Exploring the Relationship between E-Cadherin and ß-Catenin Cell Adhesion Proteins and Periacinar Retraction Clefting in Prostatic Adenocarcinoma.

BACKGROUND: Periacinar retraction clefts represent a histopathological criterion supporting the diagnosis of prostatic adenocarcinoma. The origin of these clefts in prostatic adenocarcinoma remains unclear. Exploring the established functions of E-cadherin and ß-catenin as intercellular adhesion proteins, and aiming to elucidate the origin of periacinar retraction clefting, we conducted a correlation study between the immunohistochemical expression of E-cadherin and ß-catenin and the presence of periacinar retraction clefts in prostatic adenocarcinoma. METHODS: We examined 53 cases of morphologically diagnosed prostatic adenocarcinoma, assessing both the neoplastic and adjacent nonneoplastic prostatic tissues for the existence and degree of periacinar retraction clefts. Additionally, we analyzed the immunohistochemical expression of E-cadherin and ß-catenin proteins in prostatic tissue and explored their correlation with periacinar retraction clefts, and Gleason score, Grade Group, preoperative serum prostate specific-antigen (sPSA) levels, surgical margin status, and Tumor, Node, Metastasis (TNM) stage in prostatic adenocarcinoma. RESULTS: Our study confirms that periacinar retraction clefting is significantly more extensive in prostatic adenocarcinoma than in nonneoplastic prostatic tissue (p < 0.001). We report a decreased expression of E-cadherin and ß-catenin immunostaining in prostatic adenocarcinoma and a negative correlation with Gleason score and Grade Group. Periacinar retraction clefting positively correlated with E-cadherin and ß-catenin ((rho = 0.350; p = 0.010) and (rho = 0.340; p = 0.012)) immunostaining in prostatic adenocarcinoma. CONCLUSIONS: Periacinar retraction clefts stand out as a dependable criterion in the diagnosis of prostatic adenocarcinoma. E-cadherin and ß-catenin proteins are potential markers indicative of tumor progression and invasiveness in prostatic adenocarcinoma. Our discovery of a positive correlation between immunostaining of E-cadherin and ß-catenin proteins and periacinar retraction clefts in prostatic adenocarcinoma aligns with the notion that periacinar retraction clefting is more characteristic of Gleason Grade3 pattern in prostatic adenocarcinomas, whereas the immunohistochemical expression of E-cadherin and ß-catenin shows a decrease with increasing histopathological tumor grade.

Primary undifferentiated carcinoma of rete testis with extensive peritoneal carcinomatosis and fatal outcome: Case report.

Carcinoma of rete testis is an extremely rare malignant tumor arising from its epithelium. Prognosis is poor with mean survival of 8 months. Lymph node metastases and the size of the tumor larger than 5 cm are poor prognostic factors. We report a case of primary undifferentiated carcinoma of the rete testis in a 46-year-old man who presented with testicular enlargement without previous trauma or cryptorchidism, and with extensive peritoneal carcinomatosis, retroperitoneal lymph node metastases and fatal outcome. We present this case because of the rarity of the carcinoma of the rete testis and its challenging diagnosis.

Melanoma Developing from an Intradermal Nevus: Report on Two Patients.

Dear Editor, Approximately 25-33% of cutaneous melanomas arise from nevi (1). Shitara et al. suggested that junctional and compound nevi are more likely give rise to melanoma than intradermal nevi, but this has not been definitively confirmed (2). Based on these results and our own clinical observation on rare malignant transformation in intradermal nevi, we present two patients with melanoma developing from an intradermal nevus. The first patient, a 63-year-old woman, presented with a suspicious lesion in 2017 on the upper back in the form of a dark brown macula juxtapositioned next to the dermal nevus (Figure 1, a). Dermoscopy of a flat part showed a dark-brown reticular, slightly structureless pattern (Figure 1, b). The patient was therefore referred to surgical excision. Histopathology of the elevated part showed aggregates of intradermal nevus cells of normal morphological characteristics. Atypical and irregularly sized melanocytes were observed in the flat part, infiltrating the entire depth of the epidermis and the upper parts of the papillary dermis. The diagnosis of malignant melanoma developing from a dermal nevus was established (Breslow 0.4 mm, pT1A) (Figure 1, c). The second patient, a 71-year-old man, presented in 2018 with a pendular non pigmented intradermal nevus on middle part of the back. The left-hand lateral side of the intradermal nevus showed a brown to dark-brown spot which measured 12 mm (Figure 2, a). A central blue white veil, atypical pigment network, and dots and globules of various sizes and shapes were observed on dermoscopy (Figure 2, b). The base of the nevus showed an asymmetric pigmentation. Because the lesion was highly suspicious of melanoma, an urgent excision was indicated. The histopathology of the elevated part (dermal nevus) showed a regular maturation of the nest of nevus cells in the dermis. The histopathology of the dark-brown macule showed proliferation of atypical melanocytes with well-marked nucleoli throughout the epidermis with the infiltration of the suprabasal epidermal layers and papillary dermis. The lesion was classified as melanoma with a partial regression (Breslow 1.3 mm, pT2A), arising in association with an acquired intradermal nevus (Figure 2, c). Case reports with melanoma developed from a small congenital or acquired dermal nevus are extremely rare in the literature. In all published cases, histopathology revealed a melanoma component situated below or laterally, next to the merging dermal nevus (3) and in one case next to and above the dermal component (4), which is very similar to our cases. In both of our cases, melanoma presented an epidermal component with atypical, large melanocytes next to or above the typical and small intradermal melanocytes of the Unna nevus. Despite the fact that the reported statistical occurrence of malignant transformation of every individual nevus is very low in the elderly population (>60 years of age), 1 in 33,000 (5), we believe our two presented cases show a striking similarity in the melanoma manifesting in the vicinity of a previously existing lesion, indicating nevus-associated melanoma (NAM). This letter presents an interesting finding of two cases, with a form of melanoma (NAM) that is statistically very rare in older patients but occurred twice within the span of a year within the same town and was diagnosed in the same hospital. Intradermal nevi are most commonly considered to be benign skin lesions. However, previous research and our two cases shows that intradermal nevi are not immune to malignant alteration. Based on these results, we suggest a detailed clinical and dermoscopic evaluation of each skin lesion, including intradermal nevi. Flat melanocytic parts in the vicinity of intradermal nevi should always raise suspicion and warrant excision with histopathological evaluation of the lesion so as to allow timely response to any malignant alteration.

Cystic dysplasia of the rete testis accompanying ipsilateral renal agenesis in a young adult: a case report.

A 31-year-old man with left-sided testicular pain lasting a couple of months was referred to our urology department due to a suspected testicular tumor. Physical examination showed a hard, thickened, and small left testis on palpation with a diffuse, inhomogeneous ultrasonographic appearance. After a urologic examination, a left-sided inguinal orchiectomy was performed. The testis, epididymis, and spermatic cord were sent to pathology. Gross examination revealed a cystic cavity filled with brown fluid and the surrounding brownish parenchyma measuring up to 3.5 cm in diameter. Histologic examination showed a cystically dilated rete testis lined with cuboidal epithelium and a positive immunohistochemical reaction to cytokeratins. Microscopically, the cystic cavity was a pseudocyst filled with extravasated erythrocytes and abundant clusters of siderophages. The siderophages extended into the testicular parenchyma, surrounding the seminiferous tubules and spreading out around the ducts of the epididymis, which were also cystically dilated with siderophages inside their lumina. On the basis of clinical data, histological, and immunohistochemical analysis, the patient was diagnosed with cystic dysplasia of the rete testis. The literature shows an association between cystic dysplasia of the rete testis and ipsilateral genitourinary anomalies. Therefore, our patient underwent a multi-slice computed tomography scan, which revealed ipsilateral renal agenesis, a right seminal vesicle cyst reaching up to the iliac arteries, and a multicystic formation cranial to the prostate.

Dose imbalance of DYRK1A kinase causes systemic progeroid status in Down syndrome by increasing the un-repaired DNA damage and reducing LaminB1 levels.

BACKGROUND: People with Down syndrome (DS) show clinical signs of accelerated ageing. Causative mechanisms remain unknown and hypotheses range from the (essentially untreatable) amplified-chromosomal-instability explanation, to potential actions of individual supernumerary chromosome-21 genes. The latter explanation could open a route to therapeutic amelioration if the specific over-acting genes could be identified and their action toned-down. METHODS: Biological age was estimated through patterns of sugar molecules attached to plasma immunoglobulin-G (IgG-glycans, an established "biological-ageing-clock") in n = 246 individuals with DS from three European populations, clinically characterised for the presence of co-morbidities, and compared to n = 256 age-, sex- and demography-matched healthy controls. Isogenic human induced pluripotent stem cell (hiPSCs) models of full and partial trisomy-21 with CRISPR-Cas9 gene editing and two kinase inhibitors were studied prior and after differentiation to cerebral organoids. FINDINGS: Biological age in adults with DS is (on average) 18.4-19.1 years older than in chronological-age-matched controls independent of co-morbidities, and this shift remains constant throughout lifespan. Changes are detectable from early childhood, and do not require a supernumerary chromosome, but are seen in segmental duplication of only 31 genes, along with increased DNA damage and decreased levels of LaminB1 in nucleated blood cells. We demonstrate that these cell-autonomous phenotypes can be gene-dose-modelled and pharmacologically corrected in hiPSCs and derived cerebral organoids. Using isogenic hiPSC models we show that chromosome-21 gene DYRK1A overdose is sufficient and necessary to cause excess unrepaired DNA damage. INTERPRETATION: Explanation of hitherto observed accelerated ageing in DS as a developmental progeroid syndrome driven by DYRK1A overdose provides a target for early pharmacological preventative intervention strategies. FUNDING: Main funding came from the "Research Cooperability" Program of the Croatian Science Foundation funded by the European Union from the European Social Fund under the Operational Programme Efficient Human Resources 2014-2020, Project PZS-2019-02-4277, and the Wellcome Trust Grants 098330/Z/12/Z and 217199/Z/19/Z (UK). All other funding is described in details in the "Acknowledgements".

Molecular classification of muscle-invasive bladder cancer based on a simplified immunohistochemical panel using GATA3, CK5/6 and p16.

The choice of therapy for muscle-invasive bladder cancer (MIBC) could be influenced by the tumor's molecular subtype. Currently, well-defined consensus subtypes are based on tumor microarray mRNA data. Clearly defined and easy-to-use surrogate molecular subtypes, based on immunohistochemistry (IHC) performed on whole slides, are needed to make subtyping cost-effective and useful in routine work and future research. To aid in the development of a simple immunohistochemical classifier, a retrospective single-center series of 92 cases of localized bladder cancer was identified. Routine IHC for GATA3, cytokeratins 5 and 6 (CK5/6), and p16 was performed on whole tissue blocks containing muscle-invasive disease. Electronic medical records were retrieved and searched for clinical variables, treatment, and survival data. The mean age was 69.6 years, and 73% were males. Conservative treatment was used in 55% of cases, while cystectomy with chemotherapy was used in 45%. GATA3 and CK5/6 expression divided cases into broad luminal and basal subtypes, respectively, while p16 expression was used to subclassify luminal cases into luminal papillary and luminal unstable types according to the consensus molecular classification. When subtyped in this way, GATA3 and CK5/6 negative cases showed worse overall survival. Molecular subtyping of MIBC on whole slides containing muscle-invasive tumor using only three commonly used, consensus-based antibodies, is a feasible and cost-effective method for detecting subtypes of invasive bladder cancer. Future work combining morphological analysis and IHC is needed to fully translate the consensus molecular classification into a comprehensive, cost-effective subtyping strategy.

Circulating Tumor Cells in Colorectal Cancer: Detection Systems and Clinical Utility.

Colorectal cancer (CRC) is the third most common cancer worldwide. The high mortality from CRC is mainly related to metastasis affecting distant organs and their function. Dissemination of tumor cells from the primary tumor and hematogeneous spread are considered crucial in the formation of tumor metastases. The analysis of circulating tumor cells (CTCs) and CTC clusters in the blood can be used for the early detection of invasive cancer. Moreover, CTCs have a prognostic significance in the monitoring of a malignant disease or the response to chemotherapy. This work presents an overview of the research conducted on CTCs with the aim of finding suitable detection systems and assessing the possibility of clinical applications in patients with CRC.

REVIEW OF THE BLADDER CANCER MOLECULAR CLASSIFICATION PROPOSED: A NEW ERA - NEW TAXONOMY.

The management of bladder cancer patients largely depends on pathologic staging and grading, and current morphological classification does not always show the individual patient's risk. Despite modern surgical techniques, pre- and postoperative therapies, clinical outcomes of these patients have not changed over decades. Today, there are new biomarkers for bladder cancer showing changes in tumor biology and progression, as a result of changes in the pathways affecting cell signaling, proliferation, apoptosis, epigenetic changes, angiogenesis, and modulation of host immune response. Assessment of multiple biomarkers associated with those pathways offers new understanding of tumor behavior while identifying important panels of predicting patient management and outcomes. In this review, the most important molecules and basics of the novel molecular classification of bladder cancer are presented.

CORRELATION OF EXPRESSION OF TGF- ß AND MMP2 BETWEEN PROSTATIC ADENOCARCINOMA AND ADJACENT UNAFFECTED PARENCHYMA.

In prostate adenocarcinoma, both tumorous stroma and epithelium have important role in tumor progression. Transforming growth factor beta (TGF- ß) is a promotor in advanced stages of prostate cancer. Matrix Metalloproteinase 2 (MMP2), the endopeptidase that degrades extracellular matrix is considered to be overexpressed in prostatic carcinoma related to its growth and aggressiveness. Therefore, the aim was to analyze the expression of proteins TGF- ß and MMP2 between both epithelium and stroma of prostatic adenocarcinoma and adjacent unaffected parenchyma. The intensity of TGF- ß and MMP2 expression in epithelium, tumorous stroma and adjacent unaffected parenchyma was analyzed in 62 specimens of prostatic adenocarcinoma by microarray-based immunohistochemistry. TGF- ß was more expressed in tumorous than in prostate stroma (p =0.000), while no statistical significance in case of MMP2 (p = 0.097) was found. MMP2 was more expressed in tumorous than in prostate epithelium (p =0.000), while no statistical significance in case of TGF- ß (p = 0.096) was observed. The study results indicate that both tumorous stroma and epithelium have a role in tumor progression and support potential role of TGF- ß and MMP2 in prostatic adenocarcinoma progression.

COMPARISON OF GRADING ACCURACY OF PROSTATE CANCER IN SAMPLES ACQUIRED BY A TARGETED AND SYSTEMIC PROSTATE BIOPSY.

Introduction: All malignancies, including prostate cancer, require accurate diagnosing and staging before making a treatment decision. The introduction of targeted biopsies based on prostate MRI findings has raised prostate biopsy accuracy. Guided biopsies target the tumor itself during the biopsy instead of the most common tumor sites as is the case with a systemic biopsy. Some studies report that targeted biopsies should lower prostate cancer biopsy undergrading and overgrading. Goals: To determine the incidence of prostate cancer biopsy undergrading in patients who underwent a classic systemic biopsy compared to patients who underwent a mpMRI cognitive targeted biopsy. Materials and methods: We identified the patients from our database who underwent a radical prostatectomy at our institution from January 1st, 2021, to June 30th, 2021.There were 112 patients identified. Patients were stratified into two groups based on the type of biopsy that confirmed prostate cancer. The mpMRI (N=50) group had a mpMRI cognitive guided transrectal ultrasound (TRUS) prostate biopsy performed, and the non-mpMRI group (N=62) received a classic, systemic TRUS biopsy. We compared the biopsy results with the final pathological results, and searched for undergrading or overgrading in the biopsies compared to the final histological report. Results: The undergrading was found in 17,7% (N=11) cases in the non-mpMRI group and in 12,0% (N=6) of cases in the mpMRI group (p=0,02, Mann-Whitney U test). No overgrading was found in our cohort. All cases of undergrading had Grade Group 1 in the biopsy report and Grade Group 2 in the final specimen report. The charasteristics of patients are listed in Table 1. Discussion and conclusion: In our cohort, the patients who underwent a mpMRI targeted biopsy had a lower undergrading incidence. During a systemic TRUS biopsy, the urologist targets the areas of the prostate where cancer is most commonly located, which is usually the peripheral zone of the prostate. Since different areas of the tumor have different areas of differentiation, only a low-grade part of the tumor is sometimes biopsied, which results in a sampling error. Once the prostate is removed, the whole tumor is analyzed, so the obtained pathological results related to the removed prostate are far more accurate than the analysis of prostate cores obtained by biopsy.

Atypical Mixed Tumor of the Skin in the Gluteal Region with Strong and Diffuse Nuclear Expression of the p16 Stain: A Case Report.

Benign, atypical, or malignant chondroid syringoma (mixed tumor of the skin) have almost identical clinical presentation with similar histological features, except for infiltrative growth, and perineural and vascular invasion in the malignant type. Tumors with borderline features are described as atypical chondroid syringoma. Immunohistochemical profiles in all three types are similar, with the the main difference in the expression of the p16 stain. We present a case of an atypical chondroid syringoma in an 88-year-old female patient with a subcutaneous, painless nodule in the gluteal region and with diffuse, strong nuclear immunohistochemical staining for p16. To our knowledge, this is the first such reported case.

Prostate Cancer-Focus on Cholesterol.

Prostate cancer (PC) is the most common malignancy in men. Common characteristic involved in PC pathogenesis are disturbed lipid metabolism and abnormal cholesterol accumulation. Cholesterol can be further utilized for membrane or hormone synthesis while cholesterol biosynthesis intermediates are important for oncogene membrane anchoring, nucleotide synthesis and mitochondrial electron transport. Since cholesterol and its biosynthesis intermediates influence numerous cellular processes, in this review we have described cholesterol homeostasis in a normal cell. Additionally, we have illustrated how commonly deregulated signaling pathways in PC (PI3K/AKT/MTOR, MAPK, AR and p53) are linked with cholesterol homeostasis regulation.

Multiple Primary Angiosarcomas of the Colon.

INTRODUCTION: Gastrointestinal angiosarcomas are rare and represent less than 1% of all gastrointestinal tract malignancies, with most occurring in the stomach and small intestine. Occurrence in the colorectal segments is considered extremely rare. Case Report. We describe the case of a 61-year-old male with multiple primary angiosarcomas of the colon who presented with fever and abdominal pain. The patient was initially hospitalized and treated as having an infectious disease. A multislice computed tomography (MSCT) scan revealed multiple soft tissue tumors in the region of the left iliopsoas and gluteus medius muscles. After developing hematochezia, a colonoscopy was performed which found an ulcerated tumor in the sigmoid colon. The small tissue biopsy taken during the procedure presented diagnostic difficulties and was given a preliminary diagnosis of gastrointestinal stromal tumor (GIST). Examination of the resected colon segment and surrounding fat tissue revealed four separate tumors. Microscopically, the tumors were composed of solid sheets of spindle and epithelioid neoplastic cells with prominent nucleoli and numerous mitotic figures and immunohistochemically positive for ERG, CD31, CD34, vimentin, and CD117, while negative for CK7, CK20, CD20, CD3, CD45, TTF-1, PAN-CK, ALK, Mpox, S-100, and DOG1, leading to the final diagnosis of multiple colonic angiosarcomas. The patient's condition declined rapidly and he passed away from multiple organ failures 60 days after initial hospitalization. CONCLUSION: Both clinical and pathological diagnoses of colorectal angiosarcoma are challenging. Patients are present with nonspecific symptoms leading to mismanagement and late diagnosis. A definitive pathological diagnosis relies on immunohistochemical staining for endothelial markers. Misdiagnosis as poorly differentiated adenocarcinoma or GIST is possible in limited tissue biopsies.

Genetics of Prostate Carcinoma.

The aim of this review is to provide a brief overview of some current approaches regarding diagnostics, pathologic features, treatment, and genetics of prostate carcinoma (PCa). Prostate carcinoma is the most common visceral tumor and the second most common cancer-related cause of death in males. Clinical outcomes for patients with localized prostate cancer are excellent, but despite advances in prostate cancer treatments, castrate-resistant prostate cancer and metastatic prostate cancer patients have a poor prognosis. Advanced large-scale genomic studies revealed a large number of genetic alterations in prostate cancer. The meaning of these alterations needs to be validated in the specific prostate cancer molecular subtype context. Along these lines, there is a critical need for establishing genetically engineered mouse models, which would include speckle type BTB/POZ protein and isocitrate Dehydrogenase (NADP (+)) 1 mutant, as well as androgen receptor neuroendocrine subtypes of prostate cancer. Another urgent need is developing highly metastatic prostate cancer models, as only up to 17% of available models display bone metastases and exhibit a less typical neuroendocrine prostate cancer or sarcomatoid carcinoma. Moreover, androgen deprivation and relapse should be mimicked in the genetically engineered mouse models, as androgen independence may yield a better model for metastatic castrate-resistant prostate cancer. The development of such refined animal models should be guided by comparative genomics of primary versus corresponding metastatic tumors. Such an approach will have the potential to illuminate the key genetic events associated with specific molecular prostate cancer subsets and indicate directions for effective therapy. CONCLUSION: Despite excellent results in the treatment of localized prostatic carcinoma, castrate-resistant prostate cancer and metastatic prostate cancer have a poor prognosis. Advanced large-scale genomic studies revealed a large number of genetic alterations in PCa. Experimental models of prostate carcinoma in genetically modified mice could provide new data about the genetic changes in such cancers and help in developing better animal models for treatment resistant prostate carcinomas.

New Insights into the Diagnosis, Molecular Taxonomy, and Treatment of Bladder Cancer.

This review aims to emphasize new insights into the diagnosis, classification, and therapy of bladder cancer (BC). Bladder cancer is a heterogeneous, complex disease on a morphological, molecular, diagnostic, and prognostic level. Cancer stage is still the most important attribute for prognosis and treatment, while early detection with optimal and rapid individual therapeutic and surveillance approach is crucial. The vast majority of patients have a superficial, non-muscle-invasive tumor associated with a good prognosis after resection and adjuvant intravesical maintenance immuno or chemotherapy if needed. On the other hand, muscle-invasive bladder cancer is a highly aggressive disease with high morbidity and mortality. However, it has become a model for oncology success over the last five years with many available targeted therapeutic modalities. Metastatic BC is now amenable to multimodal treatment combining cystectomy and neoadjuvant chemotherapy and immunotherapy and is a target for precision medicine. CONCLUSION: A new molecular taxonomy for bladder cancer has been proposed and provided insight into BC's carcinogenesis, with some possible effects on therapy decisions. However, this classification is still not applicable in routine clinical practice. It opens new questions regarding the interplay between tumor genetic signature, intratumoral heterogeneity, therapy implications, and tumor progression.

Neglected tuberculous trochanteric bursitis in an adolescent girl: A case report and literature review.

Tuberculous trochanteric bursitis (TTB) is an extremely rare form of extrapulmonary tuberculosis. Due to a low clinical suspicion and poor collaboration among medical professionals, the diagnosis of TTB can be often delayed. In this report, we describe a case of neglected TTB in an adolescent girl that initially presented with right thigh swelling and fluctuance. The patient underwent repeated unsuccessful surgical treatment; however, dull pain and periodic wound drainage remained for eight years. Complete excision of fistula and trochanteric bursa and one year of oral antituberculous drug therapy led to complete recovery. This case report highlights tuberculosis as a diagnostic challenge, when rare localizations are affected. In addition, this report addresses several diagnostic pitfalls and reviews the literature regarding TTB in adolescent patients. Orthopedic surgeons need to consider TTB, when swelling, fluctuance or repeated wound drainage are present on the thigh.

Comparison of hypofractionation and standard fractionation for post-prostatectomy salvage radiotherapy in patients with persistent PSA: single institution experience.

BACKGROUND: Hypofractionated post-prostatectomy radiotherapy is emerging practice, however with no randomized evidence so far to support it's use. Additionally, patients with persistent PSA after prostatectomy may have aggressive disease and respond less well on standard salvage treatment. Herein we report outcomes for conventionally fractionated (CFR) and hypofractionated radiotherapy (HFR) in patients with persistent postprostatectomy PSA who received salvage radiotherapy to prostate bed. METHODS: Single institution retrospective chart review was performed after Institutional Review Board approval. Between May 2012 and December 2016, 147 patients received salvage postprostatectomy radiotherapy. PSA failure-free and metastasis-free survival were calculated using Kaplan-Meier method. Cox regression analysis was performed to test association of fractionation regimen and other clinical factors with treatment outcomes. Early and late toxicity was assessed using Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. RESULTS: Sixty-nine patients who had persistent PSA (≥ 0.1 ng/mL) after prostatectomy were identified. Median follow-up was 67 months (95% CI 58-106 months, range, 8-106 months). Thirty-six patients (52.2%) received CFR, 66 Gy in 33 fractions, 2 Gy per fraction, and 33 patients (47.8%) received HFR, 52.5 Gy in 20 fractions, 2.63 Gy per fraction. Forty-seven (68%) patients received androgen deprivation therapy (ADT). 5-year PSA failure- and metastasis-free survival rate was 56.9% and 76.9%, respectively. Thirty patients (43%) experienced biochemical failure after salvage radiotherapy and 16 patients (23%) experienced metastatic relapse. Nine patients (13%) developed metastatic castration-resistant disease and died of advanced prostate cancer. Median PSA failure-free survival was 72 months (95% CI; 41-72 months), while median metastasis-free survival was not reached. Patients in HFR group were more likely to experience shorter PSA failure-free survival when compared to CFR group (HR 2.2; 95% CI 1.0-4.6, p = 0.04). On univariate analysis, factors significantly associated with PSA failure-free survival were radiotherapy schedule (CFR vs HFR, HR 2.2, 95% CI 1.0-4.6, p = 0.04), first postoperative PSA (HR 1.02, 95% CI 1.0-1.04, p = 0.03), and concomitant ADT (HR 3.3, 95% CI 1.2-8.6, p = 0.02). On multivariate analysis, factors significantly associated with PSA failure-free survival were radiotherapy schedule (HR 3.04, 95% CI 1.37-6.74, p = 0.006) and concomitant ADT (HR 4.41, 95% CI 1.6-12.12, p = 0.004). On univariate analysis, factors significantly associated with metastasis-free survival were the first postoperative PSA (HR 1.07, 95% CI 1.03-1.12, p = 0.002), seminal vesicle involvement (HR 3.48, 95% CI 1.26-9.6,p = 0.02), extracapsular extension (HR 7.02, 95% CI 1.96-25.07, p = 0.003), and surgical margin status (HR 2.86, 95% CI 1.03-7.97, p = 0.04). The first postoperative PSA (HR 1.04, 95% CI 1.00-1.08, p = 0.02) and extracapsular extension (HR 4.24, 95% CI 1.08-16.55, p = 0.04) remained significantly associated with metastasis-free survival on multivariate analysis. Three patients in CFR arm (8%) experienced late genitourinary grade 3 toxicity. CONCLUSIONS: In our experience, commonly used hypofractionated radiotherapy regimen was associated with lower biochemical control compared to standard fractionation in patients with persistent PSA receiving salvage radiotherapy. Reason for this might be lower biological dose in HFR compared to CFR group. However, this observation is limited due to baseline imbalances in ADT use, ADT duration and Grade Group distribution between two radiotherapy cohorts. In patients with persistent PSA post-prostatectomy, the first postoperative PSA is an independent risk factor for treatment failure. Additional studies are needed to corroborate our observations.

MiR-182-5p and miR-375-3p Have Higher Performance Than PSA in Discriminating Prostate Cancer from Benign Prostate Hyperplasia.

Prostate cancer (PCa) is the most commonly diagnosed neoplasm among men. Since it often resembles benign prostate hyperplasia (BPH), biomarkers with a higher differential value than PSA are required. Epigenetic biomarkers in liquid biopsies, especially miRNA, could address this challenge. The absolute expression of miR-375-3p, miR-182-5p, miR-21-5p, and miR-148a-3p were quantified in blood plasma and seminal plasma of 65 PCa and 58 BPH patients by digital droplet PCR. The sensitivity and specificity of these microRNAs were determined using ROC curve analysis. The higher expression of miR-182-5p and miR-375-3p in the blood plasma of PCa patients was statistically significant as compared to BPH (p = 0.0363 and 0.0226, respectively). Their combination achieved a specificity of 90.2% for predicting positive or negative biopsy results, while PSA cut-off of 4 µg/L performed with only 1.7% specificity. In seminal plasma, miR-375-3p, miR-182-5p, and miR-21-5p showed a statistically significantly higher expression in PCa patients with PSA >10 µg/L compared to ones with PSA ≤10 µg/L. MiR-182-5p and miR-375-3p in blood plasma show higher performance than PSA in discriminating PCa from BPH. Seminal plasma requires further investigation as it represents an obvious source for PCa biomarker identification.

Profiling Colorectal Cancer in the Landscape Personalized Testing-Advantages of Liquid Biopsy.

Drug-specific therapeutic approaches for colorectal cancer (CRC) have contributed to significant improvements in patient health. Nevertheless, there is still a great need to improve the personalization of treatments based on genetic and epigenetic tumor profiles to maximize the quality and efficacy while limiting cytotoxicity. Currently, CEA and CA 19-9 are the only validated blood biomarkers in clinical practice. For this reason, laboratories are trying to identify new specific prognostics and, more importantly, predictive biomarkers for CRC patient profiling. Thus, the unique landscape of personalized biomarker data should have a clinical impact on CRC treatment strategies and molecular genetic screening tests should become the standard method for diagnosing CRC. This review concentrates on recent molecular testing in CRC and discusses the potential modifications in CRC assay methodology with the upcoming clinical application of novel genomic approaches. While mechanisms for analyzing circulating tumor DNA have been proven too inaccurate, detecting and analyzing circulating tumor cells and protein analysis of exosomes represent more promising options. Blood liquid biopsy offers good prospects for the future if the results align with pathologists' tissue analyses. Overall, early detection, accurate diagnosis and treatment monitoring for CRC with specific markers and targeted molecular testing may benefit many patients.

TERT Gene Fusions Characterize a Subset of Metastatic Leydig Cell Tumors.

OBJECTIVE: Metastatic Leydig cell tumors (LCT) are rare, difficult-to-treat malignancies without known underlying molecular-genetic events. An index case of metastatic LCT showed an LDLR-TERT gene fusion upon routine genetic profiling for detection of therapeutic targets, which was then followed by an investigation into a cohort of additional LCTs. PATIENTS AND METHODS: Twenty-nine LCT (27 male and 2 female patients) were profiled using next-generation sequencing and immunohistochemistry. RESULTS: TERT gene fusions were detected only in testicular metastatic LCTs, in 3 of 7 successfully analyzed cases (RMST:TERT, LDLR:TERT, and B4GALT5:TERT). TOP1 and CCND3 amplifications were identified in the case with a B4GALT5:TERT fusion. A TP53 mutation was detected in 1 metastatic tumor without a TERT fusion. Five primary (4 testicular and 1 ovarian) LCTs showed multiple gene amplifications, without a consistent pattern. A single metastatic ovarian LCT showed BAP1 mutation and copy number amplifications affecting the NPM1, PCM1, and SS18 genes. At the protein level, 4 of 7 metastatic and 6 of 10 primary testicular LCTs overexpressed Topo1. Androgen receptor was overexpressed in 10 of 13 primary testicular tumors and 2 of 5 metastatic testicular LCTs (without detectable ARv7 messenger RNA or ARv7 protein). Only 1 metastatic testicular LCT exhibited a high tumor mutational burden; all tested cases were microsatellite instability stable and did not express programmed cell death ligand 1. CONCLUSIONS: Our study for the first time identified TERT gene fusions as a main genetic alteration and a potential therapeutic target in metastatic LCTs. Topo1 and androgen receptor may guide decisions on chemotherapy and/or hormone therapy for selected individual patients.