[Role of computed tomography in the preoperative diagnosis of otosclerosis]. / Stellenwert der Computertomographie in der präoperativen Diagnostik der Otosklerose.

BACKGROUND: Otosclerosis is an osteodystrophy of the otic capsule and presents with progressive conductive hearing loss. Imaging studies, especially computed tomography (CT) and cone-beam CT, have gained increased relevance in the diagnosis of otosclerosis. OBJECTIVE: This study investigated whether there is a correlation between the extent of otosclerosis in high-resolution or cone-beam CT and hearing loss in pure-tone audiometry. MATERIALS AND METHODS: Based on an existing classification of otosclerotic foci, a classification was established. Preoperative CT scans of patients undergoing stapedotomy between 2015 and 2019 were evaluated and classified by two independent otorhinolaryngologists. The preoperative pure-tone audiograms were analysed and compared to the results of CT. RESULTS: A total of 168 CT studies (i.e., 168 ears) in 156 patients with intraoperatively confirmed otosclerosis were included in our study. A correlation between the extent of the otosclerotic focus or the calculated scores and hearing loss in pure-tone audiometry (air conduction, bone conduction and air-bone-gap) could not be proven. CONCLUSION: Preoperative CT is not obligatory. However, preoperative imaging using CT or cone-beam CT can be helpful to confirm the diagnosis and exclude other middle or inner ear pathologies as well as in planning of the surgical procedure in the overall context of otoscopy and audiometry. A correlation with the degree of hearing impairment could not be demonstrated and remains unclear.

Clinicopathological prognostic factors of oral squamous cell carcinoma: An experience of a tertiary care hospital.

Locoregional recurrence accounts for majority of the treatment failures in oral cancer patients. Current study aimed to determine the predictors of recurrence and survival in patients with biopsy proven Squamous Cell Carcinoma (SCC) of the oral cavity. This study included 88 patients of squamous cell carcinoma treated at our institution from 2007 till 2013. Primary intervention was surgery in all patients with radiation and chemotherapy in selected patients. Primary end point was locoregional recurrence, distant metastasis and death. Out of 88 patients, 23 (26.1%) patients developed locoregional recurrence and 6 (6.8%) patients developed distant metastasis. Overall survival rate was 77.3%. Follow up ranged from 1 month to 63 months with mean of 17.8±16.2. On multivariate analysis, lymph node involvement and loco-regional recurrence were independent parameters related to decrease overall survival. Lymphovascular invasion, perineural spread, TNM stage and lymph node involvement had significant impact on recurrence.

Methods and matrices: approaches to identifying miRNAs for nasopharyngeal carcinoma.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is a solid tumor of the head and neck. Multimodal therapy is highly effective when NPC is detected early. However, due to the location of the tumor and the absence of clinical signs, early detection is difficult, making a biomarker for the early detection of NPC a priority. The dysregulation of small non-coding RNAs (miRNAs) during carcinogenesis is the focus of much current biomarker research. Herein, we examine several miRNA discovery methods using two sample matrices to identify circulating miRNAs (c-miRNAs) associated with NPC. METHODS: We tested two miRNA discovery workflows on two sample sources for miRNAs associated with NPC. In the first workflow, we assumed that NPC tumor tissue would be enriched for miRNAs, so we compared miRNA expression in FFPE from NPC cases and controls using microarray and RNA-Seq technologies. Candidate miRNAs from both technologies were verified by qPCR in FFPE and sera from an independent NPC sample set. In a second workflow, we directly interrogated NPC case and control sera by RNA-Seq for c-miRNAs associated with NPC, with candidate c-miRNAs verified by qPCR in the sera from the same independent NPC sample set. RESULTS: Both microarray and RNA-Seq narrowed the miRNA signature to 1-5% of the known mature human miRNAs. Moreover, these two methods produced similar results when applied to the same sample type (FFPE), with RNA-Seq additionally indicating "unknown" miRNAs associated with NPC. However, we found different miRNA profiles in NPC sera compared to FFPE using RNA-Seq, with the few overlapping miRNAs found to be significantly up-regulated in FFPE significantly down-regulated in sera (and vice versa). Despite the different miRNA profiles found in FFPE and sera, both profiles strongly associated with NPC, providing two potential sources for biomarker signatures for NPC. CONCLUSIONS: We determined that the direct interrogation of sera by RNA-Seq was the most informative method for identifying a c-miRNA signature associated with NPC. We also showed that there are different miRNA expression profiles associated with NPC for tumor tissue and sera. These results reflect on the methods and meaning of miRNA biomarkers for NPC in tissue and peripheral blood.

Calcified granulomatous disease: occupational associations and lack of familial aggregation.

PURPOSE: The acute host response to histoplasma capsulatum infection varies according to exposure and susceptibility. Late sequelae include calcifications in the lung, thoracic lymphatics, and spleen. Determinants of calcified granuloma formation are poorly studied and may differ from those affecting acute response. We examined the occupational associations and familial aggregation of radiographic calcified granulomatous disease to characterize the determinants of calcified granuloma formation. METHODS: We analyzed prospectively collected cross-sectional data including computed tomograms from 872 adult members of the Old Order Amish of Lancaster County. RESULTS: Granulomas were present in 71 % of participants. Granulomas were present in the lung of 57 % of participants, in the hilar or mediastinal lymph nodes of 55 % of participants, and in the spleen of 29 % of participants. No significant differences were observed in the presence of granulomas between men and women. Each year of age was associated with 4 % higher odds of splenic calcifications, and a primary occupation of farming was associated with an 84 % higher odds of splenic calcifications. A compelling pattern of familial aggregation was not observed. CONCLUSIONS: Calcified granulomatous disease does not appear to aggregate in families. Determinants influencing patterns of granulomatous disease include occupation, age, and geographic location.

Informed consent in balloon Eustachian tuboplasty: a systematic review of possible complications and preventive measures.

OBJECTIVE: To systematically identify the complications associated with balloon Eustachian tuboplasty and their frequency of occurrence. This study will also highlight the measures that can be employed to avoid these complications and perform this procedure more safely. METHODS: Systematically reviewed relevant papers published until January 2023. Each reference was checked and evaluated for any potential manuscripts. There was no registered protocol; the Preferred Reporting Items for Systematic Reviews and Meta-Analyses was used. RESULTS: Sixty-nine publications were found, from which 14 publications met our inclusion criteria: 2 randomised clinical trials, 5 retrospective studies, 2 systematic reviews, 2 case series and 3 case reports. Studies with balloon Eustachian tuboplasty procedure only were included, regardless of ethnicity, gender and age. All studies were excluded in which more than one procedure was performed. CONCLUSION: Balloon Eustachian tuboplasty is a relatively safe procedure with an overall complication risk of 1.66 per cent. Major complication rate was 0.43 per cent. Surgical emphysema was the most common, around 0.40 per cent.

Aseptic meningitis after 20 years of endoscopic transsphenoidal pituitary surgery: a rare complication.

A transsphenoidal surgical (TSS) approach is used for pituitary gland surgery involving pituitary adenomas, as well as for the biopsy of various neurosurgical tumors. TSS, although a relatively safe procedure, can lead to complications like hypopituitarism, visual impairment, nasal septal perforation, diabetes insipidus, carotid artery injury, and cerebrospinal fluid (CSF) leaks. Aseptic meningitis is also one of the complications of this procedure with an incidence of 1-2%, presenting with symptoms similar to bacterial meningitis, but with a low-grade fever of <102 F or even apyrexia. Here, we present a rare case of aseptic meningitis due to CSF leakage, presenting after 20 years of endoscopic surgery. A ventriculoperitoneal shunt was placed to stem the leak after two unsuccessful attempts of endonasal repair.

The glucose metabolite methylglyoxal inhibits expression of the glucose transporter genes by inactivating the cell surface glucose sensors Rgt2 and Snf3 in yeast.

Methylglyoxal (MG) is a cytotoxic by-product of glycolysis. MG has inhibitory effect on the growth of cells ranging from microorganisms to higher eukaryotes, but its molecular targets are largely unknown. The yeast cell-surface glucose sensors Rgt2 and Snf3 function as glucose receptors that sense extracellular glucose and generate a signal for induction of expression of genes encoding glucose transporters (HXTs). Here we provide evidence that these glucose sensors are primary targets of MG in yeast. MG inhibits the growth of glucose-fermenting yeast cells by inducing endocytosis and degradation of the glucose sensors. However, the glucose sensors with mutations at their putative ubiquitin-acceptor lysine residues are resistant to MG-induced degradation. These results suggest that the glucose sensors are inactivated through ubiquitin-mediated endocytosis and degraded in the presence of MG. In addition, the inhibitory effect of MG on the glucose sensors is greatly enhanced in cells lacking Glo1, a key component of the MG detoxification system. Thus the stability of these glucose sensors seems to be critically regulated by intracellular MG levels. Taken together, these findings suggest that MG attenuates glycolysis by promoting degradation of the cell-surface glucose sensors and thus identify MG as a potential glycolytic inhibitor.

Hyperactivated mTOR and JAK2/STAT3 Pathways: Molecular Drivers and Potential Therapeutic Targets of Inflammatory and Invasive Ductal Breast Cancers After Neoadjuvant Chemotherapy.

INTRODUCTION: Inflammatory breast cancer (IBC) is an aggressive and rare cancer with a poor prognosis and a need for novel targeted therapeutic strategies. Preclinical IBC data showed strong activation of the phosphatidylinositide-3-kinase/mammalian target of rapamycin (mTOR) and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathways, and expression of inflammatory cytokines and tumor-associated macrophages (TAMs). PATIENTS AND METHODS: Archival tumor tissue from 3 disease types (IBC treated with neoadjuvant chemotherapy [NAC], n = 45; invasive ductal carcinoma [IDC] treated with NAC [n = 24; 'treated IDC'; and untreated IDC [n = 27; 'untreated IDC']) was analyzed for the expression of biomarkers phospho-S6 (pS6) (mTOR), phospho-JAK2 (pJAK2), pSTAT3, interleukin (IL)-6, CD68 (monocytes, macrophages), and CD163 (TAMs). Surrounding nontumor tissue was also analyzed. RESULTS: Biomarker levels and surrogate activity according to site-specific phosphorylation were shown in the tumor tissue of all 3 disease types but were greatest in IBC and treated IDC and least in untreated IDC for pS6, pJAK2, pSTAT3, and IL-6. Of 37 IBC patients with complete biomarker data available, 100% were pS6-positive and 95% were pJAK2-positive. In nontumor tissue, biomarker levels were observed in all groups but were generally greatest in untreated IDC and least in IBC, except for JAK2. CONCLUSION: IBC and treated IDC display similar levels of mTOR and JAK2 biomarker activation, which suggests a potential mechanism of resistance after NAC. Biomarker levels in surrounding nontumor tissue suggested that the stroma might be activated by chemotherapy and resembles the oncogenic tumor-promoting environment. Activation of pS6 and pJAK2 in IBC might support dual targeting of the mTOR and JAK/STAT pathways, and the need for prospective studies to investigate combined targeted therapies in IBC.

Hyperbilirubinaemia and haemolytic anaemia in acute alcoholic hepatitis: there's oil in them thar veins.

A Caucasian woman in her late 30s was evaluated after a period of binge drinking and found to have hyperbilirubinaemia for which she was referred for consideration of cholecystectomy. After exclusion of other possibilities, Zieve's syndrome was diagnosed. This is a condition of hyperbilirubinaemia, Coombs' negative haemolytic anaemia and hyperlipidaemia associated with alcoholism. Abstinence from alcohol remains the only known effective treatment, and appreciation of the entity can prevent unnecessary biliary procedures. The patient improved with supportive measures and was discharged in stable condition.

Inflammatory breast cancer clusters: A hypothesis.

Cancer clusters have long been a focus of interest because of the possibility of identifying etiologic agents. Only on rare occasions, however, have such cluster investigations been successful. One major difficulty in cluster investigations, particularly in the area of breast cancer, is the long latent period. There have been a number of publications providing a discouraging picture regarding cancer cluster investigations. The possibility of learning from a cluster investigation, however, is greatly increased if the cancer involved is relatively rare and if it has a short latent period. Inflammatory breast cancer (IBC) fits these criteria and is worth pursuing because of the strong evidence that environmental factors play a major role. In this report we describe our experience with several clusters and the lessons learned which are now being utilized to improve investigation of future IBC clusters. The first IBC cluster that we evaluated was in 2000, when we were asked to investigate an apparent cluster of IBC in Castro Valley, California where three women in an office setting of 24 people were diagnosed with IBC in a ten month period from May 1999 to March 2000. Our investigation of this striking cluster did not yield a specific trigger for this cluster but it did indicate that the women involved all had at least two IBC risk factors that may well have made them susceptible to getting IBC. We are now investigating another apparent cluster in Texas and are aware of several others requiring careful consideration. We see a need for a consistent protocol for the evaluation of IBC clusters focusing on the laboratory investigation of environmental triggers, primarily infectious agents and chemical carcinogens.

Profiling miRNAs in nasopharyngeal carcinoma FFPE tissue by microarray and Next Generation Sequencing.

Nasopharyngeal carcinoma (NPC) is a non-lymphomatous, squamous-cell carcinoma that occurs in the epithelial lining of the nasopharynx. Nasopharyngeal carcinoma has a geographically well-defined distribution worldwide, with the highest prevalence in China, Southeast Asia, and Northern Africa. Symptoms of nascent NPC may be unapparent or trivial, with diagnosis based on the histopathology of biopsied tissue following endoscopy of the nasopharynx. The tumor node metastasis (TNM) staging system is the benchmark for the prognosis of NPC and guides treatment strategy. However, there is a consensus that the TNM system is not sufficiently specific for the prognosis of NPC, as it does not reflect the biological heterogeneity of this tumor, making another biomarker for the detection of NPC a priority. We have previously reported on different approaches for microRNA (miRNA) biomarker discovery for Formalin Fixed Paraffin Embedded (FFPE) NPC tissue samples by both a targeted (microarray) and an untargeted (small RNA-Seq) discovery platform. Both miRNA discovery platforms produced similar results, narrowing the miRNA signature to 1-5% of the known mature human miRNAs, with untargeted (small RNA-Seq approach) having the advantage of indicating "unknown" miRNAs associated with NPC. Both miRNA profiles strongly associated with NPC, providing two potential discovery platforms for biomarker signatures for NPC. Herein, we provide a detailed description of the methods that we used to interrogate FFPE samples to discover biomarkers for NPC.

Does secondary inflammatory breast cancer represent post-surgical metastatic disease?

The phenomenon of accelerated tumor growth following surgery has been observed repeatedly and merits further study. Inflammatory breast carcinoma (IBC) is widely recognized as an extremely aggressive malignancy characterized by micrometastasis at the time of diagnosis, with one interesting subgroup defined as secondary IBC where pathologically identifiable IBC appears after surgical treatment of a primary non-inflammatory breast cancer. One possible mechanism can be related to the stimulation of dormant micrometastasis through local angiogenesis occurring as part of posttraumatic healing. In this report, we review cases of secondary IBC and others where localized trauma was followed by the appearance of IBC at the traumatized site that have been identified by our IBC Registry (IBCR) and hypothesize that angiogenesis appearing as part of the healing process could act as an accelerant to an otherwise latent breast malignancy. It is therefore possible that secondary IBC can be used as a model to support local angiogenesis as an important contributor to the development of an aggressive cancer.

Unraveling the paradox of cardiac tamponade: case presentation and discussion of physiology.

A 53-year-old man on warfarin for postoperative pulmonary embolism presented with chest pain and was found to be in cardiac tamponade due to an atraumatic haemopericardium. Findings of tamponade and a novel approach to the pathophysiology of pericardial disease to explain these finding are presented.

Coronary artery disease is under-diagnosed and under-treated in advanced lung disease.

BACKGROUND: Coronary artery disease is a potentially treatable comorbidity observed frequently in both chronic obstructive pulmonary disease and interstitial lung disease. The prevalence of angiographically proven coronary artery disease in advanced lung disease is not well described. We sought to characterize the treatment patterns of coronary artery disease complicating advanced lung disease and to describe the frequency of occult coronary artery disease in this population. METHODS: We performed a 2-center, retrospective cross-sectional study of patients with either chronic obstructive pulmonary disease or interstitial lung disease evaluated for lung transplantation. Medications and diagnoses before the transplant evaluation were recorded in conjunction with left heart catheterization results. RESULTS: Of 473 subjects, 351 had chronic obstructive pulmonary disease, and 122 had interstitial lung disease. In subjects diagnosed clinically with coronary artery disease, medical regimens included a statin in 78%, antiplatelet therapy in 62%, angiotensin-converting enzyme inhibitor or angiotensin receptor blocker in 42%, and a beta-blocker in 37%. Ten percent were on no medication from these 4 classes. Fifty-seven percent of these subjects were on an antiplatelet agent as well as a statin, and 13% were on neither. Beta-blockers were less frequently prescribed in chronic obstructive pulmonary disease than interstitial lung disease (23% vs 58%, P=.007). Coronary angiography was available in 322 subjects. It demonstrated coronary artery disease in 60% of subjects, and severe coronary artery disease in 16%. Occult coronary artery disease and severe occult coronary artery disease were found in 53% and 9%, respectively. There were no significant differences in angiographic results between chronic obstructive pulmonary disease and interstitial lung disease, despite imbalanced risk factors. CONCLUSIONS: Coronary artery disease is common in patients with advanced lung disease attributable to chronic obstructive pulmonary disease or interstitial lung disease and is under-diagnosed. Guideline-recommended cardioprotective medications are suboptimally utilized in this population.

Impact of lung transplantation on serum lipids in COPD.

BACKGROUND: Severe chronic obstructive pulmonary disease is associated with high HDL cholesterol (HDL-C). We sought to examine the effect of lung transplantation on lipid profiles in patients with COPD. METHODS: We analyzed 101 lung transplant recipients in a retrospective cohort of patients from two centers in whom lipid values were available both before as well as after transplantation. Sixty-one subjects were transplanted for severe COPD (93% GOLD stage 4). RESULTS: Eighty-nine percent of subjects with COPD exhibited a decline in HDL-C. Median decline for the COPD cohort was 25 mg/dL (IQR 12-38 mg/dL, p < 0.0001). Non-COPD subjects exhibited no significant changes in HDL-C. Other lipid changes in the COPD cohort included a rise in triglycerides of 70 mg/dL (IQR 35 to 140, p < 0.0001). Decreases in HDL-C levels were independent from the rise in triglyceride levels. Neither LDL-C nor non-HDL-C demonstrated significant changes. Subjects with greater increases in prednisone exposure post-transplant exhibited lesser declines in HDL-C. Compared with tacrolimus, cyclosporine had no effect on observed changes in HDL-C or triglycerides, but was associated with a greater median rise in LDL-C. CONCLUSIONS: In patients with COPD, lung transplantation results in reductions in the serum levels of HDL-C. These changes are not observed in patients undergoing lung transplantation for diagnoses other than COPD.