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Crude oil atmospheric distillation units consume substantial amounts of energy, as equivalent to a 2 % of the total crude oil processed (Errico, 2009). An existing crude distillation unit is costly to modify due its complex configuration and existing limitations of structure, space area, matches, bottlenecked equipments, etc. Thus, a few new crude distillation units are built and most projects are directed to revamping existing equipments. Modifying an existing plant is a tedious task, more complex than a new process. While revamping, many parameters must be considered and structure limitations need to be met. This paper develops a new revamping method based on rigorous simulation and optimisation procedures. This method accounts for both the distillation column and the associated heat exchanger network at the same time to maximise the use of existing equipments. The methodology considers process changes and structural modifications together with the interactions between the existing distillation process and heat recovery system. The new method is valid for multiple objective functions, i.e. saving energy, reducing emissions, enhancing production capacity, and profit improvement. The new presented methodology is applied to a local atmospheric plant for MIDOR, as an Egyptian refinery case study. Many revamping options were obtained, including no structural modifications, simple additional exchanger areas, and additional units or equipments.

This study was aimed to investigate the possibility of using C-reactive protein (CRP) as a marker for 11 types of cancer include (Ovarian, Bone, Pancreas, Liver, Lung, Cervical, Head, Kidney, Breast, Stomach and Prostate cancer) and poising thyroid gland disease by qualitative test for CRP. 50 serum samples from health human and about 150 serum samples were examined from patients with cancer and poising thyroid gland disease (aged between 14 and 85 years old). Qualitative test was done to detect the presence of CRP in the patient’s serum. The qualitative test showed that all normal samples 50 (100%) give negative result for the presence of CRP in the serum. While 116 (89.9%) patients give negative result and 13 (10.1%) patients with cancer diseases give positive result to presence of CRP in the serum. And also 21 (100%) patients with poising thyroid gland disease give positive result to CRP. According to the results of this study C-reactive protein consider non-specific marker for all types of cancer diseases but can be used as marker for bone cancer. On the other hand CRP which demonstrated that, it a useful marker for patients with poising thyroid gland.

Nuclear pore proteins control nucleocytoplasmic transport; however, certain nucleoporins play regulatory roles in activities such as transcription and chromatin organization. The fission yeast basket nucleoporin Nup211 is implicated in mRNA export and is essential for cell viability. Nup211 preferentially associates with heterochromatin, however, it is unclear whether it plays a role in regulating transcription. To better understand its functions, we constructed a nup211 "shut-off" strain and observed that Nup211 depletion led to severe defects in cell cycle progression, including septation and cytokinesis. Using RNA-Seq and RT-qPCR, we revealed that loss of Nup211 significantly altered the mRNA levels of a set of genes crucial for cell division. Using domain analysis and CRISPR/cas9 technology, we determined that the first 655 residues of Nup211 are sufficient for viability. This truncated protein was detected at the nuclear periphery. Furthermore, exogenous expression of this domain in nup211 shut-off cells effectively restored both cell morphology and transcript abundance for some selected genes. Our findings unveil a novel role for Nup211 in regulating gene expression., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Kamel et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: An in silico screen was performed to identify FDA approved drugs that inhibit SARS-CoV-2 main protease (M pro ), followed by in vitro viral replication assays, and in vivo pharmacokinetic studies in mice. These studies identified atovaquone as a promising candidate for inhibiting viral replication. Methods: A 2-center, randomized, double-blind, placebo-controlled trial was performed among patients hospitalized with COVID-19 infection. Enrolled patients were randomized 2:1 to atovaquone 1500 mg BID versus matched placebo. Patients received standard of care treatment including remdesivir, dexamethasone, or convalescent plasma as deemed necessary by the treating team. Saliva was collected at baseline and twice per day for up to 10 days for RNA extraction for SARS-CoV-2 viral load measurement by quantitative reverse-transcriptase PCR. The primary outcome was the between group difference in log-transformed viral load (copies/mL) using a generalized linear mixed-effect models of repeated measures from all samples. Results: Of the 61 patients enrolled; 41 received atovaquone and 19 received placebo. Overall, the population was predominately male (63%) and Hispanic (70%), with a mean age of 51 years, enrolled a mean of 5 days from symptom onset. The log 10 viral load was 5.25 copies/mL vs . 4.79 copies/mL at baseline in the atovaquone vs . placebo group. Change in viral load did not differ over time between the atovaquone plus standard of care arm versus the placebo plus standard of care arm. Pharmacokinetic (PK) studies of atovaquone plasma concentration demonstrated a wide variation in atovaquone levels, with an inverse correlation between BMI and atovaquone levels, (Rho -0.45, p = 0.02). In post hoc analysis, an inverse correlation was observed between atovaquone levels and viral load (Rho -0.54, p = 0.005). Conclusion: In this prospective, randomized, placebo-controlled trial, atovaquone did not demonstrate evidence of enhanced SARS-CoV-2 viral clearance compared with placebo. However, based on the observed inverse correlation between atovaquone levels and viral load, additional PK-guided studies may be warranted to examine the antiviral effect of atovaquone in COVID-19 patients., Competing Interests: MKJ has received research funding from Gilead Sciences and Regeneron and was on Advisory Board for Gilead Sciences. SM received research funding from Regeneron. JADL has received consulting income from Regeneron and Eli Lilly unrelated to COVID-19. JWS serves as a consultant for the Federal Trade Commission on matters related to COVID-19 treatments. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Jain, De Lemos, McGuire, Ayers, Eitson, Sanchez, Kamel, Meisner, Thomas, Hegde, Mocherla, Strebe, Li, Williams, Xing, Ahmed, Wang, Sadek and Schoggins.)

The protection provided by natural versus hybrid immunity from COVID-19 is unclear. We reflect on the challenges from trying to conduct a randomized post-SARS-CoV-2 infection vaccination trial study with rapidly evolving scientific data, vaccination guidelines, varying international policies, difficulties with vaccine availability, vaccine hesitancy, and a constantly evolving virus., Competing Interests: Declaration of interests D.L.B is on the advisory boards of Gilead, MerckSharpe & Dohme, Pfizer, and ViiV, and receives travel grants from ViiV Healthcare. G.M. receives research grants from Gilead, AbbvieInc., ViiV Healthcare, and Janssen, and is on the advisory boards of Gileadand AstraZeneca. The other authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Quackery in medicine is as old as medicine itself. In times of crisis, desperate patients often believe extraordinary claims. In the annals of pain-killer quack medicine, snake oil, elixirs, nostrums and Indian liniments hold a special position. NYU College of Dentistry (NYUCD) has a collection of 234 bottles of such medicines dating from the mid-1800s through 1940. This paper is the fifth in a series of articles featuring "Elixirs of the Past" in which we bring to light six more samples with claims to traditional Chinese or American Indian medicine using snake oil: Virex Compound, Rattlesnake Bill's Oil, Electric Indian Liniment, The King of All Indian Oils, Millerhaus Antiseptic Oil and Celebrated Indian Lotion . The six examples are just a few quack medications linked to fraud, overdose, addiction or death. In 1906, Congress enacted The Pure Food and Drug Act and reinforced it with the Federal Food, Drug and Cosmetic Act of 1938, to stop unsubstantiated medicinal claims and control the use of addictive and dangerous substances. The modern-day use of social media to advertise quack medicine is in some ways even more brazen than selling patent medicine a century ago., (Copyright 2021 © American Academy of the History of Dentistry.)

Quackery in medicine is as old as medicine itself. In times of crisis desperate patients often believe extraordinary claims. In the annals of pain killer quack medicine, elixirs, nostrums and liniments hold a special position. The College of Dentistry at NYU received a collection of 234 bottles of nostrums and liniments dating from approximately 1850 through 1940. In this paper, the FOURTH in a series of articles featuring "Elixirs of the Past" we bring to light four more samples claiming to have magnetic properties: Dr. J.R. Miller's Magnetic Balm, Havens' Electromagnetic Liniment, Headman's Magnetic Liniments , and Magnetic Cream . It goes without saying that none of these had any magnetic properties. In 1906, Congress enacted The Pure Food and Drug Act to prohibit exaggerated or unsubstantiated claims in the marketing and labeling of household products and to control the use of potentially harmful ingredients. The modern-day use of internet advertisements to make unsupported claims is in some ways even more brazen than the advertisements from a century ago., (Copyright 2021 © American Academy of the History of Dentistry.)

Background: In 2012, the American Society for Clinical Oncology (ASCO) identified five key opportunities in oncology to improve patient care, recommending against imaging tests for the staging of patients with early breast cancer (EBC) at low risk for metastases. Similarly, the European Society of Medical Oncology (ESMO) guideline does not support radiological staging in asymptomatic EBC (aEBC). The purpose of this study was to assess local practice and outcomes of staging investigations (SIs) in aEBC at the Cancer Centre of Southeastern Ontario (CCSEO)., Methods: A retrospective electronic and paper chart review was undertaken to identify all aEBC patients treated at our institution between January 2012 and December 2014. Patients with pathological staging of T1-T2 and N0-1 with any receptor status were included. We collected patient demographics, treatment and pathologic tumor characteristics. The use and outcomes of initial and follow-up SIs were recorded. Data were analyzed to determine associations between the use of SIs and clinical characteristics (chi-square tests, independent samples t-tests and Mann-Whitney U tests)., Results: From 2012 to 2014, 295 asymptomatic EBC patients were identified. The mean age was 64, 81% were postmenopausal and 76% had breast conserving surgery. Stage distribution was as follows: stage I 42%, stage IIA 37% and stage IIB 21%. Receptor status was as follows: ER+ 84%, HER2+ 13% and triple negative 12%. Adjuvant chemotherapy was received by 36%, Trastuzumab by 10% and endocrine therapy by 76% of patients. Baseline SIs were performed in 168 patients (57%) for a total of 332 tests. Overt metastatic disease was found in five patients (one bone scan and four CT scans). Seventy-one out of the 168 patients (42%) who received initial staging imaging underwent 138 follow-up imaging tests, none of which were diagnostic for metastases. Nine patients with suspicious CT findings underwent biopsies, of which four were malignant (one metastatic breast cancer and three new primaries). Factors significantly associated with SI were as follows: younger age ( p = 0.001), premenopausal status ( p = 0.01), T2 stage ( p < 0.001), N1 stage ( p < 0.001), HER2 positive ( p < 0.001), triple negative status ( p = 0.007) and use of adjuvant chemotherapy ( p < 0.001)., Conclusions: Over a 3-year period at our institution, more than 50% of aEBC patients underwent a total of 470 initial and follow-up staging tests, yielding a cancer diagnosis (metastatic breast cancer or second primary cancer) in four patients. We, therefore, conclude that routine-staging investigations in aEBC patients have low diagnostic value, supporting current guidelines that recommend against the routine use of SI in this population.

Quackery in medicine is as old as medicine itself. In times of crisis, desperate patients often believe extraordinary claims. In the annals of pain-killer quack medicine, elixirs, nostrums and liniments hold a prominent position. NYU College of Dentistry (NYUCD) has a collection of 234 bottles of such medicines dating from the mid-1800s through 1940. This paper is the second in a series of articles featuring "Elixirs of the Past" in which we bring to light five more samples containing opium: Dr. B.J. Kendall's Instant Relief for Pain , Dr. Munn's Elixir of Opium, Dill's Balm of Life, Foley's Pain Relief, and Brown's Instant Relief for Pain . These are just five examples out of countless syrups, nostrums, balm or liniments that contained narcotics and were linked to overdose, addiction and sometimes death. In 1906, Congress enacted The Pure Food and Drug Act to stop unsubstantiated medicinal claims and control the use of addictive substances. The modern-day use of internet advertisements to make unsupported claims is in some ways even more brazen than the advertisements from a century ago. Indeed, the recent widespread use of prescription painkillers, along with the resulting epidemic in opiate addiction that has caused upwards of 50,000 deaths is a case in point., (Copyright 2021 © American Academy of the History of Dentistry.)

Background and objectives : The primary objective was to evaluate the benefit of training with virtual reality simulation. The secondary objective was to describe the short-term skill acquisition obtained by simulation training and to determine the factors affecting its magnitude. Materials and Methods : We prospectively performed a three-stage evaluation: face, constructive, and predictive to evaluate the training with a laparoscopic simulator with haptic feedback. The participants ( n = 63) were divided according to their level of experience into three groups: 16% residents; 46% specialists and 38% were consultants. Results : Face evaluation demonstrates the acceptance of the design and realism of the tasks; it showed a median score of eight (IQR 3) on a Likert scale and 54% of participants ( n = 34) gave the tissue feedback a moderate rating. Constructive evaluation demonstrates the improvement of the participants in the training session and the ability of the designed task to distinguish the experienced from the inexperienced surgeon based on the performance score, at task I (transfer of pegs) and II (laparoscopic salpingectomy). There was an improvement in both tasks with a significant increase in score and reduction in time. The study showed that those with a high score at the pre-test recorded a high score post-test, showing a significant pair-wise comparison ( Z ) and correlation ( p ) showing a significant statistical significance ( p < 0.001). The predictive evaluation demonstrates the beneficiary effect of training four weeks afterward on the practice of surgeons addressed with five questions. It showed an improvement regarding implementation into daily routine, performance of procedure, suturing, shortening of the operative time, and complication management. Conclusions : Virtual reality simulation established high ratings for both realism and training capacity, including clinical relevance, critical relevance, and maintaining training enthusiasm.

We describe the clinical course of a 64-year-old woman with stage IVa lung adenocarcinoma who presented with over 1 month of fatigue, unintentional weight loss and emesis. She initiated treatment with nivolumab immunotherapy 1 year prior and had been tolerating the treatment well. A comprehensive workup revealed multiple endocrinological abnormalities consistent with hypophysitis leading to hypopituitarism in the form of central adrenal insufficiency and hypogonadism as well as a partially empty sella on imaging. This case demonstrates that while receiving novel forms of treatment such as immunotherapy, patients should be monitored closely for a wide range of adverse effects., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Hypothalamic-pituitary-adrenal (HPA) axis dysfunction is a well-documented complication of transsphenoidal craniotomy (TSC) for sellar lesions. The authors aimed to assess their multidisciplinary approach to the diagnosis and treatment of postoperative hypocortisolemia utilizing conservative screening methods., Methods: The authors performed a retrospective review of 257 patients who underwent TSC for pituitary adenoma (PA) or Rathke cleft cyst (RCC) at the University of Southern California between 2012 and 2017. Patients with preoperative adrenal insufficiency, Cushing's disease, or < 3 months of postoperative follow-up were excluded. Patient demographics, pathology, tumor characteristics, and complications were recorded. Postoperative day 1 (POD1) morning serum cortisol was assessed in all patients. Hypocortisolemia on POD1 (serum cortisol < 5 μg/dl) prompted a 7 am cortisol level measurement on POD 2 (POD2). Clinical signs and symptoms of hypocortisolemia were consistently monitored. After two serum cortisol levels < 5 μg/dl, or one serum level < 5 μg/dl plus a high clinical suspicion for HPA dysfunction, high-risk patients received glucocorticoid supplementation., Results: Data on 165 patients were included in the analysis; there were 101 women (61.2%) and 64 men (38.7%). Preoperative diagnoses included nonfunctional adenoma (n = 97, 58.7%), growth hormone-secreting adenoma (n = 37, 22.4%), RCC (n = 18, 10.9%), prolactinoma (n = 8, 4.8%), and other (n = 5, 3.0%). One hundred thirty-eight patients (63.0%) had either suprasellar extension or cavernous sinus invasion. POD1 hypocortisolemia was diagnosed in 8 patients (4.8%). Of these patients, 2 (1.2%) were clinically asymptomatic and had normalized POD2 cortisol levels. Six patients (3.6%) had clinical symptoms and POD2 cortisol levels confirming HPA axis deficiency. Of these 6 patients treated with early glucocorticoid replacement, 2 patients recovered HPA axis function during follow-up, making the incidence of new, permanent HPA axis deficiency 2.5%., Conclusions: In the authors' institutional review, all patients warranting postoperative glucocorticoid replacement had both complicated surgical courses and associated clinical symptoms of hypocortisolemia. The authors' algorithm of withholding steroids until patients demonstrate clear evidence of postoperative hypocortisolemia is safe and clinically efficacious. Their data further suggest that routine postoperative cortisol screening may not be necessary following an uncomplicated operative resection, with gland preservation and the absence of clinical symptoms indicative of HPA dysfunction.

There has been an increasing awareness of post gastric bypass hypoglycemia (PGBH). Histopathologic findings from such patients who underwent partial/total pancreatomy, however, can vary widely from minimal changes to classic nesidioblastosis, making the pathologic diagnosis challenging. PGBH typically presents as postprandial hypoglycemia, as opposed to insulinoma, which presents as fasting hypoglycemia. Herein, we describe an unusual case of a patient with PGBH who initially presented with postprandial hypoglycemia three years after surgery, but later developed fasting hyperinsulinemic hypoglycemia as the disease progressed. Our hypothesis for this phenomenon is that this disease is progressive, and later in its course, the insulin release becomes dissociated from food stimulation and is increased at baseline. Future studies are needed to investigate the prevalence as well as etiology of this progression from postprandial to fasting hypoglycemia. Learning points: •• There has been an increasing awareness of post gastric bypass hypoglycemia (PGBH). •• Histopathologically, PGBH can vary from minimal changes to nesidioblastosis. •• Although uncommon, patients with PGBH after Roux-en-Y gastric bypass may present with both postprandial and fasting hyperinsulinemic hypoglycemia as disease progresses. •• Our hypothesis for this phenomenon is that the insulin release becomes dissociated from food stimulation and is increased at baseline with disease progression., (© 2018 The authors. This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License.)

Importance: Systemic chemotherapy can be administered either through a peripheral vein (IV), or centrally through peripherally inserted central catheter (PICC), totally implanted vascular access devices (PORTs) or tunnelled cuffed catheters. Despite the widespread use of systemic chemotherapy in patients with breast cancer, the optimal choice of vascular access is unknown., Objective: This systematic review evaluated complication rates and patient satisfaction with different access strategies for administering neo/adjuvant chemotherapy for breast cancer., Evidence Reviewed: Ovid Medline, EMBASE and the Cochrane Central Register of Controlled Trials were searched from 1946 to September 2017. Two reviewers independently assessed each citation. The Newcastle-Ottawa scale was used to assess the quality of cohort and case-control studies., Findings: Of 1584 citations identified, 15 unique studies met the pre-specified eligibility criteria. There were no randomised studies comparing types of vascular access. Reports included six single-institution retrospective cohort studies, one retrospective multi-institution cohort, one retrospective cohort database study, five prospective single-institution studies, one prospective multi-institution study and one nested case-control study. Median complication rates were infection: 6.0% PICC (2 studies) versus 2.1% PORT (8 studies); thrombosis: 8.9% PICC (2 studies) versus 2.6% PORT (9 studies); extravasation: 0 PICC (1 study) versus 0.4% PORT (4 studies) and mechanical issues: PICC 3.8% (1 study) versus 1.8% PORT (9 studies). Satisfaction/quality of life appeared high with each device., Conclusion: In the absence of high-quality data comparing vascular access strategies, randomised, adequately powered, prospective studies would be required to help inform clinical practice and reduce variation.

Background: PARP inhibitors appear to offer a promising role in the accompaniment of many of the cytotoxic agents used in the present day to combat cancer proliferation in BRCA ½ deficient tumors. Current species of PARP inhibitors have yet to demonstrate a superior effect to that of existing therapies when administered as a single agent; however, they have appeared to amplify the effect of these existing chemotherapies when utilized together. This suggests that PARP inhibitors could play an effective maintenance role in current cancer-combating strategies. In the immediate future, PARP inhibitors may only be applicable to a select group of cancers (i.e., those caused by defective HR pathways), though research is emerging that could indicate an extension of applicability to HR proficient cancer types as well. For the time being, however, the current literature suggests that a viable PARP inhibitorchemotherapy hybrid targeting HR deficient cancers could be well on its way very soon., Objective: In this manuscript we explores the ongoing and the completed clinical trials for different PARP inhibitors., Conclusion: Since the approval of Olaparib by both FDA and EMA, further clinical trials continue to investigate the use of Olaparib and other PARP inhibitors. The anticipating outcome of these trials may clarify the benefit of PARP inhibitors in management of various BRCA mutated solid tumors., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Sclerosing mucoepidermoid carcinoma of the salivary gland (SMEC) is a rare subtype of mucoepidermoid carcinoma (MEC), first described in 1987 by Chan and Saw. As far as we are aware, only 30 cases have been published since then. Most cases were located in the parotid gland with some cases described in the submandibular and minor salivary glands. SMEC typically presents as a long-standing mass, with a non-specific enhancing appearance on imaging and is often non-diagnostic on fine needle aspiration, making pre-operative diagnosis very difficult. It is characterised by dense sclerosis within an otherwise typical MEC, frequently with lymphoid proliferation and eosinophils at the periphery. The histological diagnosis of SMEC can be challenging, as the sclerosis may obscure the other morphological features, which can lead to misdiagnosis. Grading can also be difficult, and the prognostic value of grading for SMEC remains unclear. Herein is described a new case of SMEC, presenting clinically as chronic sialadenitis in the left submandibular gland of a 41 year old male. A brief literature review and the issues surrounding diagnosis and grading are also discussed.

Objectives: This study evaluated the incidence of ventricular arrhythmia and implantable cardioverter-defibrillator (ICD) therapies in patients with a diagnosis of cancer., Background: Cardiac disease and cancer are prevalent conditions and share common predisposing factors. No studies have assessed the impact of cancer on the burden of ventricular arrhythmia in patients with cancer and ICDs., Methods: Retrospective study of patients with an ICD and cancer who were followed from January 2007 to June 2015. Rates of ventricular tachycardia (VT) and ventricular fibrillation (VF) before and after patients' cancers were diagnosed were evaluated by searching device data collection systems. Rates were adjusted for length of follow-up and compared using the Wilcoxon test, and times to first therapy following diagnosis (stages I to III vs. IV) were compared using Kaplan-Meier curves and log-rank test., Results: Among 1,598 patients with an ICD, 209 patients (13.1%) had a pathological diagnosis of malignancy; and in 102 patients (6.4%), malignancy was diagnosed following device insertion. After the diagnosis of cancer, 32% of patients experienced VT/VF over 23.2 ± 23.6 months, and the frequency of arrhythmic events was significantly increased after the diagnosis (1.19 ± 0.32 vs. 0.12 ± 0.21 episodes per month, respectively; p = 0.03). The incidence of VT/VF was markedly higher in patients with stage IV cancer than in those with earlier stages (p = 0.03). In this group, the incidence of VT/VF was 41.2%, with an average of 7.2 ± 18.5 events per patient, all of whom received ICD shocks. The rate of ICD deactivation in stage IV patients was 35.3%. Inappropriate therapies occurred in 13.7%, and atrial fibrillation was the most frequent cause., Conclusions: One-third of patients who had received ICDs developed ventricular arrhythmia after a diagnosis of cancer. The incidence was significantly higher in those with advanced metastatic disease. Findings underscore the need to discuss ICD management as part of end-of-life care., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Introduction: Tumours of the parapharyngeal space are rare. Only 0.5% of head and neck tumours occur in this space. Surgical excision of parapharyngeal space lesions is challenging because of the anatomical complexity of the area., Presentation of Case: A 31-year-old male patient was referred by his general dental practitioner for removal of lower wisdom teeth due to multiple episodes of pericoronitis. At the initial examination, an incidental finding was made of a large fluctuant posterior oropharyngeal swelling. A fluid aspirate was taken from the lesion but this was inconclusive. The patient underwent an urgent MRI and CT neck revealing a large parapharyngeal mass. An incisional biopsy of the lesion confirmed the presence of a vagal nerve schwannoma which was subsequently removed via a transcervical approach., Discussion: Due to their slow growing and painless nature, they are often not detected until they are large enough to palpate or visualise. It may cause secondary symptoms such as dysphagia, hoarseness and nasal obstruction. This case represents a typical presentation of a parapharyngeal schwannoma and reiterates the subtle and often ambiguous nature of the lesion., Conclusion: Vagal schwannomas in the parapharyngeal space are rare. They usually present in the form of an isolated intraoral or neck mass. A positive diagnosis is made on imaging and confirmed by histopathological examination. Complete surgical excision is the treatment of choice and recurrence rates are low., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Immunosuppressive therapy may aggravate the clinical course of a burned patient, primarily affecting wound healing and thus complicating permanent wound coverage. We hereby present the successful management of a 48-year-old female liver transplant recipient with a major burn injury, aiming to elucidate the effects of the patient's immunosuppression on surgical treatment. After admission to the Burns ITU, the patient underwent serial debridement of the burn and coverage with cryopreserved allografts. Despite immunosuppression, no prolonged survival of the allo-epidermis was documented. Nevertheless, a variable degree of vascularized allo-dermis was clinically identified. She subsequently underwent skin autografting and was discharged home with most of the wounds healed. Although there are isolated reports of survival of skin allografts in immunocompromised patients, in our case the allografted skin did not provide permanent wound coverage. However, it permitted a staged surgical management, allowing the immunosuppressive regime to change, the skin donor sites to heal and it also provided a dermal scaffold for successful skin autografting.

Unlabelled: Polyurethane breast implants were first introduced by Ashley (Plast Reconstr Surg 45:421-424, 1970), with the intention of trying to reduce the high incidence of capsular contracture associated with smooth shelled, high gel bleed, silicone breast implants. The sterilization of the polyurethane foam in the early days was questionable. More recently, ethylene oxide (ETO)-sterilized polyurethane has been used in the manufacturing process and this has been shown to reduce the incidence of biofilm. The improved method of attachment of polyurethane onto the underlying high cohesive gel, barrier shell layered, silicone breast implants also encourages bio-integration. Polyurethane covered, cohesive gel, silicone implants have also been shown to reduce the incidence of other problems commonly associated with smooth or textured silicone implants, especially with reference to displacement, capsular contracture, seroma, reoperation, biofilm and implant rupture. Since the introduction of the conical polyurethane implant (Silimed, Brazil) into the United Kingdom in 2009 (Eurosurgical, UK), we have had the opportunity to review histology taken from the capsules of polyurethane implants in three women ranging from a few months to over 3 years after implantation. All implants had been inserted into virgin subfascial, extra-pectoral planes. The results add to the important previously described histological findings of Bassetto et al. (Aesthet Plast Surg 34:481-485, 2010). Five distinct layers are identified and reasons for the development of each layer are discussed. Breast capsule around polyurethane implants, in situ for fifteen and 20 years, has recently been obtained and analysed in Brazil, and the histology has been incorporated into this study. After 20 years, the polyurethane is almost undetectable and capsular contracture may appear. These findings contribute to our understanding of polyurethane implant safety, and give reasoning for a significant reduction in clinical capsular contracture rate, up to 10 years after implantation, compared to contemporary silicone implants. A more permanent matrix equivalent to polyurethane may be the solution for reducing long-term capsular contracture., Level of Evidence V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Background: Recently there have been concerns raised about anaplastic large cell lymphoma (ALCL) associated with breast implants., Objectives: The main aim of this article was to review and analyze the published literature specifically for hematopoietic malignancies associated with breast implants and postulate a hypothesis for their etiology and pathogenesis., Methods: The PubMed database was searched using key words "lymphoma" and "breast implants" for published papers and abstracts on implant-associated hematopoietic malignancies., Results: The authors found 83 published cases reported of lymphomas associated with breast implants in the medical literature. The reported cases involved various subtypes of lymphomas and the majority were ALCL, of which 66 were confirmed as ALK negative; however there was no association with any particular type of implant. The more aggressive cases and reported low death rate appeared to be related to the presence of breast masses at the time of presentation rather than effusion. The remaining reports were occasional case reports of T-cell lymphoma, follicular lymphoma, marginal zone B-cell lymphoma, primary effusion lymphoma and lymphoplasmacytic lymphoma., Conclusions: Considering the many thousands of women that have breast implants every year; the compiled data show that there is a very small risk of developing lymphoma. Increased awareness of association between implants and ALCL is needed globally and prospective patients considering breast implants should be fully informed of the risk. As the behavior of ALCL in these cases was indolent as compared with other primary breast lymphomas, it could suggest an abnormal reactive process., Level of Evidence: 3, (© 2015 The American Society for Aesthetic Plastic Surgery, Inc. Reprints and permission: journals.permissions@oup.com.)

Background: Sarcoidosis is a multisystem granulomatous disease of unknown origin with pulmonary and extrapulmonary manifestations. Worldwide it is most often diagnosed in the third and fourth decades and most often affects Swedish, Danish and black patients. The association between malignancy and sarcoidosis has not been conclusively proven. Cancer can eventually occur in patients who have an established diagnosis of sarcoidosis for example, in sarcoidosis-lymphoma syndrome. Sarcoidosis can also subsequently develop in an oncology patient. There are multiple obstacles to confirming epidemiologically the linkage between sarcoidosis and malignancy. Histological verification and clinical acumen are needed to avoid misdiagnosis. The 18 fluorodeoxyglucose (18-FDG) PET has failed to provide a non invasive diagnostic method to differentiate neoplasia from benign sarcoid lesions and tissue diagnosis is essential before commencing a new therapeutic intervention in patients with lymphoma., Methods: We report 3 cases of co-diagnosis of sarcoidosis and lymphoma that were seen in an oncology unit in Drogheda, Co. Louth., Results: Our patients varied in the temporal association between the diagnosis of sarcoidosis and lymphoma as well as their demographic characteristics., Conclusion: These cases help to demonstrate the need for careful clinical, histological and radiological assessment.

Being a significant health problem that affects patients in various age groups, breast cancer has been extensively studied to date. Recently, molecular breast cancer classification has advanced significantly with the availability of genomic profiling technologies. Proteomic technologies have also advanced from traditional protein assays including enzyme-linked immunosorbent assay, immunoblotting and immunohistochemistry to more comprehensive approaches including mass spectrometry and reverse phase protein lysate arrays (RPPA). The purpose of this manuscript is to review the current protein markers that influence breast cancer prediction and prognosis and to focus on novel advances in proteomic classification of breast cancer.

Endoscopic mucosal resection (EMR) is increasingly being utilized in the management of early gastric cancer. Metastatic cancer of the stomach is uncommon. We report a case of solitary gastric metastasis from renal cell carcinoma (RCC) that was successfully excised with EMR. A 71-year-old man presented with iron deficiency anemia, he had undergone a radical nephrectomy for RCC 3 years previously. Upper gastrointestinal endoscopy revealed a malignant-appearing 10 × 12 mm polyp in the stomach. Histopathology of the biopsy revealed that it was a metastasis from RCC, confirmed by immunohistochemistry with Vimentin and CAM 5.2 positivity. Computed tomography and bone scanning revealed no other metastases. Simultaneous laparoscopy and upper gastrointestinal endoscopy revealed that the lesion was localized to the gastric mucosa. EMR of the tumor en bloc was performed successfully. Histology confirmed a complete excision. He had an uneventful postoperative course and is well 15 months after surgery, without any tumor recurrence.

Introduction: Lymphadenopathy is a common finding in toxoplasmosis. A breast mass due to toxoplasmosis is very rare, and only a few cases have been reported. We present a case of toxoplasmosis that presented as a swelling in the axillary tail of the breast with a palpable axillary lymph node which mimicked breast cancer., Case Presentation: A 45-year-old otherwise healthy Caucasian woman presented with a lump on the lateral aspect of her left breast. Her mother had breast cancer that was diagnosed at the age of 66 years. During an examination, we discovered that our patient had a discrete, firm lump in the axillary tail of her left breast and an enlarged, palpable lymph node in her left axilla. Her right breast and axilla were normal. The clinical diagnosis was malignancy in the left breast. Ultrasound and mammographic examinations of her breast suggested a pathological process but were not conclusive. She had targeted fine-needle aspiration cytology (FNAC) and core biopsy of the lesions. FNAC was indeterminate (C3) but suggested a possibility of toxoplasmosis. The core biopsy was not suggestive of malignancy but showed granulomatous inflammation. She had a wide local excision of the breast lump and an axillary lymph node biopsy. Histopathology and immunohistochemical studies excluded carcinoma or lymphoma but suggested the possibility of intramammary and axillary toxoplasmic lymphadenopathy. The results of Toxoplasma gondii IgM and IgG serology tests were positive, supporting a diagnosis of toxoplasmosis., Conclusions: Toxoplasmosis rarely presents as a pseudotumor of the breast. FNAC and histology are valuable tools for a diagnosis of toxoplasmosis, and serology is an important adjunct for confirmation.

Background: Most cases of dialysis-dependent acute kidney injury due to myeloma cast nephropathy do not recover renal function. Renal biopsy typically shows cast formation, direct tubular injury and interstitial inflammation caused by nephrotoxic monoclonal free light chains (FLC). Established scarring at presentation is rarely severe. There is little data on in situ evolution of renal injury., Aims: To conduct a detailed histological study of four patients with cast nephropathy., Methods: Cast nephropathy was confirmed by renal biopsy. Treatment consisted of chemotherapy and high cut-off dialysis to maximise extracorporeal removal of FLC and reduce renal toxicity. All four patients remained dialysis dependent at 6 weeks, at which time they underwent a further biopsy., Results: Three patients achieved independence from dialysis. Six-week biopsies showed differential changes in chronic damage from no progression, to accelerated progression of scarring from 10% to 42%, despite a rapid and sustained fall in FLC in all patients. In three patients there was a major reduction in intratubular cast numbers; these patients subsequently recovered renal function. In one patient who continued to have high cast formation at 6 weeks there was no subsequent renal recovery., Conclusions: Some FLC clones can promote rapid renal scarring. Significant reductions in cast formation on repeat biopsy may identify the potential for late renal recovery. Early diagnosis and treatment may prove crucial in determining renal recovery. Patients who have not recovered renal function after a period of treatment may be usefully reassessed by repeat biopsy for quantitative analysis of chronic damage and cast numbers.

Background: The use of topical negative pressure (TNP) dressings with dermal regeneration template (DRT), Integra, has improved outcomes and simplified aftercare. Previous clinical studies have suggested accelerated vascularisation; with a reduction in the duration of the 1st stage after the application of Integra, from 2 to 4 weeks to as little as 4 days, but with no histological evidence. However, histological studies, without TNP, have shown that vascularisation occurs between the second and the fourth week. This study set out to examine histologically the rate of DRT neovascularisation when combined with TNP., Methods: Eight patients with nine reconstruction sites were enlisted. Unmeshed Integra and fibrin sealant to promote adherence were used. TNP was applied for the duration between the 1st and the 2nd stages. Patients underwent serial biopsies on days 7, 14, 21 and 28 post-application. The biopsies were stained with H&E and endothelial markers CD31 and CD34. Template vascularisation was assessed as a percentage of the template depth in which patent, canalised vascular channels could be demonstrated., Results: The median percentage of the template depth which demonstrated canalised channels was 0%, 20%, 61% and 80% for days, 7, 14, 21 and 28, respectively., Conclusion: The application of TNP dressings to dermal templates can reduce shearing forces, restrict seroma and haematoma formation, simplify wound care and improve patient tolerance. However, this study could not demonstrate that TNP accelerates neovascularisation as verified by the presence of histologically patent vascular channels., (Crown Copyright 2010. Published by Elsevier Ltd. All rights reserved.)

Introduction: Acute renal failure in multiple myeloma is most frequently caused by cast nephropathy, when excess monoclonal free light chains co-precipitate with Tamm-Horsfall protein in the distal nephron, causing tubular obstruction. The natural history of cast nephropathy after diagnosis is unknown. This report provides supporting histological evidence that, as serum free light chain concentrations fall, intratubular casts may resolve within weeks., Case Presentation: We report the case of a 61-year-old Caucasian woman who presented with multiple myeloma and dialysis-dependent acute renal failure, with serum kappa free light chain concentrations of 15,700 mg/litre (normal range 3.3 to 19.4 mg/litre). Renal biopsy demonstrated cast nephropathy with waxy casts in distal tubules and collecting ducts. There was an interstitial inflammatory cell infiltrate with diffuse fibrosis and tubular atrophy. Following rehydration, chemotherapy and free light chain removal using high cut-off haemodialysis, free light chain concentrations fell to less than 5% of the starting level (500 mg/litre). A repeat renal biopsy 6 weeks after the first showed resolution of cast nephropathy., Conclusion: These observations indicate that cast nephropathy can quickly resolve on rapid reduction of monoclonal serum free light chains. This has important implications for the development of treatment strategies aimed at improving renal recovery rates for patients in this setting.

Anti-myeloperoxidase (anti-MPO) antibodies have been implicated in the pathogenesis of small-vessel vasculitis, but the molecular mechanisms by which these antibodies contribute to disease are unknown. For determination of how anti-MPO antibodies affect inflammatory cell recruitment in small-vessel vasculitis, intravital microscopy was used to monitor leukocyte behavior in the accessible cremasteric microvessels under various experimental conditions. After local pretreatment of the cremaster muscle with cytokines (TNF-alpha, IL-1beta, or keratinocyte-derived chemokine), administration of anti-MPO IgG to wild-type mice reduced leukocyte rolling in favor of augmented adhesion to and transmigration across the endothelium. This led to a decrease in the number of systemic circulating leukocytes and, similar to the early events in the development of vasculitic lesions, an increase in leukocyte recruitment to renal and pulmonary tissue. TNF-alpha led to the greatest recruitment of inflammatory cells, and IL-1beta led to the least. When anti-CD18 was co-administered, anti-MPO IgG did not affect leukocyte rolling, adhesion, or transmigration; similarly, anti-MPO IgG did not produce these effects in Fc receptor gamma chain-/- mice. This study provides direct in vivo evidence of enhanced leukocyte-endothelial cell interactions in the presence of anti-MPO IgG and highlights the critical roles of Fcgamma receptors and beta2 integrins in mediating these interactions. In addition, it suggests that neutrophils primed by cytokines in the presence of anti-MPO IgG can have systemic effects and target specific vascular beds.

Antineutrophil cytoplasmic antibody-associated vasculitides often cause small-vessel vasculitis, usually involving the kidney. Involvement of other organ systems and medium to large arteries is recognized, but free-vessel rupture is rare. A case of a man with classic renal involvement caused by microscopic polyangiitis associated with multiple episodes of hemoperitoneum secondary to splanchnic vasculitis is described. Although his renal vasculitis responded to conventional immunosuppressive treatment, relentless progression of splanchnic vasculitis ultimately proved fatal.

Aggressive angiomyxoma (AAM) was first reported in 1983 as a distinct, slow growing, benign but locally infiltrative, soft tissue tumour. It usually arises in the pelvic and perineal organs, mostly in women. A 47-year-old woman was found to have a large encapsulated retroperitoneal aggressive angiomyxoma. The mass was completely excised via abdomino-perineal approach, and no recurrence noted on MRI at 19 months' follow-up. The encapsulation of this tumour together with other reported rare presentations, suggest an isolated mesenchymal cell origin. A review of the literature is provided.

The overall goal of this study was to determine the effects of subchronic nicotine (0.4 mg/kg) treatment for 7 or 14 days on striatal glutamate function in both naïve and in 6-hydroxydopamine (6-OHDA)-treated rats in which the nigrostriatal dopamine pathway was lesioned. In lesioned animals, the effect of nicotine on apomorphine-induced contralateral rotations was also assessed. In naïve rats, once daily nicotine administration for 7 or 14 days resulted in a decrease and then an increase, respectively, in the basal extracellular level of striatal glutamate compared to the saline-treated group. Ultrastructurally, 14-day treatment with nicotine resulted in an increase in the density of striatal glutamate immunolabeling within nerve terminals making an asymmetrical synaptic contact compared to the saline-treated group. In 6-OHDA-lesioned animals, coadministration of nicotine with apomorphine or nicotine alone for 7 days resulted in an increase in the density of nerve terminal glutamate immunolabeling, compared to the apomorphine- or saline-treated groups. However, coadministration of nicotine with apomorphine for 14 days resulted in a decrease in the density of nerve terminal glutamate immunolabeling compared to the nicotine-treated group. Following subchronic treatment of 6-OHDA-lesioned rats with apomorphine for 7 or 14 days, there was an increase in the number of apomorphine-induced contralateral rotations compared to the saline treated group. There was a decrease in the number of apomorphine-induced contralateral rotations in the group coadministered nicotine with apomorphine for 7 or 14 days compared to the apomorphine treated group. The data suggests that in this 6-OHDA lesion model of Parkinson's disease, treatment with nicotine may be useful in counteracting the increased behavioral effect (i.e., contralateral rotations) observed after treatment with a dopamine agonist, such as apomorphine., (Copyright 2002 Elsevier Science (USA).)

Dinucleotide deletions (e.g. DeltaGA, DeltaGU) are created by molecular misreading in or adjacent to GAGAG motifs of neuronal mRNAs. As a result, the reading frame shifts to the +1 frame, and so-called "+1 proteins" are subsequently synthesized. +1 Proteins have a wild-type N-terminus, but an aberrant C-terminus downstream from the site of the dinucleotide deletion. Molecular misreading was discovered in the rat vasopressin gene associated with diabetes insipidus and subsequently in human genes linked to Alzheimer's disease (AD), e.g. beta amyloid precursor protein (betaAPP) and ubiquitin-B (UBB). Furthermore, betaAPP(+1) and UBB(+1) proteins accumulate in the neuropathological hallmarks (i.e. in the tangles, neuritic plaques, and neuropil threads) of AD. As these +1 proteins were also found in elderly nondemented controls, but not in younger ones (<51 years), molecular misreading in nondividing cells might act as a factor that only becomes manifest at an advanced age. Frameshift mutations (UBB(+1)) and pretangle staining (Alz-50 and MC1) seem to occur independently of each other during early stages of AD. We recently detected +1 proteins, not only in proliferating cells present in non-neuronal tissues such as the liver and epididymis, but also in neuroblastoma cell lines. These observations suggest that molecular misreading is a general source of transcript errors that are involved in cellular derangements in various age-related pathologies.

DNA copy number changes were investigated in 69 samples of schistosoma-associated (SA) and non-schistosoma-associated (NSA) squamous cell carcinoma (SCC) and transitional cell carcinoma (TCC) of the bladder by comparative genomic hybridization (CGH). DNA copy number changes were detected in 47 tumors. SA tumors had more changes than NSA tumors (mean, 7 vs. 4), whereas the number of changes in SCC and TCC tumors was similar. SA tumors displayed more gains than losses (1.7:1), whereas NSA tumors showed an equal number of gains and losses. Changes that were observed at similar frequencies in SCC and TCC, irrespective of the schistosomal status, included gains and high-level amplifications at 1q, 8q, and 20q and losses in 9p and 13q. These changes may be involved in a common pathway for bladder tumor development and progression independent of schistosomal status or histological subtype. Losses in 3p and gains at 5p were seen only in SCC (P < 0.01) and losses in 5q were more frequent in SA-SCC than in other tumors (P < 0.05). However, changes that were more frequent in TCC than those in SCC included gains at 17q (P < 0.01) and losses in 4q (P < 0.05) and 6q (P < 0.01). Gains and high-level amplifications at 5p were seen only in SA-SCC (P < 0. 01), whereas gains and high-level amplifications with minimal common overlapping regions at 11q13 were more frequently seen both in SA-SCC and SA-TCC tumors (P < 0.01). In addition to the above mentioned alterations, several other changes were also seen at lower frequencies. The variations in the DNA copy number changes observed in TCC, SCC, SA, and NSA bladder carcinomas suggest that these tumors have different genetic pathways.

Previous studies on DNA polymerase epsilon indicate that this enzyme is involved in replication of chromosomal DNA. In this study, we examined the expression of DNA polymerases alpha, delta, and epsilon during mouse testis development and germ cell differentiation. The steady-state levels of mRNAs encoding DNA polymerase epsilon and the recombination enzyme Rad51 remained constant during testis development, whereas the mRNA levels of DNA polymerases alpha and delta declined from birth until sexual maturity. Immunohistochemical staining methods, using a stage-specific model of the seminiferous epithelium, revealed dramatic differences between DNA polymerase alpha and epsilon distribution. As expected, DNA polymerase alpha and proliferating cell nuclear antigen showed relatively strong immunostaining in mitotically proliferating spermatogonia and even stronger staining in preleptotene cells undergoing meiotic DNA replication. The distribution of Rad51 was similar, but there was a dramatic peak in late pachytene cells. In contrast, DNA polymerase epsilon was detectable in mitotically proliferating spermatogonia but not in the early stages of meiotic prophase. However, DNA polymerase epsilon reappeared in late pachytene cells and remained through the two meiotic divisions, and was present in haploid spermatids up to the stage at which the flagellum starts developing. Overall, the results suggest that DNA polymerase epsilon functions in mitotic replication, in the completion of recombination in late pachytene cells, and in repair of DNA damage in round spermatids. In contrast, DNA polymerases alpha and delta appear to be involved in meiotic DNA synthesis, which occurs early in meiotic prophase, in addition to functioning in DNA replication in proliferating spermatogonia.

Background: In some carcinomas inactivation of the tumour suppressor gene product p53, either by point mutation or indirectly by the human papillomavirus (HPV), has been suggested as two alternative routes to malignant transformation. To test this hypothesis in lung tumours, 43 lung carcinomas were analysed by in situ hybridisation and polymerase chain reaction (PCR) for the presence of HPV DNA, and the results were compared with p53 protein immunohistochemical analysis., Methods: The presence of HPV DNA in lung carcinoma was detected by nucleic acid in situ hybridisation for HPV types 6, 11, 16, 18, 31, and 33 using nonradioactively labelled DNA probes. Polymerase chain reaction (PCR) analysis was performed on all cases showing positive HPV DNA labelling by in situ hybridisation and in an additional 13 negative cases. Abnormal nuclear accumulation of the p53 protein was revealed by immunohistochemistry using the avidin-biotin-peroxidase complex method and a CM-1 polyclonal anti-human p53 antibody and a monoclonal mutation-specific Pab 240 p53 antibody., Results: HPV DNA was found by in situ hybridisation in 13 lung carcinomas (30%). In all these cases subtype-specific HPV DNA could also be detected by PCR. Abnormal p53 protein accumulation was seen in 21 of the 43 carcinomas (49%), of which 18 were HPV negative. Twelve (57%) of the CM-1 positive cases were also positive for the mutation-specific antibody Pab 240. There was an obvious inverse relationship between the presence of papilloma viral DNA and abnormal p53 protein accumulation., Conclusions: p53 plays an important part in the development of lung carcinomas and, in some cases, HPV may contribute to it by binding and inactivating the p53 protein.

Accumulation of the tumour suppressor gene p53 product due to a gene mutation is frequently seen in human carcinomas, including lung carcinoma. Another indirect mechanism involving p53 in malignant growth relates to the E6 protein of the human papillomavirus (HPV), which is able to bind and degrade wild-type p53 protein, thus eliminating its tumour suppressor activities. Bronchiolo-alveolar carcinoma (BAC) is a rare type of lung carcinoma. The aim of our study was to examine the occurrence of p53 accumulation and the presence of HPV DNA in BAC. Sections of 22 BACs were immunohistochemically stained using a p53 antibody, CM-1. The presence of HPV DNA in BACs was verified by in situ hybridisation for HPV types 6, 11, 16, 18, 31 and 33 and confirmed by PCR. Thirty-six percent of the tumours showed abnormal p53 nuclear accumulation, and HPV DNA, revealed by in situ hybridisation, was found in 36%. Unexpectedly, only 13% of the type 1 BACs were positive for p53, whereas 45% of the type 2 BACs were positive. During a follow-up of 12-176 months, only 10% of the patients with BACs negative for both p53 and HPV died of the disease, compared with 42% of the patients with either p53 or HPV positivity. No inverse relationship between abnormal p53 protein accumulation and the presence of HPV DNA was found.

In this study we analysed 47 bladder carcinomas for the presence of DNA-HPV subtypes 6, 11, 16, 18, 31 and 33 by nucleic acid in situ hybridization, and for the abnormal accumulation of p53 protein by immunohistochemistry. HPV DNA was found in 27/47 (57%) bladder carcinomas, with multiple subtypes in 20 cases. In squamous cell carcinoma (SCC), HPV DNA was only detected in the superficial layer of the neoplastic epithelium and was found mainly in the nuclear compartment. In contrast, in transitional cell carcinoma (TCC), HPV DNA was also found in deeper parts of the tumour. In about half the cases it was mainly found in the cytoplasmic compartment. In SCC, the HPV DNA labelling occurred in koilocytic cells, while no such association was found in TCC. Abnormal accumulation of p53 protein was found in 24/47 (51%) carcinomas. p53 positivity was found significantly more often in SCC than in TCC (p = 0.05). Concurrent HPV positivity and abnormal p53 protein accumulation was found in 18 cases, 14 showing the presence of HPV subtypes 16 and/or 18 DNA. The results demonstrate that HPV DNA occurs widely in urinary tract tumours. Unlike in some other carcinomas, there was no inverse relationship between HPV positivity and abnormal p53 protein accumulation in bladder carcinomas. Thus HPV infection may play a role in the pathogenesis of bladder carcinomas by some mechanism other than inactivation of the p53 protein.

Sixty-two skin samples from patients with a variety of benign disorders (20 cases of psoriasis, 14 cases of chronic dermatitis, 11 seborrhoeic keratoses, 11 cases of lichen planus), and seven normal skin samples, were stained immunohistochemically with a polyclonal antibody (CM-1) to p53, and a monoclonal antibody to Ki67, using the avidin-biotin complex method. p53-positive keratinocytes could be found in most of these lesions. The percentage of p53-positive cells was, however, far lower than usually seen in p53-positive malignant tumours. No p53 reactivity was observed in the normal skin samples. Variable Ki67 reactivity was observed in all skin samples. Overall, the number of Ki67-positive cells was higher in skin samples in which the proportion of p53-positive cells was high (> 0.5% of total epidermal cell population) (P = 0.004). This also applied separately to psoriatic and non-psoriatic lesions (P = 0.028 and P = 0.033, respectively). In cases with > 10% of Ki67-positive cells, there were significantly more mitoses (P < 0.001). This association applied to both psoriasis and the other lesions studied (P = 0.024 and P < 0.001, respectively). The results show that immunohistochemically detectable accumulation of p53 is a frequent finding in non-neoplastic skin lesions. As p53 positivity was associated with the proliferation marker Ki67, the accumulation of p53 is possibly a response to an increased proliferation rate of the keratinocytes in these skin diseases, or alternatively it may be associated with apoptosis.

In this study we investigated 56 renal cell carcinomas immunohistochemically for the expression of proliferating cell nuclear antigen (PCNA) and tumour suppressor protein p53. We also analyzed for the presence of human papilloma virus (HPV) DNA subtypes 6, 11, 16, 18, 31 and 33 by in situ hybridization. In carcinomas which showed more than 10% of PCNA positive nuclei there were significantly more cases with invasion (P = 0.032) or metastatic disease (P = 0.047). Nine out of 22 grade III-IV tumours (40.9%) but only six out of 30 grade I-II tumours (20%) showed more than 10% of PCNA positive cells (P = 0.097). Patients with 10% or more PCNA positive cells in kidney tumours had more advanced disease at the time of diagnosis than those showing less PCNA positive cells (P = 0.05). Six p53 positive cases were found among 56 tumours (11%), but only one case had more than 10% positive cell nuclei. The presence of HPV DNA was found in 29 out of 56 cases (52%). Multiple subtypes were found in 19 cases (34%). The most commonly occurring subtypes were 18 and 33. There was no association between PCNA, p53 and the presence of HPV DNA subtypes. Because of the association of PCNA with invasion and metastatic disease, it would be worth while to study PCNA further as a possible marker for aggressiveness of renal carcinomas. Both this study and those concentrated on mutational analysis suggest that p53 is generally not important for the development of renal cell carcinoma. On the other hand, the presence of HPV DNA in these tumours implicates HPV viral infection in the aetiology of renal cancer.

The frequency and scale of positive p53 immunohistochemistry in 107 intracranial tumours of different types was studied as a possible prognostic marker using a polyclonal antibody CM-1 which detects both the wild-type and mutated p53 proteins. Fifty of the tumours (46.7%) showed nuclear p53 positivity with different percentages of positive nuclei. The positivity was concentrated in glial tumours of which 52.8% were positive. Forty-two of seventy-four astrocytomas (56.8%), 4 of 12 oligodendrogliomas (33.3%), and 1 of 3 ependymomas (33.3%) showed p53-positive nuclei. Cytoplasmic positivity, found in 25 astrocytomas, was always associated with nuclear positivity. Some p53-positive nuclei were seen in 16.7% of the non-gliomatous tumours, but in all cases p53 positivity was seen in less than 1% of the nuclei. The patients with astrocytomas containing more than 5% p53-positive nuclei were younger (mean 27.3 years) (p = 0.016) and their tumours larger in diameter (mean 4.4 cm) (p = 0.05) than those with p53-negative astrocytomas (mean 41.0 years and mean 3.3 cm, respectively). In p53-positive (> or = 1% of nuclei) grade IV astrocytomas, survival time was significantly shorter (mean 7.2 months) than in p53-negative grade IV astrocytomas (mean 15.5 months (p = 0.024). The results indicate frequent p53 expression in intracranial tumours, especially in gliomas. The association of p53 positivity with young age, larger tumour size, and poor prognosis in high-grade astrocytomas suggests that p53 may be involved in the development of more aggressive types of intracranial tumours. According to these results, p53 immunohistochemical positivity may serve as a prognostic marker in high-grade astrocytomas.

Primary lung carcinomas often carry mutations in the p53 tumor suppressor gene. Most of these mutations alter the conformation of the p53 protein into a more stable phenotype that makes it immunohistochemically detectable. Asbestos is a carcinogen that can cause deletions in chromosomes and possibly also gene mutations. In this study we examined 70 primary lung carcinomas for p53 protein accumulation using a polyclonal antihuman p53 antibody, CM-1. Patients were interviewed about their occupational and smoking history and classified according to their anamnestical asbestos exposure. Presence of asbestos bodies (AB) was evaluated from histologic samples of peripheral nontumorous lung tissue using both 5-microns-thick sections stained with Perls' iron and 30-microns-thick unstained sections. Abnormal accumulation of p53 protein was found in 36 tumors (51%), more often in patients exposed to asbestos than in patients without exposure (67% versus 40%, p = 0.027). Significant association was also noticed between the accumulation of p53 and the asbestos content of lung tissue: 35% of the p53-positive patients had more than one AB/cm2 compared with 14% of p53-negative cases (p = 0.046). Patients with strongly p53-positive tumors were heavier smokers (57.2 +/- 38.2 pack-years) than patients with p53-negative or lightly positive tumors (38.9 +/- 19.9 pack-years) (p = 0.017). Our findings indicate that both asbestos exposure and heavy smoking can cause abnormal p53 protein accumulation suggestive of mutated p53.

Thirteen consecutive fine-needle aspirates of breast carcinoma and five selected breast tumor cell lines were analyzed for ERBB2 and MYC mRNA expression by in situ hybridization. To compare the level of mRNA synthesis with those of gene amplification and oncoprotein synthesis, all tumors were also analyzed by Southern blot analysis, and for ERBB2 also by immunohistochemistry. Expression of ERBB2 mRNA was observed in eight tumors. MYC expression was observed in all tumors studied. Three tumor cell lines expressed both ERBB2 and MYC (SK-BR-3, HeLa, HT-29) and two only MYC (SK-LU-1, HL-60). Only one tumor showed amplification of ERBB2 and two of MYC. In all three cases there was a considerable increase in corresponding mRNA synthesis as detected by in situ hybridization. By immunohistochemistry, four cases showed either patchy areas or uniformly distributed, membrane-bound ERBB2 immunoreactivity. All except one case showed increased ERBB2 mRNA synthesis. There was a clear association between the quantity of ERBB2 mRNA and oncoprotein expression. The results show that in situ hybridization of fine-needle aspiration material is a sensitive method to detect increased expression of the ERBB2 and MYC oncogenes in breast carcinoma. Furthermore, this study indicates that in a majority of cases some other mechanism that gene amplification appears responsible for the increased gene expression. It is also possible that Southern blot analysis is not a sensitive enough method to detect gene amplifications in the heterogeneous breast tumors, which usually also contain stromal tissue. The fact that not all cases with elevated ERBB2 mRNA synthesis were immunohistochemically positive suggests that either immunohistochemistry (after fixation with 10% formalin) is a less sensitive method than in situ hybridization to detect abnormal gene expression or that there are cases in which the oncoprotein synthesis is for some reason depressed, even though there is an increase in gene transcription.

Immunoreactivity for p53 and c-erbB-2 proteins was studied in 31 schistosomal urinary bladder carcinomas and 21 cases of schistosomal cystitis with hyperplastic, metaplastic and/or dysplastic (premalignant) lesions. The results were compared with 30 carcinomas and 21 premalignant lesions of the urinary bladder without schistosomiasis. Abnormal nuclear p53 protein accumulation was found in 17/31 schistosomal and in 15/30 non-schistosomal carcinomas and in 8/21 schistosomal cystitis with premalignant lesions of which five showed hyperplasia. No case of non-schistosomal hyperplasia or squamous metaplasia examined showed p53-positivity. In non-schistosomal carcinomas p53 positivity was significantly associated with tumour grade (grade I-II vs grade III tumours: P = 0.021) and greater age (P = 0.004) while in schistosomal carcinomas no such associations were found. Cytoplasmic membrane-bound positivity for c-erbB-2 oncoprotein was found in comparable percentages in schistosomal and non-schistosomal bladder carcinomas (10%), and in both groups was co-expressed with p53. p53 gene alteration is an important event in the development of both schistosomal and non-schistosomal bladder carcinoma.

Immunohistochemically detectable p53 protein using a polyclonal antibody (CM-1) was studied in 42 carcinomas of which 11 were grade I, 22 grade II and nine grade III carcinomas. Additionally 14 urothelial dysplasias were studied. In 11 of these a diagnosis of transitional cell carcinoma was established before and in one after the dysplasia diagnosis. Twenty-one out of 42 (50%) cases of transitional cell carcinoma were positive for the p53 protein. Eleven out of 14 (78%) dysplasias and 10/12 (83%) related carcinomas were p53 positive. One out of 11 grade I (9%), 12/22 grade II (55%) and 8/9 grade III (89%) tumours showed positivity for p53. There were significantly more p53 positive cases in grade II-III tumours than in grade I tumours (P = 0.004). There were significantly more p53 positive cases in stage T2-T4 tumours than in stage T1 tumours (P = 0.035). In only one case among the 11 dysplastic lesions following the treatment of a carcinoma the dysplastic lesion was p53 negative while the preceding carcinoma was p53 positive. All dysplasias and 28 carcinomas were also immunostained for laminin and type IV collagen to evaluate the continuity of basement membranes (BMs). Clearly disrupted BMs were observed only in grade III carcinomas. These cases showed the most p53 immunopositivity. The results show a strong association of p53 staining between dysplasias and transitional cell carcinomas of the urinary bladder indicating that these lesions might share similar p53 changes. The correlation to grade, clinical stage and to disrupted BM suggests that p53 mutations may be associated with the evolution of aggressive growth characteristics in transitional cell carcinomas or, alternatively, that p53 positive tumours of a more aggressive type from the start. Whether p53 staining can be used as an adjunct in the assessment and follow-up of epithelial changes of patients treated for a p53 positive bladder carcinoma deserves to be studied.

The distribution of tenascin immunoreactivity was analyzed in nonneoplastic lung tissue, benign lung tumors, and different types of lung carcinomas. In nonneoplastic lung tissue, tenascin could be observed in the basement membranes of the bronchial epithelium and endothelial cells, smooth muscle cells, and bronchial cartilage. Strong tenascin immunoreactivity was seen in the stroma of all the carcinomas of various histologic types. The staining intensity was stronger in the stroma of squamous cell carcinomas than in the stroma of the other types of lung carcinomas. In 10 of 27 squamous cell carcinomas, a granular intracytoplasmic reactivity could also be observed in a subpopulation of tumor cells. Similar intracytoplasmic reactivity was observed in 2 of 27 adenocarcinomas and in both adenosquamous carcinomas. In other types of lung tumors, individual cells did not have intracytoplasmic tenascin, except for one case of leiomyoma, which showed a weak, linear, intracytoplasmic tenascin reactivity. In lung hamartomas, tenascin could be seen in the cartilaginous component of the tumor and in the areas of basement membranes of the bronchial epithelium. In the carcinoid tumors, the stroma displayed a faint positivity for tenascin. These results show that tenascin is widely expressed in the stroma of lung carcinomas. A proportion of lung carcinomas also expressed intracytoplasmic tenascin immunoreactivity, suggesting that tumor cells may be able to synthesize tenascin. In the lung, tenascin positivity is not, however, restricted to malignant neoplasms, as evidenced by the presence of tenascin in nonneoplastic lung parenchyma and in some benign lung tumors.

In this study we investigated immunohistochemically the expression of p53 and c-erbB-2 proteins in 30 gall bladder adenocarcinomas, one carcinoma in situ, eight gall bladder epithelial dysplasias, and four cases of chronic cholecystitis. p53 expression could be found in 14 (47 per cent) adenocarcinomas and in two out of eight epithelial dysplasias. There were significantly more p53-positive grade II-III tumours than grade I tumours (P = 0.032 according to Fisher's exact probability test). c-erbB-2 expression was found in three (10 per cent) adenocarcinomas, but all dysplasias were c-erbB-2-negative. All three c-erbB-2-positive cases were also p53-positive. The results indicate that p53 mutations and c-erbB-2 gene alterations play a role in the neoplastic transformation of gall bladder epithelial cells. Co-expression of p53 and c-erbB-2 suggests that alterations of these genes might act in concert in the neoplastic transformation. The occurrence of p53 expression in gall bladder dysplasias suggests that p53 mutations could be an early event in the evolution of some gall bladder carcinomas, as has been suggested for some other types of tumours, such as lung squamous cell carcinomas.

We analyzed the p53 protein immunohistochemically in bronchial dysplasias or squamous cell carcinomas in situ and in squamous cell lung carcinomas occurring in the same patients. The polyclonal antibody used (CM-1) is directed against the wild-type p53 protein, but also recognizes the mutated p53 in formalin-fixed and paraffin-embedded sections. To study the integrity of basement membranes (BMs) and the possible invasion of the dysplastic epithelium, immunostainings for the BM proteins laminin and type IV collagen were used. Nine of the 17 dysplasias showed p53 protein expression (53%); it was significantly more often seen in severe dysplasias and carcinomas in situ than in mild or moderate dysplasias (P = 0.04). The p53 antigenicity was generally located in the basal part of the epithelium. The BMs beneath mildly dysplastic epithelia were continuous. In contrast, those under moderately or severely dysplastic epithelia showed occasional disruptions. p53 protein expression was also found in dysplastic epithelium above a continuous BM suggesting an ominous process before signs of invasion. Twelve of the 17 squamous cell carcinomas showed p53 protein expression (71%). There was a significant concurrent p53 expression in bronchial dysplasias and their related squamous cell carcinomas (P = 0.009), so that all nine cases of p53 positive bronchial dysplasia also showed p53 positivity in the associated squamous cell carcinomas. These findings indicate that p53 protein expression is possible in premalignant bronchial lesions, and suggests that the p53 expression could, at least in some cases, be an early event in the development of a squamous cell carcinoma of the lung.