PATZ1-Rearranged Tumors of the Central Nervous System: Characterization of a Pediatric Series of Seven Cases.

PATZ1-rearranged sarcomas are well-recognized tumors as part of the family of round cell sarcoma with EWSR1-non-ETS fusions. Whether PATZ1-rearranged central nervous system (CNS) tumors are a distinct tumor type is debatable. We thoroughly characterized a pediatric series of PATZ1-rearranged CNS tumors by chromosome microarray analysis (CMA), DNA methylation analysis, gene expression profiling and, when frozen tissue is available, optical genome mapping (OGM). The series consisted of 7 cases (M:F=1.3:1, 1-17 years, median 12). On MRI, the tumors were supratentorial in close relation to the lateral ventricles (intraventricular or iuxtaventricular), preferentially located in the occipital lobe. Two major histologic groups were identified: one (4 cases) with an overall glial appearance, indicated as "neuroepithelial" (NET) by analogy with the corresponding methylation class (MC); the other (3 cases) with a predominant spindle cell sarcoma morphology, indicated as "sarcomatous" (SM). A single distinct methylation cluster encompassing both groups was identified by multidimensional scaling analysis. Despite the epigenetic homogeneity, unsupervised clustering analysis of gene expression profiles revealed 2 distinct transcriptional subgroups correlating with the histologic phenotypes. Interestingly, genes implicated in epithelial-mesenchymal transition and extracellular matrix composition were enriched in the subgroup associated to the SM phenotype. The combined use of CMA and OGM enabled the identification of chromosome 22 chromothripsis in all cases suitable for the analyses, explaining the physical association of PATZ1 to EWSR1 or MN1. Six patients are currently disease-free (median follow-up 30 months, range 12-92). One patient of the SM group developed spinal metastases at 26 months from diagnosis and is currently receiving multimodal therapy (42 months). Our data suggest that PATZ1-CNS tumors are defined by chromosome 22 chromothripsis as causative of PATZ1 fusion, show peculiar MRI features (eg, relation to lateral ventricles, supratentorial frequently posterior site), and, although epigenetically homogenous, encompass 2 distinct histologic and transcriptional subgroups.

Role of targeted biopsy, perilesional biopsy, and random biopsy in prostate cancer diagnosis by mpMRI/transrectal ultrasonography fusion biopsy.

PURPOSE: It is still not clear the role of perilesional biopsy (PL) and the extension of the random biopsy (RB) scheme to be adopted during mpMRI-guided ultrasound fusion biopsy (FB). To evaluate the increase in diagnostic accuracy achieved by PL and different RB schemes over target biopsy (TB). METHODS: We collected prospectively 168 biopsy-naïve patients with positive mpMRI receiving FB and concurrent 24-core RB. The diagnostic yields of the different possible biopsy schemes (TB only; TB + 4 PL cores; TB + 12-core RB; TB + 24-core RB) were compared by the McNemar test. Clinically significant (CS) prostate cancer (PCA) was defined according to the definition of the PROMIS trial. Regression analyses were used to identify independent predictors of the presence of any cancer, csPCA. RESULTS: The detection rate of CS cancers increased to 35%, 45%, and 49% by adding 4 PL cores, 12, and 24 RB cores, respectively (all p < 0.02). Notably, the largest scheme including 3 TB and 24 RB cores identified a small but statistically significant 4% increase in detection rate of CS cancer, as compared with the second largest scheme. TB alone identified only 62% of the CS cancers. Such figure increased to 72% by adding 4 PL cores, and to 91% by adding 14 RB cores. CONCLUSIONS: We found that PL biopsy increased the detection rate of CS cancers as compared with TB alone. However, the combination of those cores missed about 30% of the CS cancers identified with larger RB cores, notably including a considerable 15% of cases located contralaterally to the index tumor.

Fatal hyperprogression induced by nivolumab in metastatic renal cell carcinoma with sarcomatoid features: a case report.

In the past few years, the immune checkpoint inhibitor (ICI) nivolumab has become standard of care in the treatment of metastatic renal cell carcinoma (mRCC) progressing after antiangiogenic agents. To date, neither expression of programmed death ligand-1 (PD-L1) nor any other biomarker can be used to predict responses to ICIs, although intermediate-poor International Metastatic Database of Renal Carcinoma (IMDC) risk patients and those with sarcomatoid tumors appear to achieve superior benefit from immunotherapy. Paradoxically, ICIs may sometimes increase the speed of tumor growth. This rare phenomenon, called hyperprogression, has first been described in patients with melanoma and lung cancer treated with ICIs and is associated with poor survival. Here, we present the case of a patient affected by an intermediate IMDC risk mRCC with diffuse sarcomatoid features who achieved long disease control with first-line sunitinib and then started a second-line treatment with nivolumab. Unexpectedly, he experienced a dramatic acceleration of tumor growth and died soon after the third infusion of nivolumab. Then, we review the frequency of hyperprogression in mRCC and discuss the biological peculiarity of sarcomatoid RCC in terms of different responses to ICIs and antiangiogenic agents.

Rapid disease progression in patient with mismatch-repair deficiency pituitary ACTH-secreting adenoma treated with checkpoint inhibitor pembrolizumab.

Secreting pituitary adenomas are tumors for which few treatment options are available, including surgical treatment and management of hormonal imbalance due to altered pituitary secretion. In case of inoperable relapse, radiotherapy or chemotherapeutic treatment can be considered; the effectiveness of these treatments, however, remains limited. In the immunotherapy era, it is necessary to select patients who can benefit from immunotherapeutic treatment. Mismatch repair deficiency is strongly associated with responsiveness to anti-PD-1 in other cancers and can be detected using immunohistochemistry for MLH1, MSH2, MHS6, and PMS2. In this case report, we report a case of rapid disease progression to pembrolizumab in a patient with a MMRd pituitary adrenocorticotropic hormone (ACTH)-secreting adenoma. For the best of our knowledge, we described for the first time, a poor efficacy of pembrolizumab in a patient with ACTH-secreting pituitary adenoma having mismatch repair deficiency probably caused by high levels of cortisol in this patient. Prospective study should be performed to assess the activity of immune checkpoint inhibitor alone or in association with temozolomide in this subsetting of pituitary adenomas.

Long-course temozolomide in aggressive pituitary adenoma: real-life experience in two tertiary care centers and review of the literature.

PURPOSE: Aggressive pituitary adenomas (APAs) and pituitary carcinomas (PCs) are challenging for their invasive nature, resistance to treatment and recurrences. Temozolomide (TMZ) is used with benefit and well-tolerated toxicity profile in APAs and PCs. In most studies patients received ≤ 12 cycles but the best length of treatment is debated since other options after discontinuation are scarce and a second course is mainly unsuccessful. METHODS: We report outcomes of 8 patients with APAs and PCs treated with TMZ for more than 12 continuous cycles with a literature review. Data were retrospectively collected from Padua and Milan University Hospitals. TMZ was used as a single agent (150-200 p.o. mg/m2 daily, 5/28 days) for 14 to 45 cycles. RESULTS: Eight patients (7 M), 7 APAs and 1 PC. Previous treatments included neurosurgery and radiotherapy in all cases except two giant masses (ACTH-silent APA and prolactinoma). No patient had progression disease (PD) during long-term treatment nor toxicities. No one had complete response (CR) but four had partial response (PR). Four ACTH+ tumors maintained stable disease (SD) but the secretion pattern improved in all. After drug withdrawal, three had delayed PD (2 after 18 and one after 29 months, all ACTH+); two are still in SD. CONCLUSIONS: TMZ may be useful and well-tolerated in APAs and PCs as a long-term therapy. PR appears within the first cycles with no escape throughout the treatment; most patients achieve SD. We suggest extended protocols particularly in responsive ACTH+ PAs and PCs, when further therapies may be unsuccessful.

Mismatch-Repair Protein Expression in High-Grade Gliomas: A Large Retrospective Multicenter Study.

BACKGROUND: DNA mismatch repair (MMR) is a system for repairing errors in DNA replication. Cancer cells with MMR deficiency can have immunohistochemical loss of MMR protein expression leading to a hypermutable phenotype that may correlate with anti-PD1 efficacy. Scant data exist about immunohistochemical loss of MMR protein expression in high-grade gliomas (HGG). MATERIALS AND METHODS: We performed a large multicenter retrospective study to investigate the frequency and the prognostic role of immunohistochemical loss of MMR protein expression in HGG patients; we nevertheless evaluated the association between this status and clinical or molecular characteristics. Immunohistochemical loss of MMR protein expression was recorded as partial or complete loss of at least 1 MMR protein. RESULTS: We analyzed the expression of MMR proteins in tumor tissue of 355 consecutive patients. Partial and complete immunohistochemical loss of MMR proteins was found in 43/355 samples (12.1%) and among these, 15 cases (4.2%) showed a complete loss of at the least one MMR protein. Alteration of MSH2 expression was found in 55.8%, MSH6 in 46.5%, PMS2 in 34.9%, and MLH1 in 30.2%. Alteration of MMR protein expression was statistically more frequent in anaplastic gliomas, in recurrent disease, in patients treated with temozolomide, and in IDH-mut gliomas. Immunohistochemical loss of MMR proteins was not associated with survival, adjusting for clinically relevant confounders. CONCLUSIONS: MMR protein expression status did not affect survival in HGG patients. We identified clinical and molecular characteristics correlating with immunohistochemical loss of MMR proteins expression. A large study should be performed to analyze its predictive role of immune checkpoint inhibitor efficacy in these subgroups of patients.

Regorafenib compared with lomustine in patients with relapsed glioblastoma (REGOMA): a multicentre, open-label, randomised, controlled, phase 2 trial.

BACKGROUND: Glioblastoma is a highly vascularised tumour and there are few treatment options after disease recurrence. Regorafenib is an oral multikinase inhibitor of angiogenic, stromal, and oncogenic receptor tyrosine kinases. We aimed to assess the efficacy and safety of regorafenib in the treatment of recurrent glioblastoma. METHODS: REGOMA is a randomised, multicentre, open-label phase 2 trial done in ten centres in Italy. Eligible patients (aged ≥18 years) with histologically confirmed glioblastoma, Eastern Cooperative Oncology Group performance status 0 or 1, and documented disease progression after surgery followed by radiotherapy and temozolomide chemoradiotherapy were randomly assigned (1:1) by a web-based system, stratified by centre and surgery at recurrence (yes vs no), to receive regorafenib 160 mg once daily for the first 3 weeks of each 4-week cycle or lomustine 110 mg/m2 once every 6 weeks until disease progression, death, unacceptable toxicity, or consent withdrawal. The primary endpoint was overall survival in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02926222, and is currently in follow-up. FINDINGS: Between Nov 27, 2015, and Feb 23, 2017, 124 patients were screened and 119 eligible patients were randomly assigned to receive regorafenib (n=59) or lomustine (n=60). Median follow-up was 15·4 months (IQR 13·8-18·1). At the analysis cutoff date, 99 (83%) of 119 patients had died: 42 (71%) of 59 in the regorafenib group and 57 (95%) of 60 in the lomustine group. Overall survival was significantly improved in the regorafenib group compared with the lomustine group, with a median overall survival of 7·4 months (95% CI 5·8-12·0) in the regorafenib group and 5·6 months (4·7-7·3) in the lomustine group (hazard ratio 0·50, 95% CI 0·33-0·75; log-rank p=0·0009). Grade 3-4 treatment-related adverse events occurred in 33 (56%) of 59 patients treated with regorafenib and 24 (40%) of 60 with lomustine. The most frequent grade 3 or 4 adverse events related to regorafenib were hand-foot skin reaction, increased lipase, and blood bilirubin increased (in six [10%] of 59 patients each). In the lomustine group, the most common grade 3 or 4 adverse events were decreased platelet count (eight [13%] of 60 patients), decreased lymphocyte count (eight [13%]), and neutropenia (seven [12%]). No death was considered by the investigators to be drug related. INTERPRETATION: REGOMA showed an encouraging overall survival benefit of regorafenib in recurrent glioblastoma. This drug might be a new potential treatment for these patients and should be investigated in an adequately powered phase 3 study. FUNDING: Veneto Institute of Oncology and Bayer Italy.

Does 1.5 T mpMRI play a definite role in detection of clinically significant prostate cancer? Findings from a prospective study comparing blind 24-core saturation and targeted biopsies with a novel data remodeling model.

BACKGROUND: Multiparametric-magnetic resonance imaging (mpMRI) can accurately detect high-grade and larger prostate cancers (PC). AIMS: To evaluate the ability of 1.5 T magnetic field mpMRI-targeted Prostate Biopsies (PBx) in predicting PC in comparison with blind 24-core saturation PBx (sPBx). METHODS: We prospectively collected data from patients undergoing transrectal sPBx and, if needed, targeted PBx of suspected lesions based on the 16-'region-of-interest' (ROI) PI-RADS graph. Data remodeling: for each 'target' (each suspected lesion at mpMRI), we identified all the 16 'ROIs' into which the lesion extended: these single 'ROIs' were identified as 'macro-targets'. For each 'ROI' and 'macro-target', we compared the mpMRI result with that of a saturation and targeted biopsy (if performed). RESULTS: 1.5T mpMRI showed a PI-RADS value ≥ 3 in 101 patients (82.1%). We found a PC in 50 (40.6%). Negative-positive predictive values for mpMRI were 82-45%, respectively. Of the 22 patients with normal mpMRI, four had a PC, but none had a clinically significant cancer. After the data remodeling, we demonstrated the presence of PC in 228 'ROIs': (a) only in targeted biopsies in 15 'ROIs'/'macro-targets' (6.6%); (b) only in sPBx in 177 'ROIs' (77.6%); (c) in both targeted and sPBx in 36 'ROIs' (15.8%). DISCUSSION: 81.8% of patients with normal 1.5T mpMRI were negative at PBx. Performing only targeted PBx may lead to lack of PC diagnosis in about 50% of patients. CONCLUSIONS: In patients with suspected PC and a previous negative PBx, a normal mpMRI may exclude a clinically significant PC, avoiding sPBx.

Novel insights on testicular volume and testosterone replacement therapy in Klinefelter patients undergoing testicular sperm extraction. A retrospective clinical study.

STUDY QUESTION: To investigate whether sperm recovery is related to clinical features, hormone parameters and testosterone replacement therapy (TRT) in patients with Klinefelter syndrome (KS). SUMMARY ANSWER: This study provides three interesting insights: (i) the probability to retrieve sperm is not related to testicular volume; (ii) TRT does not affect sperm retrieval rate (SRR); and (iii) reduced levels of LH and FSH represent a negative predictor of sperm retrieval in patients with TRT. WHAT IS KNOWN ALREADY: Classical KS shows a karyotype with one extra X chromosome in all of somatic cells and clinical manifestations characterized by hypergonadotropic hypogonadism and infertility. STUDY DESIGN, SIZE AND DURATION: We performed a retrospective cohort study. Data from 111 consecutive KS azoospermic patients undergoing testicular sperm extraction (TESE) were collected from 2005 to 2016. PARTICIPANTS/MATERIALS, SETTING AND METHODS: Data on anthropometric parameters, reproductive hormones and testicular volumes were collected. SRR was related to clinical characteristics and compared between TRT and untreated patients. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 38 patients (34.2%) had successful sperm recovery. The comparison of clinical characteristics did not differ between patients with and without sperm recovery. Sperm retrieval was successful also in subjects with smaller testes. The comparison of SRR in patients with or without TRT was not different (33.3% vs 34.6%). In TRT group, LH and FSH levels were significantly lower in subjects with no sperm retrieval (P values, respectively, <.05 and <.001). LIMITATIONS AND REASONS FOR CAUTION: Well-designed controlled studies are necessary to confirm these data aimed to set the best therapeutic approach for fertility management in hypogonadal patients with nonmosaic KS. WIDER IMPLICATIONS OF THE FINDINGS: Age at TESE, anthropometric measures, testis volume, sex hormones levels and semen parameters are not predictive parameters of SRR. Among TRT patients, reduced gonadotropin is related to failure in sperm retrieval.

Good tolerability of maintenance temozolomide in glioblastoma patients after severe hematological toxicity during concomitant radiotherapy and temozolomide treatment: report of two cases.

Glioblastoma is the most common and aggressive primitive brain tumor in adults. Temozolomide (TMZ) administered daily with radiation therapy, followed by adjuvant TMZ has become the standard treatment. Although TMZ treatment has been considered to have a low toxicity profile, studies have noted the development of a severe myelosuppression, especially during the concomitant treatment; this toxicity may in some cases be prolonged and consequently treatment must be definitively discontinued. We analyzed two cases treated at our oncological center who developed severe and prolonged hematological toxicity during concomitant chemoradiotherapy treatment with TMZ. Hypothesizing that radiation therapy and daily TMZ could be the major causes of severe hematological toxicity during the concomitant phase, we decided to treat both patients with maintenance TMZ at the time of recovery of hematological values. Patients showed good tolerability without important myelosuppression. In conclusion, we suggest that glioblastoma patients with severe myelotoxicity during daily TMZ and radiation therapy be treated with maintenance TMZ at the time of blood value recovery.

Study of diagnostic accuracy of Fagan's two-step nomogram in increasing the value of predictive tools for prostate cancer: application of specific spatial distribution of positive/negative bioptic cores to predict extracapsular extension.

BACKGROUND: Prostate cancer (PC) represents the second most frequent cancer in the male population worldwide. It is mandatory to have a very accurate staging to choice the best possible treatment. AIMS: To test the possibility of improving the performance of Partin's tables in predicting the pathological staging of PC by introducing bioptic parameters through an innovative statistic tool (Fagan's two-step nomogram). METHODS: We prospectivelly collected data of all 1048 consecutive patients undergoing saturation 24-core transrectal prostate biopsy. Then, in eligible 94 patients, we compared the prediction of presence/absence of extracapsular extension of neoplasm (EPE+/-), with pathological assessment of invasion through (pseudo)capsule in the prostatectomy specimens. Starting from the probability of EPE- (pre-test probability, calculated with formula "100%-risk of EPE+"), we used Fagan's nomogram to examine the diagnostic sensitivity (DSe) and specificity (DSp) of negative "lateral" bioptic cores. RESULTS: We specifically analyzed the status of "lateral" cores in each side (94 patients × 2 sides = 188 sides). "Lateral" cores were negative in 42.5% of sides (80/188) with a DSe and DSp of 91.7 and 45.4%, respectively. In these sides, the mean probability of EPE+ according to Partin's tables was 21.6%. With Fagan's nomogram, the post-test probability of EPE+ when all "lateral" cores were negative was 14.1%, with a substantial gain of 7.5%. DISCUSSION: The spatial distribution of bioptic positive cores allowed us to demonstrate the role Fagan's nomogram in increasing the accuracy of already existing, predictive tools for PC. CONCLUSIONS: This pioneering study may justify the use of the above nomogram in testing "local" predictive parameters in combination with pre-existing nomograms.

Early recognition of aggressive pituitary adenomas: a single-centre experience.

BACKGROUND: Pituitary adenomas are usually considered benign tumours, although some of them can exhibit an aggressive behaviour. Patients with clinically aggressive pituitary adenomas are frequently diagnosed with larger masses, and may present an earlier recurrence (or persistence) after surgery. Our aim was to characterise the clinical, histopathological and radiological features of patients with aggressive pituitary adenoma, in order to correlate their clinical behaviour with the response to treatment plan. METHOD: We considered an aggressive pituitary adenoma on the basis of radiological features (size, local invasion), pathological reports (atypical adenoma: MIB-1 >3%, p53 immunoreactivity, increased mitotic activity) and clinical aspects (response to surgery, radiotherapy and medical treatment). RESULTS: Among our cohort of 582 patients, we considered 102 subjects with aggressive pituitary adenomas (18%, 56 male and 46 female): 14 adrenocorticotrophic hormone (ACTH)-secreting, 18 growth hormone (GH)-secreting, 23 prolactin (PRL)-secreting and 47 non-secreting, with a median follow-up of 5 years. In the whole cohort, 75% of patients with aggressive pituitary adenomas presented invasion of surrounding structure, especially GH-secreting, PRL-secreting and non-secreting. Besides invasion, their remission rate after surgery, radiotherapy or medical treatment was similar, irrespective of hormonal secretion. Surgery was the most performed treatment (overall remission rate of 24%), especially in those patients with ACTH- or GH-secreting adenoma, and 22% of patients were submitted to radiotherapy, with a remission rate of 45% after a median of 3 years. Two consecutive years of medical treatment, in patients with secreting pituitary adenoma, achieved disease control in 41% of them. Considering pathological reports, 24% of cases were defined as atypical adenomas; radiological characteristics, responses to medical treatment and remission rates were similar among patients with typical and atypical adenoma. CONCLUSIONS: We proposed a new and comprehensive definition of aggressive pituitary adenoma, based upon radiological, clinical and pathological features. In a selected cohort of patients, radiological invasion resulted in the most common marker to describe the aggressive behaviour of pituitary adenoma. Surgery, radiotherapy and medical treatment (the latter only in secreting adenoma) achieved disease control in half of the patients with aggressive adenoma, especially surgery in those with ACTH-oma and medical treatment in those with GH- and PRL-secreting adenoma. Nevertheless, radiological, clinical or atypical features did not affect the outcome.

Outcome of patients affected by newly diagnosed glioblastoma undergoing surgery assisted by 5-aminolevulinic acid guided resection followed by BCNU wafers implantation: a 3-year follow-up.

The purpose of the study was to evaluate the clinical outcome of the association of BCNU wafers implantation and 5-aminolevulinic acid (5-ALA) fluorescence in the treatment of patients with newly diagnosed glioblastoma (ndGBM). Clinical and surgical data from patients who underwent 5-ALA surgery followed by BCNU wafers implantation were retrospectively evaluated (20 patients, Group I) and compared with data of patients undergoing surgery with BCNU wafers alone (42 patients, Group II) and 5-ALA alone (59 patients, Group III). Patients undergoing 5-ALA assisted resection followed by BCNU wafers implantation (Group I) resulted long survivors (>3 years) in 15 % of cases and showed a median PFS and MS of 11 and 22 months, respectively. Patients treated with BCNU wafers presented a significantly higher survival when tumor was removed with the assistance of 5-ALA (22 months with vs 18 months without 5-ALA, p < 0.0001); these data could be partially explained by the significantly higher CRET achieved in patients operated with 5-ALA assistance (80 % with vs 47 %% without 5-ALA). Moreover, patients of Group I showed a significant increased survival compared with Group III (5-ALA without BCNU) (22 months with vs 21 months without BCNU wafers, p = 0.0025) even with a comparable CRET (80 % vs 76 %, respectively). The occurrence of adverse events related to wafers did not significantly increase with 5-ALA (20 % with and 19 % without 5-ALA) and did not impact in survival outcome. In conclusion, our experience shows that on selected ndGBM patients 5-ALA technology and BCNU wafers implantation show a synergic action on patients' outcome without increasing adverse events occurrence.

Diagnostic value of plasma and urinary 2-hydroxyglutarate to identify patients with isocitrate dehydrogenase-mutated glioma.

BACKGROUND: Mutant isocitrate dehydrogenase (IDH) 1/2 enzymes can convert α-ketoglutarate into 2-hydroxyglutarate (2HG). The aim of the present study was to explore whether 2HG in plasma and urine could predict the presence of IDH1/2 mutations in patients with glioma. MATERIALS AND METHODS: All patients had histological confirmation of glioma and a recent brain magnetic resonance imaging scan showing the neoplastic lesion. Plasma and urine samples were taken from all patients, and the 2HG concentrations were determined using liquid chromatography tandem mass spectrometry. RESULTS: A total of 84 patients were enrolled: 38 with R132H-IDH1 mutated and 46 with wild type. Among the 38 patients with mutant IDH1, 21 had high-grade glioma and 17 had low-grade glioma. Among the 46 patients with IDH1 wild-type glioma, 35 and 11 had high- and low-grade glioma, respectively. In all patients, we analyzed the mean 2HG concentration in the plasma, urine, and plasma/urine ratio (Ratio_2HG). We found a significant difference in the Ratio_2HG between patients with and without an IDH1 mutation (22.2 ± 8.7 vs. 15.6 ± 6.8; p < .0001). The optimal cutoff value for Ratio_2HG to identify IDH1 mutation was 19 (sensitivity, 63%; specificity, 76%; accuracy, 70%). In the patients with high-grade glioma only, the optimal cutoff value was 20 (sensitivity, 76%; specificity, 89%; accuracy, 84%; positive predictive value, 80%; negative predictive value, 86%). In 7 of 7 patients with high-grade glioma, we found a correlation between the Ratio_2HG value and the response to treatment. CONCLUSION: Ratio_2HG might be a predictor of the presence of IDH1 mutation. The measurement of 2HG could be useful for disease monitoring and also to assess the treatment effects in these patients.

Profiling of expression of human papillomavirus-related cancer miRNAs in penile squamous cell carcinomas.

Penile squamous cell carcinoma (PSCC) is a rare tumor associated with high-risk human papillomavirus (HR-HPV) infection in 30% to 60% of cases. Altered expression of miRNAs has been reported in HPV-related cervical and head and neck cancers, but such data have not been available for PSCC. We analyzed a series of 59 PSCCs and 8 condylomata for presence of HPV infection, for p16(INK4a), Ki-67, and p53 immunohistochemical expression, and for expression of a panel of cellular miRNAs (let-7c, miR-23b, miR-34a, miR-145, miR-146a, miR-196a, and miR-218) involved in HPV-related cancer. HR-HPV DNA (HPV16 in most cases) was detected in 17/59 (29%) PSCCs; all penile condylomata (8/8) were positive for low-risk HPV6 or HPV11. HR-HPV(+) PSCCs overexpressed p16(INK4a) in 88% cases and p53 in 35% of cases, whereas HR-HPV(-) PSCCs were positive for p16(INK4a) and p53 immunostaining in 9% and 44% of cases, respectively. Among the miRNAs investigated, expression of miR-218 was lower in PSCCs with HR-HPV infection and in p53(-) cancers. Hypermethylation of the promoter of the SLIT2 gene, which contains miR-218-1 in its intronic region, was frequently observed in PSCCs, mainly in those with low miR-218 expression. Epigenetic silencing of miR-218 is a common feature in HR-HPV(+) PSCCs and in HR-HPV(-) PSCCs without immunohistochemical detection of p53.

Histopathological characteristics of microfocal prostate cancer detected during systematic prostate biopsy.

OBJECTIVE: To evaluate the prevalence of adverse pathological features and the percentage of multifocal and/or bilateral disease in a series of patients who underwent radical prostatectomy (RP) for unique, microfocal prostate cancer (miPCa) detected on prostate biopsy in the pre-active surveillance (AS) era. PATIENTS AND METHODS: In this retrospective, multi-institutional study, we analysed the clinical records of 131 consecutive patients who underwent either retropubic or robot-assisted RP for miPCa at two referral centres from January 2000 to December 2011. miPCa was defined as a neoplastic lesion present in ≤10% of core with biopsy Gleason score not applicable or biopsy Gleason score 6. RESULTS: There were 17 (13%) pT3-4 prostate cancers and a single case (0.8%) of pN+ tumour. Moreover, 31 (24.1%) patients had a Gleason score of >6 in the RP specimen. Therefore, unfavourable pathological features (pT3-4/N+ and/or Gleason score >6) were present in 40 (30.5%) patients. The median (interquartile range) prostate-specific antigen (PSA) density was 0.11 (0.09-0.17) and 0.16 (0.11-0.24) ng/mL/mL in patients with favourable and unfavourable pathological characteristics, respectively (P = 0.003). The receiver operating characteristic curve had an area under the curve value of 0.67 (95% confidence interval 0.56-0.77) for PSA density to predict the risk of unfavourable pathological features. CONCLUSION: Patients with miPCa who are candidates for an AS protocol should be adequately informed that in ≈30% of cases the cancer might be locally advanced and/or with a Gleason score of >6. Those unfavourable pathological characteristics could be predicted by the PSA density value. Further studies should investigate the role of a more extensive biopsy sampling to reduce the risk of under-staging and/or under-grading in patients with an initial diagnosis of miPCa.

Temozolomide and pasireotide treatment for aggressive pituitary adenoma: expertise at a tertiary care center.

Aggressive pituitary adenomas (PAs) are clinically challenging for endocrinologists and neurosurgeons due to their locally invasive nature and resistance to standard treatment (surgery, medical or radiotherapy). Two pituitary-directed drugs have recently been proposed: temozolomide (TMZ) for aggressive PA, and pasireotide for ACTH-secreting PA. We describe the experience of our multidisciplinary team of endocrinologists, neurosurgeons, neuroradiologists, oncologists, otolaryngologists and pathologists with TMZ and pasireotide treatment for aggressive PAs in terms of their radiological shrinkage and genetic features. We considered five patients with aggressive PA, three of them non-secreting (two ACTH-silent and one becoming ACTH secreting), and two secreting (one GH and one ACTH). TMZ was administrated orally at 150-200 mg/m(2) daily for 5 days every 28 days to all 5 patients, and 2 of them also received pasireotide 600-900 µg bid sc. We assessed the MRI at the baseline and during TMZ or pasireotide treatment. We also checked for MGMT promoter methylation and IDH, BRAF and kRAS mutations. Considering TMZ, two patients showed PA progression, one stable disease and two achieved radiological and clinical response. Pasireotide was effective in reducing hypercortisolism and mass volume, combined with TMZ in one case. Both treatments were generally well tolerated; one patient developed a grade 2 TMZ-induced thrombocytopenia. None of patients developed hypopituitarism while taking TMZ or pasireotide treatment. No genetic anomalies were identified in the adenoma tissue. TMZ and pasireotide may be important therapies for aggressive PA, alone or in combination.

Intra-operative 5-aminolevulinic acid (ALA)-induced fluorescence of medulloblastoma: phenotypic variability and CD133(+) expression according to different fluorescence patterns.

5-Aminolevulinic acid (5-ALA) fluorescence has been proved advantageous in glioma surgery. Conflicting results have been reported by few studies published in literature about intra-operative 5-ALA-induced fluorescence of medulloblastoma (MDB). The aim of this study is to verify if these conflicting results could be explained by intra-tumoral histological and phenotypic differences. In the present case of a 45-year-old patient affected by a cerebellar MDB, histological analysis of cell phenotype and 5-ALA and CD133 correlation were performed in multiple samples according to different fluorescence patterns. Intra-operatively, the tumor appeared unevenly fluorescent under blue-violet light. Histologically, 5-ALA-intense biopsies from inner areas were characterized by a significant amount of cancer cells, whereas 5-ALA faint regions from peripheral areas displayed normal cerebellar features, with MDB cells infiltrating healthy tissues. Presenting our findings, we show the correlation between different 5-ALA fluorescence patterns of medulloblastoma with specific histological and phenotypical features. Thus, we hypothesize that a distinct relationship between CD133 expression and fluorescence accumulation presented in our study could partially explain the divergent results published in literature.

Peripheral primitive neuroectodermal tumor of seminal vesicles: is there a role for relatively aggressive treatment modalities?

A 50 year old white man received an incidental ultrasound diagnosis of hypoechoic mass interesting the right seminal vesicle. A CT scan showed the presence of a 7.8 cm roundish cyst, originating from the right seminal vesicle. He had been followed by the removal of the right seminal vesicle and both the cystic lesion. The histological findings of the specimen documented the presence of small round cells compatible with Ewing's sarcoma/PPNET. The patient received also adjuvant chemotherapy and radiation treatment. After 10 years, the follow-up is still negative.

Role of targeted biopsy, perilesional biopsy, random biopsy, and their combination in the detection of clinically significant prostate cancer by mpMRI/transrectal ultrasonography fusion biopsy in confirmatory biopsy during active surveillance program.

BACKGROUND: Based on the findings of different trials in biopsy naïve patients, target biopsy (TB) plus random biopsy (RB) during mpMRI-guided transrectal ultrasound fusion biopsy (FB) are often also adopted for the biopsy performed during active surveillance (AS) programs. At the moment, a clear consensus on the extent and modalities of the procedure is lacking. OBJECTIVE: To evaluate the increase in diagnostic accuracy achieved by perilesional biopsy (PL) and different RB schemes during FB performed in AS protocol. DESIGN, SETTING, AND PARTICIPANTS: We collected prospectively the data of 112 consecutive patients with low- or very-low-risk prostate cancer; positive mpMRI underwent biopsy at a single academic institution in the context of an AS protocol. INTERVENTION(S): mpMRI/transrectal US FB with Hitachi RVS system with 3 TB and concurrent transrectal 24-core RB. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The diagnostic yield of the different possible biopsy schemes (TB only; TB + 4 perilesional (PL) cores; TB + 12-core RB; TB + 24-core RB) was compared by the McNemar test. Univariable and multivariable regression analyses were adopted to identify predictors of any cancer, Gleason grade group (GGG) ≥2 cancers, and the presence of GGG≥2 cancers in the larger schemes only. RESULTS AND LIMITATIONS: The detection rate of GGG ≥2 cancers increased to 30%, 39%, and 49% by adding 4 PL cores, 14, and 24 RB cores, respectively, to TB cores (all p values <0.01). On the whole, TB alone, 14-core RB, and 24-core-RB identified 38%, 47%, and 56% of all the GGG ≥2 cancers. Such figures increased to 62% by adding to TB 4 PL cores, and to 80% by adding 14 RB cores. Most of the differences were observed in PI-RADS 4 lesions. CONCLUSIONS: We found that PL biopsy increased the detection rate of GGG ≥2 cancers as compared with TB alone. However, the combination of those cores missed a large percentage of the CS cancers identified with larger RB cores, including a 20% of CS cancers diagnosed only by the combination of TB plus 24-core RB.