In solid tumors, the presence of lymph node–like structures called tertiary lymphoid structures (TLS) is associated with improved patient survival. However, little is known about how TLS develop in cancer, how their function affects survival, and whether they are affected by cancer therapy. In this study, we used multispectral microscopy, quantitative pathology, and gene expression profiling to analyze TLS formation in human lung squamous cell carcinoma (LSCC) and in an experimental model of lung TLS induction. We identified a niche of CXCL13⁺ perivascular and CXCL12⁺LTB⁺ and PD-L1⁺ epithelial cells supporting TLS formation. We also characterized sequential stages of TLS maturation in LSCC culminating in the formation of germinal centers (GC). In untreated patients, TLS density was the strongest independent prognostic marker. Furthermore, TLS density correlated with GC formation and expression of adaptive immune response–related genes. In patients treated with neoadjuvant chemotherapy, TLS density was similar, but GC formation was impaired and the prognostic value of TLS density was lost. Corticosteroids are coadministered with chemotherapy to manage side effects in LSCC patients, so we evaluated whether they impaired TLS development independently of chemotherapy. TLS density and GC formation were each reduced in chemotherapy-naïve LSCC patients treated with corticosteroids before surgery, compared with untreated patients, a finding that we confirmed in the experimental model of lung TLS induction. Overall, our results highlight the importance of GC formation in TLS during tumor development and treatment. Significance: Corticosteroid treatment during chemotherapy negatively affects the development of tertiary lymphoid structures and abrogates their prognostic value in patients with lung cancer. Cancer Res; 78(5); 1308–20. ©2018 AACR.

Introduction: Population-based eradication of Helicobacter pylori has been suggested to be cost-effective and is recommended by international guidelines. However, the potential adverse effects of widespread antibiotic use that this would entail have not been sufficiently studied. An alternative way to decrease gastric cancer mortality is by non-invasive search for precancerous lesions, in particular gastric atrophy; pepsinogen tests are the best currently available alternative. The primary objective of GISTAR is to determine whether H pylori eradication combined with pepsinogen testing reduces mortality from gastric cancer among 40–64-year-old individuals. The secondary objectives include evaluation of H pylori eradication effectiveness in gastric cancer prevention in patients with precancerous lesions and evaluation of the potential adverse events, including effects on microbiome. Methods and analysis: Individuals are recruited from general population (50% men) in areas with high gastric cancer risk in Europe and undergo detailed lifestyle and medical history questionnaire before being randomly allocated to intervention or control groups. The intervention group undergoes H pylori testing and is offered eradication therapy if positive; in addition, pepsinogen levels are detected in plasma and those with decreased levels are referred for upper endoscopy. All participants are offered faecal occult blood testing as an incentive for study participation. Effectiveness of eradication and the spectrum of adverse events are evaluated in study subpopulations. A 35% difference in gastric cancer mortality between the groups is expected to be detectable at 90% power after 15 years if 30 000 individuals are recruited. Biological materials are biobanked for the main and ancillary studies. The study procedure and assumptions will be tested during the pilot phase. Ethics and dissemination: The study was approved by the respective ethics committees. An independent Data Safety and Monitoring Board has been established. The findings will be published in peer-reviewed journals and presented at scientific meetings. Trial registration number: NCT02047994

CD4+CD25+ FOXP3-positive T-regulatory cells have an important role in controlling immune and inflammatory reactions. The present authors hypothesise that these cells may be involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). The aim of the present study was to characterise the expression of FOXP3 in large and small airways of nonsmokers, smokers with normal lung function and COPD patients.A total of 19 nonsmokers, 20 smokers with normal lung function and 20 smokers with moderate COPD, undergoing lung resection for a solitary peripheral nonsmall cell carcinoma, were enrolled in the study. Immunohistochemical methods were used to evaluate FOXP3 expression in large and small airways.Smokers with normal lung function and COPD patients had increased numbers of FOXP3-positive cells in large airways compared with nonsmokers. A positive correlation was observed between FOXP3 expression in large airways and smoked pack-yrs. In small airways, COPD patients had decreased numbers of FOXP3-positive cells, compared with asymptomatic smokers and nonsmokers, that negatively correlated with airflow obstruction.To conclude, chronic obstructive pulmonary disease is characterised by upregulation of FOXP3-positive cells in large airways but a downregulation in small airways that correlated with airflow limitation. The results of the present study contribute to a better understanding of the pathogenesis of chronic obstructive pulmonary disease.

It is important to stratify patients according to the magnitude of risk for gastric cancer development; the OLGA (Operative Link for Gastritis Assessment) and OLGIM (Operative Link on Gastric Intestinal Metaplasia) staging systems of lesions in the stomach mucosa have been proposed for this purpose. There are some discrepancies in the current guidelines regarding the value of incisura angularis biopsies. The aim of our study was to assess the value of incisura angularis biopsy in staging gastritis according to the OLGA and OLGIM systems by examining the atrophic, metaplastic and inflammatory changes in the antrum, incisura angularis and corpus. We enrolled 835 patients undergoing upper endoscopy. Three expert gastrointestinal pathologists graded biopsy specimens according to the Sydney classification and the stage of gastritis was assessed by the OLGA and OLGIM systems. The results demonstrated that severe atrophic, metaplastic and chronic inflammatory changes were more frequently observed in the incisura angularis mucosa than in the antrum or corpus mucosae (P<0.05). There was a general downgrading of stage by 18.0% for OLGA and by 4.0% for OLGIM when the incisura angularis was excluded from the staging. Furthermore, there was a 30-35% downgrading for high-risk OLGA/OLGIM stages. The incisura angularis undergoes more severe atrophic, metaplastic and chronic inflammatory changes than the antrum and corpus. Incisura angularis biopsies should be routinely included in the biopsy sampling protocol.

Oncolytic virotherapy is a recent addition to cancer treatment. Here, we describe positive treatment outcomes in three patients using Rigvir virotherapy. One of the patients is diagnosed with melanoma stage IV M1c, one with small cell lung cancer stage IIIA, and one with histiocytic sarcoma stage IV. The diagnoses of all patients are verified by histology or cytology. All patients started Rigvir treatment within a few months after being diagnosed and are currently continuing Rigvir treatment. The degree of regression of the disease has been determined by computed tomography. Safety assessment of adverse events graded according to NCI CTCAE did not show any value above grade 1 during Rigvir^® treatment. Using current standard treatments, the survival of patients with the present diagnoses is low. In contrast, the patients described here were diagnosed 3.5, 7.0, and 6.6 years ago, and their condition has improved and been stabile for over 1.5, 6.5, and 4 years, respectively. These observations suggest that virotherapy using Rigvir can successfully be used in long‐term treatment of patients with melanoma stage IV M1c, small cell lung cancer stage IIIA, and histiocytic sarcoma stage IV and therefore could be included in prospective clinical studies.