Baseline serum levels of osteopontin predict clinical response to treatment with nivolumab in patients with non-small cell lung cancer Abstract Treatment with nivolumab improves survival and response rate in non-small cell lung cancer (NSCLC). Nevertheless, due to its high financial cost, identifying predictors of response to treatment has become an urgent need. Here, we focused on serum osteopontin (OPN), a pleiotropic protein overexpressed in lung cancer and involved in the immune response. A cohort of NSCLC patients (n = 72) treated with nivolumab was enrolled. Blood samples were collected at the time of first five nivolumab administrations. OPN and high-sensitivity C-reactive protein (hs-CRP) were assayed at each time point. The primary endpoint was to assess the predictive value of baseline serum levels of OPN towards overall survival (OS). Secondary endpoints included the potential association between OPN, hs-CRP and response to nivolumab. OPN and hs-CRP correlate with each other, with neutrophil count and biochemical markers of metastatic disease. At baseline, serum OPN increased with increasing Eastern Cooperative Oncology Group scale of Performance Status (ECOG PS). When Eastern Cooperative Oncology Group scale of Performance Status) (RECIST) criteria were considered, high baseline OPN levels were associated with a worse response to nivolumab. Cox hazard regression further confirmed baseline serum OPN as a predictor of mortality with the best predictive accuracy for serum levels above 37.7 ng/mL. Patients above the cut-off value had a higher mortality rate as compared to low serum OPN levels during follow up. Serum OPN may have a predictive role in NSCLC patients treated with nivolumab. Although larger confirmatory studies are needed, measuring serum OPN levels at baseline can be a clinically useful tool in a near future.

Peritoneal Surface Disease Severity Score (PSDSS), AGO-score and TIAN model in patients with platinum-sensitive recurrent ovarian cancer treated by cytoreductive surgery plus HIPEC Abstract In patients with platinum sensitive recurrent ovarian cancer selected for a secondary cytoreduction, the use of prognostic scores allows predicting the possibilities of a new complete cytoreduction. The aim of this work is to evaluate the usefulness of PSDSSov, the AGO-score and the TIAN-model as prognostic tools in these patients. Sixty four patients with recurrent platinum sensitive ovarian cancer treated by cytoreduction and HIPEC were analyzed between January 2008 and December 2016. Since 2012, the data needed to calculate the PSDSS, AGO-score and TIAN model were collected prospectively. Fifty patients (78%) received systemic chemotherapy before cytoreduction and HIPEC. In 57 patients (89%) a CC-0 was achieved. Patients with PSDSSov I–II and TIAN model of “low risk” had a DFS at 1 and 5 years of 71% and 57%, respectively, without reaching the median of DFS. PSDSSov is a useful prognostic tool and can be used in decision making in patients with peritoneal carcinomatosis due to recurrent platinum-sensitive ovarian cancer. Its combination with the Tian model makes it possible to identify patients with an especially favorable prognosis.

The prognostic impact of lymph node metastasis in patients with non-small cell lung cancer and distant organ metastasis Abstract This study aimed to identify the prognostic value of lymph node metastasis in patients with non-small cell lung cancer (NSCLC) and distant organ metastasis. A total of 42,613 NSCLC patients with distant metastasis from the surveillance, epidemiology, and end results database between 2010 and 2013 were included for analysis. The proportion of N0 stage in M1a patients was significantly higher than that in M1b patients, 34.0% and 22.7% respectively (P < 0.001). Compared with N0 patients, patients had higher odds of experiencing multiorgan metastases (MOM) if they had higher N stage at diagnoses (P < 0.001). The Kaplan–Meier curves suggested both M1a and M1b groups patients at stage N0 had better survival than those at higher N stage (P < 0.001). Further analysis indicated that better survival was observed in N0 stage compared with N2 or N3 stage if patients had bone metastasis, brain metastasis, or MOM (P < 0.001, P < 0.001, and P = 0.002, respectively), but there was no significant difference in survival among each N stage patients with liver metastasis only. Cox regression analysis showed that compared with N0 patients, higher hazard for disease-specific mortality was observed for patients with higher N stage. Among NSCLC patients with distant organ metastasis, lymph node metastasis was associated with higher odds of experiencing MOM and a worse prognosis in terms of longer survival except patients with liver metastasis. Better understandings of the role of lymphatic metastasis in M1 NSCLC could help clinicians with better management of the disease.

Factors related to the quality of life in patients with bone metastases Abstract Treatment for bone metastases aims to preserve patients’ quality of life (QOL). Therefore, assessment of patients’ reported QOL is important, especially in this field. This cross-sectional study sought to investigate the clinical factors of QOL in patients with bone metastasis in different cancer settings, at any treatment status, and examined the effect of these factors on systemic symptoms and psychological disorders. This study was conducted by a multidisciplinary team for bone metastases at a university hospital in Japan. One-hundred seventy-four patients who could complete the self-report questionnaires were selected. The questionnaire included the EQ-5D, EORTC QLQ-C15-PAL, BM22, and K6 distress scale. We obtained clinical data on tumor progression, bone metastasis, pain, and ECOG-PS. The mean (SD) EQ-5D score was 0.58 (0.24), which was lower than that of the general Japanese and US population (0.85). Skeletal-related events (SREs), pain, and ECOG-PS were significantly related to lower EQ-5D scores in the multivariable analysis (p < 0.01), whereas primary lesion or expected prognosis at the first examination was not. These three factors were also related to systemic symptoms and emotional functioning. Radiologically lytic bone metastasis and lower limb/acetabular metastases were related to SREs and ECOG-PS, respectively. In conclusion, for improving the QOL of patients with bone metastases, we should focus on SRE prevention, treatment for pain, and modifying ADL, and a multidisciplinary team might be useful.

Co-expression of carcinoembryonic antigen-related cell adhesion molecule 6 and 8 inhibits proliferation and invasiveness of breast carcinoma cells Abstract The carcinoembryonic antigen-related cell adhesion molecule (CEACAM) 6 and CEACAM8 form heterodimers and exert their effects. Therefore, we examined the effects of CEACAM6 and CEACAM8 co-expression in breast cancer. We first studied CEACAM6/8 expression using immunohistochemistry in 109 patients with breast cancer. We then established MCF-7 cells that were stably transfected with CEACAM8 and studied cell proliferation, invasion and adhesion. The number of CEACAM6 and CEACAM8 double-positive breast carcinoma cells significantly increased in patients with low histopathological grade and stage. Proximity ligation assay (PLA) confirmed high CEACAM6/8 expression in MCF-7 cells. CEACAM6/8 expression promoted the adhesion of MCF-7 cells to endothelial cell monolayers but inhibited their invasion and proliferation. Furthermore, CEACAM6 status in carcinoma cells was significantly higher in bone than in lung metastases. CEACAM6/8 expression is associated with the inhibition of vascular invasion and cell proliferation. CEACAM6 expression was also considered to be involved in bone metastases of breast cancer. This is the first study to demonstrate the possible role of CEACAM6/8 heterodimer and CEACAM6 expression in breast cancer patients.

Quantification of PpIX-fluorescence of cerebral metastases: a pilot study Abstract 5-ALA fluorescence-guided surgery (FGS) is a major advance in neuro-oncological surgery. So far, Protoporphyrin IX (PpIX)-fluorescence has been observed in about half of cerebral metastases resected with routinely equipped microscopes during 5-ALA FGS. The aim of the present pilot study was to quantify PpIX-induced fluorescence of cerebral metastases with a spectrometer. We hypothesize that non-fluorescing metastases under the operating microscope may have spectrometrically measurable levels of fluorescence. A second aim was to analyze correlations between quantified 5-ALA fluorescence and histology or primary tumor type, respectively. Standard FGS was performed in all patients. The fluorescence intensity of the metastasis was semi-quantitatively determined in vivo by a senior surgeon using a special surgical microscope equipped for FGS. A systematic spectrometric ex vivo evaluation of tumor specimens and PpIX-induced fluorescence was performed using a spectrometer connected by optic fibers to a handheld probe. Quantification of 5-ALA-derived fluorescence was measured in a standardized manner with direct contact between mini-spectrometer and metastasis. The difference between the maximum PpIX-fluorescence at 635 nm and the baseline fluorescence was defined as the PpIX fluorescence intensity of the metastasis and given in arbitrary units (AU). Diagnosis of a cerebral metastasis was confirmed by histopathological analysis. A total of 29 patients with cerebral metastases were included. According to neuropathological analysis, 11 patients suffered from non-small cell lung cancer, 10 patients from breast cancer, 6 patients from cancer originating in the gastro-intestinal tract, 1 patient suffered from a malignant melanoma and one patient from renal cancer. The mean age was 63 years (37–81 years). 15 patients were female, 14 patients male. 13 cerebral metastases were considered as ALA-positive by the surgeon. In nine metastases, 5-ALA fluorescence was not visible to the naked eye and could only be detected using the spectrometer. The threshold for an ALA signal rated as “positive” by the surgeon was PpIX fluorescence above 1.1 × 106 AU. The mean PpIX fluorescence of all analyzed cerebral metastases was 1.29 × 106 ± 0.23 × 106 AU. After quantification, we observed a significant difference between the mean 5-ALA-derived fluorescence in NSCLC and breast cancer metastases (Mean Diff: − 1.2 × 106; 95% CI of difference: − 2.2 × 106 to − 0.15 × 106; Šidák-adjusted p = 0.026). In our present pilot series, about half of cerebral metastases showed a 5-ALA fluorescence invisible to the naked eye. Over 50% of these non-fluorescent metastases show a residual 5-ALA fluorescence which can be detected and quantified using a spectrometer. Moreover, the quantified 5-ALA signal significantly differed with respect to the primary tumor of the corresponding cerebral metastasis. Further studies should evaluate the predictive value of the 5-ALA signal and if a quantified 5-ALA signal enables a reliable intraoperative differentiation between residual tumor tissue and edematous brain—in particular in metastases with a residual fluorescence signal invisible to the naked eye.

Cullin 3 overexpression inhibits lung cancer metastasis and is associated with survival of lung adenocarcinoma Abstract Cullin 3 (CUL3), a molecular scaffold of Cullin-RING ubiquitin ligase, plays an important role in regulating biological processes through modulating the ubiquitylation and degradation of various protein substrates. Dysfunction of CUL3 is implicated in the development of several human diseases. However, the clinical significance and prognostic value of CUL3 in lung cancer have not been investigated. This study investigated the CUL3-modulating potential of non-small cell lung cancer cell lines, H1299, H358, H2170 and H520, by using immunoblotting, MTT, migration, invasion, colony formation and in vivo tumorigenicity assays. The prognostic significance of CUL3 was measured by public KM plotter database (http://kmplot.com/analysis/index.php?p=service&cancer=breast) and tissue immunohistochemistry analysis. The public online database analysis revealed that elevated mRNA expression of CUL3 was associated with better prognosis for non-small cell lung cancer and lung adenocarcinoma. In vitro experiments showed that ectopic overexpression of CUL3 significantly inhibited lung adenocarcinoma cell proliferation and migration, and the tumor-suppressive effect of CUL3 was dependent on the Nrf2/RhoA axis. In vivo mice model demonstrated that overexpression of CUL3 lead to a significant reduction of lung adenocarcinoma growth and metastasis. Importantly, tissue immunohistochemistry analysis showed that about 47% of non-small cell lung cancer tissues were expressed of CUL3 at high levels. Overexpression of CUL3 predicted favorable overall survival in non-small cell lung cancer patients, especially in lung adenocarcinoma, but not in lung squamous cell carcinoma patients. CUL3 could serve as a prognostic biomarker for lung adenocarcinoma. Loss of CUL3 might be driving tumorigenesis by activating the Nrf2/RhoA pathway.

Ureteral involvement by metastatic malignant disease Abstract Ureteral metastases from other primary cancers are very rare. Treatment of these metastases is difficult and outcomes are poor. A thorough literature review was done with the aim of finding characteristics that may influence survival rates of patients with ureteral metastases. Systematic literature searches of PubMed and Web of Science were performed in Jan 2019. A total of 79 papers that included 265 patients with cancer metastases to their ureters were finally considered for evidence synthesis. Prostate, bladder, breast, gut cancer and lymphoma were the predominant primary tumors. The median interval time from primary tumor diagnosis to ureter metastasis was 28.5 months. The median survival time after diagnosis of ureter metastasis was 18 months. Risk factors of survival were analyzed. Age, sex, hydronephrosis, ureter side, and segment were not associated with survival. Interval time and treatment were associated with overall survival. Further analysis indicated that patients who underwent surgery had better outcomes.

Metastatic dissemination patterns of different primary tumors to the spine and other bones Abstract Metastatic spine disease (MSD) is a severe event in cancer patients. Experimental data indicate that bone metastasis is mostly mediated by blood flow-dependent, passive arrest of circulating tumor cells to the bone metastatic niche (BMN). Here, we have set out to test these experimental observations in a clinical, human setting to improve our understanding of MSD. 507 patients, treated on spinal metastases in our institution from 2005 to  2015 were retrospectively evaluated. We identified 259 patients with accessible staging reports of the skeleton before and at initial diagnosis of MSD. Data analysis comprised localizations of bone metastases, underlying malignancy and time to development of MSD. Dissemination pattern of bone metastasis was correlated with red bone marrow (RBM) content of the respective bone as a measure of blood flow. Spinal metastases occurred most frequently in lung cancer (21%), prostate cancer (19%), and breast cancer (12%). At the diagnosis of MSD, majority of patients have multiple extra-spinal bone metastases (2/3). The distribution of metastases to extra-spinal bones and to the spine is mostly proportional to the RBM content of the involved bone. Corresponding to the high RBM content, thoracic spine, pelvic bones and ribs represent a predilection site for bone metastasis. We confirm a distinct preference of cancer types to metastasize to bones. When it comes to bone metastases all primaries show uniform distribution pattern, which supports the hypothesis of a predominantly blood flow-dependent distribution of tumor cells and passive arrest to the BMN rather than a spine-specific homing mechanism.

Diagnostics of metastasis: an increasing challenge with high clinical importance