Programmed death ligand-1 (PD-L1) clone 22C3 expression in resected colorectal cancer as companion diagnostics for immune checkpoint inhibitor therapy: A comparison study and inter-rater agreement evaluation across proposed cut-offs and predictive (TPS, CPS and IC) scores.

BACKGROUND: Expression of programmed death ligand-1 (PD-L1) guides the use of immune checkpoint inhibitors (ICI) in several cancers. In colorectal cancer (CRC), ICI are only approved for metastatic CRC, while several studies suggest high efficacy even in operable CRC. The aim of this study was to investigate the inter-rater agreement of PD-L1 as a companion diagnostic marker. METHODS: Specimens from resected stage I-III CRC (n = 166 tumors) were stained with PD-L1 22C3 clone. PD-L1 expression was scored by two pathologists as tumor proportion score (TPS), combined positive score (CPS) and immune cell score (IC). Inter-rater agreement was tested using three different agreement coefficients. RESULTS: Raw scores of the two pathologists had 'good' to 'excellent' correlation. Spearman's rho for TPS=0.917 (95 %CI 0.839-0.995), for CPS=0.776 (95 %CI 0.726-0.826) and IC=0.818 (95 %CI 0.761-0.875). For TPS, kappa (κ)-agreements for both the ≥1 % and ≥10 % cutoffs had excellent correlation. For CPS the ≥1 % and ≥10 % cutoffs demonstrated κ=0.32 (95 %CI 0.12-0.51) and κ=0.36 (95 %CI 0.25-0.48) respectively. Cutoffs for IC showed κ=0.53 (95 %CI 0.18-0.79) for the ≥1 % cutoff, and κ=0.61 (95 %CI 0.48-0.73) for the ≥10 % cutoff. Gwet's agreement coefficient (AC1) showed higher agreement coefficients than κ-values for most, but not all cut-offs. CONCLUSION: Agreement for PD-L1 was good to excellent for raw scores. Agreement variation across several criteria and cut-offs suggests the need for more robust criteria for PD-L1 as a companion diagnostic marker.

Early Diagnosis of Pancreatic Cancer: Clinical Premonitions, Timely Precursor Detection and Increased Curative-Intent Surgery.

BACKGROUND: The overall poor prognosis in pancreatic cancer is related to late clinical detection. Early diagnosis remains a considerable challenge in pancreatic cancer. Unfortunately, the onset of clinical symptoms in patients usually indicate advanced disease or presence of metastasis. ANALYSIS AND RESULTS: Currently, there are no designated diagnostic or screening tests for pancreatic cancer in clinical use. Thus, identifying risk groups, preclinical risk factors or surveillance strategies to facilitate early detection is a target for ongoing research. Hereditary genetic syndromes are a obvious, but small group at risk, and warrants close surveillance as suggested by society guidelines. Screening for pancreatic cancer in asymptomatic individuals is currently associated with the risk of false positive tests and, thus, risk of harms that outweigh benefits. The promise of cancer biomarkers and use of 'omics' technology (genomic, transcriptomics, metabolomics etc.) has yet to see a clinical breakthrough. Several proposed biomarker studies for early cancer detection lack external validation or, when externally validated, have shown considerably lower accuracy than in the original data. Biopsies or tissues are often taken at the time of diagnosis in research studies, hence invalidating the value of a time-dependent lag of the biomarker to detect a pre-clinical, asymptomatic yet operable cancer. New technologies will be essential for early diagnosis, with emerging data from image-based radiomics approaches, artificial intelligence and machine learning suggesting avenues for improved detection. CONCLUSIONS: Early detection may come from analytics of various body fluids (eg 'liquid biopsies' from blood or urine). In this review we present some the technological platforms that are explored for their ability to detect pancreatic cancer, some of which may eventually change the prospects and outcomes of patients with pancreatic cancer.

Histopathological Growth Pattern in Colorectal Liver Metastasis and The Tumor Immune Microenvironment.

Almost half of all patients with colorectal cancer present with or eventually develop metastasis, most frequently in the liver. Understanding the histopathological growth patterns and tumor immune microenvironment of colorectal liver metastases may help determine treatment strategies and assess prognosis. A literature search was conducted to gather information on cancer biology, histopathological growth patterns, and the tumor immune microenvironment in colorectal liver metastases, including their mechanisms and their impact on clinical outcomes. A first consensus on histopathological growth patterns emerged in 2017, identifying five growth patterns. Later studies found benefits from a two-tier system, desmoplastic and non-desmoplastic, incorporated into the updated 2022 consensus. Furthermore, the tumor immune microenvironment shows additional characteristic features with relevance to cancer biology. This includes density of T-cells (CD8+), expression of claudin-2, presence of vessel co-option versus angiogenesis, as well as several other factors. The relation between histopathological growth patterns and the tumor immune microenvironment delineates distinct subtypes of cancer biology. The distinct subtypes are found to correlate with risk of metastasis or relapse, and hence to clinical outcome and long-term survival in each patient. In order to optimize personalized and precision therapy for patients with colorectal liver metastases, further investigation into the mechanisms of cancer biology and their translational aspects to novel treatment targets is warranted.

Risk of More Advanced Lesions at Hysterectomy after Initial Diagnosis of Non-Atypical Endometrial Hyperplasia in Patients with Postmenopausal Bleeding and Oral Anticoagulant Treatment.

Background and Objectives: Endometrial hyperplasia (EH) is a precursor lesion to endometrial cancer (EC), and when cellular atypia is present, in 40% of cases, they are diagnosed with EC on hysterectomy. Usually, EH is clinically manifested by uterine bleeding. In patients with oral anticoagulant therapy (OAT), the uterus is the second most common source of bleeding. The aim of the study was to show that uterine bleeding in postmenopausal patients undergoing OAT may reveal precancerous endometrial lesions with atypia, or neoplastic lesions in patients with an initial diagnosis of endometrial hyperplasia without atypia (non-atypical endometrial hyperplasia, NAEH) on dilation and curettage (D&C). We will be able to estimate the risk of a postmenopausal female patient with uterine bleeding during an OAT to have a precancerous endometrial lesion. Materials and Methods: The subjects of the study were 173 female patients with uterine bleeding, who have had total hysterectomy with bilateral salpingoovarectomy, of whom 99 underwent an OAT. There were 101 female patients initially diagnosed with NAEH, of which 60 did not have anticoagulant treatment (mean age 57.36 ± 6.51) and 41 had anticoagulant treatment (mean age 60.39 ± 7.35) (p = 0.006). From the pathology diagnosis moment, the surgery was performed at 42.09 ± 14.54 days in patients without OAT and after 35.39 ± 11.29 days in those who received such treatment (p = 0.724). Results: Initial diagnosis of NAEH established at D&C was changed at the final diagnosis after hysterectomy in EH with cellular atypia (atypical endometrial hyperplasia AEH) or EC in 18.18% of patients without OAT, and in 40.54% of patients who received this treatment. Conclusions: Based on a logistic regression model, it is estimated that female patients with an initial histopathological diagnosis of NAEH and who underwent OAT have, on average, 4.85 times greater odds (OR = 4.85, 95% CI 1.79-14.06) than the others of being identified postoperatively with more advanced lesions.

Prostate-specific membrane antigen (PSMA) expression in breast cancer and its metastases.

The present study was undertaken to investigate the expression of prostate-specific membrane antigen (PSMA) in normal breast tissues, in cancerous breast tissues and in distant metastases from patients with breast cancer. Immunohistochemical analysis was performed to determine PSMA expression and angiogenic activity using anti-PSMA mAb and anti-CD31 mAb respectively. Immunofluorescence staining was applied to confirm the exact co-localization of PSMA and CD31. We observed different patterns of PSMA expression between normal and cancerous tissues. Normal breast tissues showed PSMA expression only in normal glandular cells. However, primary breast tumors and distant metastases showed PSMA expression in tumor cells and in tumor-associated neovasculature. PSMA score group status in primary breast tumors was significantly associated with histologic type and tumor grade (p = 0.026 and p = 0.004 respectively). Distant metastases showed higher PSMA expression in tumor-associated neovasculature comparing with primary tumors. Moreover, brain tumor-associated neovasculture had significantly higher expression of PSMA comparing with bone tumor-associated neovasculture. The localized binding of PSMA mAb to the neovasculature endothelium was confirmed with the double Immunofluorescence staining. 68Ga-PSAM imaging of a patient with metastatic breast cancer showed strong tracer uptake in all known skeletal metastases. To the best of our knowledge, this study is the second one that has assessed PSMA expression in a large number of breast cancer patients. Our findings showed that PSMA is particularly expressed in tumor-associated neovasculature of breast tumors and its distant metastases, thus enhancing the evidence on the potential usefulness of PSMA as a therapeutic vascular target.