Shmt2: a stat3 signaling new player in prostate cancer energy metabolism

Prostate cancer (PCa) is a multifactorial disease characterized by the aberrant activity of different regulatory pathways. STAT3 protein mediates some of these pathways and its activation is implicated in the modulation of several metabolic enzymes. A bioinformatic analysis indicated a STAT3 binding site in the upstream region of SHMT2 gene. We demonstrated that in LNCaP, PCa cells' SHMT2 expression is upregulated by the JAK2/STAT3 canonical pathway upon IL-6 stimulation. Activation of SHTM2 leads to a decrease in serine levels, pushing PKM2 towards the nuclear compartment where it can activate STAT3 in a non-canonical fashion that in turn promotes a transient shift toward anaerobic metabolism. These results were also confirmed on FFPE prostate tissue sections at different Gleason scores. STAT3/SHMT2/PKM2 loop in LNCaP cells can modulate a metabolic shift in response to inflammation at early stages of cancer progression, whereas a non-canonical STAT3 activation involving the STAT3/HIF-1α/PKM2 loop is responsible for the maintenance of Warburg effect distinctive of more aggressive PCa cells. Chronic inflammation might thus prime the transition of PCa cells towards more advanced stages, and SHMT2 could represent a missing factor to further understand the molecular mechanisms responsible for the transition of prostate cancer towards a more aggressive phenotyp

Stapled hemorrhoidopexy: “mucosectomy or not only mucosectomy, this is the problem”

Introduction: Stapled hemorrhoidopexy was originally defined as a rectal mucosectomy. The aims of our retrospective, single-center study were to demonstrate if the excised specimen comprises only the mucosa or more wall rectal layers and if the latter excision should be considered a technical mistake with an increase in complications. Materials and Methods: We histopathologically analyzed surgical samples from patients who underwent stapled hemorrhoidopexy performed between 2014 and 2019. Patients were divided into three groups, according to the stapler used: Group A (single PPH®), Group B (double PPH®), and Group C (CPH34 HVTM). We evaluated the actual wall layers included in the stapled rectal ring. For every specimen, we reconstructed the history of the corresponding patient and the incidence of complications. Results: Of the 137 histological slides available, 13 were only mucosectomies (9.5%), and 124 presented also the submucosa and muscularis propria (90.5%)−50/58 patients in Group A, 28/28 in Group B, and 46/51 in Group C. No statistically significant difference in the rate of complications was found when stratifying patients according to the thickness of the resection [mucosectomy (M) or “full thickness” (FT)]. Discussion: Stapled hemorrhoidopexy is not a simple mucosectomy but a resection of the rectal wall with almost all its layers. This concept defines the entity of the surgical procedure and excludes a direct correlation with an increased rate of complications

Routine pathology examination in the era of value-based healthcare: the case of haemorrhoids specimens

Routine pathologic examination of specimens is a common practice with ill-defined value. The present study is the first to investigate the incidence and cost of incidental microscopic lesions in both haemorrhoidectomy and stapled haemorrhoidopexy specimens. Pathological reports of specimens obtained from haemorrhoidectomy and stapled haemorrhoidopexy procedures performed from January 2003 to May 2017 were analysed. Specimens resulting from patients treated for any disease other than haemorrhoids alone were excluded from the study. Unexpected diagnoses in the pathological report were defined as incidental diagnoses. A cost analysis was then performed. In the considered period we performed a total of 3017 procedures complying with our criteria. We found 65 (2.15%) unexpected lesions. Of the incidental diagnosis, 30 (0.99%) altered either the follow-up or the treatment. The incidences of both findings were extremely higher in haemorrhoidectomies specimens (p < 0.0001). We estimated that the cost of 14 years of routine pathological examination of haemorrhoids specimens was 133,351.4 euros, each consequential incidental diagnosis costing 4445.03 euros. The incidence of unexpected lesions in routine pathologic examination of haemorrhoidectomy and haemorrhoidopexy specimens is low but not negligible. The vast majority of incidental findings were found among haemorrhoidectomy specimens. Even though the real value of routine pathological examination of haemorrhoids specimens is still uncertain, from a clinical standpoint we were glad to suggest each patients the best follow-up and/or treatment. Future studies should assess preoperative patient's risk stratification and careful intraoperative macroscopic inspection strategies for selective pathology examination of haemorrhoids specimens

Incidental prostatic stromal tumor of uncertain malignant potential (STUMP): histopathological and immunohistochemical findings

Stromal prostate tumors are rare neoplastic proliferative lesions that have been classified into prostatic stromal tumor of uncertain malignant potential (STUMP) and prostatic stromal sarcoma (SS) based on these criteria: stromal cellularity, presence of mitotic figures, necrosis, and stromal overgrowth. A prostatic stromal tumor of uncertain malignant potential (STUMP) is a non-epithelial, mesenchymal spindle-cell tumor that can be classified as a specialized stromal tumor of the prostate. STUMPs have the capability to diffusely infiltrate the prostate gland and extend into adjacent tissues. Furthermore, they often recur and this is why they are considered as neoplastic entities. STUMPs usually tend to be not aggressive, but occasional cases have been reported with an extension into adjacent tissues. A few cases develop a sarcomatous dedifferentiation. A 67-year-old male referred to the Department of Urology, Sapienza Rome University, with acute urinary retention (AUR) and bladder overdistention. Digital rectal examination (DRE) showed the presence of a severe prostatic hyperplasia and a transvesical prostatic adenomectomy (TVPA) was performed. The pathological evaluation performed at the Department of Pathology, Sapienza Rome University, revealed an incidental diagnosis of prostatic STUMP. The patient’s follow-up is made every year with transrectal ultrasonography and nuclear magnetic resonance with spectroscopy, and every two years with a transperineal prostate biopsy to exclude a progression to a stromal sarcoma. After 5 years of follow-up the STUMP is still detectable but there is no sign of sarcoma. As a result of its relative rarity and lack of long-term follow-up, the prognosis of STUMP is unclear. Therapy varies from a wait-andsee approach to a radical retropubic prostatectomy

Prospective assessment of two-gene urinary test with multiparametric magnetic resonance imaging of the prostate for men undergoing primary prostate biopsy

Purpose To evaluate the diagnostic accuracy of SelectMDx and its association with multiparametric magnetic resonance (mpMRI) in predicting prostate cancer (PCa) and clinically significant PCa (csPCa) on prostate biopsies among men scheduled for initial prostate biopsy. Methods In this single-center prospective study, 52 men scheduled for initial prostate biopsy, based on elevated total PSA level (> 3 ng/ml) or abnormal digital rectal examination, were consecutively included. All subjects underwent SelectMDx, PSA determination and mpMRI. Results SelectMDx score was positive in 94.1 and 100% of PCa and csPCa, respectively, and in only 8.6% of negative cases at biopsy. The probability for a csPCa at the SelectMDx score was significantly (p = 0.002) higher in csPCa (median value 52.0%) than in all PCa (median value 30.0%). SelectMDx showed slightly lower sensitivity (94.1 versus 100.0%) but higher specificity (91.4%) than total PSA (17.1%), and the same sensitivity but higher specificity than mpMRI (80.0%) in predicting PCa at biopsy. The association of SelectMDx plus mpMRI rather than PSA density (PSAD) plus mpMRI showed higher specificity (both 91.4%) compared to the association of PSA plus mpMRI (85.7%). In terms of csPCa predictive value, SelectMDx showed higher specificity (73.3%) than PSA (13.3%) and mpMRI (64.4%); as for the association of SelectMDx plus mpMRI (75.6%) versus PSA plus mpMRI (68.9%), the association of PSAD plus mpMRI showed the highest specificity (80.0%). Conclusion Our results of SelectMDx can be confirmed as significant but their impact on clinical practice together with a cost-effectiveness evaluation should be investigated in a larger prospective multicenter analysis

Cribriform pattern does not have a significant impact in Gleason Score ≥7/ISUP Grade ≥2 prostate cancers submitted to radical prostatectomy

The aim of this study was to correlate cribriform pattern (CP) with other parameters in a large prospective series of Gleason score ≥7/ISUP grade ≥2 prostate cancer (PC) cases undergoing radical prostatectomy (RP)

Impact of uni- or multifocal perineural invasion in prostate cancer at radical prostatectomy

Background: Aim of this study was to correlate perineural invasion (PNI) with other clinical-pathological parameters in terms of prognostic indicators in prostate cancer (PC) cases at the time of radical prostatectomy (RP). Methods: Prospective study of 288 consecutive PC cases undergoing RP. PNI determination was performed either in biopsy or in RP specimens classifying as uni- and multifocal PNI. The median follow-up time was 22 (range, 6-36) months. Results: At biopsy PNI was found in 34 (11.8%) cases and in 202 (70.1%) cases at the time of surgery. Among those identified at RP 133 (46.1%) and 69 (23.9%) cases had uni- and multi-PNI, respectively. Presence of PNI was significantly (P<0.05) correlated with unfavorable pathological parameters such higher stage and grade. The percentage of extracapsular extension in PNI negative RP specimens was 18.6% vs. 60.4% of PNI positive specimens. However, the distribution of pathological staging and International Society of Urological Pathology (ISUP) grading did not vary according to whether PNI was uni- or multifocal. The risk of biochemical progression increased 2.3 times in PNI positive cases was significantly associated with the risk of biochemical progression (r=0.136; P=0.04). However, at multivariate analysis PNI was not significantly associated with biochemical progression [hazard ratio (HR): 1.87, 95% confidence interval (CI): 0.68-3.12; P=0.089]. Within patients with intermediate risk disease, multifocal PNI was able to predict cases with lower mean time to biochemical and progression free survival (chi-square 5.95; P=0.04). Conclusions: PNI at biopsy is not a good predictor of the PNI incidence at the time of RP. PNI detection in surgical specimens may help stratify intermediate risk cases for the risk of biochemical progression