Prospective Assessment of Clinical Risk Factors and Biomarkers of Hypercoagulability for the Identification of Patients with Lung Adenocarcinoma at Risk for Cancer-Associated Thrombosis: The Observational ROADMAP-CAT Study.

BACKGROUND: The aim of this prospective study was to identify the most clinically relevant hypercoagulability biomarkers in lung adenocarcinoma patients for elaboration of an improved risk assessment model (RAM) for venous thromboembolism (VTE). SUBJECTS, MATERIALS, AND METHODS: One hundred fifty ambulatory patients with lung adenocarcinoma were prospectively enrolled. Thrombin generation, procoagulant phospholipid-dependent clotting time (Procoag-PPL), tissue factor activity (TFa), factor VIIa (FVIIa), factor V (FV), antithrombin, D-Dimers, P-selectin, and heparanase levels were assessed in platelet-poor plasma at inclusion (baseline) and at the end of the third chemotherapy cycle (third chemotherapy). Cox regression analysis was used to identify independent VTE predictors. RESULTS: At baseline, patients had significantly attenuated thrombin generation, shorter Procoag-PPL, higher levels of TFa, D-Dimers, and heparanase, and lower levels of FVIIa and P-selectin, compared with controls. A significant increase in Procoag-PPL, FV, and FVIIa and a decrease of P-selectin levels were observed between baseline and third chemotherapy. Hospitalization within the last 3 months prior to assessment, time since cancer diagnosis less than 6 months, mean rate index (MRI) of thrombin generation, and Procoag-PPL were independently associated with symptomatic VTE. Accordingly, a prediction model including Procoag-PPL and MRI showed significant discriminating capacity (area under the curve: 0.84). CONCLUSION: Ambulatory patients with lung adenocarcinoma may display pronounced blood hypercoagulability due to decreased Procoag-PPL, increased endothelial cell activation, and increased degradation of fibrin. Incorporation of Procoag-PPL and MRI of thrombin generation may improve the accuracy of a VTE-RAM in the above setting. IMPLICATIONS FOR PRACTICE: The prospective ROADMAP-CAT study identified two biomarkers of hypercoagulability, the procoagulant phospholipid-dependent clotting time (Procoag-PPL) and the mean rate index (MRI) of the propagation phase of thrombin generation assessed with the Calibrated Automated Thrombinoscope, as being clinically relevant for the classification of ambulatory patients with lung adenocarcinoma receiving a maximum of one cycle of chemotherapy into high and intermediate/low risk for venous thromboembolism. Measurement of Procoag-PPL and MRI within 1 month after the administration of the first chemotherapy cycle provides significant accuracy of the assessment. Association of the Procoag-PPL and MRI with the clinical risk assessment model for cancer-associated thrombosis in ambulatory patients with solid tumors (COMPASS-CAT RAM) further improved its accuracy.

Filaggrin and Periostin Expression Is Altered in Eosinophilic Esophagitis and Normalized With Treatment.

OBJECTIVES: Previous data have suggested that filaggrin (FLG) and periostin (POSTN) genes may be dysregulated in eosinophilic esophagitis (EoE). We aimed to further evaluate the expression patterns of FLG and POSTN proteins in esophageal tissue samples of patients with EoE, as compared to those of patients with gastroesophageal reflux disease (GERD) and normal controls. METHODS: A total of 61 prospectively collected cases, including 40 children with EoE and 21 children with GERD, and a control group of 14 sex- and age-matched healthy children were enrolled. Patients with EoE were treated with skin testing-driven elimination diet and/or corticosteroids. The immunohistochemical expression of FLG and POSTN was evaluated in esophageal biopsies obtained from patients and controls, and the results were correlated with EoE-related clinicopathological parameters. RESULTS: Positive FLG and negative POSTN staining were observed in all esophageal biopsies from normal controls. In contrast, FLG and POSTN stained negative and positive, respectively, in all pretreatment biopsies obtained from patients with EoE, whereas FLG and POSTN stained positive in 57.1% and 95.2% of GERD cases, respectively (P < 0.001). A statistically significant decrease of the proportion of cases with negative FLG and positive POSTN staining was observed from the first (pretreatment) to the second (post-treatment) biopsy in the subgroup of patients with EoE (P < 0.001 in both correlations). CONCLUSIONS: FLG and POSTN expression may be downregulated and upregulated, respectively, in the esophageal mucosa of patients with active EoE, and these changes may be restored with treatment in a significant percentage of cases.

Molecular assays in detecting EGFR gene aberrations: an updated HER2-dependent algorithm for interpreting gene signals; a short technical report.

Purpose: Among oncogenes that have already been identified and cloned, Epidermal Growth Factor Receptor (EGFR) remains one of the most significant. Understanding its deregulation mechanisms improves critically patients' selection for personalized therapies based on modern molecular biology and oncology guidelines. Anti-EGFR targeted therapeutic strategies have been developed based on specific genetic profiles and applied in subgroups of patients suffering by solid cancers of different histogenetic origin. Detection of specific EGFR somatic mutations leads to tyrosine kinase inhibitors (TKIs) application in subsets of them. Concerning EGFR gene numerical imbalances, identification of pure gene amplification is critical for targeting the molecule via monoclonal antibodies (mAbs). In the current technical paper we demonstrate the main molecular methods applied in EGFR analyses focused also on new data in interpreting numerical imbalances based on ASCO/ACAP guidelines for HER2 in situ hybridization (ISH) clarifications.

The diverse roles of adiponectin in non-small-cell lung cancer: current data and future perspectives.

In recent years, there is growing research interest for the biological role of adipose tissue-derived bioactive factors, mainly including adipokines, in various forms of cancer. Adiponectin (APN) is the most abundant circulating adipokine, and a key mediator of several cancer-related processes, such as cell proliferation, apoptosis, regulation of tumor cell invasion and angiogenesis. In this review we summarize and critically discuss the published literature on the diverse roles of APN in non-small-cell lung cancer, including its implication in lung cancer development, its use as a diagnostic and prognostic biomarker, and its correlation with cancer-related cachexia. The main challenges and future perspectives, mainly with regard to the potential development of APN-targeted therapeutic agents in cancer therapeutics, are also briefly presented and discussed.

Chromosome 7 deregulation in non-small cell lung carcinoma molecular landscape.

Lung cancer exhibits an increasing incidence and a high mortality rate worldwide. Non-small cell lung carcinoma (NSCLC)constitutes the majority of patients with lung cancer (about 85% of all pathologically defined lung cancer cases). A broad spectrum of genomic imbalances, including chromosome polysomy/aneuploidy or specific gene deregulation mechanisms, such as point mutations, deletions and amplifications has been already identified in the corresponding patients, modifying their response rates to novel targeted therapeutic regimens, and affecting also their life span. Among all chromosomes, chromosome 7 seems to play a critical role in NSCLC development and progression. Aberrations in significant genes located on it, such as EGFR, cMET, BRAF combined with numerical abnormalities of the whole chromosome are cytogenetic events that lead to specific molecular signatures in patients with NSCLC. Detection of these chromosome/gene imbalances based on polymerase chain reaction (PCR) and in situ hybridization provides to oncologists the right genetic substrate for handling these patients in a rational therapeutic way regarding their isolated molecular profile. In the current paper, we present the structural and functional profile of chromosome 7 focused on its alterations in NSCLC.

Giant tuberculin reaction associated with the homeopathic drug tuberculinum: a case report.

Giant reactions to the tuberculin skin test are extremely rare and have been previously reported almost exclusively in patients with lepromatous leprosy. We herein report a giant tuberculin reaction associated with the homeopathic drug Tuberculinum in a patient with no evidence of active tuberculosis or leprosy.

Immunohistochemical expression of p53, p63, c-myc, p21(WAF1/cip1) and p27(kip1) proteins in urothelial bladder carcinoma: correlation with clinicopathological parameters.

PURPOSE: To reevaluate the expression levels of p53, p63, c-myc, p21(WAF1/cip1) and p27(kip1) proteins and their potential association with standard clinicopathological parameters, including tumor stage and grade, in urothelial bladder carcinoma (UBC). METHODS: Immunohistochemistry was performed in 100 transurethral resection specimens obtained from prospectively identified patients with primary UBC. RESULTS: Overall, 26, 41 and 75% of the cases showed positive staining for p53, p63 and c-myc, respectively, while p21(WAF1/cip1) and p27(kip1) expression levels were altered in 75 and 88% of the cases, respectively. Positive staining for p53 was associated with increased tumor stage (pT2) (p=0.037), while altered expression of p27(kip1) was strongly associated with male gender (p=0.009). CONCLUSION: The results of our study imply that p53 overexpression may be a useful marker of tumor invasion in UBC. In contrast, we failed to demonstrate any statistically significant correlation between the remaining markers evaluated and tumor stage or grade.

The Role of Decoy Receptor DcR3 in Gastrointestinal Malignancy.

Malignancies are among the leading causes of mortality worldwide. Early detection and treatment are the primary targets of clinical and translational research, and may be facilitated by the recognition of novel diagnostic and prognostic biomarkers. Decoy receptor 3 (DcR3) is a soluble receptor of the tumor necrosis factor receptor superfamily of proteins (TNFRSF), which associates with its respective TNF-like ligands, Fas-L, LIGHT, and TL1A. DcR3 has been recognised as a significant anti-apoptotic factor with prominent involvement in various inflammatory and neoplastic conditions. Increased intratumor expression of DcR3 and elevated soluble DcR3 protein content in the sera of patients has been reported for various malignancies. Recent published work has suggested that monitoring of local and systemic DcR3 may provide an attractive biomarker, mainly for defining subgroups of patients with aggressive tumor behaviour and poor prognosis. The aim of the present review is to summarize and critically present existing evidence regarding the potential clinical importance of monitoring DcR3 expression in patients with malignancies of the gastrointestinal tract, as well as liver and pancreatic cancer. We also present a detailed description of the pathophysiological basis that may underlie the involvement of DcR3 in gastrointestinal carcinogenesis. Based on these data, we comment on the potential applicability of DcR3 monitoring in the diagnosis and, most importantly, the prognostic stratification of patients.

Limited Cerebral Metastases in NSCLC: A Literature Review of SRS Versus Whole-brain Radiotherapy.

BACKGROUND/AIM: Brain metastases (BMs) are common in patients with non-small cell lung cancer (NSCLC). Whole-brain radiotherapy (WBRT) with or without corticosteroid use has historically been the first choice for most patients with BMs despite its negative impact on cognition and quality of life. However, stereotactic radiosurgery (SRS) has emerged as a safe and effective treatment and has been established for patients with limited, inoperable BMs. SRS and WBRT are either used separately or together, in an attempt to achieve the best possible local and distal control rates and even improve overall survival. A number of phase III trials have focused on answering the question which modality - SRS, WBRT or both - can achieve the best possible results. In this review, we present the existing data regarding the use of SRS compared with WBRT and their combination for NSCLC patients with limited, non-operable BMs. MATERIALS AND METHODS: A literature review was performed in PubMed, Medline, and the Cochrane Library databases from 1995 up to 2021. Principles outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement were followed. RESULTS: We identified seven randomised control trials (RCTs) that compared WBRT with WBRT plus SRS boost and four RCTs that compared SRS alone with SRS plus WBRT. CONCLUSION: Overall, addition of WBRT to SRS did not improve survival but had a positive effect on locoregional control.

Acute and Late Rectal Toxicity Following Hypofractionated Radiotherapy in Patients With Prostate Cancer: Results of a Prospective Study.

BACKGROUND/AIM: Previous randomized clinical trials have shown that moderate hypofractionation has a non-inferior or even superior efficacy to conventionally fractionated external beam radiation therapy (EBRT) in low and intermediate-risk prostate cancer. We herein aimed to evaluate the acute and late gastrointestinal (GI) toxicity of hypofractionated radiotherapy (HRT) in a real-world setting. PATIENTS AND METHODS: Patients with intermediate-risk prostate adenocarcinoma eligible to receive HRT were prospectively enrolled. All patients were submitted to rectoscopy after completion of HRT, every three months after radiotherapy for the first year and every six months for the second year. Toxicity events were classified as acute, when presenting during radiotherapy or within the first three months following its completion, and as late when appearing three months to three years post-HRT. RESULTS: Twenty prostate cancer patients participated in this study and received 22 sessions of HRT (5 sessions a week; 2.75 Gy per session) and an overall dose of 60.5 Gy. None of our patients developed acute GI toxicity; late GI toxicity (RTOG/EORTC grade 3 rectal bleeding) was observed in 1 patient only (1/20, 5%), at 6- and 12-months post-HRT. No rectal mucosa damage was observed on follow-up rectoscopy in the acute phase in any of our patients; five patients (5/20, 25%) developed late telangiectasias. Vienna retroscopy score (VRS) was 1 in 4/5 patients (80%) and 2 in 1/5 (20%). CONCLUSION: Minimal radiation-induced rectal mucosal damage was observed in our patient population, and only as a late event, further attesting to the safety of HRT in this setting.

Significant Increase in Blood Pressure Following BNT162b2 mRNA COVID-19 Vaccination among Healthcare Workers: A Rare Event.

This brief report examined the frequency and characteristics of a significant blood-pressure (BP) increase after Pfizer-BioNTech BNT162b2 vaccination among healthcare workers who were advised to measure their BP at home. A total of 797 participants (mean age 48.1 ± 10.8 years, 63% women, 39% smokers) were included in the analysis. Seven participants reported an increase in their BP (three in the range of grade 2 and four in the range of grade 3 hypertension). Only one participant had a history of treated hypertension. The BP increase was observed at the end of the first week after the first dose, lasted for 3 to 4 days, and recurred promptly after the second dose. Only one case required hospitalization, mainly due to a history of cardiovascular disease (follow-up). Individuals experiencing a BP increase compared with those not reporting issues with their BP had a higher mean age and similar distribution of sex and non-smoking status. In conclusion, a significant BP increase after Pfizer-BioNTech vaccination seems to be rare and of a benign and transient nature. Monitoring the BP before and after vaccination might be advisable only for selected individuals with a high cardiovascular risk.

Efficacy of a Quail Eggs-Based Dietary Supplement for Allergic Rhinitis: Results of a Single-Arm Trial.

Previous data suggested the potential treatment effect of a proprietary quail eggs-based blend on allergic rhinitis (AR) symptoms, induced by allergen challenge. We herein aimed to investigate the efficacy and safety of a similar dietary supplement, comprising the bioactive ingredients of quail eggs and the zinc mineral, in the setting of active AR. Adult patients (n = 77), aged 18- 60 years, with mild, intermittent AR were enrolled in this single-arm, open-label trial. Patients' responses were assessed based on peak nasal inspiratory flow (PNIF) measurements at two visits (Day 1/Visit 1 and Day 7/Visit 2) and self-rating of AR-associated symptoms on a Visual Analog Scale (VAS) throughout the entire 7-day study period. PNIF values at 15, 30, 60, 90 and 120 min (Visit 1) following administration of an oral dose of the study product were the primary efficacy endpoint. PNIF values (Visit 1) gradually increased from baseline (pre-treatment), with statistical significance first reached 30 min later (p = 0.002). VAS scores (Visit 1) for all AR symptoms gradually decreased with statistical significance first reached at 15 min (rhinorrhea, p = 0.042; itchy nose, p = 0.001; sneezing p < 0.001), 30 min (nasal congestion, p < 0.001; itchy eyes, p = 0.003) or 60 min (watery eyes, p = 0.04). PNIF improvement and decline of VAS scores were significantly more apparent at Visit one vs. Visit 2. Treatment-emergent adverse events were limited to cough and muscle strain (one patient each). Our results support the efficacy, rapid mode of action and tolerability of the investigated product for symptomatic treatment of mild intermittent AR.

Ascitic fluid cytology of yolk sac tumor of the ovary: a case report.

BACKGROUND: Yolk sac tumor (YST) of the ovary is a rare neoplasm typically affecting children and young women. We describe the cytomorphology of this tumor in ascitic fluid and discuss its differential diagnosis from other neoplasms. CASE: Smear preparations of the ascitic fluid showed a predominance of clusters of malignant cells with vacuolated cytoplasm, mimicking a mucinous adenocarcinoma, and fewer syncytial-like and glandular structures. Hyaline globules were extremely rare. Immunocytochemistry was positive for alpha-fetoprotein. CONCLUSION: The diagnosis of YST in ascitic fluid specimens may be challenging and requires the use of immunocytochemistry and the correlation of cytology with the remaining clinical and laboratory data.

Bone marrow micrometastases in different solid tumors: pathogenesis and importance.

Early dissemination of cancer cells from the primary tumor via the circulatory system may result in the formation of microscopic metastatic deposits (micrometastases, MMs) in secondary compartments such as the bone marrow (BM), where there is a favorable environment for their subsequent growth and spread. MMs are considered the main reason for metastatic relapse in patients with early stage solid cancers after resection of the primary tumor. Although the molecular pathways leading to MMs remain only partly understood, there is increasing evidence that the detection of MMs in BM aspirates at the time of primary diagnosis is an independent prognostic factor, with a major influence in the stratification of these patients for adjuvant clinical treatment. Further potential applications of the detection of MMs include their use in monitoring therapeutic response or even in revealing targets for novel systemic therapies. All these intriguing possibilities are intensely investigated and carry great promise for radical improvements in the assessment and treatment of several epithelial cancers which are currently to blame for the majority of cancer-related deaths in the industrialized world.

The prognostic significance of COX-2 and survivin expression in ovarian cancer.

We investigated the prognostic significance of cyclooxygenase-2 (COX-2) and survivin in ovarian carcinoma. Imprint smears were obtained from 100 ovarian carcinoma specimens and were studied immunocytochemically for the expression of COX-2 and survivin. The results were correlated with several clinicopathological parameters, including 5-year survival. Increased COX-2 staining pattern correlated with a non-mucinous histological type (p=0.008), increased stage (p<0.0001), high histological grade (p<0.0001), and reduced survival rates (p<0.00001). Survivin expression was strongly associated with increased stage (p<0.0001), increased histological grade (p<0.0001), and reduced survival (p<0.00001). Elevated survivin expression also correlated significantly with pre-menopausal status (p=0.033). In addition, COX-2 and survivin staining patterns correlated strongly with one another (p<0.0001). However, on multivariate analysis, an independent prognostic value was found only for tumor stage and grade. The findings of our study indicate that the increased expression of COX-2 and survivin in ovarian cancer is associated with one another and with several adverse clinicopathologic parameters, including reduced survival, thus suggesting a role of these molecules in disease progression. Further investigations of the exact prognostic and therapeutic implications of COX-2 and survivin expression are strongly warranted.

Value of endoscopic retrograde cholangiopancreatography-guided brushings in preoperative assessment of pancreaticobiliary strictures: what's new?

Brush cytology plays a prominent role in confirming the presence of extrahepatic biliary tract malignancy. However, its value is limited by its relatively low and widely variable sensitivity values. Various factors seem to influence the accuracy of cytologic diagnosis and are attributed to sampling, technical and interpretation errors. Ancillary methods, such as immunocytochemistry, flow cytometry, image analysis, fluorescence in situ hybridization (FISH) and the newly discovered method of global analysis of gene expression are helpful in resolving cases with inconclusive cytology and are vigorously investigated for their value in assessing the expression of novel tumor markers for the diagnosis and prognosis of pancreatic and bile duct carcinomas. However, their routine use in clinical practice remains in doubt. To increase the sensitivity of brush cytology and strengthen its role in the preoperative assessment of patients with pancreaticobiliary malignancies, the following are of the utmost importance: improvement of current sampling and cytopreparation techniques, introduction of a uniform system for reporting epithelial abnormalities based on strict and clearly distinct morphologic criteria for each pathologic entity and incorporation of experience and knowledge derived from standard cytologic methods and novel diagnostic technologies in clinical practice without compromising the high specificity associated with brush cytology.

Circulating tumor cells count as a predictor of survival in lung cancer.

The presence of circulating tumor cells (CTCs) in the peripheral blood of cancer patients was first described in the second half of the 19th century, but research interest in their potential clinical utility has intensified and greatly expanded only in recent years. Herein, we summarize and critically discuss current knowledge on CTC count as a predictor of survival in lung cancer, and comment on the existing challenges and future perspectives in this field. The majority of data published to date, including the results of almost all large cohorts, are strongly supportive of the value of CTC enumeration as a predictor of survival, mainly in advanced/metastatic non-small and small cell lung cancer (NSCLC and SCLC, respectively). Nonetheless, additional research is warranted to establish the prognostic relevance of CTC count in other clinical settings, mainly encompassing earlier-stage disease as well as specific molecular subtypes of NSCLC (e.g. EGFR mutation-positive or ALK-positive cases).