Constrictive bronchiolitis associated with paraneoplastic autoimmune multi-organ syndrome

Background and objective:   Constrictive bronchiolitis is a rare and potentially fatal manifestation of paraneoplastic autoimmune multi-organ syndrome (PAMS), also called paraneoplastic pemphigus. The current review aimed to assess the frequency and clinical features of constrictive bronchiolitis occurring in patients with PAMS.
Methods:   A computer-assisted search of medical records identified 17 patients with PAMS seen during the period 1994–2007. Medical records, radiological studies and biopsy results were reviewed.
Results:   There were 10 men and 7 women; the median age at diagnosis of PAMS was 60 years (range 33–72 years). Non-Hodgkin's lymphoma and chronic lymphocytic leukaemia were the underlying neoplasms in over two-thirds of these patients. Constrictive bronchiolitis was diagnosed in three patients who had respiratory symptoms, severe airflow obstruction on pulmonary function testing and evidence of air trapping on CT scanning with no other identifiable cause for these findings. In contrast to previous reports, two of the three patients with constrictive bronchiolitis presented with skin and respiratory manifestations in the absence of a known neoplasm. Seven patients with PAMS died (41%) after a median interval of 13 months (range 1–33 months) and the deaths included two of the constrictive bronchiolitis patients who continued to worsen despite immunosuppressive therapy.
Conclusions:   In a minority of patients with PAMS, constrictive bronchiolitis occurs and tends to cause progressive airflow obstruction that responds poorly to immunosuppressive therapy. Constrictive bronchiolitis in these patients may be manifest prior to the discovery of the underlying neoplasm and the diagnosis of PAMS.     

Classification and staging of thymoma

The appropriate therapy and prognosis of patients with thymic malignancies is decisively influenced by the local extent and dissemination of the tumor. For this reason, a staging system that reflects these factors is essential. Mainly the Masaoka-Koga classification, which was introduced in 1994, has been applied for this purpose. The rarity of thymic malignancies makes it difficult not only to establish internationally standardized diagnostics and treatment, but also to progress staging. Besides, efforts were made to adapt the classification into a tumor-node-metastasis-based (TNM) system for standardization with the staging of other tumor entities. The 2017 published 8th edition of the TNM Classification of Malignant Tumors introduced several adjustments based on a proposal of the International Association for the Study of Lung Cancer (IASLC) and the International Thymic Malignancy Interest Group (ITMIG). Compared to the Masaoka-Koga classification, surgically good resectable tumor involvements like pericardium, mediastinal fat or mediastinal pleura have been shifted to lower stages. Thus, even more than in Masaoka-Koga classification, tumors are basically divided into completely resectable and thus surgically treatable tumors (stage I, II, IIIA) and advanced stages (stage IIIB, IVA and IVB) that require multimodal therapy.     

Autoimmune cholangitis in a patient with thymoma

Autoimmune cholangitis is characterized biochemically by chronic cholestasis and histopathologically by chronic non-suppurative destructive cholangitis. It is associated with positive antinuclear antibody test and negative antimitochondrial antibody test results. Recently, we experienced a case of a 35-year-old woman with autoimmune cholangitis associated with thymoma who presented with pruritis, jaundice, chronic fatigue and anterior chest discomfort. Her laboratory examinations revealed marked increases in levels of serum alkaline phosphatase and gamma-glutamyl transpeptidase. In serological tests, antinuclear antibody was found, but antimitochondrial antibody was not. Liver biopsy findings were compatible with chronic non-suppurative destructive cholangitis. On computed tomography (CT) of the chest, a large anterior mediastinal mass was found. The mass was totally resected and the patient was treated with ursodeoxy cholic acid. Thereafter, her clinical symptoms improved and liver functions completely returned to the normal range. We describe here an uncommon association of autoimmune cholangitis with thymoma, which has not been reported previously in the English-written literature.     

Autoimmune hepatitis and overlap syndromes

Autoimmune hepatitis is a well-established chronic liver disease. It primarily affects women, is characterized by circulating autoantibodies and elevated gammaglobulins and is associated with extrahepatic immune-mediated syndromes. Treatment regimens have remained unchanged for a number of years because of the high efficacy of steroid monotherapy, or combination therapy of azathioprine and steroids. In approximately 90% of patients remission of the disease is reached by medical therapy, which is usually administered lifelong because long-term remission after drug withdrawal is achieved in only 17% of patients. In 10% of patients treatment failure is observed. The challenge of remission induction involves the use of transplant immunosuppressants such as cyclosporine, mycophenolate moffetil, and tacrolimus. The challenge of maintenance therapy minimizing steroid side-effects involves the evaluation of topical steroids and the use of azathioprine monotherapy. Overlap syndromes occur in approximately 20% of autoimmune liver diseases. The diagnosis is broadly based on serological, biochemical, clinical and histological parameters. Most common are the overlap of autoimmune hepatitis and primary biliary cirrhosis, as well as autoimmune hepatitis with primary sclerosing cholangitis. These yet incompletely defined syndromes are an important differential diagnosis in the difficult-to-treat patient with autoimmune hepatitis.     

Autoimmune Pancreatitis with Gastric Cancer: Some IgG4-related Diseases May Be Paraneoplastic Syndrome

A 70-year-old man was referred to our department for the treatment of early gastric cancer. Contrast-enhanced computed tomography (CT) incidentally showed diffuse enlargement of the pancreas with a capsule-like rim, and blood tests showed elevated serum IgG4 levels, leading to a diagnosis of autoimmune pancreatitis (AIP). Endoscopic treatment for gastric cancer was performed, and pathological findings showed adenocarcinoma with abundant IgG4-positive plasma cell infiltration. Thereafter, the serum IgG4 levels normalized, and the findings of AIP disappeared on CT without steroid treatment. These findings suggest that the gastric cancer activated an IgG4-related immune response, resulting in the development of AIP.     

CT-based radiomics analysis for differentiation between thymoma and thymic carcinoma

BackgroundThe purpose of our study was to differentiate between thymoma and thymic carcinoma using a radiomics analysis based on the computed tomography (CT) image features.MethodsThe CT images of 61 patients with thymic epithelial tumors (TETs) who underwent contrast-enhanced CT with slice thickness <1 mm were analyzed. Pathological examination of the surgical specimens revealed thymoma in 45 and thymic carcinoma in 16. Tumor volume and the ratio of major axis to minor axis were calculated using a computer-aided diagnostic software. Sixty-one different radiomics features in the segmented CT images were extracted, then filtered and minimized by least absolute shrinkage and selection operator (LASSO) regression to select the optimal radiomics features for predicting thymic carcinoma. The association between the quantitative values and a diagnosis of thymic carcinoma were analyzed with logistic regression models. Parameters identified as significant in univariate analysis were included in multiple analyses. Receiver-operating characteristic (ROC) curves were assessed to evaluate the diagnostic performance.ResultsThymic carcinoma was significantly predominant in men (P=0.001). Optimal radiomics features for predicting thymic carcinoma were as follows: gray-level co-occurrence matrix (GLCM)-homogeneity, GLCM-energy, compactness, large zone high gray-level emphasis (LZHGE), solidity, size of minor axis, and kurtosis. Multiple logistic regression analysis of these features revealed solidity and GLCM-energy as independent indicators associated with thymic carcinoma [odds ratio, 14.7 and 14.3; 95% confidence interval (CI): 1.6–139.0 and 3.0–68.7; and P=0.045 and 0.002, respectively]. Area under the curve (AUC) for diagnosing thymic carcinoma was 0.882 (sensitivity, 81.2%; specificity, 91.1%). Multivariate analysis adjusted for sex similarly revealed two features (solidity and GLCM-energy) as independent indicators associated with thymic carcinoma (odds ratio, 14.6 and 23.9; 95% CI: 2.4–89.2 and 1.9–302.8; P=0.004 and 0.014, respectively). Adjusted AUC for diagnosing thymic carcinoma was 0.921 (95% CI: 0.82–0.97): sensitivity, 62.5% and specificity, 100%.ConclusionsTwo texture features (GLCM-energy and solidity) were significant predictors of thymic carcinoma.     

Persistent paraneoplastic neurologic syndrome after successful therapy of Hodgkin's disease

Paraneoplastic neurologic syndromes may develop in Hodgkin's disease (HD). We describe three young female patients with neurological disorders, not explained by other causes, preceding diagnosis or relapse of HD. The lack of response of the paraneoplastic syndrome to successful treatment of HD among our three patients emphasizes the poor prognosis of longstanding paraneoplastic neurologic symptoms in HD.     

Autoimmune manifestations associated with myelodysplastic syndrome predict a poor prognosis

We evaluated the clinical characteristics of autoimmune manifestations (AIMs) associated with myelodysplastic syndrome (MDS) to elucidate whether AIMs impacted MDS outcomes in Japan.This retrospective study including 61 patients who received a new diagnosis of MDS between January 2008 and December 2015 was conducted by the review of electronic medical records for the presence of AIMs within a 1-year period prior to or following the diagnosis of MDS.AIMs were identified in 12 of the 61 (20.0%) patients with MDS. The neutrophil counts and C-reactive protein levels in peripheral blood were significantly elevated in patients with AIMs, and the survival was shorter in those with AIMs compared to those without AIMs. Multivariate analysis demonstrated that the presence of AIMs and higher-risk disease according to the International Prognositic Scoring System (IPSS) were independent risk factors for increased mortality (hazard ratio, 4.76 and 4.79, respectively).This retrospective study revealed that the prognosis was poor in patients with MDS-associated AIMs. The treatment of MDS using the current algorithms is based on prognostic scoring systems such as IPSS. Treatment strategies for patients with MDS-associated AIMs should be reconsidered, even in those with low-risk MDS according to the IPSS.     

Hypertension as a paraneoplastic syndrome in hepatocellular carcinoma

We report a 66-year-old man with hepatocellular carcinoma who was positive for hepatitis B surface antigen, and was hospitalized because of hypoglycemia and hypertension. His plasma renin activity was normal (2.3 ng/ml per h), but concentrations of angiotensin I (>2500 pg/ml) and II (86 pg/ml) were high. Increased angiotensin I level at sites proximal and distal from the confluence of the hepatic vein and the inferior vena cava indicated that the hypertension was provoked by overproduction of angiotensin I from the hepatocellular carcinoma. Previous reports of patients with hepatocellular carcinoma with hypertension due to abnormality of renin-angiotensin system are reviewed. Received: September 24, 1998 / Accepted: January 22, 1999     

瘦素与自身免疫病

瘦素是一种主要由脂肪组织分泌的蛋白质类激素，除在能量消耗方面发挥效应外，在免疫应答和自身免疫病发病机制中也发挥着重要作用，本文就瘦素的生物学特性和功能、免疫调节作用及与自身免疫病的关系做一综述。     

Immunotherapy for thymoma

Thymic epithelial tumors (TETs) are rare thymic neoplasms. There are approximately 1.5 cases per million TETs per year. They are the most common anterior mediastinal tumors in adults. Due to limited activity of available treatment options novel strategies and treatment options are needed and treatment with immune checkpoint inhibitors is an attractive option. Thymic epithelial tumors have one of the lowest tumor mutational burden among all cancer in adults, but high expression of PD-L1 on tumor cells and abundant CD8+ lymphocytes provide a strong rational for implementing immune checkpoint inhibitors (ICIs) which target PD-1/PD-L1 pathway in the treatment of TETs. Few small early stage clinical trials were published so far evaluating efficacy of pembrolizumab and avelumab in thymoma and thymic carcinoma patients. Al trials showed reasonable response rates and progression-free survival. Higher PD-L1 expression was predictor of response in all trials. However, increased incidence of immune-related adverse events was seen in TET patients treated with immune checkpoint inhibitors compared to patients with other cancers. At the moment, ICIs are not standard of care for patients with TET and larger trials are needed to establish the right role of ICIs regarding efficacy and safety of these agents.     

Autoimmune hepatitis in a demographically isolated area of Australia

Background: Previous studies describing autoimmune hepatitis (AIH) come from liver transplant centres in which a skewed distribution of cases may give a misleading picture of the incidence of AIH and its natural history. This series describes AIH in a stable and demographically discrete population of patients in the Australian Capital Territory (ACT) and the surrounding region. Methods: In 42 patients with type 1 AIH (point prevalence 8 per 100 000 population), clinical, laboratory and histological features at presentation, response to initial therapy, details of maintenance therapy and outcome were recorded. Results: Consistent with other publications, the male‐to‐female ratio was 1:3, mean age at presentation was 53 years and 24% had cirrhosis at diagnosis. Most patients (86%) responded to initial therapy and 67% went into long‐term remission. One patient died from liver failure and none required liver transplantation. Azathioprine was included in the treatment regimen in 74% of cases with doses generally <2 mg/kg. Azathioprine dose greater than or equal to 2 mg/kg was associated with better clinical outcome, but this did not reach statistical significance. A higher proportion of female patients had cirrhosis at presentation (9/10 vs 1/10; P= 0.24). Conclusion: In this Australian community‐based study, type 1 AIH was primarily a disease of later life, responded to conventional immunosuppressive therapy and generally has a good prognosis. Further study of the use of azathioprine is warranted to determine the optimal dose.     

Autoimmune hepatitis in Singapore: a rare syndrome affecting middle-aged women

BACKGROUND AND AIM: The prevalence of autoimmune hepatitis in Singapore is unknown. Over a period of 7 years, 24 cases were diagnosed in a district general hospital in Singapore (Toa Payoh Hospital) by using the scoring system proposed by the International Autoimmune Hepatitis Group in 1993. The aims of our study were to determine the prevalence of autoimmune hepatitis in Singapore, and to investigate the characteristics and prognosis in the mainly Chinese population. METHODS: The case records of all 24 patients were reviewed, and the following parameters were recorded: age at presentation, sex, symptoms and signs at presentation, past exposure to hepatotoxic drugs, alcohol intake, blood transfusion laboratory and histological tests used to determine autoimmune hepatitis, response to treatment, complications, and survival. RESULTS: The mean age of patients was 57 years old. There was a female-male ratio of 11:1. Forty-two percent of the patients were cirrhotic at presentation. The prevalence of autoimmune hepatitis was four per 100 000, with no significant difference between Chinese, Malay and Indian patients (Odds ratio of 0.38 by the chi-squared test). Eighty-nine percent of the patients responded to treatment with the induction of prednisolone, but the relapse rate was 61%. Treatment failure occurred in one patient. The mortality rate during the 7 years of follow up was 21%, and all were caused by complications of cirrhosis. The survival at 5 years was 71%, with a standard error of 0.13. CONCLUSION: Autoimmune hepatitis in Singapore is mainly a disease in older women. The response to steroid treatment is good, with a 5-year survival rate of 71%.     

高半胱氨酸蛋白61与自身免疫性疾病

高半胱氨酸蛋白61(cysteine rich 61,Cyr61)是即刻早期基因表达蛋白,受到血清生长因子刺激后可在数分钟内活化并转录。Cyr61通过直接与细胞表面整合素受体结合而发挥作用。Cyr61可参与炎性反应过程,促进血管形成或协同细胞因子间作用。Cyr61可介导滑膜细胞的增殖,促进滑膜细胞产生白细胞介素(interleukin,IL)-6、IL-8等炎性细胞因子,并在辅助性T细胞(helper T cell,Th)17分化和中性粒细胞浸润中发挥一定作用。Cyr61在炎症性肠病、IgA肾病、糖尿病肾病、Graves眼病中的作用均有研究。另外,Cyr61也不同程度参与了胚胎发育、创伤修复、血管疾病、肿瘤等过程。     

Comparative study of video-assisted thoracic surgery versus open thymectomy for thymoma in one single center

Background

Due to the popularity of video-assisted thoracic surgery (VATS) techniques in clinical, thymoma patients via VATS thymectomy are increasing rapidly. However, compared with open thymectomy, the potential superiorities and defects of VATS thymectomy remain controversial.

Methods

A number of 129 patients who underwent thymectomy of early stage thymoma (Masaoka stage I and stage II) in one single center from January 2007 to September 2013 were selected in this retrospective study. Of those patients, 38 thymoma patients underwent VATS thymectomy (VATS group) and 91 underwent open thymectomy (open group) via either transsternal [44] or transthoracic approach [47] in the same period. The postoperative variables, which included postoperative hospital length of stay (LOS), the intensive care unit (ICU) LOS, the entire resection ratio, the number of thoracic drainage tubes, the quantity of output and duration of drainage, were analyzed. Meanwhile, the operation time and blood loss were considered as intraoperative variables.

Results

All thymoma patients in the analysis included 19 thymoma patients with myasthenia gravis, among which five patients via VATS thymectomy and 14 patients via open thymectomy respectively. There was no death or morbidity due to the surgical procedures perioperatively. The ICU LOS, operation time, entire resection ratio, and the number of chest tubes were not significantly different in two groups. The postoperative hospital LOS of VATS thymectomy was shorter than that of open thymectomy (5.26 versus 8.32 days, P<0.001). The blood loss of VATS thymectomy was less than open thymectomy (114.74 versus 194.51 mL, P=0.002). Postoperatively, the quantity of chest tubes output in VATS group was less than that in open thymectomy group (617.86 versus 850.08 mL, P=0.007) and duration of drainage in VATS group was shorter than that in open thymectomy group (3.87 versus 5.22 days, P<0.001).

Conclusions

VATS thymectomy is a safe and practicable treatment for early-stage thymoma patients. Thymoma according with Masaoka staging I-II without evident invading seems to be performed through VATS approach appropriately, which has shorter postoperative hospital LOS, less blood loss and less restrictions to activities, hence patients will recover sooner.     

Pancytopenia with hypercellular bone marrow—a possible paraneoplastic syndrome in carcinoma of the lung: A report of three cases

Three patients with idiopathic pancytopenia and hypercellular bone marrow who developed carcinoma of the lung within two years of diagnosis are reported. All three patients had macrocytic anemia associated with a megaloblastic marrow in the presence of normal serum vitamin B12 and folic acid levels. Neutropenia with monocytosis, elevated serum muramidase and LAP scores, and increased fetal hemoglobin levels were also found. In all cases Ham's tests were negative with a normal bone marrow karyotype. In all three patients, pancytopenia due to myelodysplasia, a probable preleukemic state, was diagnosed initially prior to the appearance of carcinoma of the lung. One of the patients showed improved leukocyte and platelet counts during chemotherapy, while the other two died before chemotherapy could be administered. In the light of the above findings we suggest that carcinoma of the lung may be the cause of a paraneoplastic syndrome with pancytopenia, particularly in patients with a hypercellular marrow with a normal karyotype.     

端粒与自身免疫性疾病

端粒是真核细胞染色体末端的特殊结构,其功能是保护染色体末端结构完整和功能稳定,染色体末端失去保护将出现染色体重组、融合、降解。端粒酶是维护端粒的核蛋白复合体,端粒酶缺乏会导致端粒长度随细胞分裂不断缩短而失去稳定性。端粒蛋白由端粒保护蛋白和端粒相关蛋白组成,是参与维护染色体结构稳定的蛋白复合体,在参与调节端粒长度、保护端粒结构和功能中发挥着重要作用。端粒的相关研究主要集中在肿瘤、遗传性疾病等领域,但越来越多的研究认为端粒与自身免疫性疾病的发病同样有着密切的关系。通过对端粒的研究可能对自身免疫性疾病的发病和治疗等提供新的方向。