Horner's Syndrome: An Uncommon Complication of Thyroidectomy and Selective Lateral Neck Dissection.

BACKGROUND: Horner's Syndrome is defined by myosis, enophthalmos, lack of sweating and eyelid ptosis, as well as vascular dilatation of one half of the face, caused by damage of the ipsilateral cervical sympathetic chain. It is known that Horner's syndrome is an unusual complication of thyroidectomy and selective lateral neck dissection. Its exact pathophysiology is not totally explained and its treatment remains conservative. CASE PRESENTATION: A 27-year-old man developed one-sided partial eyelid ptosis, enophthalmos and myosis two hours after a total thyroid gland excision and a selective lateral neck dissection for papillary carcinoma. A clinical diagnosis of Horner's syndrome was formed. He was treated conservatively and presented with an incomplete recovery at a 2-month follow up. CONCLUSIONS: The present case report underlines the adjacent anatomical correlation between the thyroid gland, the celluloadipose tissue and the cervical sympathetic trunk throughout thyroidectomy and selective lateral neck dissection. Every surgeon should be familiar with the potential complications in order to preoperatively counsel patients, as well as avoid them during the surgical procedure.

Galactorrhea, mastodynia and gynecomastia as the first manifestation of lung adenocarcinoma. A case report.

Gynecomastia with mastodynia and galactorrhea as a paraneoplastic syndrome due to lung cancer with complete response after surgical excision is rare. A 62-year-old Caucasian male presented with mastodynia, galactorrhea and right breast enlargement. Chest x-ray revealed a left upper lobe tumor. The patient had high levels of serum beta-human chorionic gonadotropin (b-HCG) and prolactine. Complete staging was negative for metastases. A typical left upper lobectomy with radical mediastinal lymph node dissection was performed. Pathology report was consistent with a poorly differentiated adenocarcinoma (T2N1M0). Immunohistochemically, multinucleate cells and occasional mononucleate tumor cells showed positivity for human chorionic gonadotropin. The patient received adjuvant chemotherapy with cisplatin - navelbine. One year later physical examination showed regression of both gynecomastia and mastodynia and there was no nipple discharge, while he is free from local or distant metastatic disease and the b-HCG level is normal (1,59 mIU/ml). This case represents a very rare, first manifestation of lung cancer. Galactorrhea, mastodynia and gynecomastia were the initial symptoms, which totally resolved following the successful surgical resection and adjuvant chemotherapy. In this case, prolactin and b-HCG are useful biomarkers during follow up for checking local or distal recurrence of the disease.

Comorbidities in coexisting chronic obstructive pulmonary disease and obstructive sleep apnea - overlap syndrome.

OBJECTIVE: Chronic Obstructive Pulmonary Disease (COPD) and Obstructive Sleep Apnea (OSA) are separately associated with several comorbidities. The coexistence of the two diseases, referred to as overlap syndrome, may act as a predisposing factor for a higher prevalence of comorbidities compared to those associated with each disease separately. The objective of the study was to evaluate the relative prevalence of cardiovascular as well as other comorbidities, in patients with the overlap syndrome, as compared to patients that are diagnosed solely with OSA. PATIENTS AND METHODS: We examined thirty-eight (38) patients (27 men, 11 women) with coexisting COPD and OSA - overlap syndrome (Group 1) vs. 38 patients with OSA-only (Group 2), matched for sex, age, and Body Mass Index (BMI). All patients underwent pulmonary function tests (PFTs), oximetry and overnight polysomnography and were asked about other coexisting chronic diseases and medications. RESULTS: The two groups differed significantly, as expected, in PFTs (Forced Vital Capacity - FVC, p=0.005, Forced Expiratory Volume in 1 s - FEV1, p<0.001) and in daytime oximetry (p=0.007). Three (3) overlap (7.89%) and 9 OSA patients (23.69%) had no other known diseases. All others suffered from 1 - ≥ 4 comorbidities. Overlap patients suffered more often from multiple (≥ 4) comorbidities than OSA-only patients (11, 28.95% vs. 4, 10.52%, respectively). The most common coexisting diseases were hypertension (50% vs. 42.1%), cardiovascular disease (CVD) (44.74% vs. 26.31%), diabetes mellitus (DM) (28.95% vs. 13.16%), dyslipidemia (21.05% vs. 26.31%) and depression (7.89% vs. 13.16%). CONCLUSIONS: We conclude that comorbidities, especially cardiovascular, in patients with overlap syndrome are at least as prevalent as in sleep apneic only patients and may contribute to the overall severity and prognosis of the disease.

Efficient utilization of EBUS-TBNA samples for both diagnosis and molecular analyses.

BACKGROUND: The assessment of an increasing number of molecular markers is becoming a standard requirement from endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) specimens. However, it is unclear how many needle passes should be performed and the amount of lung cancer cells that should be sent for molecular analyses. The objective of this study was to determine if it is feasible to divide the material obtained by EBUS-TBNA to allow for molecular analysis without compromising the accuracy of mediastinal staging. OBJECTIVE: We aimed to determine if dividing EBUS-TBNA specimens has a negative impact on either histopathological diagnosis or molecular analysis. METHODS: EBUS-TBNA was performed in 249 enlarged lymph nodes. Negative or ambiguous histopathological results were confirmed by surgical means and clinical follow-up over 6 months. The tissue obtained by EBUS-TBNA was placed onto a glass slide and divided for histopathological workup and molecular analysis. The number of passes was recorded. Both the accuracy of the mediastinal lymph node staging and the applicability of the sample division for molecular analysis were assessed. RESULTS: Each lymph node was punctured an average of 3.18 times and division of the obtained material for diagnosis and molecular analysis was feasible in all cases. The sensitivity and accuracy of the mediastinal lymph node staging were 96.6% and 97.6%, respectively. A cytokeratin (CK)-19-mRNA concentration-based molecular test was feasible in 74.1% of cases. CONCLUSION: Dividing EBUS-TBNA samples for both histopathological diagnosis and molecular testing is feasible and does not compromise the accuracy of mediastinal staging. This method may be an alternative to taking additional needle passes for molecular analyses.

A case of pulmonary infiltrates in a patient with colon carcinoma.

A 31-year-old white male with a known history of colon carcinoma was referred to the Interventional Pulmonary service for right lower lobe infiltrates and mucous plugging on computed tomography with concern for pneumonia. Bronchoscopy was performed revealing a broad based mass completely obstructing the bronchus intermedius. It was possible to pass a probe into the right lower lobe, and subsequent photoablation and mechanical debulking revealed that the mass was arising near the origin of the superior basal segment of the right lower lobe (RB6) and could be resected. Pathology confirmed this was consistent with the patient's known primary colon carcinoma. The potential for endobronchial metastasis in patients with colorectal carcinoma should be investigated in those patients with new or worsening pulmonary symptoms and signs.

Intratumoral gene therapy versus intravenous gene therapy for distant metastasis control with 2-diethylaminoethyl-dextran methyl methacrylate copolymer non-viral vector-p53.

Lung cancer still remains to be challenged by novel treatment modalities. Novel locally targeted routes of administration are a methodology to enhance treatment and reduce side effects. Intratumoral gene therapy is a method for local treatment and could be used either in early-stage lung cancer before surgery or at advanced stages as palliative care. Novel non-viral vectors are also in demand for efficient gene transfection to target local cancer tissue and at the same time protect the normal tissue. In the current study, C57BL/6 mice were divided into three groups: (a) control, (b) intravenous and (c) intatumoral gene therapy. The novel 2-Diethylaminoethyl-Dextran Methyl Methacrylate Copolymer Non-Viral Vector (Ryujyu Science Corporation) was conjugated with plasmid pSicop53 from the company Addgene for the first time. The aim of the study was to evaluate the safety and efficacy of targeted gene therapy in a Lewis lung cancer model. Indeed, although the pharmacokinetics of the different administration modalities differs, the intratumoral administration presented increased survival and decreased distant metastasis. Intratumoral gene therapy could be considered as an efficient local therapy for lung cancer.

Assessment of SHOX2 methylation in EBUS-TBNA specimen improves accuracy in lung cancer staging.

BACKGROUND: Endobronchial ultrasound with transbronchial needle aspiration (EBUS-TBNA) is a well-established method to assess mediastinal lymph nodes for lung cancer. However, a proportion of patients require further investigation, due to the low negative predictive value (NPV). The objective of this study was to determine whether the assessment of short stature homeobox 2 (SHOX2) DNA methylation level in lymph node tissue obtained by EBUS-TBNA improves the accuracy of mediastinal staging. PATIENTS AND METHODS: EBUS-TBNA was carried out for suspicious lymph nodes of 154 patients. Negative or ambiguous histological results were confirmed by surgical means and clinical follow-up over 6 months. EBUS-TBNA was assessed on 80 positive and 85 negative classified lymph nodes and compared with the result of the SHOX2 DNA methylation real-time PCR analysis. Relative methylation measured by delta-delta cycle threshold (ΔΔCt) was used to classify the samples. Clinical performance of the EBUS-TBNA procedure with and without the additional SHOX2 assessment was calculated against the final classification according to the gold standard. RESULTS: Based on data from 105 patients, an average 80-fold increase in the SHOX2 methylation level was measured for positive compared with negative lymph nodes. SHOX2 results with a ΔΔCt value of <6.5 indicate positive lymph nodes. Applying this molecular analysis to EBUS-TBNA cases, not diagnosed by pathologic assessment, the sensitivity of staging was improved by 17%-99%. The NPV increased from 80% to 99%. CONCLUSIONS: The combination of EBUS-TBNA and SHOX2 methylation level strongly improves the assessment of the nodal status by identifying additional malignant lesions and confirming benign nodes and therefore avoiding invasive follow-up procedures.

2-diethylaminoethyl-dextran methyl methacrylate copolymer nonviral vector: still a long way toward the safety of aerosol gene therapy.

Revealing the lung tumor genome has directed the current treatment strategies toward targeted therapy. First line treatments targeting the genome of lung tumor cells have been approved and are on the market. However, they are limited by the small number of patients with the current investigated genetic mutations. Novel treatment administration modalities have been also investigated in an effort to increase the local drug deposition and disease control. In the current study, we investigated the safety of the new nonviral vector 2-diethylaminoethyl-dextran methyl methacrylate copolymer (DDMC; Ryujyu Science), which belongs to the 2-diethylaminoethyl-dextran family by aerosol administration. Thirty male BALBC mice, 2 month old, were included and divided into three groups. However, pathological findings indicated severe emphysema within three aerosol sessions. In addition, the CytoViva technique was applied for the first time to display the nonviral particles within the pulmonary tissue and emphysema lesions, and a spectral library of the nonviral vector was also established. Although our results in BALBC mice prevented us from further investigation of the DDMC nonviral vector as a vehicle for gene therapy, further investigation in animals with larger airways is warranted to properly evaluate the safety of the vector.

Management of malignant pleural effusion by suicide gene therapy in advanced stage lung cancer: a case series and literature review.

Gene therapy can be defined as the transfer of genetic material into a cell for therapeutic purposes. Cytosine deaminase (CD) transferred into tumor cells by an adenoviral vector (Ad.CD), can convert the antifungal drug fluorocytosine (5-FC) to the antimetabolite 5-fluorouracil (5-FU), which kills not only the transfected tumor cells but also their neighbors by the so-called 'bystander effect'. After testing a protocol for Ad.CD transfer and lung tumor burden control in a Lewis mouse model, we used this technique in the management of lung cancer patients with malignant pleural effusion (MPE): two cases are presented investigating the possible enhancement of anticancer effect in both non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC) by local activation of the pro-drug 5-FC. Results were discussed in parallel to a literature review on the topic. 5-FC and Ad.CD were administered intratumorally to Lewis mouse lung carcinoma and the effect was monitored by tumor size and electromicroscopy. Two patients with advanced stage lung cancer (1SCLC, 1NSCLC), which developed MPE during first-line treatment were administered 10(12) plaque-forming unit (pfu) Ad.CD by intrapleural instillation, in two doses (day 1 and day 7). Instillation was performed when the pleural fluid was ≤200 ml. In addition, they received 5-FC 500 mg four times daily for 14 days. Lung tumor regression and successful transfer of adenoviral particles were observed in treated animals. Patients presented complete regression of pleural effusion as monitored by computerized tomography scan. Neutrapenia and anemia were the most severe adverse effect presented (grade III/grade IV 100%). The increased toxicity followed by the intrapleural gene therapy indicates the augmentation of anticancer effect of transformed pro-drug 5-FC to active 5-FU. The obtained data indicate that intrapleural gene therapy may be a useful tool, adjunct to chemotherapy, in the management of MPE related to lung cancer.

Fibrates: therapeutic potential for diabetic nephropathy?

Despite intensive glucose-lowering treatment and advanced therapies for cardiovascular risk factors, such as hypertension and dyslipidaemia, diabetes mellitus with its macro- and microvascular complications remains a major health problem. Especially diabetic nephropathy is a leading cause of morbidity and mortality, and its prevalence is increasing. Peroxisome proliferator-activated receptor-α (PPAR-α), a member of a large nuclear receptor superfamily, is expressed in several tissues including the kidney. Recently, experimental data have suggested that PPAR-α activation plays a pivotal role in the regulation of fatty acid oxidation, lipid metabolism, inflammatory and vascular responses, and might regulate various metabolic and intracellular signalling pathways that lead to diabetic microvascular complications. This review examines the role of PPAR-α activation in diabetic nephropathy and summarises data from experimental and clinical studies on the emerging therapeutic potential of fibrates in diabetic nephropathy.

Macrolides: from in vitro anti-inflammatory and immunomodulatory properties to clinical practice in respiratory diseases.

BACKGROUND: Macrolides have long been recognised to exert immunomodulary and anti-inflammatory actions. They are able to suppress the "cytokine storm" of inflammation and to confer an additional clinical benefit through their immunomodulatory properties. METHODS: A search of electronic journal articles was performed using combinations of the following keywords: macrolides, COPD, asthma, bronchitis, bronchiolitis obliterans, cystic fibrosis, immunomodulation, anti-inflammatory effect, diabetes, side effects and systemic diseases. RESULTS: Macrolide effects are time- and dose-dependent, and the mechanisms underlying these effects remain incompletely understood. Both in vitro and in vivo studies have provided ample evidence of their immunomodulary and anti-inflammatory actions. Importantly, this class of antibiotics is efficacious with respect to controlling exacerbations of underlying respiratory problems, such as cystic fibrosis, asthma, bronchiectasis, panbrochiolitis and cryptogenic organising pneumonia. Macrolides have also been reported to reduce airway hyper-responsiveness and improve pulmonary function. CONCLUSION: This review provides an overview on the properties of macrolides (erythromycin, clarithromycin, roxithromycin, azithromycin), their efficacy in various respiratory diseases and their adverse effects.

Long acting somatostatin analogues in combination to antineoplastic agents in the treatment of small cell lung cancer patients.

BACKGROUND: Long acting somatostatin analogues combined with platinum analogues have demonstrated an antiproliferative effect on growth of human SCLC xenographs. METHOD: 130 previously untreated SCLC patients--54 with limited disease (LD) and positive somatostatin receptors were included in the study. All patients performed 111In-Octreotide scanning before chemotherapy (CHT), every 3 months and up to 4 times. All patients were treated with paclitaxel 190 mg/m2+carboplatin AUC=5.5 for up to 6 cycles. 47/130 patients (Group A, control group) received only CHT. Forty eight hours after each CHT 43/130 patients (Group B) were also administered 30 mg somatuline® (lanreotide) by a single subcutaneous (s.c.) injection to stimulate somatostatin receptors (SSTRS) for 2 weeks. 40/130 patients (Group C) received 60 mg somatuline® autogel to stimulate SSTRS for 4 weeks. Patients in Groups A and B after the completion of the CHT continued maintenance therapy with somatuline. NSE, IGF1, VEGFA, VEGFC, VEGFR2, HER2 levels were monitored. In histological samples Bcl-2 and VEGF were also explored by immunohistochemistry. RESULTS: No statistically significant differences were observed between the 3 Groups regarding LD and extensive disease (ED) patient ratios, age and PS. Group B had a survival benefit in comparison to Groups A and C (p=0.029). LD patients of Group B had a significant benefit compared to Groups A and C (p=0.012, Breslow test). In LD Group B had a significant longer TTP (p=0.02) in comparison to Groups A and C. Adverse effects had no statistically significant difference between the Groups and toxicity was well managed. INTERPRETATION: Long acting somatostatin analogues could be used as an additive therapy in combination to antineoplastic agents in patients positive for somatostatin receptors. A dose of 30 mg improved survival only in LD SCLC patients.

Mean Platelet Volume and Platelet Distribution Width in non-diabetic subjects with obstructive sleep apnoea syndrome: new indices of severity?

UNLABELLED: To evaluate Mean Platelet Volume (MPV) and Platelet Distribution Width (PDW) in non-diabetic subjects, according to obstructive sleep apnoea syndrome (OSAS) severity and the associations of these indices with anthropometric characteristics and parameters of breathing function during sleep. MATERIALS AND METHODS: We included 610 non-diabetic subjects with suspected OSAS, evaluated by polysomnography. According to their apnoea-hypopnoea index (AHI), patients were divided into Group A (n=148) with AHI<5/h; Group B (n=121) with AHI: 5-14.9/h; Group C (n=85) with AHI: 15-29.9/h and Group D (n=256) with AHI ≥ 30/h. MPV and PDW were measured using an automated blood cell counter. RESULTS: MPV was significantly higher in group D (mean value 12.1 ± 1.3 fl) than in groups A (9.8 ± 1.1 fl), B (9.8 ± 1.6 fl), and C (11.5 ± 1.3 fl) (p<0.001). The same pattern was observed in PDW values (15.9 ± 2.2 fl for group D and 13.2 ± 2.2 fl for group A, 14.1 ± 2.8 fl for group B, and 15 ± 2.2 fl for group C, p<0.001). Significant correlations were seen between MPV and AHI (p<0.001), average pulse oxygen saturation (SpO(2)) (p<0.001), minimum SpO(2) (p<0.001) and percent of the total sleep time with SpO(2) lower than 90% (t<90%) (p<0.001) during sleep, Arousal Index (p<0.001) and Epworth sleepiness scale (ESS) (p=0.028). Similarly, PDW was correlated with AHI (p<0.001), average SpO(2) (p=0.001), minimum SpO(2) (p<0.001), t<90% (p=0.002), and Arousal Index (p<0.001). CONCLUSIONS: MPV and PDW are higher in non-diabetic patients with severe OSAS and are correlated with different parameters of breathing function during sleep.

Molecular pathogenesis of pancreatic cancer and clinical perspectives.

Pancreatic cancer remains stubbornly resistant to many key cytotoxic chemotherapeutic agents and novel targeted therapies. The molecular heterogeneity of this cancer may account for therapy failures to date, although our growing arsenal of novel targeted agents could translate into patient survival. The main objectives of this review are to elucidate histological subtypes of pancreatic neoplasms that exhibit the characteristic of a gradual process of differentiation from benign entities to malignant ones. In addition, important genes, molecular abnormalities, and significant pathways of pancreatic cancer are analyzed and a potential clinical interpretation is presented (p16/cdkn2a, k-ras mutations, smad-4/tgf-/stat3, stk-11, braf, brca-2, neurotensin, mucs proteins, palb2, mitochondrial mutations, DNA mismatch repair genes, methylation, microrna expression, epithelial-to-mesenchymal transition, egfr mutations, the pi3k-akt-mtor pathway, the vegf pathway, heat shock proteins, cxcr4, the cox pathway, the src pathway, the hedgehog pathway, pancreatic stellate cells, a progression model, and molecular events in uncommon pancreatic tumors). Finally, future therapeutic directions are elucidated.

A 26-year-old male with mesothelioma due to asbestos exposure.

Mesothelioma is a malignancy with poor prognosis, with an average 5-year survival rate being less than 9%. This type of cancer is almost exclusively caused by exposure to asbestos. A long exposure can cause mesothelioma and so can short ones, as each exposure is cumulative. We report a case of a 26-year-old male who was exposed to asbestos during his primary school years from the age of 6 to 12. Although the tumor mainly affects older men who in their youth were occupationally exposed to asbestos, malignant mesothelioma can also occur in young adults. A medical history was carefully taken and asbestos exposure was immediately mentioned by the patient. We conducted biopsy on the right supraclavicular lymph node. The patient was not a candidate for surgery, and chemotherapy treatment was initiated. While patient's chemotherapy is still ongoing, no other similar cases of students or teachers have been traced up to date from his school. The school building was demolished in January 2009.

Acute respiratory distress due to thymoma in a patient treated with TK inhibitor: a case report and review of the current treatment options.

Thymic malignancies are rare intrathoracic tumors that may be aggressive and difficult to treat in advanced stage. Surgery is the cornerstone of the management of thymomas: it is significant for the definite histopathological diagnosis and staging, and in most cases, it constitutes the first step of the treatment strategy. For patients with primary unresectable thymomas, the multimodal treatment schedule nowadays includes neoadjuvant chemotherapy, extensive surgery, adjuvant radiotherapy, and in some cases, adjuvant chemotherapy. A patient with a history of stage III COPD and an undiagnosed thoracic mass was admitted to the intensive care unit with acute respiratory distress. A radiologic evaluation by CT scan revealed a mass of 13 cm in diameter at the mediastinum. Fine needle aspiration was performed and revealed a thymoma. Due to poor performance status, the patient was not able to undergo surgery. He refused to be treated with neither chemotherapy nor radiotherapy, but due to EGFR overexpression, treatment with TK inhibitor was suggested. Fine needle aspiration biopsy is commonly used to identify metastasis to the mediastinum. However, it is less often employed as a primary diagnostic tool for tumors, particularly thymic neoplasms. The use of targeted therapies for the treatment of thymic malignancies has been described in the literature. Over the past years, significant efforts have been made to dissect the molecular pathways involved in the carcinogenesis of these tumors. Insights have been obtained following anecdotal clinical responses to targeted therapies, and large-scale genomic analyses have been conducted.

Statins in prevention and treatment of severe sepsis and septic shock.

Severe sepsis is an infection-induced inflammatory syndrome that can lead to multi-organ dysfunction and continues to be a major cause of morbidity and mortality worldwide. Because numerous cascades are triggered during sepsis, selective blocking of inflammatory mediators may be insufficient to arrest this process, and recent therapeutic approaches have proven controversial. Statins are the most commonly prescribed agents for hypercholesterolaemia and dominate the area of cardiovascular risk reduction. Moreover, these drugs have a variety of actions that are independent of their lipid lowering effect. Such anti-inflammatory, antioxidant, immunomodulatory, and antiapoptotic features have been collectively referred to as pleiotropic effects. By virtue of their pleiotropic effects, statins have also emerged as potentially useful in various critical care areas such as bacteraemia, the early phases of sepsis and septic shock, as well as the management of serious infections. This review outlines current evidence on the use of statins for preventing and treating sepsis.

Exophthalmos as a first manifestation of small cell lung cancer: a long-term follow-up.

Small cell lung cancer is characterized by rapid growth and early metastasis. Despite its sensitivity to cytotoxic therapy, until now treatments have failed to control or cure this disease in most patients. Orbital metastases are a rare manifestation of systemic malignancies. Breast and lung cancers represent more than two thirds of the primary cancer sites. Metastases to the eye and orbit develop in approximately 0.7-12% of patients with lung cancer. Here, we report a rare case of exophthalmos as the first manifestation of a metastatic carcinoma due to small cell lung cancer, and a 6-months follow-up with complete exophthalmic response to chemotherapy.