Cancer of unknown primary (CUP) through the lens of precision oncology: a single institution perspective.

PURPOSE: For patients with cancer of unknown primary (CUP), treatment options are limited. Precision oncology, the interplay of comprehensive genomic profiling (CGP) and targeted therapies, aims to offer additional treatment options to patients with advanced and hard-to-treat cancers. We aimed to highlight the use of a molecular tumor board (MTB) in the therapeutic management of CUP patients. METHODS: In this single-center observational study, CUP patients, presented to the MTB of the Comprehensive Cancer Center Munich LMU, a tertiary care center, were analyzed retrospectively. Descriptive statistics were applied to describe relevant findings. RESULTS: Between June 2016 and February 2022, 61 patients with unfavorable CUP were presented to the MTB, detected clinically relevant variants in 74% (45/61) of patients, of which 64% (29/45) led to therapeutic recommendation. In four out of 29 patients (14%), the treatment recommendations were implemented, unfortunately without resulting in clinical benefit. Reasons for not following the therapeutic recommendation were mainly caused by the physicians' choice of another therapy (9/25, 36%), especially in the context of worsening of general condition, lost to follow-up (7/25, 28%) and death (6/25, 24%). CONCLUSION: CGP and subsequent presentation to a molecular tumor board led to a high rate of therapeutic recommendations in patients with CUP. Recommendations were only implemented at a low rate; however, late GCP diagnostic and, respectively, MTB referral were found more frequent for the patients with implemented treatment. This contrast underscores the need for early implementation of CGP into the management of CUP patients.

Prognosis and tumor biology of pancreatic cancer patients with isolated lung metastases: translational results from the German multicenter AIO-YMO-PAK-0515 study.

BACKGROUND: Pulmonary metastasis (M1-PUL) as first site of dissemination in pancreatic ductal adenocarcinoma (PDAC) is a rare event and may define a distinct biological subgroup. PATIENTS AND METHODS: Arbeitsgemeinschaft Internistische Onkologie-Young Medical Oncologists-Pankreas-0515 study (AIO-YMO-PAK-0515) was a retrospective German multicenter study investigating clinical and molecular characteristics of M1-PUL PDAC patients; 115 M1-PUL PDAC patients from 7 participating centers were included. Clinical characteristics and potential prognostic factors were defined within the M1-PUL cohort. Archival tumor samples were analyzed for Her2/neu, HNF1A and KRT81 expression. Additionally, messenger RNA (mRNA) expression analysis (using a 770-gene immune profiling panel) was carried out in the M1-PUL and in a control cohort (M1-ANY). RESULTS: Median overall survival in the entire M1-PUL cohort was 20 months; the most favorable prognosis (median survival: 28 months) was observed in the subgroup of 66 PDAC patients with metachronous lung metastases after previous curative-intent surgery. The number of metastatic lesions, uni- or bilateral lung involvement as well as metastasectomy were identified as potential prognostic factors. Her2/neu expression and PDAC subtyping (by HNF1A and KRT81) did not differ between the M1-PUL and the M1-ANY cohort. mRNA expression analysis revealed significant differentially expressed genes between both cohorts: CD63 and LAMP1 were among the top 20 differentially expressed genes and were identified as potential mediators of organotropism and favorable survival outcome of M1-PUL patients. CONCLUSION: M1-PUL represents a clinically favorable cohort in PDAC patients. Site of relapse might already be predetermined at the time of surgery and could potentially be predicted by gene expression profiling.

Biomarker alterations associated with distinct patterns of metastatic spread in colorectal cancer.

Metastatic spread is the most important life-threatening feature of colorectal cancer and is supposed to be mainly driven by alterations in different carcinogenic pathways. The present study compared mutation and expression profiles of distinctive biomarkers in colorectal cancer patients with different clinical metastatic patterns. As for a case-control study, patients were matched according to T category, grading and primary tumour site. Overall, 246 patients with either exclusive lung metastasis (N = 82), exclusive liver metastasis (N = 82) or non-metastatic colorectal cancer (N = 82) were identified. Paraffin-embedded specimens were examined for mutations in the RAS and RAF genes and for the expression of ß-catenin and CD133. Clinical endpoints were presence or absence of distant metastasis, formation of metastasis in lungs versus the liver and survival. MAPK pathway mutations in either the KRAS, NRAS or BRAF gene were associated with the development of lung metastasis (63.4%) compared to the control group (47.6%; p = 0.04). MAPK pathway alterations plus high ß-catenin expression were associated with metastasis to the lungs but not to the liver (28.0% vs. 13.4%; p = 0.02). High CD133 expression correlated with the development of liver metastasis compared to the control group (30.5% vs. 14.6%; p = 0.02). This data indicates that different patterns of distant spread are associated with specific biomarker alterations and may represent different molecular subtypes of colorectal cancer. However, underlying mechanisms of metastasis formation in different anatomic sites remains unclear. Since knowledge of the anticipated site of distant spread would substantially impact clinical management, further research is needed to identify solid biomarkers for different metastatic patterns.

Bifunctional effect of Zoledronic Acid (ZA) on human mesenchymal stem cells (hMSCs) based on the concentration level.

BACKGROUND: Treatment of massive bone defects is a great challenge. Mesenchymal stem cells (MSCs) enhance bone regeneration by differentiating into osteoblasts. Bisphosphonates (BPs) are antiresorptives reducing bone resorption. Despite Medication-related osteonecrosis of the jaw (MRONJ) is a known side effect of antiresorptives, evidences suggest that BPs have positive effect on bone formation. The aims of this study were to investigate the effect of zoledronic acid (ZA) and geranylgeraniol (GGOH) on human mesenchymal stem cells (hMSCs) being a part of the bone microenvironment and evaluate whether low dose of bisphosphonate has enhanced osteogenic differentiation of hMSCs. MATERIALS AND METHODS: The effect of ZA and GGOH on MSCs was investigated in addition to the effect of low doses of ZA on osteogenic differentiation of MSCs and analysed by WST-1, Live/Dead staining and coefficient of drug index (CDI). The osteogenic differentiation of the cells was confirmed by ALP activity, xylenol orange and alizarin red staining, microarray and PCR with levels of statistical significance indicated at *P<0.05, **P<0.01 and ***P<0.0001. MAIN FINDINGS: Although, high concentration of ZA had significantly decreased the cell viability in MSCs, GGOH reversed the action of ZA on the cells while at very high concentration; it caused severe reduction in the cell viability. CDI showed antagonism or synergism depending on the concentrations of ZA and GGOH. CONCLUSION: The treatment of cells with ZA has increased the mineralization and osteogenic differentiation of MSCs. Our study supported the hypothesis that zoledronic acid plays a bifunctional role depending on the concentration.