Urine Molecular Biomarkers for Detection and Follow-Up of Small Renal Masses.

Active surveillance (AS) is the best strategy for small renal masses (SRMs) management; however, reliable methods for early detection and disease aggressiveness prediction are urgently needed. The aim of the present study was to validate DNA methylation biomarkers for non-invasive SRM detection and prognosis. The levels of methylated genes TFAP2B, TAC1, PCDH8, ZNF677, FLRT2, and FBN2 were evaluated in 165 serial urine samples prospectively collected from 39 patients diagnosed with SRM, specifically renal cell carcinoma (RCC), before and during the AS via quantitative methylation-specific polymerase chain reaction. Voided urine samples from 92 asymptomatic volunteers were used as the control. Significantly higher methylated TFAP2B, TAC1, PCDH8, ZNF677, and FLRT2 levels and/or frequencies were detected in SRM patients' urine samples as compared to the control. The highest diagnostic power (AUC = 0.74) was observed for the four biomarkers panel with 92% sensitivity and 52% specificity. Methylated PCDH8 level positively correlated with SRM size at diagnosis, while TFAP2B had the opposite effect and was related to SRM progression. To sum up, SRMs contribute significantly to the amount of methylated DNA detectable in urine, which might be used for very early RCC detection. Moreover, PCDH8 and TFAP2B methylation have the potential to be prognostic biomarkers for SRMs.

Cloacal reconstruction after a complex treatment of perineal haemangioma in a variant of PELVIS syndrome.

BACKGROUND: PELVIS is an acronym defining the association of perineal hemangioma, malformations of external genitalia, lipomyelomeningocele, vesicorenal abnormalities, imperforate anus and skin tag. Eleven cases have been reported according to the Orphanet data. Acronyms of LUMBAR and SACRAL syndrome have been used and most probably represent a spectrum of the same entity. Very little is known about the success and timing of cloacal reconstruction after the treatment of hemangioma. We present a variant of PELVIS syndrome and discuss the possibilities and optimal timing of surgical reconstruction. CASE PRESENTATION: Female infant was born with persistent cloaca and multiple hemangiomas of genitals, perineal area and left thigh. Colostomy was performed after birth. In order to treat hemangioma and to make the reconstruction of cloaca possible, corticosteroid treatment orally and multiple laser treatments were performed alternating Nd:YAG laser and pulsed dye laser therapy. Cystoscopy confirmed hemangiomatosis in the mucosa of the common channel, bladder neck and septate vagina. Oral propranolol treatment was started at the age of 18 months and continued for 1 year. It induced rapid improvement of hemangiomas. Two more pulsed dye laser treatments were performed to remove residuals of hemangiomas from the perineum and genital area. Posterior sagital reconstruction by separation of the rectum, mobilization of urogenital sinus and vaginal reconstruction was performed with no major bleeding at the age of 4 years. Postoperatively, after a period of progressive rectal dilatation colostomy was closed. Girl is now 6 years old, dry day and night without residual urine and normal upper tracts. Rectal calibration is normal, fecal continence is still to be evaluated but constipation is easily manageable. CT of the spine and the perineum showed sacral dysplasia and spina bifida with lumbo-sacral lipoma and tethering of terminal filum without neurological deterioration at the moment but requiring close neurological monitoring. CONCLUSIONS: Large perineal hemangiomas are commonly associated with extracutaneous abnormalities. Successful reconstructive surgery is possible after significant reduction of hemangioma by complex treatment.

Efficacy of Sunitinib in Patients With Favorable and Intermediate Risk Metastatic Renal Cell Carcinoma - Lithuanian National Cancer Institute Experience.

BACKGROUND/AIM: According to the European Society for Medical Oncology (ESMO) and National Comprehensive Cancer Network (NCCN) recommendations, sunitinib is one of the recommended regimens for favorable and intermediate-risk metastatic renal cell carcinoma (mRCC) patients. The objective of this study was to evaluate sunitinib efficacy as a first-line treatment for mRCC patients with favorable/intermediate prognostic risk in a real-world setting. PATIENTS AND METHODS: Patients diagnosed with mRCC and confirmed as appropriate candidates for the first-line systemic treatment were included in this retrospective study. The prognostic risk was evaluated according to the model of the International Metastatic RCC Database Consortium (IMDC). RESULTS: Patients received sunitinib as a first-line treatment. A total of 94 patients were enrolled from 2019 to the 2020and 67 of them were included in the detailed analysis. Median progression-free survival (PFS) was 23.4 (95%CI=17.3-29.5), and median overall survival (OS) was 66 months (95%CI=44.9-87.1). The age over 60 years was a significant negative predictor for PFS and OS. Regarding the IMDC model for disease risk prediction, the number of two risk factors in the intermediate risk group was a significant predictor for a shorter response to the first-line therapy. CONCLUSION: Sunitinib is an effective tyrosine kinase inhibitor, which can be used as a first-line treatment in favorable/intermediate-risk groups of patients with mRCC, especially in countries where novel systemic treatment modalities are not yet available.

Clinical significance of novel DNA methylation biomarkers for renal clear cell carcinoma.

OBJECTIVE: Clear cell renal cell carcinoma (ccRCC) is the most common type of kidney tumor characterized by the highest mortality rate of the genitourinary cancers, and, therefore, new diagnostic and/or prognostic biomarkers are urgently needed. METHODS: Based on genome-wide DNA methylation profiling in 11 pairs of ccRCC and non-cancerous renal tissues (NRT), the methylation at regulatory regions of ZNF677, FBN2, PCDH8, TFAP2B, TAC1, and FLRT2 was analyzed in 168 renal tissues and 307 urine samples using qualitative and quantitative methylation-specific PCR (MSP). RESULTS: Significantly higher methylation frequencies for all genes were found in ccRCC tissues compared to NRT (33-60% vs. 0-11%). The best diagnostic performance demonstrated a panel of ZNF677, FBN2, PCDH8, TFAP2B & TAC1 with 82% sensitivity and 96% specificity. Hypermethylation of ZNF677 and PCDH8 in the tissue samples was significantly related to numerous adverse clinicopathologic parameters. For the urine-based ccRCC detection, the highest diagnostic power (AUC = 0.78) was observed for a panel of ZNF677 & PCDH8 (with or without FBN2 or FLRT2) with 69-78% sensitivity and 69-80% specificity, albeit with lower values in the validation cohort. Besides, methylation of PCDH8 was significantly related to higher tumor stage and fat invasion in the study and validation cohorts. Moreover, PCDH8 was strongly predictive for OS (HR, 5.7; 95% CI 1.16-28.12), and its prognostic power considerably increased in combination with ZNF677 (HR, 12.5; 95% CI 1.47-105.58). CONCLUSION: In summary, our study revealed novel, potentially promising DNA methylation biomarkers of ccRCC with the possibility to be applied for non-invasive urine-based ccRCC detection and follow-up.

Clinical Significance of ADAMTS19, BMP7, SIM1, and SFRP1 Promoter Methylation in Renal Clear Cell Carcinoma.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney tumors, accounting for the majority of deaths from genitourinary cancers. The currently used nomograms for predicting patient outcomes are based on clinical-pathological characteristics only; however, a significant number of ccRCC survivors with similar radiological and histological features still demonstrate a different clinical course of the disease. This study aimed at the identification of novel DNA methylation biomarkers for the monitoring of patients with ccRCC. METHODS: Gene expression profiling by SurePrint G3 Human GE 8×60K Microarrays was performed in 4 ccRCC tissues and adjacent non-cancerous renal tissue (NRT) samples. Four down-regulated genes were selected for further DNA methylation status analysis in 123 ccRCC and 45 NRT samples using methylation-specific PCR (MSP). RESULTS: DNA methylation changes of ADAMTS19, BMP7, SIM1, and SFRP1 were cancer-specific with significantly (P<0.050) higher methylation frequency (37%, 20%, 18%, and 42%, respectively) in tumor tissues. The methylated status of at least one gene was significantly related to various clinical-pathological parameters, including tumor size, Fuhrman and WHO/ISUP grades, intravascular invasion, and necrosis. Moreover, the methylated status of multimarker panel ADAMTS19, BMP7 & SFRP1 was predictive for poorer overall survival (HR, 4.11; 95% CI, 1.22-13.86). CONCLUSION: In conclusion, DNA methylation of the three-gene panel consisting of ADAMTS19, BMP7 & SFRP1 supposedly predicts the outcome of patients diagnosed with ccRCC and possibly might be used to enrich the current prognostic tools.

The Impact of the COVID-19 Pandemic on Cancer Patient's Management-Lithuanian Cancer Center Experience.

The pandemic spread of the COVID-19 virus significantly affected daily life, but the highest pressure was piled on the health care system. Our aim was to evaluate an impact of COVID-19 pandemic management measures on cancer services at the National Cancer Institute (NCI) of Lithuania. We assessed the time period from 1 February 2020 to 31 December 2020 and compared it to the same period of 2019. Data for our analysis were extracted from the NCI Hospital Information System (HIS) and the National Health Insurance Fund (NHIF). Contingency table analysis and ANOVA were performed. The COVID-19 pandemic negatively affected the cancer services provided by NCI. Reductions in diagnostic radiology (-16%) and endoscopy (-29%) procedures were accompanied by a decreased number of patients with ongoing medical (-30%), radiation (-6%) or surgical (-10%) treatment. The changes in the number of newly diagnosed cancer patients were dependent on tumor type and disease stage, showing a rise in advanced disease at diagnosis already during the early period of the first lockdown. The extent of out-patient consultations (-14%) and disease follow-up visits (-16%) was also affected by the pandemic, and only referrals to psychological/psychiatric counselling were increased. Additionally, the COVID-19 pandemic had an impact on the structure of cancer services by fostering the application of modified systemic anticancer therapy or hypofractionated radiotherapy. The most dramatic drop occurred in the number of patients participating in cancer prevention programs; the loss was 25% for colon cancer and 62% for breast cancer screening. Marked restriction in access to preventive cancer screening and overall reduction of the whole spectrum of cancer services may negatively affect cancer survival measures in the nearest future.

Partial nephrectomy can be a successful treatment option for renal epithelioid angiomyolipoma: a case report and literature review.

BACKGROUND: Renal epithelioid angiomyolipoma is a rare tumour which involves kidneys in most cases. It is known for its aggressive behaviour as a significant number of cases have been associated with metastatic epithelioid angiomyolipoma. Usually, radical treatment with systemic therapy is recommended. Only a small number of cases of epithelioid angiomyolipomas have been reported with the standard treatment being radical or partial nephrectomy. We present a  case report showing that partial nephrectomy can be a successful treatment option for renal epithelioid angiomyolipoma. This is the first case of this nature in Lithuania. CASE PRESENTATION: In this case, a 40-year-old male with epithelioid angiomyolipoma of the left kidney is presented. In 2012, a cystic left renal mass 40 × 41 mm in size was diagnosed incidentally while performing ultrasound and later confirmed by MRI. Due to the size of the tumour and the possibility of renal cell carcinoma, surgery was scheduled. Left partial nephrectomy was performed successfully. Final pathology report came back with the diagnosis of renal epithelioid angiomyolipoma. The patient had yearly follow-up for six years by CT scan, and neither recurrence nor progression were observed. CONCLUSIONS: Early detection and diagnosis are crucial for treatment as the tumour tends to have malignancy potential. With early diagnosis, partial nephrectomy can be performed with yearly follow-up and no systemic treatment required.

DNA methylation of metallothionein genes is associated with the clinical features of renal cell carcinoma.

Metallothioneins are low­weight cysteine­rich proteins responsible for metal ion homeostasis in a cell and, thus, capable of regulating cell proliferation and differentiation. Deregulation of metallothionein genes has been reported in various human tumors. However, their role in renal cell carcinoma (RCC) has been poorly investigated. In the present study, we aimed to evaluate the importance of promoter DNA methylation of selected metallothionein genes for RCC. Based on the initial analysis of kidney renal clear cell carcinoma dataset from The Cancer Genome Atlas, genes MT1E, MT1F, MT1G and MT1M were selected for qualitative methylation analysis in 30 tumors (including 10 multifocal cases), 10 pericancerous, and 30 non­cancerous renal tissues (NRT). Methylation of MT1E and MT1M was tumor­specific (P=0.0056 and P=0.0486, respectively) and showed moderate interfocal variation in paired tumor foci. Methylated promoter status of the two genes was associated with larger tumor size (P=0.0110 and P=0.0156, respectively). Furthermore, aberrant MT1E methylation was more frequent in tumors having necrotic zones (P=0.0449) or characterized with higher differentiation grade (P=0.0144), while MT1M was more commonly methylated in tumors with higher Fuhrman grade (P=0.0272). Only unmethylated MT1F promoter status was observed in all analyzed samples. Gene expression analysis (51 RCC and 9 NRT) revealed MT1G downregulation in tumors (P<0.0001), while lower MT1E expression levels were associated with the promoter methylation (P=0.0077). In clear cell RCC, MT1E, MT1G and MT1M expression was higher than that noted in other histological tumor subtypes (all P<0.0500). In addition, some associations were observed between metabolic syndrome­related clinical parameters and promoter methylation or gene expression. In conclusion, the present study revealed the potential role of MT1E and MT1M promoter methylation in RCC development.

Malignant mixed epithelial and stromal tumour of the kidney: a case report and a literature review.

INTRODUCTION: Mixed epithelial and stromal tumour of the kidney (MEST) is a rare and distinctive neoplasm accounting for 0.2% of all renal cancers. Most of these tumours behave in a benign fashion but 13 cases with malignant transformation have already been reported. We present the first case of an extremely aggressive MEST with rapid recurrence after radical treatment, demonstrating objective response to chemotherapy. CASE PRESENTATION: A 31-year-old female presented to the hospital complaining of gross hematuria. Computed tomography (CT) revealed an intraparenchymal mass in the left kidney forming a tumour thrombus in the inferior vena cava (IVC). Metastatic disease was ruled out and, under the clinical diagnosis of renal cell carcinoma, left radical nephrectomy with IVC thrombectomy was performed. The histopathological examination confirmed malignant MEST of the kidney. At the follow-up 12 months after surgery, a recurrent tumour in the left paravertebral area and a tumour thrombus in the IVC were detected. A second surgery was recommended and the mass from the paravertebral area was removed, so resection of the IVC with prosthetic replacement was performed. The histopathologic examination confirmed a recurrent malignant MEST. At the follow-up three months after the second surgery disease progression was diagnosed, so chemotherapy with ifosfamide and doxorubicin was initiated. The CT scan performed 14 months after the chemotherapy confirmed a stable process of the disease with no signs of progression. CONCLUSIONS: A literature review and our case report confirm the existence of extremely aggressive malignant MEST that shows response to chemotherapy. However, more reports are needed to improve our understanding about the biology of the MEST to develop any recommendations on personalized therapy.