Approximately 60% of colorectal cancer (CRC) precursor lesions are the genuinely-dysplastic conventional adenomas (cADNs). The others include hyperplastic polyps (HPs), sessile serrated lesions ...(SSL), and traditional serrated adenomas (TSAs), subtypes of a class of lesions collectively referred to as "serrated." Endoscopic and histologic differentiation between cADNs and serrated lesions, and between serrated lesion subtypes can be difficult.
We used in situ hybridization to verify the expression patterns in CRC precursors of 21 RNA molecules that appear to be promising differentiation markers on the basis of previous RNA sequencing studies.
SSLs could be clearly differentiated from cADNs by the expression patterns of 9 of the 12 RNAs tested for this purpose (VSIG1, ANXA10, ACHE, SEMG1, AQP5, LINC00520, ZIC5/2, FOXD1, NKD1). Expression patterns of all 9 in HPs were similar to those in SSLs. Nine putatively HP-specific RNAs were also investigated, but none could be confirmed as such: most (e.g., HOXD13 and HOXB13), proved instead to be markers of the normal mucosa in the distal colon and rectum, where most HPs arise. TSAs displayed mixed staining patterns reflecting the presence of serrated and dysplastic glands in the same lesion.
Using a robust in situ hybridization protocol, we identified promising tissue-staining markers that, if validated in larger series of lesions, could facilitate more precise histologic classification of CRC precursors and, consequently, more tailored clinical follow-up of their carriers. Our findings should also fuel functional studies on the pathogenic significance of specific gene expression alterations in the initiation and evolution of CRC precursor subtypes.
Targeted proteomic methods can accelerate the verification of multiple tumor marker candidates in large series of patient samples. We utilized the targeted approach known as selected/multiple ...reaction monitoring (S/MRM) to verify potential protein markers of colorectal adenoma identified by our group in previous transcriptomic and quantitative shotgun proteomic studies of a large cohort of precancerous colorectal lesions. We developed SRM assays to reproducibly detect and quantify 25 (62.5%) of the 40 selected proteins in an independent series of precancerous and cancerous tissue samples (19 adenoma/normal mucosa pairs; 17 adenocarcinoma/normal mucosa pairs). Twenty-three proteins were significantly up-regulated (n = 17) or downregulated (n = 6) in adenomas and/or adenocarcinomas, as compared with normal mucosa (linear fold changes ≥ ±1.3, adjusted p value <0.05). Most changes were observed in both tumor types (up-regulation of ANP32A, ANXA3, SORD, LDHA, LCN2, NCL, S100A11, SERPINB5, CDV3, OLFM4, and REG4; downregulation of ARF6 and PGM5), and a five-protein biomarker signature distinguished neoplastic tissue from normal mucosa with a maximum area under the receiver operating curve greater than 0.83. Other changes were specific for adenomas (PPA1 and PPA2 up-regulation; KCTD12 downregulation) or adenocarcinoma (ANP32B, G6PD, RCN1, and SET up-regulation; downregulated AKR1B1, APEX1, and PPA1). Some changes significantly correlated with a few patient- or tumor-related phenotypes. Twenty-two (96%) of the 23 proteins have a potential to be released from the tumors into the bloodstream, and their detectability in plasma has been previously reported. The proteins identified in this study expand the pool of biomarker candidates that can be used to develop a standardized precolonoscopy blood test for the early detection of colorectal tumors.
Although ejaculatory dysfunction is common for patients undergoing benign prostatic hyperplasia surgery, no clear evidence is present to counsel men seeking to preserve ejaculation. Our aim was to ...evaluate ejaculatory dysfunction in relation to benign prostatic hyperplasia surgery. We carried out a web and manual search using MEDLINE and Embase including randomized controlled trials reporting ejaculatory dysfunction after benign prostatic hyperplasia surgery: 42 randomized controlled trials comprising a total of 3857 patients were included. Only one study had ejaculatory dysfunction as a primary outcome, and just 10 evaluated ejaculatory dysfunction before and after surgery. The definition of ejaculatory dysfunction was not standardized. Similarly, just seven studies used internationally validated questionnaires to address ejaculatory dysfunction. The reported rates of ejaculatory dysfunction after resectional elecrosurgery, laser procedures, coagulation, ablation and implant techniques were assessed and compared. Transurethral resection of the prostate and recent laser procedures including holmium, thulium and GreenLight cause similar rates of ejaculatory dysfunction, occurring in almost three out of four to five men. Although providing less symptomatic benefit compared with transurethral resection of the prostate, transurethral incision of the prostate, transurethral needle ablation and transurethral microwave thermotherapy should be considered for men aiming to maintain normal ejaculation. UroLift is also a recent promising option for this category of patients. The vast majority of studies reporting ejaculatory dysfunction after benign prostatic hyperplasia surgery used poor methodology to investigate this complication. Future studies able to address clear hypothesis and considering ejaculatory dysfunction anatomical and pathophysiological features are required to develop ejaculation preserving techniques and to increase the evidence to counsel men aiming to preserve ejaculation.
Background
Whether focal therapy (FT) jeopardizes subsequent prostate cancer (PCa) salvage treatments, when needed, remains a major concern and is largely unknown.
Objectives
To describe and report ...safety, oncological and functional outcomes of salvage treatments following PCa recurrence and/or persistence after FT.
Materials and methods
A systematic review on salvage treatments for PCa recurrence/persistence after FT was carried out according to the PRISMA guidelines using an ‘a priori protocol’. A comprehensive literature review was also performed to investigate options to treat FT PCa recurrence/persistence that have not yet been reported after FT.
Results
Four retrospective series were included (
n
= 67 men); overall quality of the studies was low. Salvage treatments yielded 32.8% (
n
= 22 of 67) biochemical recurrence rate (BCR) after a 7–62-months mean follow-up. No cancer-related deaths occurred. Patients experienced acceptable complications (
n
= 12 patients;
n
= 8 Clavien 3) and rare severe incontinence (4.5% using > 2 pads/day). Erectile function (EF) was rarely assessed (62.8% no information available), being overall poor. Other salvage options have been reported following whole-gland ablation and include: (1) re-do ablation yielding worst BCR and EF but similar complications and continence compared to first line ablation; (2) salvage radiotherapy yielding 16.6–38.8% BCR and acceptable toxicity profile with urinary and EF being poorly assessed.
Conclusions
Current evidence is weak and limited to a few retrospective series. Oncological control is acceptable although it seems lower compared to a primary treatment setting. Functional outcomes are comparable to primary treatment with the exception of EF; overall, suggesting FT has little impact on subsequent salvage treatments. Future studies are needed to confirm the current findings.
Introduction
Focal therapy (FT) for localized prostate cancer (PCa) is a promising treatment strategy. Although, according to guidelines, it should be regarded as an experimental option, its ...introduction into clinical practice has occurred at an accelerated speed. It is, thus, crucial for Urologists to understand FT limitations and potential drawbacks that may derive from its use.
Methods
We performed a literature search of peer-reviewed English language articles using Pubmed and the words “focal therapy” AND “prostate cancer” to identify relevant articles. Web search was complemented by manual search.
Results
From a biological perspective, in contrast with the index lesion theory, which still needs to be better supported, PCa is a multifocal and multiclonal entity. Also, the effects of FT on PCa microenvironment are unclear. From a clinical perspective, patient selection is still not precisely defined. Even when all variables potentially decreasing mpMRI and biopsy accuracy are optimized, up to one out of two men may be incorrectly selected for FT, leaving a significant proportion of clinically significant PCa (csPCa) untreated. Underestimation of PCa volume and variant histologies are other additional mpMRI potential limitations. No RCTs have been performed against the standard of care to support FT. There is absence of long-term results and FT series reaching medium-term follow-up have non-optimal oncological control with significant re-treatment needs. When PCa recurs/persists after FT, little is known about the appropriate management strategies and their outcomes. Finally, the optimal follow-up scheme post-FT remains unclear.
Conclusions
Several arguments are present against the use of FT for localized PCa. Studies are needed to overcome current limitations and support FT before it can be included as part of the standard management of prostate cancer.
Identifying molecular differences between primary and metastatic colorectal cancers-now possible with the aid of omics technologies-can improve our understanding of the biological mechanisms of ...cancer progression and facilitate the discovery of novel treatments for late-stage cancer. We compared the DNA methylomes of primary colorectal cancers (CRCs) and CRC metastases to the liver. Laser microdissection was used to obtain epithelial tissue (10 to 25 × 10
μm
) from sections of fresh-frozen samples of primary CRCs (n = 6), CRC liver metastases (n = 12), and normal colon mucosa (n = 3). DNA extracted from tissues was enriched for methylated sequences with a methylCpG binding domain (MBD) polypeptide-based protocol and subjected to deep sequencing. The performance of this protocol was compared with that of targeted enrichment for bisulfite sequencing used in a previous study of ours.
MBD enrichment captured a total of 322,551 genomic regions (249.5 Mb or ~ 7.8% of the human genome), which included over seven million CpG sites. A few of these regions were differentially methylated at an expected false discovery rate (FDR) of 5% in neoplastic tissues (primaries: 0.67%, i.e., 2155 regions containing 279,441 CpG sites; liver metastases: 1%, i.e., 3223 regions containing 312,723 CpG sites) as compared with normal mucosa samples. Most of the differentially methylated regions (DMRs; 94% in primaries; 70% in metastases) were hypermethylated, and almost 80% of these (1882 of 2396) were present in both lesion types. At 5% FDR, no DMRs were detected in liver metastases vs. primary CRC. However, short regions of low-magnitude hypomethylation were frequent in metastases but rare in primaries. Hypermethylated DMRs were far more abundant in sequences classified as intragenic, gene-regulatory, or CpG shelves-shores-island segments, whereas hypomethylated DMRs were equally represented in extragenic (mainly, open-sea) and intragenic (mainly, gene bodies) sequences of the genome. Compared with targeted enrichment, MBD capture provided a better picture of the extension of CRC-associated DNA hypermethylation but was less powerful for identifying hypomethylation.
Our findings demonstrate that the hypermethylation phenotype in CRC liver metastases remains similar to that of the primary tumor, whereas CRC-associated DNA hypomethylation probably undergoes further progression after the cancer cells have migrated to the liver.
Background We previously identified 16,772 colorectal cancer-associated hypermethylated DNA regions that were also detectable in precancerous colorectal lesions (preCRCs) and unrelated to normal ...mucosal aging. We have now conducted a study to validate 990 of these differentially methylated DNA regions (DMRs) in a new series of preCRCs. Methods We used targeted bisulfite sequencing to validate these 990 potential biomarkers in 59 preCRC tissue samples (41 conventional adenomas, 18 sessile serrated lesions), each with a patient-matched normal mucosal sample. Based on differential DNA methylation tests, a panel of candidate DMRs was chosen on a subset of our cohort and then validated on the remaining part of our cohort and two publicly available datasets with respect to their stratifying potential between preCRCs and normal mucosa. Results Strong statistical significance for the difference in methylation levels was observed across the full set of 990 investigated DMRs. From these, a selected candidate panel of 30 DMRs correctly identified 58/59 tumors (area under the receiver operating curve: 0.998). Conclusions These validated DNA hypermethylation markers can be exploited to develop more accurate noninvasive colorectal tumor screening assays. Keywords: Colorectal adenoma, Sessile serrated lesion, Colorectal cancer, DNA methylation, Biomarkers.
To date, although some benefits resulting from a software-guided technique are
undeniable, no clear superiority of fusion over cognitive targeted biopsy (COG-TB) has
been supported by strong ...evidence. We discuss potential causes of trials failing to show
the superiority of fusion TB (FUS-TB) and highlight its advantages over the cognitive
approach.One possible reason why current literature showed contradictory evidence in
supporting FUS-TB may be the lack of high-quality well-designed trials. Indeed, most of
the studies addressing this issue have considerable limitations, such as underpowering,
small sample size, lack of randomization, and poor generalizability. A second reason may
be the inclusion in the majority of trials of a wide spectrum of MRI-lesions, a scenario
in which the benefits of FUS-TB may be less evident. In fact, some of the few studies
considering smaller targets demonstrated higher accuracy for the FUS technique. As
concerns the advantages of FUS-TB, the opportunity offered by some fusion systems of
storing information useful for planning and/or follow-up active surveillance, focal
therapy, and radical prostatectomy, as well as a reported faster learning curve, are
strong points supporting the fusion approach.In conclusion, the potential advantages
when targeting smaller lesions together with the storage capability to guide patient
management after the biopsy and an easier learning curve may make the FUS approach the
more appropriate technique for performing TB.
Purpose
Salvage radical prostatectomy (sRP) represents a curative option for prostate cancer (PCa) biochemical recurrence (BCR) after radiation therapy (RT). In this review, we aimed to outline the ...contemporary results and use of sRP.
Methods
A web search was performed on the Ovid platform using Embase and Medline databases from January 2010 using pre-defined search terms. Web search was implemented by manual search. Oncological and functional outcomes and complications were summarized using standard classification systems, when feasible.
Results
sRP is currently underused, being chosen for radio-recurrent PCa treatment in around 1% of the cases. Surgery is complex due to radiation-induced tissue changes making posterior planes and apex dissection particularly challenging. Patient selection is paramount to maximize the oncological benefit. Most series report a BCR-free survival > 60%, mainly at the end of a short- to intermediate-term follow-up. Five-year progression-free survival is nearly 50% and 5-year cancer-specific survival rates are around 90%. Major peri-operative complications, anastomotic leaks and strictures, still more frequent than in a primary RP setting, have been steering towards more acceptable rates in recent years, when compared to historical series. Continence rates are widely variable, often in between 39 and 60%. Potency remains difficult to recover.
Conclusions
sRP represents a curative option with promising short- to medium-term oncological results and acceptable side effects, in high
-
volume institutions. In appropriately selected patients, the procedure should not be underused due to the fear of poor functional outcomes and/or complications. Prospective studies are needed to assess the long-term outcomes and to further refine patient selection criteria.
Background
Aim of this study was to evaluate and compare perioperative outcomes of transperitoneal (TP) and retroperitoneal (TR) approaches in a multi-institutional cohort of minimally invasive ...partial nephrectomy (MI-PN).
Material and methods
All consecutive patients undergone MI-PN for clinical T1 renal tumors at 26 Italian centers (RECORd2 project) between 01/2013 and 12/2016 were evaluated, collecting the pre-, intra-, and postoperative data. The patients were then stratified according to the surgical approach, TP or RP. A 1:1 propensity score (PS) matching was performed to obtain homogeneous cohorts, considering the age, gender, baseline eGFR, surgical indication, clinical diameter, and PADUA score.
Results
1669 patients treated with MI-PN were included in the study, 1256 and 413 undergoing TP and RP, respectively. After 1:1 PS matching according to the surgical access, 413 patients were selected from TP group to be compared with the 413 RP patients. Concerning intraoperative variables, no differences were found between the two groups in terms of surgical approach (lap/robot), extirpative technique (enucleation vs standard PN), hilar clamping, and ischemia time. Conversely, the TP group recorded a shorter median operative time in comparison with the RP group (115 vs 150 min), with a higher occurrence of intraoperative overall, 21 (5.0%) vs 9 (2.1%);
p
= 0.03, and surgical complications, 18 (4.3%) vs 7 (1.7%);
p
= 0.04. Concerning postoperative variables, the two groups resulted comparable in terms of complications, positive surgical margins and renal function, even if the RP group recorded a shorter median drainage duration and hospital length of stay (3 vs 2 for both variables),
p
< 0.0001.
Conclusions
The results of this study suggest that both TP and RP are feasible approaches when performing MI-PN, irrespectively from tumor location or surgical complexity. Notwithstanding longer operative times, RP seems to have a slighter intraoperative complication rate with earlier postoperative recovery when compared with TP.
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