Step forward in early recognition of systemic sclerosis: data from the Leiden CCISS cohort.

BACKGROUND: Since 2009, Dutch patients with a confirmed diagnosis/suspicion of systemic sclerosis (SSc) can be referred to the Leiden Combined Care in Systemic Sclerosis (CCISS) cohort. This study evaluated whether early recognition of SSc has improved over time and whether disease characteristics and survival has changed over time. METHODS: 643 SSc patients fulfilling American College of Rheumatology/European Alliance of Associations for Rheumatology 2013 SSc criteria were included and categorised into three groups based on cohort-entry year: (1) 2010-2013 (n=229 (36%)), (2) 2014-2017 (n=207 (32%)) and (3) 2018-2021 (n=207 (32%)). Variables including disease duration, interstitial lung disease (ILD), digital ulcers (DU), diffuse cutaneous SSc (dcSSc), antitopoisomerase (ATA) and anticentromere (ACA) antibodies, and survival from disease onset were compared between cohort-entry groups, including analyses stratified for sex and autoantibodies. RESULTS: Over time, duration between onset of disease symptoms and cohort entry decreased in males and females, but was always longer in females than in males.The proportion of patients presenting with DU decreased, especially in ACA+SSc patients. Almost no ACA+ patients presented with ILD, while in ATA+ patients this proportion was 25% in 2010-2013 and decreased to 19% in 2018-2021. A reduction in patients presenting with clinically meaningful ILD and dcSSc was observed.Overall 8-year survival for males was 59% (95% CI 40% to 73%) and for females 89% (95% CI 82% to 93%). Eight-year survival showed a trend for improvement over time, and was always worse in males. CONCLUSION: We observed a decrease in disease duration in Leiden CCISS cohort at cohort entry, possibly indicating more timely diagnosis of SSc. This could provide opportunities for early interventions. While symptom duration at presentation is longer in females, mortality is consistently higher in males, underlining the urge for sex-specific treatment and follow-up.

Immunoglobulin-like transcript 3 is expressed by myeloid-derived suppressor cells and correlates with survival in patients with non-small cell lung cancer.

Myeloid-derived suppressor cells (MDSCs) play an important role in immune suppression and accumulate under pathologic conditions such as cancer and chronic inflammation. They comprise a heterogeneous population of immature myeloid cells that exert their immunosuppressive function via a variety of mechanisms. Immunoglobulin-like transcript 3 (ILT3) is a receptor containing immunoreceptor tyrosine-based inhibition motifs (ITIMs) that can be expressed on antigen-presenting cells and is an important regulator of dendritic cell tolerance. ILT3 exists in a membrane-bound and a soluble form and can interact with a yet unidentified ligand on T cells and thereby induce T-cell anergy, regulatory T cells, or T suppressor cells. In this study, we analyzed freshly isolated peripheral blood mononuclear cells (PBMCs) of 105 patients with non-small cell lung cancer and 20 healthy controls and demonstrated for the first time that ILT3 is expressed on MDSCs. We show that increased levels of circulating MDSCs correlate with reduced survival. On the basis of ILT3 cell surface expression, an ILT3low and ILT3high population of polymorphonuclear (PMN)-MDSCs could be distinguished. Interestingly, in line with the immunosuppressive function of ILT3 on dendritic cells, patients with an increased proportion of PMN-MDSCs and an increased fraction of the ILT3high subset had a shorter median survival than patients with elevated PMN-MDSC and a smaller ILT3high fraction. No correlation between the ILT3high subset and other immune variables was found. ILT3 expressed on MDSCs might reflect a previously unknown mechanism by which this cell population induces immune suppression and could therefore be an attractive target for immune intervention.

Arginase-1 mRNA expression correlates with myeloid-derived suppressor cell levels in peripheral blood of NSCLC patients.

Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immature and progenitor myeloid cells with immunosuppressive activity that are increased in cancer patients. Until now, the characterization of MDSC in humans was very challenging. The aim of this study was to determine the characterization and optimal assessment of MDSC and to investigate their presence and function in blood of advanced-stage NSCLC patients. We determined MDSC and lymphocyte populations in peripheral blood mononuclear cells (PBMC) samples of 185 treatment-naïve NSCLC patients and 20 healthy controls (HC). NSCLC patients had an increased population of PMN-MDSC compared to HC (p < 0.0001). Frequencies of CD4(+) and CD8(+) T-cells were significantly decreased in NSCLC patients (p < 0.0001 and p = 0.05). We found that PMN-MDSC were able to suppress T-cell proliferation in vitro. qRT-PCR showed that arginase-1 (Arg-1) mRNA is mainly expressed by MDSC and that the level of Arg-1 in PBMC correlates with the frequency of MDSC in PBMC (Spearman's rho: 0.797). There were significant differences in MDSC and lymphocyte populations between NSCLC patients and HC. We found that MDSC frequencies are stable up to six hours at room temperature after blood was drawn and that cryopreservation leads to a strong decrease of MDSC in PBMC. We show that Arg-1 mRNA expression is a valuable method to determine the levels of MDSC in peripheral blood of cancer patients. This method is therefore a useful alternative for the complex flowcytometric analysis in large multicenter patient studies.

Improving lung cancer survival; time to move on.

BACKGROUND: During the past decades, numerous efforts have been made to decrease the death rate among lung cancer patients. Nonetheless, the improvement in long-term survival has been limited and lung cancer is still a devastating disease. DISCUSSION: With this article we would like to point out that survival of lung cancer could be strongly improved by controlling two pivotal prognostic factors: stage and treatment. This is corresponding with recent reports that show a decrease in lung cancer mortality by screening programs. In addition, modulation of the patient's immune system by immunotherapy either as monotherapy or combined with conventional cancer treatments offers the prospect of tailoring treatments much more precisely and has also been shown to lead to a better response to treatment and overall survival of non-small cell lung cancer patients. SUMMARY: Since only small improvements in survival can be expected in advanced disease with the use of conventional therapies, more research should be focused on lung cancer screening programs and patient tailored immunotherapy with or without conventional therapies. If these approaches are clinically combined in a standard multidisciplinary policy we might be able to advance the survival of patients with lung cancer.

Patient-tailored modulation of the immune system may revolutionize future lung cancer treatment.

Cancer research has devoted most of its energy over the past decades on unraveling the control mechanisms within tumor cells that govern its behavior. From this we know that the onset of cancer is the result of cumulative genetic mutations and epigenetic alterations in tumor cells leading to an unregulated cell cycle, unlimited replicative potential and the possibility for tissue invasion and metastasis. Until recently it was often thought that tumors are more or less undetected or tolerated by the patient's immune system causing the neoplastic cells to divide and spread without resistance. However, it is without any doubt that the tumor environment contains a wide variety of recruited host immune cells. These tumor infiltrating immune cells influence anti-tumor responses in opposing ways and emerges as a critical regulator of tumor growth. Here we provide a summary of the relevant immunological cell types and their complex and dynamic roles within an established tumor microenvironment. For this, we focus on both the systemic compartment as well as the local presence within the tumor microenvironment of late-stage non-small cell lung cancer (NSCLC), admitting that this multifaceted cellular composition will be different from earlier stages of the disease, between NSCLC patients. Understanding the paradoxical role that the immune system plays in cancer and increasing options for their modulation may alter the odds in favor of a more effective anti-tumor immune response. We predict that the future standard of care of lung cancer will involve patient-tailor-made combination therapies that associate (traditional) chemotherapeutic drugs and biologicals with immune modulating agents and in this way complement the therapeutic armamentarium for this disease.

Dendritic cell-based immunotherapy in mesothelioma.

Mesothelioma is a rare thoracic malignancy with a dismal prognosis. Current treatment options are scarce and clinical outcomes are rather disappointing. Due to the immunogenic nature of mesothelioma, several studies have investigated immunotherapeutic strategies to improve the prognosis of patients with mesothelioma. In the last decade, progress in knowledge of the modulation of the immune system to attack the tumor has been remarkable, but the optimal strategy for immunotherapy has yet to be unraveled. Because of their potent antigen-presenting capacity, dendritic cells are acknowledged as a promising agent in immunotherapeutic approaches in a number of malignancies. This review gives an update and provides a future perspective in which immunotherapy may improve the outcome of mesothelioma therapy.

Generalizability of results from the National Lung Screening Trial.

Lung cancer is the major cause of cancer-related death worldwide, with a 5-year survival of only 16%. Most lung cancer cases are diagnosed at an advanced incurable stage. As earlier stages have a better prognosis, the key to reducing mortality could be early diagnosis of the disease. At present, low-dose computed tomographic (CT) screening has shown promising data. Lung cancer death rates were reduced by 20% when CT screening is compared to chest radiography in a high-risk group. There are many advantages of CT screening in lung cancer, however there are also some important issues that should be taken into account. Therefore, the applicability of the results to clinical practice is not clear yet. In this Commentary we discuss different aspects that play important roles in the balance between harms and benefits of screening, including overdiagnosis, availability of treatment options worldwide, ethical considerations, costs, and prolonged life expectancy. We conclude that clinicians should be cautious in generalizing findings to the total population of smokers and take into account that the use of lung cancer screening in clinical practice may have limitations.

History of tuberculosis as an independent prognostic factor for lung cancer survival.

INTRODUCTION: It is well known that pulmonary tuberculosis is associated with an increased risk of lung cancer. We investigated whether a history of pulmonary tuberculosis is an independent risk factor for lung cancer survival in Caucasian patients. METHODS: The data of the prospective population-based cohort of The Rotterdam Study were used. During a mean follow-up time of 18 years, there were 214 incident cases of pathology-proven lung cancer in a source population of 7983 study participants. History of tuberculosis was assessed at baseline by interviewers using standardized questionnaires. Associations of lung cancer survival with the occurrence of pulmonary tuberculosis were assessed using Cox's proportional hazard regression analysis adjusted for age, gender, pack-years, educational level and tumor stage. RESULTS: A history of tuberculosis was reported in 13 of the 214 subjects with lung cancer. The survival of patients with lung cancer was significantly shorter in subjects with a history of pulmonary tuberculosis (HR=2.36, CI95%: 1.1-4.9), than in subjects without a history of pulmonary tuberculosis with a mean difference of 311 days. CONCLUSION: The presence of a history of pulmonary tuberculosis may be an important prognostic factor in the survival of lung cancer.