Epstein-Barr virus in tumor-infiltrating B cells of myasthenia gravis thymoma: an innocent bystander or an autoimmunity mediator?

The thymus plays a key role in myasthenia gravis (MG), a B cell-mediated autoimmune disorder affecting neuromuscular junction. Most MG patients have thymic abnormalities, including hyperplasia and thymoma, a neoplasm of thymic epithelial cells. Epstein-Barr virus (EBV) is associated with autoimmune diseases and tumors. Recently, we showed EBV persistence and reactivation in hyperplastic MG thymuses, suggesting that EBV might contribute to intra-thymic B cell dysregulation in MG patients. Here, we investigated EBV involvement in thymoma-associated MG, by searching for EBV markers in MG (n=26) and non-MG (n=14) thymomas. EBV DNA and EBV-encoded small nuclear RNA (EBER) 1 transcript were detected in 14/26 (53.8%) and 22/26 (84.6%) MG thymomas, and only in 3 of 14 (21.4%) non-MG thymomas. Latent EBNA2 and late gp350/220 lytic transcripts were undetectable in all, but one, thymomas, and early lytic BZLF1 transcript was absent in all samples, suggesting that early infection events and EBV reactivation were very rare in thymomas. EBER1 and 2-positive cells were detected in MG, but not in non-MG, thymomas, as well as cells expressing EBV latency proteins (EBNA1, LMP1, LMP2A), that were mainly of B cell phenotype, indicating EBV association with MG rather than with thymoma. Toll-like receptor (TLR) 3 transcriptional levels were higher in MG than non-MG thymomas and positively correlated with EBER1 levels, suggesting a role for EBERs in TLR3 activation. Our findings show that EBV is commonly present in thymoma-infiltrating B cells of myasthenic patients, indicating a contribution of EBV to B cell-mediated autoreactivity in MG associated with thymic tumor.

Blunt rectal trauma Case report and literature review.

Blunt colorectal traumas are rare clinical entities with a challenging diagnostic and operative management. We describe the case of a 40-year-old man, victim of an accidental fall from a height of four meters who was subsequently diagnosed to have a blunt rectal trauma. A first CT scan showed fracture of the skull and an extensive subcutaneous haematoma of the lower back associated with a fracture of the left transverse processes of lumbar vertebrae. No other visceral abdominal lesions were recognized and patient was admitted to our department for observational studies. After 48 hours from admission the patient presented a subcutaneous emphysema suspicious for hollow viscus injuries. A digital rectal examination detected a laceration both of the posterior rectal wall and the superior anal margin. The patient was successfully managed with spur colostomy, transanal evacuation of the retroperitoneal haematoma and primary repair of both the sphincteric muscle and the rectal wall. As soon as the patient achieved full recovery we performed a reversal colostomy. Diagnosis and management of rectal blunt trauma is still a matter of debate and no definitive recommendation treatments are available. The surgical treatment should be tailored on patient medical conditions and clinicians should maintain a high index of suspicious because a delay in diagnosis can result in higher morbidity and mortality rate. KEY WORDS: Colorectal blunt injury, Colostomy, Laparoscopy, Trauma.

Cutaneous metastasis from lung cancer. Case report.

UNLABELLED: Lung cancer is the most common neoplasm diagnosed worldwide. Metastatic presentation of the disease is frequent. Apart from the usual sites of metastatic disease (bone, adrenals, liver, brain), a particular site for metastases is represented by skin. The case we report is about a 66 year-old man with cutaneous metastasis from lung cancer. A 66 year-old man, with a previous history of abdominal aortic aneurism, chronic obstructive pulmonary disease, cardiopathy, diabetes mellitus, was admitted to our institution for left lower lobe lung cancer. After accurate preoperative staging, patient underwent a thoracotomic left lower lobectomy. Histological examination revealed a squamocellular carcinoma: G2-3, pT2bN0. Patient underwent oncological evaluation for the scheduled follow up. After 6 months patient went back to our observation for the appearance of a skin nodule, firm, dischromic, painful and ulcerated, localized in right iliac fossa. Biopsies demonstrated the nodule to be squamocellular carcinoma. Patient underwent a CT scan of the abdomen and thorax, which revealed the absence of infiltration of the deep fascial and muscular planes by the neoplasm. Patient underwent surgical removal of the lesion. Final histological examination confirmed the lesion to be metastasis of squamocellular lung cancer. Metastases from lung cancer occur in about 2,5-7,5% of cases. Median survival for these patients is 2,9 months. The most common type of neoplasm, according to Japanese Authors, is adenocarcinoma followed by squamocellular carcinoma. Some studies demonstrated the adequacy of surgery followed by chemotherapy, in case of single lesion. In case of multiple cutaneous metastases, many Authors suggest only chemotherapy, although the ideal scheme hasn't been discovered yet. Cutaneous metastases from lung cancer are rare; however the appearance of skin lesions, in patients with a positive oncological history, requires much attention. Accurate evaluation of the patient is paramount in choosing the adequate therapeutic algorithm. KEY WORDS: Chemotherapy, Lung Cancer, Skin Metastases.

Video-assisted thoracoscopic extended thymectomy in myasthenic children.

Myasthenia gravis (MG) is an autoimmune disease marked by weakness of voluntary musculature. Medical and surgical therapy of adult myasthenia is well documented. There is little pediatric surgical evidence, only a few case reports being available. The aim of this paper is to verify whether the surgical and anesthesiological techniques can warrant an early and safe discharge from the operating room. The secondary aim is to assess the presence of perioperative indicators that can eventually be used as predictors of postoperative care. During the years 2006-2009, 10 pediatric patients were treated according to a surgical approach based on video assisted thoracoscopic extended thymectomy (VATET). Standard preoperative evaluation is integrated with functional respiratory tests. Anesthetic induction was made with propofol and fentanyl/remifentanyl and maintenance was obtained with sevoflurane/desflurane/propofol ± remifentanyl. A muscle relaxant was used in only one patient. Right or left double-lumen bronchial tube (Rüsch Bronchopart® Carlens) placement was performed. Six patients were transferred directly to the surgical ward while 4 were discharged to the intensive care unit (ICU); ICU stay was no longer than 24 h. Length of hospital stay was 4.4±0.51 days. No patient was readmitted to the hospital and no surgical complications were reported. Volatile and intravenous anesthetics do not affect ventilator weaning, extubation or the postoperative course. Paralyzing agents are not totally contraindicated, especially if short-lasting agents are used with neuromuscular monitoring devices and new reversal drugs. Perioperative evaluation of the myasthenic patient is mandatory to assess the need for postoperative respiratory support and also predict timely extubation with early transfer to the surgical department. Availability of new drugs and of reversal drugs, the current practice of mini-invasive surgical techniques, and the availability of post anesthesia care units are the keys to the safety and successful prognosis of patients affected by MG who undergo thymectomy.

Thymoma-associated myasthenia gravis: outcome, clinical and pathological correlations in 197 patients on a 20-year experience.

We studied 197 patients with thymoma-associated myasthenia gravis (T-MG) to identify variables that can influence the natural history of the disease and the therapeutical approaches. Multivariate analysis showed that neither clinical nor pathological variables were associated with a better chance to reach complete stable remission. The video-assisted thoracoscopic extended thymectomy (VATET) was not significantly correlated with a lower chance of achieving complete stable remission compared with the classical transsternal approach (T-3b) (p=0.1090). Thymoma recurrence was not correlated with surgery by VATET or T-3b. VATET was safe and reliable for removal of thymoma. The low chance of achieving remission (9.64%) in T-MG underlines the importance of an early diagnosis as well as the need for more aggressive therapeutic strategies.

Increased toll-like receptor 4 expression in thymus of myasthenic patients with thymitis and thymic involution.

Thymic abnormalities are present in approximately 80% of myasthenia gravis (MG) patients, and the thymus seems to be the main site of autosensitization to the acetylcholine receptor. In view of findings that the innate immune system can generate an autoimmune response, we studied the expression of Toll-like receptors (TLRs) 2 to 5, key components of innate immunity signaling pathways, in 37 thymuses from patients with autoimmune MG. TLR4 mRNA levels were significantly greater in thymitis (hyperplasia with diffuse B-cell infiltration) and involuted thymus than in germinal center hyperplasia and thymoma. By immunohistochemistry and confocal microscopy, cells positive for TLR4 protein were rarely detected in thymoma. However, in thymitis TLR4 protein was mostly found on epitheliomorphic (cytokeratin-positive) cells located in close association with clusters of acetylcholine receptor-positive myoid cells in thymic medulla and also at the borders between cortical and medullary areas. B cells were never TLR4-positive. TLR4 protein was also present in remnant tissue of involuted thymus. This is the first finding of a possible link between innate immunity and MG. We speculate that in a subgroup of MG patients, an exogenous or endogenous danger signal may activate the innate immune system and give rise to TLR4-mediated mechanisms contributing to autoimmunity.

Video-assisted thoracoscopic extended thymectomy and extended transsternal thymectomy (T-3b) in non-thymomatous myasthenia gravis patients: remission after 6 years of follow-up.

The aims of this study were to assess the efficacy of video-assisted thoracoscopic extended thymectomy (VATET) as a treatment for myasthenia gravis (MG) and to identify prognostic factors for thymectomy success. Clinical efficacy and variables influencing outcome were assessed by life-table and Cox proportional hazards regression analysis. Complete stable remission (CSR), as defined by the MGFA Medical Task Force, was the end point for efficacy. VATET was performed in 159 MG patients and T-3b in 47 MG patients. At 6 years of follow-up, CSR, assessed by life-table analysis, was 50.6% in non-thymomatous VATET patients and 48.7% in non-thymomatous T-3b surgery. By univariate analysis, the presence of thymic hyperplasia (P=0.0002) and treatment only with anticholinesterases (P<0.0001) were positively associated with the probability of CSR. By multivariate analysis, the chance of complete remission was significantly increased by the use of anticholinesterases (odds ratio [OR] 2.45; 95% confidence interval [CI] 1.44-4.17; P=0.001) and the presence of thymic hyperplasia (OR 1.96; 95% CI 1.05-3.68; P=0.036). VATET seems to be effective in inducing CSR in MG with an efficiency similar to that of the T-3b transsternal (TS) approach; it is easy to perform in experienced hands and is associated with low morbidity and negligible esthetic sequelae.