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Small cell lung cancer (SCLC) is frequently found disseminated at first presentation and holds a poor prognosis due to emerging resistance to first-line platinum-based and second-line topotecan chemotherapy. The present investigation tested the antitumor activity of rovalpituzumab tesirine (ROVA-T), a cytotoxic anti-DLL3 drug conjugate, against two SCLC and a corresponding SCLC CTC cell line established from a ROVA-T-resistant patient to characterize the mechanism of recurrence. Two cell lines were established from an SCLC patient progressing under ROVA-T therapy and characterized with respect to chemosensitivity against this drug as well as against currently applied chemotherapeutics and for their delta-like 3 (DLL3) expression. The chemosensitivity assays demonstrate that most SCLC lines show IC50 values exceeding the ROVA-T in-vivo concentrations and that slow-growing cells and lines showing spheroidal growth or proliferation as corresponding circulating tumor cells (CTCs) exhibit higher resistance. Chemosensitivity of the cell lines is not correlated with DLL3 protein expression possibly due to toxicity of the free payload in tissue culture. The clinical trials and experimental results demonstrate that refractoriness to ROVA-T is linked to a low initial tumor expression of DLL3, loss of DLL3 expression, higher chemoresistance to ROVA-T and the putative formation of resistant spheroids by the SCLC cells.

About 15% of patients with non-small cell lung cancer (NSCLC) harbor the Kirsten rat sarcoma homolog G12C mutation (KRASG12C). Selective KRASG12C inhibitors offer new treatment opportunities, but little is known about the prevalence, characteristics, and outcomes of standard-of-care treatment (SOC) in this population. We retrospectively assessed the clinicopathological features of patients with KRASG12C-mutated advanced NSCLC and responses to SOC at two high-volume centers in Austria. Out of 2495 NSCLC patients tested, we identified 174 patients with advanced-stage disease carrying a KRASG12C mutation. Most patients were ≥65 years old (55%), heavy smokers (55%), and presented with comorbidities. The most frequent co-alteration was TP53 (18%). PD-L1 expression was high (TPS ≥ 50%) in 31%, very high (TPS ≥ 90%) in 11%, and negative in 31% of patients. A total of 138 patients (79%) received oncologic systemic treatment. The most common first-line therapy (1 L) was anti-PD-1/PD-L1 plus platinum-based chemotherapy. Median overall survival measured from 1 L treatment was 15.3 months (95% CI, 8.6–21.9), 9.4 (95% CI, 5.3–13.5) from 2 L treatment, and 8.4 (95% CI, 1.7–15.1) from 3 L treatment. The time-to-next-treatment was 8.4 (95% CI, 5.2–11.6) from 1 L and 6.1 (95% CI, 2.7–9.7) months from 2 L to 3 L. These poor outcomes underscore the need for the implementation of new treatment options and for specific molecular testing.

The knowledge on molecular alterations in lung cancer have increased during the last decade considerably. Almost every year new genes were detected being targetable, and drugs have been developed and provided for those patients being diagnosed with such a lung cancer. Therefore, it was necessary to update previous recommendations to facilitate a uniform handling for the diagnosis and molecular tests of lung cancer specimen all over Austria. Originally mutation of the epidermal growth factor receptor (EGFR) was the only actionable molecular alteration, now there are more than 10 driver mutations known, and more are detected, and clinical studies are performed. In addition, the technique to test for these mutations have improved, next generation sequencing has opened the option to test several genes in one test. Immuno-oncology has entered the field, and besides the checkpoint death receptor and ligand molecules PD-1/PD-L1 more molecules have been detected and are also tested in clinical studies. To provide equal opportunities to our patients the tests have to be implemented in all pathological institutes involved in lung cancer management. Because pathologists as part of the tumor board have to explain the diagnosis and the molecular alterations and suggest possible treatment options, the tests should be performed in-house, which will provide the optimal quality control.

The second-generation ALK tyrosine kinase inhibitor brigatinib has recently been approved in the European Union for use after crizotinib treatment in patients with EML4-ALK-rearranged lung cancer. In the current study, brigatinib was investigated as second-line or later-line treatment in 35 patients who had developed resistance to crizotinib, ceritinib, or alectinib. Most patients (68.6%) received brigatinib as second or third line (range: second to 12th line). In the total cohort, complete and partial responses were obtained for 9.1 and 75.8%, respectively. Overall median progression-free survival was 9.9 months, whereas the largest treatment cohort (brigatinib after crizotinib failure) showed a median progression-free survival of 8.4 months. Fifty-four percent of patients with baseline brain metastases responded to brigatinib treatment. Brigatinib was highly effective after crizotinib and ceritinib failure. Six patients had received alectinib as monotherapy, second-line, or third line before brigatinib; of these, four experienced partial responses and two progressed responses. Brigatinib treatment was well tolerated.

Anaplastic lymphoma kinase (ALK)-translocations are present in up to 5% of non-small cell lung cancer (NSCLC), most of them being adenocarcinomas. Even though the availability of five potent ALK-inhibitors for the treatment of ALK-positive NSCLC patients, there is no consensus about the ideal therapy sequence. Alectinib has been so far successfully and routinely used as first-line therapy, especially in patients presenting central nervous system lesions; however, with the very recent European approval of brigatinib in the first line, a new treatment option is now available for ALK+ patient collective. In this case series, efficient systemic and intracranial responses to alectinib late-line treatment following brigatinib therapy are reported. This therapeutic sequence is going to gain therefore more importance in a near future.

Malignant pleural mesothelioma (MPM) is a rare pleural cancer associated with asbestos exposure. According to current evidence, the combination of chemotherapy, surgery and radiotherapy improves patients’ survival. However, the optimal sequence and weighting of the respective treatment modalities is unclear. In anticipation of the upcoming results of the MARS-2 trial, we sought to determine the relative impact of the respective treatment modalities on complications and overall survival in our own consecutive institutional series of 112 patients. Fifty-seven patients (51%) underwent multimodality therapy with curative intent, while 55 patients (49%) were treated with palliative intent. The median overall survival (OS) of the entire cohort was 16.9 months (95% CI: 13.4–20.4) after diagnosis; 5-year survival was 29% for patients who underwent lung-preserving surgery. In univariate analysis, surgical treatment (p < 0.001), multimodality therapy (p < 0.001), epithelioid subtype (p < 0.001), early tumor stage (p = 0.02) and the absence of arterial hypertension (p = 0.034) were found to be prognostic factors for OS. In multivariate analysis, epithelioid subtype was associated with a survival benefit, whereas the occurrence of complications was associated with worse OS. Multimodality therapy including surgery significantly prolonged the OS of MPM patients compared with multimodal therapy without surgery.

In the setting of pseudo-progression in a cancer patient who receives immunotherapeutic treatment, discontinuation of therapy is recommended if the patient is symptomatic. Here, we present two patients with advanced adenocarcinoma of the lung who developed massive tumor growth after initiation of treatment with the anti-PD-1 antibody pembrolizumab. Even though clinical deterioration occurred in the form of severe dyspnea and weight loss, pembrolizumab therapy was continued, as the speed of tumor growth suggested pseudo-progression and the tumors showed marked PD-L1 expression. This approach was successful, and both patients experienced impressive treatment responses within a few weeks.

Squamous cell and adenocarcinomas of the lung develop different mechanisms during carcinogenesis to evade attacks of the immune system. Besides the well-known check-point control programmed death 1 and its ligand, many more mechanisms, acting either tumoricidal or in favor of tumor progression, exist. Analysis of the immune cell profiles in resected tissues and bronchoalveolar lavage samples and correlation between them and with overall survival data was performed. In all tumor samples in this study, cells of the immune system expressed a tumor-cooperating phenotype. High numbers of regulatory T cells, or alternatively expression of Vista on lymphocytes was present. Tumoricidal dendritic cells were absent in tumor tissue, and barely present in bronchoalveolar lavage, whereas tumor-friendly monocytoid and plasmocytoid dendritic cells were seen in both. Alveolar macrophages were predominantly differentiated into tumor-cooperating M2 types, whereas tumoricidal M1 macrophages were absent or rare. The expression of PDL1 on tumor cells did not correlate with any other immune cells. Expression of PD1 on lymphocytes was frequently encountered. None of analyzed immune cells showed correlation with overall survival. Immune cells in bronchoalveolar lavage and tissue did not correlate. For the first time, a tissue-based analysis of different immune cells in squamous cell and adenocarcinomas of the lung is provided, trying to explain their potential role in tumor development and progression. Discordant numbers of cells with bronchoalveolar lavage are most probably due to the fact that bronchoalveolar lavage reflects the situation in the whole lung, where chronic obstructive lung disease and other conditions are present. Electronic supplementary material The online version of this article (10.1007/s00428-018-2326-0) contains supplementary material, which is available to authorized users.

Ankylosing spondylitis (AS) is characterized by ankylosis of axial joints but osteoporosis is also a well-reported feature. T cells have been implicated as a source of receptor activator of NFκB ligand (RANKL) in inflammatory bone diseases. Hence, we assessed whether T cells in patients with AS act as a source of RANKL too. Therefore, we investigated the expression of RANKL on T cells from 21 patients with AS by flow cytometry. Bone mineral density (BMD) was evaluated by quantitative computer tomography (QCT) and dual X-ray absorptiometry (DXA) and correlated with serum levels of osteoprotegerin (OPG) and RANKL. BMD was decreased in 45% of all patients when measured with DXA (48% with QCT) and correlated negatively with OPG. Expression of intracellular RANKL was increased on CD4+ (84 vs. 70%) and CD8+ (85.2 vs. 65.3%, P < 0.05) T cells in patients with AS, whereas expression of membrane-bound RANKL was significantly lower (CD4+: 2.2 vs. 8.5% and CD8+: 0.7 vs. 3.2%, P < 0.01). Our results indicate that surface and intracellular RANKL production is differentially regulated on T cells of patients with AS.

Sprouty2 is a modulator of receptor tyrosine kinase-mediated signalling with an important role during lung carcinogenesis. Here, we characterize a Sprouty2 variant harbouring a substitution of proline 106 with serine. Serine substitution fails to influence expression, but accumulation of slower migrating phosphatase-sensitive forms indicates that its presence facilitates phosphorylation. In normal lung cells the serine variant is slightly more potent in inhibiting proliferation and migration. Additionally non-malignant cells expressing the major Sprouty2 variant attach more effective to fibronectin, while the serine variant only weakly stimulates cell adhesion. Mechanistically, the serine variant interferes less effectively with mitogen-activated protein kinase induction in response to serum. Concerning the positive Sprouty2 effect on epidermal growth factor receptor activation the serine variant is more potent. In all lung cancer-derived cell lines proliferation is more effectively inhibited if the Sprouty2 protein harbours the serine. In contrast, an increased interference of the serine Sprouty2 variant is only observed in cells with unaltered K-Ras. In cells harbouring a K-Ras mutation the serine conversion weakens the reduction of migration velocity indicating that dependent on the status of K-Ras the serine influences Sprouty2 functions differently. Accordingly, cell adhesion in cells with unaffected K-Ras is only stimulated by a Sprouty2 protein harbouring proline, while a serine conversion improves the attachment of the cells with constitutive active Ras. In summary our studies demonstrate that substitution of proline by serine at position 106 has biological significance and that the observed effects of this conversion depend on the activation status of endogenous K-Ras. J. Cell. Biochem. 117: 1822-1832, 2016. © 2016 Wiley Periodicals, Inc.

Regulatory T cells (Treg) with the capacity to suppress T-cell proliferation exert various effects on T cell function. In addition, Treg have been shown to modulate the phenotype and function of antigen-presenting cells (APC) including dendritic cells (DC), B cells and monocytes/macrophages. However, the specific mechanism(s) of how Treg affect APC have not been entirely identified so far. In this study, we analyzed the interaction of human Treg and effector T cells (Teff) with peripheral blood myeloid and monocyte-derived dendritic cells in vitro. A strong tendency for cell cluster formation between Treg and DC was observed, which was dependent on the adhesion molecules ICAM-1, LFA-3 and ICAM-3. In addition, Treg were found to express higher levels of LFA-1, LFA-2, LFA-3 and ICAM-3 both before and after activation with anti-CD3 antibodies. Using in vitro live cell imaging, we were further able to show that Treg-DC cell clusters, in contrast to Teff-DC clusters, were stable and long lasting. Co-cultures of DC with Treg diminished the up-regulation of activation induced costimulatory molecule expression on DC, and further reduced the production of tumor necrosis factor alpha and stimulated the production of IL-4. In summary, our data indicate that Treg-DC cluster formation might enable Treg to modulate phenotypic and functional characteristics of DC and help to constrain Teff activation.