Mesothelin (MSLN) represents an attractive molecule for targeted cancer therapies. To identify tumors that might benefit from such therapies, tissue microarrays including 15,050 tumors from 122 different tumor types and 76 healthy organs were analyzed for MSLN expression by immunohistochemistry. Sixty-six (54%) tumor types showed at least occasional weak staining, including 50 (41%) tumor types with at least one strongly positive sample. Highest prevalence of MSLN positivity had ovarian carcinomas (serous 97%, clear cell 83%, endometrioid 77%, mucinous 71%, carcinosarcoma 65%), pancreatic adenocarcinoma (ductal 75%, ampullary 81%), endometrial carcinomas (clear cell 71%, serous 57%, carcinosarcoma 50%, endometrioid 45%), malignant mesothelioma (69%), and adenocarcinoma of the lung (55%). MSLN was rare in cancers of the breast (7% of 1138), kidney (7% of 807), thyroid gland (1% of 638), soft tissues (0.3% of 931), and prostate (0 of 481). High expression was linked to advanced pathological tumor (pT) stage (p < 0.0001) and metastasis (p < 0.0001) in 1619 colorectal adenocarcinomas, but unrelated to parameters of malignancy in 1072 breast-, 386 ovarian-, 174 lung-, 757 kidney-, 171 endometrial-, 373 gastric-, and 925 bladder carcinomas. In summary, numerous important cancer types with high-level MSLN expression might benefit from future anti-MSLN therapies, but MSLN’s prognostic relevance appears to be limited.

An obstacle to early stem cell transplantation into the acutely injured spinal cord is poor survival of transplanted cells. Transplantation of embryonic stem cells as substrate adherent embryonic stem cell-derived neural aggregates (SENAs) consisting mainly of neurons and radial glial cells has been shown to enhance survival of grafted cells in the injured mouse brain. In the attempt to promote the beneficial function of these SENAs, murine embryonic stem cells constitutively overexpressing the neural cell adhesion molecule L1 which favors axonal growth and survival of grafted and imperiled cells in the inhibitory environment of the adult mammalian central nervous system were differentiated into SENAs and transplanted into the spinal cord three days after compression lesion. Mice transplanted with L1 overexpressing SENAs showed improved locomotor function when compared to mice injected with wild-type SENAs. L1 overexpressing SENAs showed an increased number of surviving cells, enhanced neuronal differentiation and reduced glial differentiation after transplantation when compared to SENAs not engineered to overexpress L1. Furthermore, L1 overexpressing SENAs rescued imperiled host motoneurons and parvalbumin-positive interneurons and increased numbers of catecholaminergic nerve fibers distal to the lesion. In addition to encouraging the use of embryonic stem cells for early therapy after spinal cord injury L1 overexpression in the microenvironment of the lesioned spinal cord is a novel finding in its functions that would make it more attractive for pre-clinical studies in spinal cord regeneration and most likely other diseases of the nervous system.

Forty percent of non-small cell lung cancer (NSCLC) patients develop brain metastases, resulting in a dismal prognosis. However, patients in an oligo-metastatic brain disease setting seem to have better outcomes. Here, we investigate the possibility of using circulating tumor cells (CTCs) as biomarkers to differentiate oligo-metastatic patients for better risk assessment. Using the CellSearch^® system, few CTCs were detected among NSCLC patients with brain metastases (n = 52, 12.5% ≥ two and 8.9% ≥ five CTC/7.5 mL blood) and especially oligo-metastatic brain patients (n = 34, 5.9%, and 2.9%). Still, thresholds of both ≥ two and ≥ five CTCs were independent prognostic indicators for shorter overall survival time among all of the NSCLC patients (n = 90, two CTC ≥ HR: 1.629, p = 0.024, 95% CI: 1.137–6.465 and five CTC ≥ HR: 2.846, p = 0.0304, CI: 1.104–7.339), as well as among patients with brain metastases (two CTC ≥ HR: 4.694, p = 0.004, CI: 1.650–13.354, and five CTC ≥ HR: 4.963, p = 0.003, CI: 1.752–14.061). Also, oligo-brain NSCLC metastatic patients with CTCs had a very poor prognosis (p = 0.019). Similarly, in other tumor entities, only 9.6% of patients with brain metastases (n = 52) had detectable CTCs. Our data indicate that although patients with brain metastases more seldom harbor CTCs, they are still predictive for overall survival, and CTCs might be a useful biomarker to identify oligo-metastatic NSCLC patients who might benefit from a more intense therapy.

To evaluate cytokeratin 19 (CK19) expression in normal and cancerous tissues, 15,977 samples from 122 tumor types and 608 samples of 76 normal tissue types were analyzed by immunohistochemistry (IHC). In normal tissues, CK19 expression occurred in epithelial cells of most glandular organs but was strictly limited to the basal cell layer of nonkeratinizing squamous epithelium and absent in the skin. CK19 expression in ≥90% of cases was seen in 34% of the tumor entities including the adenocarcinomas of the pancreas (99.4%), colorectum (99.8%), esophagus (98.7%), and stomach (97.7%), as well as breast cancer (90.0%-100%), high-grade serous (99.1%) or endometrioid (97.8%) ovarian cancer, and urothelial carcinoma (92.6%-100%). A low CK19 positivity rate (0.1-10%) was seen in 5 of 122 tumor entities including hepatocellular carcinoma and seminoma. A comparison of tumor versus normal tissue findings demonstrated that upregulation and downregulation of CK19 can occur in cancer and that both alterations can be linked to unfavorable phenotypes. CK19 downregulation was linked to high grade (p = 0.0017) and loss of estrogen receptor- and progesterone receptor-expression (p < 0.0001 each) in invasive breast carcinoma of no special type. CK19 upregulation was linked to nodal metastases in neuroendocrine tumors and papillary thyroid carcinomas (p < 0.05 each) and to poor grade in clear cell renal cell carcinoma (p < 0.05). CK19 upregulation was particularly common in squamous cell carcinomas. We concluded that CK19 IHC might separate primary liver cell carcinoma from liver metastases, seminoma from other testicular tumors, and helps in the detection of early neoplastic transformation in squamous epithelium.

Background/Objectives: Carcinoembryonic antigen (CEA) is a cell-surface glycoprotein serving as a drug target, diagnostic marker, and serum marker for cancer monitoring. However, prevalence data on CEA expression in cancer tissues vary considerably. This study was designed to determine CEA expression in normal and neoplastic tissues. Methods: A tissue microarray containing 13,725 samples from 120 different tumor types, as well as 76 different normal tissue types, was analyzed by immunohistochemistry (IHC). Results: CEA was detectable in 65 (54.2%) of 120 tumor categories, including 49 (40.8%) tumor types with at least one strongly positive case. CEA positivity was most common in colorectal adenomas (100%) and carcinomas (98.7%), other gastrointestinal adenocarcinomas (61.1–80.3%), medullary carcinomas of the thyroid (96.3%), pulmonary adenocarcinoma (73.7%), mucinous carcinomas of the ovary (79.8%) and the breast (43.2%), small-cell carcinomas of the lung (64.3%), and urinary bladder (38.9%). CEA overexpression was linked to high tumor grade and invasive growth (p < 0.0001 each) in urinary bladder cancer, and estrogen and HER2 receptor positivity (p ≤ 0.0158) in invasive breast cancer of no special type. In colorectal adenocarcinomas, reduced CEA expression was associated with mismatch repair deficiency (p < 0.0001). Conclusions: The comprehensive list of CEA-positive human tumor types demonstrates that CEA is expressed in a broad range of epithelial neoplasms, many of which might benefit from CEA serum monitoring and anti-CEA therapies.

The expression of the neuroendocrine markers synaptophysin and chromogranin A was analyzed by immunohistochemistry in 14,584 samples from 103 different tumor types and subtypes in a tissue microarray format. At least one of these markers was found to be positive in 96.7% of tumors from various subtypes of neuroendocrine neoplasms. In non-neuroendocrine tumors, synaptophysin and/or chromogranin A staining was seen in 6.3% (n = 584), specifically in 41 of 88 non-neuroendocrine tumor entities. Basal cell carcinomas of the skin (50% positive for chromogranin A alone) and adrenocortical carcinomas (91.7% positive for synaptophysin alone) stood out due to a frequent expression of only one specific marker. A subdivision of non-neuroendocrine neoplasms revealed "neuroendocrine differentiation" most commonly in adenocarcinomas from the female genital tract (18.9%), from pancreatico-/hepato-/biliary tract (15.8%) and the prostate (14.9%) while it was rare in urothelial (1.0%) and squamous cell carcinomas (0.6%). A comparison with clinico-pathological parameters of tumor aggressiveness did not suggest a clinical significance of neuroendocrine marker expression in 204 endometrium cancers, 249 pancreatic adenocarcinomas, 233 gastric adenocarcinomas and 1,182 colorectal adenocarcinomas. Within a cohort of 1,073 breast cancers of no special type, synaptophysin positivity was seen in 4.9% of cases and it was significantly linked to advanced tumor stage (p = 0.0427), high tumor grade (p = 0.0319) and loss of estrogen receptor expression (p = 0.0061) but unrelated to patient outcome. In conclusion, "neuroendocrine differentiation" can be observed in many different tumor types with non-neuroendocrine morphology. Evidence for a statistically significant association (p < 0.0001) between such a "neuroendocrine differentiation" and tumor aggressiveness could not be found.