Evaluation of margins during radical prostatectomy: confocal microscopy vs frozen section analysis.

OBJECTIVES: To test the performance of ex vivo fluorescence confocal microscopy (FCM; Vivascope 2500M-G4), as compared to intra-operative frozen section (IFS) analysis, to evaluate surgical margins during robot-assisted radical prostatectomy (RARP), with final pathology as the reference standard. METHODS: Overall, 54 margins in 45 patients treated with RARP were analysed with: (1) ex vivo FCM; (2) IFS analysis; and (3) final pathology. FCM margins were evaluated by two different pathologists (experienced [M.I.: 10 years] vs highly experienced [G.R.: >30 years]) as strongly negative, probably negative, doubtful, probably positive, or strongly positive. First, inter-observer agreement (Cohen's κ) between pathologists was tested. Second, we reported the sensitivity, specificity, positive predictive (PPV) and negative predictive value (NPV) of ex vivo FCM. Finally, agreement between ex vivo FCM and IFS analysis (Cohen's κ) was reported. For all analyses, four combinations of FCM results were evaluated. RESULTS: At ex vivo FCM, the inter-observer agreement between pathologists ranged from moderate (κ = 0.74) to almost perfect (κ = 0.90), according to the four categories of results. Indeed, at ex vivo FCM, the highly experienced pathologist reached the best balance between sensitivity (70.5%) specificity (91.8%), PPV (80.0%) and NPV (87.1%). Conversely, on IFS analysis, the sensitivity, specificity, PPV and NPV were, respectively, 88.2% vs 100% vs 100% vs 94.8%. The agreement between the ex vivo FCM and IFS analyses ranged from moderate (κ = 0.62) to strong (κ = 0.86), according to the four categories of results. CONCLUSION: Evaluation of prostate margins at ex vivo FCM appears to be feasible and reliable. The agreement between readers encourages its widespread use in daily practice. Nevertheless, as of today, the performance of FCM seems to be sub-par when compared to the established standard of care (IFS analysis).

A narrative review for radiation oncologists to implement preoperative partial breast irradiation.

The strategy to anticipate radiotherapy (RT) before surgery, for breast cancer (BC) treatment, has recently generated a renewed interest. Historically, preoperative RT has remained confined either to highly selected patients, in the context of personalized therapy, or to clinical research protocols. Nevertheless, in the recent years, thanks to technological advances and increased tumor biology understanding, RT has undergone great changes that have also impacted the preoperative settings, embracing the modern approach to breast cancer. In particular, the reappraisal of preoperative RT can be viewed within the broader view of personalized and tailored medicine. In fact, preoperative accelerated partial breast irradiation (APBI) allows a more precise target delineation, with less variability in contouring among radiation oncologists, and a smaller treatment volume, possibly leading to lower toxicity and to dose escalation programs. The aim of the present review, which represents a benchmark study for the AIRC IG-23118, is to report available data on different technical aspects of preoperative RT including dosimetric studies, patient's selection and set-up, constraints, target delineation and clinical results. These data, along with the ones that will become available from ongoing studies, may inform the design of the future trials and representing a step toward a tailored APBI approach with the potential to challenge the current treatment paradigm in early-stage BC.Trial registration: The study is registered at clinicaltrials.gov (NCT04679454).

Single fraction ablative preoperative radiation treatment for early-stage breast cancer: the CRYSTAL study - a phase I/II clinical trial protocol.

BACKGROUND: Breast-conserving surgery (BCS) and whole breast radiation therapy (WBRT) are the standard of care for early-stage breast cancer (BC). Based on the observation that most local recurrences occurred near the tumor bed, accelerated partial breast irradiation (APBI), consisting of a higher dose per fraction to the tumor bed over a reduced treatment time, has been gaining ground as an attractive alternative in selected patients with low-risk BC. Although more widely delivered in postoperative setting, preoperative APBI has also been investigated in a limited, though increasing, and number of studies. The aim of this study is to test the feasibility, safety and efficacy of preoperative radiotherapy (RT) in a single fraction for selected BC patients. METHODS: This is a phase I/II, single-arm and open-label single-center clinical trial using CyberKnife. The clinical investigation is supported by a preplanning section which addresses technical and dosimetric issues. The primary endpoint for the phase I study, covering the 1st and 2nd year of the research project, is the identification of the maximum tolerated dose (MTD) which meets a specific target toxicity level (no grade 3-4 toxicity). The primary endpoint for the phase II study (3rd to 5th year) is the evaluation of treatment efficacy measured in terms of pathological complete response rate. DISCUSSION: The study will investigate the response of BC to the preoperative APBI from different perspectives. While preoperative APBI represents a form of anticipated boost, followed by WBRT, different are the implications for the scientific community. The study may help to identify good responders for whom surgery could be omitted. It is especially appealing for patients unfit for surgery due to advanced age or severe co-morbidities, in addition to or instead of systemic therapies, to ensure long-term local control. Moreover, patients with oligometastatic disease synchronous with primary BC may benefit from APBI on the intact tumor in terms of tumor progression free survival. The study of response to RT can provide useful information about BC radiobiology, immunologic reactions, genomic expression, and radiomics features, to be tested on a larger scale. TRIAL REGISTRATION: The study was prospectively registered at clinicaltrials.gov ( NCT04679454 ).

Correlation between radiological and biological features and clinical outcomes in early prostate cancer: an exploratory subgroup analysis.

PTEN deletion and Ki-67 expression are two of the most promising biomarkers in prostate cancer (PCa). In the same manner, multiparametric magnetic resonance imaging (mp-MRI) guided core biopsy is a powerful tool for PCa detection and staging. The aim of the study is to assess whether a correlation can be identified between the pathological stage defined by an mp-MRI-guided core biopsy and Ki-67 expression and PTEN deletion. Such correlation might be useful for staging and treatment personalization in PCa. This investigation was conducted in the context of phase II clinical study "Short-term radiotherapy for early prostate cancer with a concomitant boost to the dominant lesion" (AIRC IG-13218), ClinicalTrials.gov identifier: NCT01913717. Nineteen patients underwent a further in-bore MRI-targeted core biopsy (MRI-TBx) on the dominant intraprostatic lesion (DIL); on this basis, an additional Gleason Score (GS) was determined. PTEN loss and Ki-67 expression on these samples were analyzed and correlated with both risk categories modifications and oncological outcomes (overall survival, biochemical and clinical relapse). GS was upgraded in 5 cases, with 4 patients re-classified as intermediate-risk and 1 patient as high-risk. The latter experienced a clinical local relapse. No correlations between up/down-staging, PTEN deletion, and Ki-67 expression were observed in this cohort. Further investigations are needed towards the identification of a pattern in the tumor aggressiveness-response in PCa treated with ultra-hypofractionated radiotherapy. Moreover, a possible relationship between biomarker analysis and imaging textural features could be explored.

Wireless ultrasound-guided vacuum-assisted breast biopsy: Experience in clinical practice at European Institute of Oncology.

In the last few years, ultrasound-guided vacuum-assisted breast biopsy (US-VABB) has replaced surgical biopsy due to higher diagnostic accuracy and lower patient discomfort, and, at present, an even greater possibility is represented by the new wireless ultrasound-guided VAB device (Wi-UVAB). The purpose of our study is to determine the diagnostic accuracy of this new device in a sizeable representative number of patients. From January 2014 to June 2018, 168 biopsies were performed in our institution using the new Wi-UVAB device. We analyzed sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy of biopsies obtained with the new device using surgical results as reference point, following patients for at least one year. In our cohort, we obtained a complete sensitivity of 97.5%, an absolute sensitivity of 94.3%, a complete specificity of 98%, and an absolute specificity of 98%. The positive predictive value of the procedure was 97.5% while the negative predictive value was 98%. The diagnostic accuracy was 98%. The Wi-UVAB is a safe procedure with high diagnostic accuracy, comparable to that of the traditional vacuum-assisted breast biopsy and even higher than that of core needle biopsy (CNB). Moreover, the Wi-UVAB is easy to use and shows low costs as core needle biopsy (CNB).

Onclarity Performance in Human Papillomavirus DNA Detection in Formalin-Fixed Paraffin-Embedded Cervical Samples.

OBJECTIVES: Diagnosis of HPV infection is usually performed from cervical liquid-based cytology specimens (LBC), but these often contain a large amount of human papillomavirus (HPV) genotypes, most of which might cause transient infections. The aim of the study was to evaluate the performance of BD Onclarity HPV test genotyping method on formalin-fixed, paraffin-embedded (FFPE) cervical specimens compared with genotyping results from LBC. MATERIALS AND METHODS: Formalin-fixed, paraffin-embedded specimens from women surgically treated for cervical intraepithelial lesions (CINs) at the European Institute of Oncology, Milan, from September 2012 to June 2013 were retrieved from the archives of the Department of Pathology of the European Institute of Oncology. The FFPE and LBC specimens were genotyped using the same extended genotyping Onclarity assay. RESULTS: We collected 99 samples (26 CIN 1, 30 CIN 2, and 43 CIN 3+), but 15 were excluded from the analysis: these 84 samples show an overall agreement of 89% for HPV status between FFPE Onclarity samples versus LBC samples. The FFPE and LBC samples showed identical genotype in 75% samples, compatible genotype (at least 1 of the genotypes detected in LBC sample was found in the tissue sample) in 14% specimens, and discrepant genotype in 11% samples. CONCLUSIONS: Our data demonstrate a very good concordance between HPV genotypes found in cytological and tissue samples, suggesting that the Onclarity method could also be used to detect HPV in tissue samples and that the HPV genotype detected in FFPE samples is one of the HPV detected in cytological samples, supporting the thesis that one lesion is caused by one HPV genotype.

Clinical performance of contrast-enhanced spectral mammography in pre-surgical evaluation of breast malignant lesions in dense breasts: a single center study.

PURPOSE: To compare the efficacy of contrast-enhanced spectral mammography, with ultrasound, full field digital mammography and magnetic resonance imaging in detection and size estimation of histologically proven breast tumors. METHODS: This open-label, single center, prospective study, included 160 dense breast women with at least one suspicious mammary lesion evaluated by ultrasound, full field digital mammography and magnetic resonance imaging in whom a mammary tumor was histologically proven after surgery performed at the European Institute of Oncology between January 2013 and December 2015. Following the complete diagnostic procedure, the patients were further investigated by contrast-enhanced spectral mammography prior to surgery. RESULTS: Overall, the detection rate of malignant breast lesions (in situ and invasive) was 93.8% (165/176) for contrast-enhanced spectral mammography, 94.4% (168/178) for ultrasound, 85.5 (147/172) for full field digital mammography and 97.7% (173/177) for magnetic resonance imaging. Radiological measurements were concordant with the post-surgical pathological measurements of the invasive tumor (i.e., within 5 mm) in: 64.6% for contrast-enhanced spectral mammography, 62.0% for ultrasound, 45.2% for full field digital mammography (p < 0.0001) and 69.9% for magnetic resonance imaging (p = 0.28); underestimated in: 17.4% for contrast-enhanced spectral mammography, 19.6% for ultrasound, 24.2% for full field digital mammography (p = 0.03) and 6.7% for magnetic resonance imaging (p = 0.0005); and overestimated in: 16.2% for contrast-enhanced spectral mammography, 16.6% for ultrasound, 16.6% for full field digital mammography and 22.7% for magnetic resonance imaging (p = 0.02). CONCLUSIONS: Our data suggest that contrast-enhanced spectral mammography improves on full field digital mammography and is comparable to ultrasound and magnetic resonance imaging in terms of detection sensitivity and size estimation of malignant lesions in dense breasts.

A novel nomogram to identify candidates for active surveillance amongst patients with International Society of Urological Pathology (ISUP) Grade Group (GG) 1 or ISUP GG2 prostate cancer, according to multiparametric magnetic resonance imaging findings.

OBJECTIVES: To develop a novel nomogram to identify candidates for active surveillance (AS) that combines clinical, biopsy and multiparametric magnetic resonance imaging (mpMRI) findings; and to compare its predictive accuracy to, respectively: (i) Prostate Cancer Research International: Active Surveillance (PRIAS) criteria, (ii) Johns Hopkins (JH) criteria, (iii) European Association of Urology (EAU) low-risk classification, and (iv) EAU low-risk or low-volume with International Society of Urological Pathology (ISUP) Grade Group (GG) 2 classification. PATIENTS AND METHODS: We selected 1837 patients with ISUP GG1 or GG2 prostate cancer (PCa), treated with radical prostatectomy (RP) between 2012 and 2018. The outcome of interest was the presence of unfavourable disease (i.e., clinically significant PCa [csPCa]) at RP, defined as: ISUP GG ≥ 3 and/or pathological T stage (pT) ≥3a and/or pathological N stage (pN) 1. First, logistic regression models including PRIAS, JH, EAU low-risk, and EAU low-risk or low-volume ISUP GG2 binary classifications (not eligible vs eligible) were used. Second, a multivariable logistic regression model including age, prostate-specific antigen density (PSA-D), ISUP GG, and the percentage of positive cores (Model 1) was fitted. Third, Prostate Imaging-Reporting and Data System (PI-RADS) score (Model 2), extracapsular extension (ECE) score (Model 3) and PI-RADS + ECE score (Model 4) were added to Model 1. Only variables associated with higher csPCa rates in Model 4 were retained in the final simplified Model 5. The area under the receiver operating characteristic curve (AUC), calibration plots and decision curve analyses were used. RESULTS: Of the 1837 patients, 775 (42.2%) had csPCa at RP. Overall, 837 (47.5%), 986 (53.7%), 348 (18.9%), and 209 (11.4%) patients were eligible for AS according to, respectively, the EAU low-risk, EAU low-risk or low-volume ISUP GG2, PRIAS, and JH criteria. The proportion of csPCa amongst the EAU low-risk, EAU low-risk or low-volume ISUP GG2, PRIAS and JH candidates was, respectively 28.5%, 29.3%, 25.6% and 17.2%. Model 4 and Model 5 (in which only PSA-D, ISUP GG, PI-RADS and ECE score were retained) had a greater AUC (0.84), compared to the four proposed AS criteria (all P < 0.001). The adoption of a 25% nomogram threshold increased the proportion of AS-eligible patients from 18.9% (PRIAS) and 11.4% (JH) to 44.4%. Moreover, the same 25% nomogram threshold resulted in significantly lower estimated risks of csPCa (11.3%), compared to PRIAS (Δ: -14.3%), JH (Δ: -5.9%), EAU low-risk (Δ: -17.2%), and EAU low-risk or low-volume ISUP GG2 classifications (Δ: -18.0%). CONCLUSION: The novel nomogram combining clinical, biopsy and mpMRI findings was able to increase by ~25% and 35% the absolute frequency of patients suitable for AS, compared to, respectively, the PRIAS or JH criteria. Moreover, this nomogram significantly reduced the estimated frequency of csPCa that would be recommended for AS compared to, respectively, the PRIAS, JH, EAU low-risk, and EAU low-risk or low-volume ISUP GG2 classifications.

Low PI-RADS assessment category excludes extraprostatic extension (≥pT3a) of prostate cancer: a histology-validated study including 301 operated patients.

OBJECTIVES: To evaluate whether low PI-RADS v2 assessment categories are effective at excluding extraprostatic extension (EPE) of prostate cancer (≥pT3a PCa). METHODS: The local institutional ethics committee approved this retrospective analysis of 301 consecutive PCa patients. Patients were classified as low- or intermediate/high-risk based on clinical parameters and underwent pre-surgical multiparametric magnetic resonance imaging. A PI-RADS v2 assessment category and ESUR EPE score were assigned for each lesion by two readers working in consensus. Histopathologic analysis of the whole-mount radical prostatectomy specimen was the reference standard. Univariate and multivariate analyses were performed to evaluate the association of PI-RADS v2 assessment category with final histology ≥pT3a PCa. RESULTS: For a PI-RADS v2 assessment category threshold of 3, the overall performance for ruling out (sensitivity, negative predictive value, negative likelihood ratio) ≥pT3a PCa was 99%/98%/0.04 and was similar in both the low-risk (96%/97%/0.12; N = 137) and the intermediate/high-risk groups (100%/100%/0.0; N = 164). In univariate analysis, all clinical and tumor characteristics except age were significantly associated with ≥pT3a PCa. In multivariate analysis, PI-RADS v2 assessment categories ≤ 3 had a protective effect relative to categories 4 and 5. The inclusion of ESUR EPE score improved the AUC of ≥pT3a PCa prediction (from 0.73 to 0.86, p = 0.04 in the overall cohort). The impact of PI-RADS v2 assessment category is reflected in a nomogram derived on the basis of our cohort. CONCLUSIONS: In our cohort, low PI-RADS v2 assessment categories of 3 or less confidently ruled out the presence of ≥pT3a PCa irrespective of clinical risk group. KEY POINTS: • Our analysis of 301 mp-MRI and RARP specimens showed that the addition of PI-RADS v2 assessment categories to clinical parameters improves the exclusion of ≥pT3a (extraprostatic) prostate cancer. • PI-RADS v2 assessment categories of 1 to 3 are useful for excluding ≥pT3a prostate cancer with a NPV of 98%; such patients can be considered as candidates for less invasive approaches. • The ability to exclude ≥pT3a prostate cancer may improve confidence in choosing nerve-sparing surgery or in avoiding pelvic nodal dissections, and similarly for patients undergoing radiotherapy, in adopting short-course adjuvant hormonal therapy or foregoing prophylactic nodal irradiation.

Thulium-yttrium-aluminium-garnet (Tm:YAG) laser treatment of penile cancer: oncological results, functional outcomes, and quality of life.

PURPOSE: To evaluate the oncological and functional outcomes of patients diagnosed with penile cancer undergoing conservative treatment through thulium-yttrium-aluminium-garnet (Tm:YAG) laser ablation. METHODS: Twenty-six patients with a penile lesion underwent ablation with a RevoLix 200 W continuous-wave laser. The procedure was carried out with a pen-like laser hand piece, using a 360 µm laser fiber and 15-20 W of power. Median (IQR) follow-up time was 24 (15-30) months. Recurrence rate and post-operative sexual function were assessed. RESULTS: Median age at surgery was 61 years. Median (inter quartile range) size of the lesions was 15 [10-20] mm. Overall, 11 (47.8%) and 12 (52.2%) at the final pathology presented in situ and invasive squamous cell carcinoma (SCC), respectively. The final pathological stage was pTis, pT1a, pT2, and pT3 in 11 (47.8%), 7 (30.4%), 3 (13.0%), and 2 (8.7%) patients, respectively. Moreover, four (17.4%) patients had a recurrence of which three (13.0%) and one (4.3%) patients developed an invasive or in situ recurrence, respectively. After treatment 6 (26.1%) patients reported a conserved penile sensitivity, while 13 (56.5%) and 4 (17.4%) patients experienced a better or worse sensitivity after ablation, respectively. Post-treatment sexual activity was achieved within the first month after laser ablation in 82.6% of the patients. CONCLUSION: Early stage penile carcinomas can be effectively treated with an organ preservation strategy. Tm:YAG conservative laser treatment is easy, safe and offers good functional outcome, with a minor impact on patient's quality of life.

Robot-assisted radical prostatectomy: Multiparametric MR imaging-directed intraoperative frozen-section analysis to reduce the rate of positive surgical margins.

PURPOSE: To investigate whether use of multiparametric magnetic resonance (MR) imaging-directed intraoperative frozen-section (IFS) analysis during nerve-sparing robot-assisted radical prostatectomy reduces the rate of positive surgical margins. MATERIALS AND METHODS: This retrospective analysis of prospectively acquired data was approved by an institutional ethics committee, and the requirement for informed consent was waived. Data were reviewed for 134 patients who underwent preoperative multiparametric MR imaging (T2 weighted, diffusion weighted, and dynamic contrast-material enhanced) and nerve-sparing robot-assisted radical prostatectomy, during which IFS analysis was used, and secondary resections were performed when IFS results were positive for cancer. Control patients (n = 134) matched for age, prostate-specific antigen level, and stage were selected from a pool of 322 patients who underwent nerve-sparing robot-assisted radical prostatectomy without multiparametric MR imaging and IFS analysis. Rates of positive surgical margins were compared by means of the McNemar test, and a multivariate conditional logistic regression model was used to estimate the odds ratio of positive surgical margins for patients who underwent MR imaging and IFS analysis compared with control subjects. RESULTS: Eighteen patients who underwent MR imaging and IFS analysis underwent secondary resections, and 13 of these patients were found to have negative surgical margins at final pathologic examination. Positive surgical margins were found less frequently in the patients who underwent MR imaging and IFS analysis than in control patients (7.5% vs 18.7%, P = .01). When the differences in risk factors are taken into account, patients who underwent MR imaging and IFS had one-seventh the risk of having positive surgical margins relative to control patients (adjusted odds ratio: 0.15; 95% confidence interval: 0.04, 0.61). CONCLUSION: The significantly lower rate of positive surgical margins compared with that in control patients provides preliminary evidence of the positive clinical effect of multiparametric MR imaging-directed IFS analysis for patients who undergo prostatectomy.

Salvage radical prostatectomy after external beam radiation therapy: a systematic review of current approaches.

BACKGROUND: Radical external beam radiotherapy (EBRT) is a standard treatment for prostate cancer patients. Despite this, the rate of intraprostatic relapses after primary EBRT is still not negligible. There is no consensus on the most appropriate management of these patients after EBRT failure. For these patients, local salvage therapy such as radical prostatectomy, cryotherapy, and brachytherapy may be indicated. OBJECTIVE: The objectives of this review were to analyze the eligibility criteria for careful selection of appropriate patients and to evaluate the oncological results and complications for each method. METHODS: A review of the literature was performed to identify studies of local salvage therapy for patients who had failed primary EBRT for localized prostate cancer. RESULTS: Most studies demonstrated that local salvage therapy after EBRT may provide long-term local control in appropriately selected patients, although toxicity is often significant. CONCLUSIONS: Our results suggest that for localized prostate cancer recurrence after EBRT, the selection of a local treatment modality should be made on a patient-by-patient basis. An improvement in selection criteria and an integrated definition of biochemical failure for all salvage methods are required to determine which provides the best oncological outcome and least comorbidity.

Underestimation rate of lobular intraepithelial neoplasia in vacuum-assisted breast biopsy.

OBJECTIVES: To evaluate the underestimation rate and clinical relevance of lobular neoplasia in vacuum-assisted breast biopsy (VABB). METHODS: A total of 161 cases of LN were retrieved from 6,435 VABB. The histological diagnosis was ALH (atypical lobular hyperplasia) in 80 patients, LCIS (lobular carcinoma in situ) in 69 patients and PLCIS (pleomorphic lobular carcinoma in situ) in 12 patients. Seventy-six patients were operated on within 2 years after VABB and 85 were clinically and radiologically monitored. The mean follow-up was 5.2 years, and the prevalence of malignancy was evaluated in the group of 85 patients. RESULTS: The clinico-pathological characteristics significantly favouring surgery were larger lesions, occurrence of a residual lesion following VABB and histological LCIS and PLCIS subtypes. The VABB underestimation rate as compared to surgery was 7.1% for ALH, 12% for LCIS and 50% for PLCIS. Overall, 11 of the 148 patients included in this survival analysis developed an ipsilateral tumour. CONCLUSION: Although obtained retrospectively in a relatively small series of patients, our data suggest that only patients with a diagnosis of PLCIS in VABB should be treated with surgery, whereas patients with ALH and LCIS could be monitored by clinical and radiological examinations. KEY POINTS: • The treatment of ALH and LCIS in VABB is still debated • Some authors favour radical treatment and others a more conservative approach • Only patients with PLCIS in VABB should be treated by surgery.

CT-guided bone biopsy in cancer patients with suspected bone metastases: retrospective review of 308 procedures.

PURPOSE: The authors assessed the adequacy and sensitivity of CT-guided bone biopsy in 308 procedures performed in 286 cancer patients with suspected bone metastases. MATERIALS AND METHODS: An electronic search of our CT-guided bone biopsy database was retrospectively performed to evaluate the adequacy of samples and, in the event of negative samples, whether the patients had radiological progression at the site of biopsy (false negative). Adequacy and false-negative rate were compared with radiological features, biopsy location, specimen length and complications to assess any statistically relevant association with a multivariate logistic regression model. RESULTS: A total of 290/308 (94.1 %) samples were adequate. Forty-five patients had normal bone marrow and were followed-up, with evidence of progression at the site of biopsy in 10 cases (false-negative cases); overall sensitivity was 96.7 %. Specimen length was significantly correlated to the probability of an adequate biopsy (p = 0.035) and inversely correlated to the probability to obtain a false-negative result (p = 0.02). We encountered 11/308 (3.5 %) minor complications and no major complications. CONCLUSION: CT-guided biopsy of bone lesions in cancer patients allows for a final diagnosis in 94 % of cases. A specimen longer than 1 cm may lead to a significant result in terms of adequacy and sensitivity. Negative biopsies with positive positron emission tomography or magnetic resonance imaging and specimen shorter than 1 cm should be repeated to avoid a false-negative result.

Intracellular osteopontin promotes the release of TNF by mast cells to restrain neuroendocrine prostate cancer.

Neuroendocrine prostate cancer (NEPC) is an aggressive form of prostate cancer that emerges as tumors become resistant to hormone therapies or, rarely, arises de novo in treatment-naïve patients. The urgent need for effective therapies against NEPC is hampered by the limited knowledge of the biology governing this lethal disease. Based on our prior observations in the TRAMP spontaneous prostate cancer model, in which the genetic depletion of either mast cells (MCs) or the matricellular protein osteopontin (OPN) increases NEPC frequency, we tested the hypothesis that MCs can restrain NEPC through OPN production, using in vitro co-cultures between murine or human tumor cell lines and MCs, and in vivo experiments. We unveiled a role for the intracellular isoform of OPN (iOPN), so far neglected compared to the secreted isoform. Mechanistically, we unraveled that iOPN promotes TNF production in MCs via the TLR2/TLR4-MyD88 axis, specifically triggered by the encounter with NEPC cells. We found that MC-derived TNFin turn, hampered the growth of NEPC. We then identified the protein syndecan-1 (SDC1) as the NEPC-specific TLR2/TLR4 ligand that triggered this pathway. Interrogating published single-cell RNA-sequencing data we validated this mechanism in a different mouse model. Translational relevance of the results was provdied by in silco analyses of available human NEPC datasets, and by immunofluorescence on patient-derived adenocarcinoma and NEPC lesions. Overall, our results show that MCs actively inhibit NEPC, paving the way for innovative MC-based therapies for this fatal tumor. We also highlight SDC1 as a potential biomarker for incipient NEPC.

A Phase 3 Prospective Randomized Trial to Evaluate the Impact of Augmented Reality During Robot-assisted Radical Prostatectomy on the Rates of Postoperative Surgical Margins: A Clinical Trial Protocol.

We designed a phase 3, prospective, randomized trial to evaluate the impact of augmented reality and augmented reality frozen section analysis in reducing the rates of positive surgical margins after robot-assisted radical prostatectomy.

Morphological parameters of lobular in situ neoplasia in stereotactic 11-gauge vacuum-assisted needle core biopsy do not predict the presence of malignancy on subsequent surgical excision.

AIMS: The management of lobular in situ neoplasia (LN) when diagnosed on core biopsy remains a controversial issue. The present study aimed to investigate the association between morphological parameters of LN on vacuum-assisted needle core biopsy (VANCB) and the presence of malignancy (ductal carcinoma in situ, pleomorphic lobular carcinoma in situ, or invasive carcinoma) at surgical excision (SE). METHODS AND RESULTS: The study included 14 pathology departments in Italy. Available slides from 859 cases of VANCB reporting an original diagnosis of flat epithelial atypia, atypical ductal hyperplasia or LN, all with subsequent surgical excision, were reviewed. Overall, 286 cases of LN, pure or associated with other lesions, were identified, and a malignant outcome was reported at excision for 51 cases (17.8%). Among the 149 cases of pure LN, an increased risk of malignancy emerged in women in mammographic categories R4-R5 as compared with those in categories R2-R3 (OR 2.46; P = 0.048). In the series, a statistically significant decreased malignancy risk emerged among cases without determinant microcalcifications (P = 0.04). CONCLUSIONS: Our results suggest that the diagnosis of pure LN on VANCB warrants follow-up excision, because clinicopathological parameters do not allow the prediction of which cases will present carcinoma at surgical excision.

The clinical relevance of micropapillary carcinoma of the breast: a case-control study.

AIMS: To ascertain the prognostic relevance of micropapillary carcinoma, a specific type of breast tumour. METHODS AND RESULTS: We interrogated the clinical records of a series of 49 pure micropapillary carcinoma patients and 13 487 invasive ductal carcinoma patients, diagnosed and treated consecutively in our institution over a 9-year time-frame. Compared with invasive ductal carcinoma, patients with micropapillary carcinoma more frequently had moderately differentiated tumours (P = 0.02) with extensive peritumoral vascular invasion (P < 0.0001), associated with a significantly higher rate of axillary lymph node involvement (P < 0.0001). Survival data obtained by comparing 49 micropapillary carcinoma patients with a set of 98 invasive ductal carcinoma patients matched for age, tumour size and grade, peritumoral vascular invasion, immunohistochemically defined molecular subtype, number of positive lymph nodes and year of surgery showed that the micropapillary histotype did not add any independent information to the risk of locoregional (P = 0.48) or distant (P = 0.79) relapse, or overall survival (P = 0.60). CONCLUSIONS: Our data reinforce the notion that micropapillary carcinoma usually arises as a locally advanced disease, and provide evidence that micropapillary histology does not add any additional information on clinical outcome independent of clinicopathological characteristics such as lymph node status and immunohistochemically defined molecular subtype.

Discordant hormone receptor and human epidermal growth factor receptor 2 status in bone metastases compared to primary breast cancer.

BACKGROUND: In patients with metastatic breast cancer, the evaluation of the biological characteristics of metastatic bone deposits may be a valuable adjunct in clinical practice. We assessed the discordance in expression levels for estrogen receptor (ER), progesterone receptor (PgR) and human epidermal growth factor receptor 2 (HER2) between primary tumor and bone metastases and its clinical impact on patient management. MATERIAL AND METHODS: We retrospectively reviewed 363 CT-guided bone biopsies performed from January 1997 to December 2009. The proportions of ER, PgR and HER2 positive tumors at primary diagnosis and bone metastases, determined by IHC and/or FISH, were compared using McNemar's test. The impact of the biopsy reassessment on treatment choice was evaluated with Fisher's exact test. RESULTS: We selected 109 metastatic breast cancer patients with histologically confirmed bone metastases. Among 107 assessable patients the overall discordance rate was detected in 22 (20.5%) and in 47 (43.9%) patients for ER and PgR, respectively, and in six of 86 assessable patients (6.9%) for HER2 status. The indication to change endocrine therapy occurred in 62% and 30% of patients with ER discordance and ER concordance, respectively (p = 0.01). The indication to change targeted therapy occurred in 67% and 8% of patients with HER2 discordance and HER2 concordance, respectively (p = 0.002). CONCLUSIONS: We confirm that biopsy of metastases, including bone metastases, for reassessment of biology should be considered, since it is likely to impact on treatment choice.

First Live-Experience Session with PET/CT Specimen Imager: A Pilot Analysis in Prostate Cancer and Neuroendocrine Tumor.

OBJECTIVE: to evaluate the feasibility of the intra-operative application of a specimen PET/CT imager in a clinical setting. MATERIALS AND METHODS: this is a pilot analysis performed in three patients who received an intra-operative administration of 68Ga-PSMA-11 (n = 2) and 68Ga-DOTA-TOC (n = 1), respectively. Patients were administrated with PET radiopharmaceuticals to perform radio-guided surgery with a beta-probe detector during radical prostatectomy for prostate cancer (PCa) and salvage lymphadenectomy for recurrent neuroendocrine tumor (NET) of the ileum, respectively. All procedures have been performed within two ongoing clinical trials in our Institute (NCT05596851 and NCT05448157). Pathologic assessment with immunohistochemistry (PSMA-staining and SSA immunoreactivity) was considered as standard of truth. Specimen images were compared with baseline PET/CT images and histopathological analysis. RESULTS: Patients received 1 MBq/Kg of 68Ga-PSMA-11 (PCa) or 1.2 MBq/Kg of 68Ga-DOTA-TOC (NET) prior to surgery. Specimens were collected, positioned in the dedicated specimen container, and scanned to obtain high-resolution PET/CT images. In all cases, a perfect match was observed between the findings detected by the specimen imager and histopathology. Overall, the PET spatial resolution was sensibly higher for the specimen images compared to the baseline whole-body PET/CT images. Furthermore, the use of the PET/CT specimen imager did not significantly interfere with any procedures, and the overall length of the surgery was not affected using the PET/CT specimen imager. Finally, the radiation exposure of the operating theater staff was lower than 40 µSv per procedure (range 26-40 µSv). CONCLUSIONS: the image acquisition of specimens obtained by patients who received intra-surgery injections of 68Ga-PSMA-11 and 68Ga-DOTA-TOC was feasible and reliable also in a live-experience session and has been easily adapted to surgery daily practice. The high sensitivity, together with the evaluation of intra-lesion tumor heterogeneity, were the most relevant results since the data derived from specimen PET/CT imaging matched perfectly with the histopathological analysis.