p53 showed a much higher expression in BE patients (up to 50%) than in controls (1-10%) (P < 0.005). Also p21 showed a downregulation in BE when compared to normal esophagus (70% of cells vs. 65%), but the difference did not show any statistical significance (P = 0.45). pRb2/p130 was detected in 80% of cells in normal controls, but showed positive in only 20% of cells in BE biopsies. Additionally, Rb2/p130 expression was inversely correlated to that of VEGF, EZH2, and PCNA (P < 0.0001, P = 0.0032, P < 0.001, respectively). p27 stained more intensely and in a widespread manner (70%) cells in normal esophageal tissues but about only 30% in BE samples (P < 0.001). Lastly, in accordance with other reports, we also found p16 expressed by immunohistochemistry at high levels in normal controls and at low levels in BE (P < 0.001). In conclusion, p16, p21, p27, and p53 staining confirmed previously published data. Interestingly, pRb2/p130 expression was found significantly decreased in metaplastic epithelium compared to normal controls and showed significant inverse correlation with the expression of other markers, such as VEGF, EZH2, and PCNA. These data, taken together, indicate that these molecular events occurring in Barrett's metaplasia (BM) may represent one of the many steps taking place during esophageal malignant progression such as impairment of cell-cycle control, altered differentiation, and unbalanced angiogenesis.

Background: Basaloid epidermal proliferations (BEP), morphologically resembling basal cell carcinoma (BCC), have been described overlying dermatofibromas. Distinguishing the two is important because of non-aggressiveness of BEP and local aggressiveness of BCC. The aim of this study is to determine whether CK20 antibody staining for Merkel cells can be used as an adjunct method to differentiate BEP from BCC., Methods: Ten cases of BEP overlying dermatofibromas were selected. Ten cases of BCC were used as control. The two groups were stained with CK20 antibody. Numerical density of CK20 stained Merkel cells in peri-lesional epidermis, BEP and BCC was determined by examining 300 cells at 400X in two separate areas by three independent pathologists. To determine statistical significance, the results were compared using t-test method., Results: Density of Merkel cells in peri-lesional epidermis was 0.2-0.3%. No merkel cells were detected in the BCC. BEP overlying dermatofibromas showed an obvious increase in CK 20 stained Merkel cells. The difference was statistically significant (P < 0.02) CONCLUSIONS: We report a significant increase in CK20 stained Merkel cells in BEP overlying dermatofibromas as compared to BCC. CK20 antibody staining for Merkel cells can be used as an adjunct method to differentiate BEP overlying dermatofibromas from BCC. Mahmoodi M, Asad H, Salim S, Kantor G, Minimo C. Anti-CK20 staining of Merkel cells helps differentiate basaloid proliferations overlying dermatofibromas from basal cell carcinoma.

The retinoblastoma family consists of the tumor suppressor nuclear phosphoprotein pRb/p105 and related proteins p107 and pRb2/p130. Recent immunohistochemical studies of the retinoblastoma family of proteins in lung and endometrial cancer and choroidal melanomas show a tight inverse correlation between the histologic grading in the most aggressive tumor types and pRb2/p130 expression. This led us to investigate the role of pRb2/p130 in salivary tumors. We studied the expression of pRb2/p130, p107, E2F4, p27, and PcNA by immunohistochemistry in a panel of 44 salivary gland tumors. We found a direct correlation between the cytoplasmic expression of pRb2/p130 and tumor grading and the presence of metastasis that was highly statistically significant (P < 0.001). Additionally, increased cytoplasmic pRb2/p130 expression was significantly correlated with a decreased probability of survival (P < 0.001). Interestingly, p107 nuclear expression showed a strong direct correlation when compared with the same variables. pRb2/p130 showed the highest percentage of undetectable nuclear levels in the specimens examined and the tightest inverse correlation (P < 0.0001) with both the histologic grading and pCNA expression in malignant salivary tumors. Additionally, E2F4 showed an identical localization pattern as to that of pRb2/p130. These data suggests an important role for pRb2/p130 in the pathogenesis and progression of certain salivary gland cancers.