Publications by authors named "Maurizio Colecchia"

121 Publications

How do endoscopic bladder tumor resection techniques affect pathology practice? EAU Section of Uro-Technology (ESUT) and Uropathology (ESUP) survey.

World J Urol 2022 May 14. Epub 2022 May 14.

SLK Kliniken Urology Department, Teaching Hospital of Heidelberg University, Heilbronn, Germany.

Purpose: We aimed to examine how different endoscopic bladder tumor resection techniques affect pathologists' clinical practice patterns.

Methods: An online survey including 28 questions clustered in four main sections was prepared by the ESUT ERBT Working Group and released to the pathologists working in the institutions of experts of the ESUT Board and the working groups and experts in the uropathology working group. A descriptive analysis was performed using the collected data.

Results: Sixty-eight pathologists from 23 countries responded to the survey. 37.3% of the participants stated that they always report the T1 sub-staging. Of those who gave sub-staging, 61.3% used T1a, b. 85.2% think that en bloc samples provide spatial orientation faster than piecemeal samples, and 60% think en bloc samples are timesaving during an inspection. 55.7% stated that whether the tissue sample is en bloc or piecemeal is essential. 57.4% think en bloc sample reduces turnaround time and is cost-effective for 44.1%. A large number of pathologists find that the pathology examination of piecemeal samples has a longer learning curve.

Conclusion: The survey shows that pathologists think that they can diagnose faster, accurately, and cost-effectively with ERBT samples, but they do not often encounter them in practice. Moreover, en bloc samples may be a better choice in pathology resident training. Evidence from real-life observational pathology practice and clinical research can reveal the current situation more clearly and increase awareness on proper treatment in endoscopic management of bladder tumors.
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http://dx.doi.org/10.1007/s00345-022-04022-2DOI Listing
May 2022

Could double stain for p53/CK20 be a useful diagnostic tool for the appropriate classification of flat urothelial lesions?

Pathol Res Pract 2022 May 6;234:153937. Epub 2022 May 6.

Pathology Unit, Maggiore Hospital, AUSL Bologna, Bologna, Italy; Department of Experimental, Diagnostic and Specialty Medicine (DIMES), S.Orsola-Malpighi University Hospital, University of Bologna, Bologna, Italy.

Background: The differential diagnosis between flat urothelial lesions [reactive urothelial atypia (RUA), atypia of unknown significance (AUS), urothelial dysplasia (UD) and carcinoma in situ (CIS)] has relevant prognostic and therapeutic implications. This crucial distinction could be very challenging but it is currently performed on hematoxylin and eosin (H&E) slides, with a great amount of partially discordant and/or not conclusive findings of the potential adjunctive role of immunohistochemistry. Herein, we tested double staining (DS) for p53/CK20 to verify if p53(+) cells, CK20(+) cells and double-positive cells (DPCs) are differentially expressed among these lesions and if p53/CK20 could be a useful tool in this diagnostic setting.

Methods: We tested 50, 9, 36 and 29 consecutive and retrospectively enrolled cases of RUA, AUS, UD and CIS, respectively. p53(+) cells, CK20(+) cells and DPCs were evaluated and compared by adopting the appropriate statistic tests (Mann-Whitney U and Kruskal-Wallis tests).

Results: We found that p53(+) cells (p = 0.000), CK20(+) cells (p = 0.000) and DPCs (p = 0.000) showed statistically significant differences among the different flat urothelial lesions. Besides, when dichotomized, both CIS and RUA are easily differentiable from their histological mimickers adopting all these markers; by contrast, AUS and UD did not reach statistically significant differences able to differentiate them from each other [p53(+) cells, p = 0.123; CK20(+) cells, p = 0.567; DPCs, p = 0.409], except if compared to CIS [AUS VS CIS: p53(+) cells, p = 0.013; CK20(+) cells, p = 0.000; DPCs, p = 0.000; UD vs CIS: p53(+) cells, p = 0.000; CK20(+) cells, p = 0.000; DPCs, p = 0.000].

Conclusions: p53(+) cells, CK20(+) cells and DPCs are differently expressed by flat urothelial lesions and p53/CK20 could be a time- and money-saving tool for the appropriate management of these lesions if applied to a routine scenario.
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http://dx.doi.org/10.1016/j.prp.2022.153937DOI Listing
May 2022

Cabozantinib as First-line Treatment in Patients With Metastatic Collecting Duct Renal Cell Carcinoma: Results of the BONSAI Trial for the Italian Network for Research in Urologic-Oncology (Meet-URO 2 Study).

JAMA Oncol 2022 Apr 14. Epub 2022 Apr 14.

Department of Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.

Importance: Metastatic collecting duct carcinoma (mCDC) is a rare type of non-clear cell renal cell carcinoma (ncRCC) with poor prognosis and no standard treatments. Despite retrospective series that have documented the benefit of cabozantinib in ncRCC, no prospective trials have evaluated this treatment in mCDC.

Objective: To determine whether cabozantinib is an active treatment in patients with mCDC.

Design, Setting, And Participants: The caBozantinib in cOllectiNg ductS Renal Cell cArcInoma (BONSAI) trial was an open-label, single-arm, phase 2 clinical trial carried out between January 2018 and November 2020 at a single academic center with data cut off in September 2021 on behalf of the the Italian Network for Research in Urologic-Oncology (Meet-URO 2). Eligible patients had histologic diagnosis of centrally confirmed mCDC with measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1). In total, 25 patients were screened.

Interventions: Patients received cabozantinib, 60 mg orally once daily, until disease progression, unacceptable toxic effects, or withdrawal of consent.

Main Outcomes And Measures: The primary end point was objective response rate (ORR) per RECIST, version 1.1.

Results: At data cut off, of 25 patients enrolled, 23 started treatment because 2 were excluded after failing the screening process at pathologic review. The median follow-up cannot be estimated using the reverse Kaplan-Meier estimator. The median time to censoring was 11 months (95% CI, 0-22 months). Median (range) age was 66 (53-74) years. As best overall response, 3 patients presented stable disease, 1 patient achieved a complete response, and 7 a partial response. The ORR was 35% (95% CI, 16%-57%). The median progression-free survival was 4 months (95% CI, 3-13 months). The median OS was 7 months (95% CI, 3-31 months). All patients reported at least 1 grade (G) 1 to 2 adverse event (AE). The most common G1 to G2 AEs were fatigue (14 [60%]), anorexia (9 [39%]), hand-foot syndrome (7 [30%]), hypothyroidism (7 [30%]), mucositis (7 [30%]), diarrhea (5 [22%]), and hypertension (3 [13%]). Six G3 AEs were reported: 2 arterial hyperthension, 1 pulmonary thromboembolism, 1 bleeding, and 2 fatigue. There were no permanent discontinuations from the study owing to AEs. Four patients (17%) required dose reduction to 40 mg, and 4 (17%) required a transitory interruption to manage toxic effects.

Conclusions And Relevance: The study met the ORR primary end point, showing encouraging efficacy of cabozantinib in untreated patients with mCDC. Further investigations to advance the molecular understanding of this tumor are ongoing.

Trial Registration: ClinicalTrials.gov Identifier: NCT03354884.
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http://dx.doi.org/10.1001/jamaoncol.2022.0238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9011175PMC
April 2022

Mediastinal germ cell tumors: a narrative review of their traits and aggressiveness features.

Mediastinum 2022 25;6. Epub 2022 Mar 25.

Department of Pathology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy.

Objective: Mediastinal extragonadal germ-cell tumors (MEGCTs) are rare neoplasms with a multifaceted clinical behavior. This paper is devoted to review their main characteristics, including histological patterns and different factors of aggressiveness in MEGCTs. Proper understanding of the latter can help to better stratify patients' prognoses and improve clinical management.

Background: Different theories exist on the origin of MEGCTs, including primordial germ cells deposition during embryogenesis. MEGCTs predominantly affects young males and aggressiveness follows the ability of local and systemic spread of each germ-cell neoplasia subtype, as well as their distinct responsiveness to therapy. Indeed, non-seminomatous MEGCTs have a worse prognosis. Unfortunately, they are also more frequent than seminomas in the mediastinum. Regardless of histological type, local aggressiveness can follow tumoral expansion with compression on or infiltration of mediastinal structures. Chemotherapy can be effective in reducing neoplastic volume, but different levels of sensitivity can be found in different MGCTs. In particular, a chemo-resistant teratoma component of a mixed MEGCTs can undergo a paradoxical enlargement after chemotherapy, while other components of the tumor regress. This is reflected by a concomitant normalization of serum tumoral markers and cardiopulmonary deterioration due to compression. Such clinical phenomenon, called growing-teratoma syndrome (GTS), requires a prompt surgical approach.

Methods: A literature research of pertinent epidemiological, pathological and clinical articles was conducted.

Conclusion: The mediastinum can harbor different kinds of neoplasia, including GCTs. The full spectrum of MEGCTs includes a variety of tumors with different clinical behaviors. Aggressiveness follows the inherent ability of local and systemic spread of each neoplastic type, as well as their distinct responsiveness to therapy.
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http://dx.doi.org/10.21037/med-21-22DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8841550PMC
March 2022

Immunohistochemical Expression of Preferentially Expressed Antigen in Melanoma (PRAME) in the Uninvolved Background Testis, Germ Cell Neoplasia In Situ, and Germ Cell Tumors of the Testis.

Am J Clin Pathol 2022 05;157(5):644-648

Department of Pathology, Maggiore Hospital, AUSL-Bologna, Bologna, Italy.

Objectives: Preferentially expressed antigen in melanoma (PRAME) has a key role in regulating pluripotency of primordial germ cells and in the development of germ cell tumors of the testis (GCTT). However, its immunohistochemical expression in normal testes and its neoplastic counterpart remain largely unknown.

Methods: We retrospectively investigated the expression of PRAME in 26 cases of GCTT, 21 cases of germ cell neoplasia in situ (GCNIS), and 17 cases of uninvolved background testes.

Results: We found that PRAME was expressed more strongly by seminomatous rather than nonseminomatous GCTT (P = .000) and by pure seminoma rather than the seminoma component of seminomatous/nonseminomatous GCTT (P = .025). In addition, GCNIS and uninvolved background testes displayed high levels of PRAME expression.

Conclusions: PRAME is an additional marker for the differential diagnosis of GCTT and could play a key role in the transition from seminomatous to nonseminomatous GCTT.
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http://dx.doi.org/10.1093/ajcp/aqab200DOI Listing
May 2022

The contributions of Juan Rosai to testicular pathology with personal remembrances.

Pathologica 2021 Oct;113(5):330-338

The James Homer Wright Pathology Laboratories, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

The authors summarize their personal interactions with someone for whom they had unbounded admiration, Dr. Juan Rosai. This varied from daily review of cases, to sharing the platform at meetings, being under his tutelage as an author, and co-directing postgraduate courses. These all highlighted the remarkable knowledge of medicine Dr. Rosai had, imparting as he did diagnostic pearls and remarks on the literature including the history of our discipline, often laced with a well-honed sense of humor. The contributions he made to the pathology of the testis are then considered beginning with his role in highlighting a tumor, at the time not particularly well publicized, spermatocytic seminoma. He wrote two major papers on it, one on standard clinical and pathologic aspects, and one on its ultrastructure. The first was associated with his diligent investigation of a prior paper reporting an unusually high number of malignant examples of this tumor but on review that was explained by their representing malignant lymphoma. The organizational skills of Dr. Rosai, and attention to detail, were second to none and shown perhaps most notably with his organizing many courses, but they were also illustrated early in his career when he moderated a symposium on germ cell tumors of the testis which laid the framework for the classification and nomenclature of premalignant lesions. Finally, his almost career-long interest in the entity he codiscovered, Rosai-Dorfman disease, was associated with his reporting testicular involvement by that disorder in his later years. This giant figure in pathology will stand forever in the top tier with other greats who have contributed to the field.
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http://dx.doi.org/10.32074/1591-951X-353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8720408PMC
October 2021

Leiomyoadenomatoid tumours of the epididymis: A new case report and review of the literature.

Andrologia 2022 Feb 17;54(1):e14280. Epub 2021 Oct 17.

Vita-Salute San Raffaele University, Milan, Italy.

Benign tumours of the epididymis are rare, and the most common tumour types include adenomatoid tumours, representing more than half of all cases, and leiomyomas. Here, we reported a case of leiomyoadenomatoid tumours of the epididymis, a very rare, benign histological entity with only few cases described in the English literature, which have been reviewed and summarised. Clinically, the lesion presented as a solitary mass growing at the level of the tail of the right epididymis. After the intraoperative frozen section analysis revealed a benign adenomatoid lesion, the mass was enucleated with a conservative surgery sparing the testis. This case highlights the importance for both pathologists and urologists to be aware of these rare, but benign, tumours, to avoid misdiagnosis, especially in the setting of frozen intraoperative consultation, or primary radical surgical procedures, as radical orchiepididymectomy without frozen section consultation.
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http://dx.doi.org/10.1111/and.14280DOI Listing
February 2022

Integrative Transcriptomic Analysis Reveals Distinctive Molecular Traits and Novel Subtypes of Collecting Duct Carcinoma.

Cancers (Basel) 2021 Jun 10;13(12). Epub 2021 Jun 10.

Platform of Integrated Biology, Department of Applied Research and Technology Development, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy.

Collecting duct carcinoma (CDC) is a rare and highly aggressive kidney cancer subtype with poor prognosis and no standard treatments. To date, only a few studies have examined the transcriptomic portrait of CDC. Through integration of multiple datasets, we compared CDC to normal tissue, upper-tract urothelial carcinomas, and other renal cancers, including clear cell, papillary, and chromophobe histologies. Association between CDC gene expression signatures and in vitro drug sensitivity data was evaluated using the Cancer Therapeutic Response Portal, Genomics of Drug Sensitivity in Cancer datasets, and connectivity map. We identified a CDC-specific gene signature that predicted in vitro sensitivity to different targeted agents and was associated to worse outcome in clear cell renal cell carcinoma. We showed that CDC are transcriptionally related to the principal cells of the collecting ducts providing evidence that this tumor originates from this normal kidney cell type. Finally, we proved that CDC is a molecularly heterogeneous disease composed of at least two subtypes distinguished by cell signaling, metabolic and immune-related alterations. Our findings elucidate the molecular features of CDC providing novel biological and clinical insights. The identification of distinct CDC subtypes and their transcriptomic traits provides the rationale for patient stratification and alternative therapeutic approaches.
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http://dx.doi.org/10.3390/cancers13122903DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8230422PMC
June 2021

A feasibility study of preoperative pembrolizumab before radical nephroureterectomy in patients with high-risk, upper tract urothelial carcinoma: PURE-02.

Urol Oncol 2022 01 17;40(1):10.e1-10.e6. Epub 2021 Jun 17.

Vita-Salute San Raffaele University; Department of Urology, IRCCS San Raffaele Hospital and Scientific Institute, Milan, Italy.

Introduction: Advances in neoadjuvant therapy for patients with localized, nonmetastatic, upper tract urothelial carcinoma (UTUC) is needed.

Patients And Methods: PURE-02 was a feasibility study enrolling individuals with UTUC, at clinical stage N0M0, with high-risk features according to the modified European Association of Urology definition, based on the presence of either: high-grade disease, multifocality, tumor size ≥2 cm, and/or hydronephrosis. The treatment consisted of 3 courses of 200 mg pembrolizumab, intravenously, every 3 weeks, followed by radical nephroureterectomy (RNU). The endpoints were to assess the safety, pathological responses, and biomarkers.

Results: Ten patients were enrolled between August 2018 and November 2020, 9 (90%) completed the neoadjuvant course. One treatment-related death occurred as a complication of severe myocarditis, myasthenia gravis, hepatitis and myositis. One (14.3%) patient achieved a clinical complete response and refused to undergo RNU. Two (20%) had disease progression and received subsequent chemotherapy, prior to RNU. Overall, 7 patients underwent RNU: one (14.3%) achieved an ypT1N0 response, although this patient was reported to have a cT1 tumor at baseline imaging. The remaining patients were nonresponders. Circulating tumor DNA assay did not identify patients likely to achieve a complete pathologic response.

Conclusion: Single-agent neoadjuvant pembrolizumab did not appear to be a promising treatment strategy for patients with biomarker-unselected, high-risk localized UTUC.
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http://dx.doi.org/10.1016/j.urolonc.2021.05.014DOI Listing
January 2022

Prediction of Grade Reclassification of Prostate Cancer Patients on Active Surveillance through the Combination of a Three-miRNA Signature and Selected Clinical Variables.

Cancers (Basel) 2021 May 18;13(10). Epub 2021 May 18.

Molecular Pharmacology Unit, Department of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy.

Active surveillance (AS) has evolved as a strategy alternative to radical treatments for very low risk and low-risk prostate cancer (PCa). However, current criteria for selecting AS patients are still suboptimal. Here, we performed an unprecedented analysis of the circulating miRNome to investigate whether specific miRNAs associated with disease reclassification can provide risk refinement to standard clinicopathological features for improving patient selection. The global miRNA expression profiles were assessed in plasma samples prospectively collected at baseline from 386 patients on AS included in three independent mono-institutional cohorts (training, testing and validation sets). A three-miRNA signature (, and ) was found to predict reclassification in all patient cohorts (training set: AUC 0.74, 95% CI 0.60-0.87, testing set: AUC 0.65, 95% CI 0.51-0.80, validation set: AUC 0.68, 95% CI 0.56-0.80). Importantly, the addition of the three-miRNA signature improved the performance of the clinical model including clinicopathological variables only (AUC 0.70, 95% CI 0.61-0.78 vs. 0.76, 95% CI 0.68-0.84). Overall, we trained, tested and validated a three-miRNA signature which, combined with selected clinicopathological variables, may represent a promising biomarker to improve on currently available clinicopathological risk stratification tools for a better selection of truly indolent PCa patients suitable for AS.
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http://dx.doi.org/10.3390/cancers13102433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8157371PMC
May 2021

Clinical Outcomes in Clinical N0 Squamous Cell Carcinoma of the Penis According to Nodal Management: Early, Delayed or Selective (following Dynamic Sentinel Node Biopsy) Inguinal Lymph-Node Dissection.

J Urol 2021 Aug 12;206(2):354-363. Epub 2021 Apr 12.

Urology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.

Purpose: We evaluated the oncologic efficacy of early inguinal lymph-node dissection, observation or dynamic sentinel node biopsy followed by delayed or selective inguinal lymph-node dissection in cN0 patients with penile squamous cell carcinoma.

Materials And Methods: Between 1980 and 2017 (inclusive), 296 evaluable consecutive cN0 penile squamous cell carcinoma patients underwent early inguinal lymph-node dissection (16), observation (114) or dynamic sentinel node biopsy (166). Median followup was 50 months. Tumor stage, grade, lympho-vascular invasion and age were considered. Kaplan-Meier plots illustrated 5-year inguinal relapse-free and cancer specific survival rates. Multivariable Cox regression models tested the treatment effect. Analyses were repeated after inverse probability of treatment weighting adjustment.

Results: The 5-year inguinal relapse-free survival and cancer specific survival rates following early, observation and dynamic sentinel node biopsy inguinal lymph-node dissection were 100%, 87%, 89%, and 84%, 81%, 85%, respectively. The 5-year crude inguinal relapse-free survival and cancer specific survival rates were 90% and 93% in low-risk patients undergoing observation. Clavien grade 3 complications were 0.6 vs 12.5% in the dynamic sentinel node biopsy and early inguinal lymph-node dissection group, respectively. After inverse probability after treatment weighting adjustment, 5-year inguinal relapse and cancer specific survival were 90% vs 73% and 90% vs 77% following dynamic sentinel node biopsy and observation, respectively. At multivariable Cox regression model, patients undergoing dynamic sentinel node biopsy had significantly lower inguinal relapse (HR 0.4, 95% CI 0.2-0.85, p 0.02) and cancer specific mortality (HR 0.29, 95% CI 0.11-0.77; p=0.01) compared to those under observation. The low number of patients undergoing early inguinal lymph-node dissection made a reliable comparison with this group impractical.

Conclusions: Selective inguinal lymph-node dissection following dynamic sentinel node biopsy significantly improved inguinal relapse and cancer specific mortality when compared with observation, providing evidence of efficacy of dynamic sentinel node biopsy in clinical stage N0 squamous cell carcinoma of the penis.
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http://dx.doi.org/10.1097/JU.0000000000001775DOI Listing
August 2021

Primary MiNEN of the urinary bladder: an hitherto undescribed entity composed of large cell neuroendocrine carcinoma and adenocarcinoma with a distinct clinical behavior : Description of a case and review of the pertinent literature.

Virchows Arch 2021 Jul 17;479(1):69-78. Epub 2021 Jan 17.

Department of Pathology, ASST Lariana, Como, Italy.

Neuroendocrine carcinomas (NECs) of the urinary bladder are very rare and can be observed in the context of mixed neuroendocrine/non-neuroendocrine neoplasms (MiNENs), most frequently in association with urothelial carcinoma. Small cell NECs are far more common than large cell NECs (LCNECs), which are exceedingly rare. We describe a primary MiNEN of the urinary bladder, composed of a LCNEC and of an adenocarcinoma, in which the neuroendocrine component reached complete pathological regression after neoadjuvant M-VAC chemotherapy, whereas the non-neuroendocrine component of the tumor progressed to metastatic disease. Compared to mixed neuroendocrine/non-neuroendocrine neoplasms described in the literature until now, this appears to be a unique case that expands the spectrum of neuroendocrine neoplasia of the urinary bladder.
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http://dx.doi.org/10.1007/s00428-021-03023-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8298318PMC
July 2021

Incidence and Clinical Impact of Inflammatory Fluorodeoxyglucose Positron Emission Tomography Uptake After Neoadjuvant Pembrolizumab in Patients with Organ-confined Bladder Cancer Undergoing Radical Cystectomy.

Eur Urol Focus 2021 Sep 7;7(5):1092-1099. Epub 2020 Nov 7.

Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. Electronic address:

Background: Data regarding the incidence and prognostic impact of immune-related imaging changes, assessed by [F] fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) scan, in patients receiving immune-checkpoint inhibitors (ICIs) are lacking. We relied on the population of patients enrolled in the PURE-01 study to evaluate such changes.

Objective: To evaluate the role of PET/CT to visualize the immune-related adverse events (irAEs) following pembrolizumab.

Design, Setting, And Participants: From February 2017 to August 2019, in 103 patients with nonmetastatic, clinical T2-4aN0M0 bladder cancer, PET/CT scan was performed before and after neoadjuvant pembrolizumab (N = 206 scans), before radical cystectomy.

Intervention: PET/CT before and after neoadjuvant pembrolizumab, before radical cystectomy.

Outcome Measurements And Statistical Analysis: We analyzed the occurrence of irAEs, evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, against the development of inflammatory FDG uptake described at PET/CT (irAEs + PET/CT). Logistic regression analyses evaluated the association between irAEs + PET/CT and the pathological response to pembrolizumab. Kaplan-Meier curves tested their association with progression-free survival (PFS) after pembrolizumab and radical cystectomy.

Results And Limitations: Forty patients (39%) developed irAEs + PET/CT in several target organs. The most frequent target organs were the thyroid (N = 18), stomach (N = 14), mediastinal lymph nodes (N = 9), and lung (N = 5). These changes were clinically evident in 18 (45%) and were not associated with the pathological response, neither in terms of complete response (ypT0N0, p = 0.07) nor as downstaging to ypT≤1N0 disease (p = 0.1), although ypT0N0 responses were numerically more frequent in patients with irAEs+ PET/CT (47.5% vs 32%). Furthermore, irAE+ PET/CT events were associated with longer, not statistically significant, 24-mo PFS: 88.3% versus 76.5% (p = 0.5). Our results warrant further validation in larger datasets.

Conclusions: We presented unique surrogate data of PET/CT that could help improve our understanding of nonclinically evident effects of ICI administration, especially in patients at the early disease stage.

Patient Summary: We evaluated the utility of PET/CT to visualize the occurrence of inflammatory changes after pembrolizumab in patients with localized bladder cancer without metastases. After immunotherapy, 39% of the patients developed [F] fluorodeoxyglucose uptake consistent of inflammatory changes. Overall, our data improve our knowledge on the effects induced by immunotherapy, which may have a clinical impact at longer follow-up. Take Home Message ● In the PURE-01 study, T2-4N0M0 muscle-invasive bladder cancer patients were staged with fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) before and after pembrolizumab. ● PET/CT after pembrolizumab revealed inflammatory FDG uptake in 39% of patients, but only 45% of these cases of uptake corresponded to clinically evident adverse events. ● The development of inflammatory uptake was associated with a higher pathological complete response rate and longer progression-free survival, although these differences were not statistically significant.
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http://dx.doi.org/10.1016/j.euf.2020.10.003DOI Listing
September 2021

Myoid gonadal tumor. Case series, systematic review, and Bayesian analysis.

Virchows Arch 2021 Apr 2;478(4):727-734. Epub 2020 Nov 2.

Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, via Venezian 1, 20133, Milano, MI, Italy.

Myoid gonadal stromal tumor represents a rare testicular neoplasm displaying smooth muscular and gonadal stromal differentiation. This entity has very few cases reported in the literature that describe heterogeneous clinical and pathological characteristics. Bayesian statistics provides a useful framework to combine information from diverse sources. We here presented a case series-the largest so far reported-of myoid gonadal stromal tumor (4 cases) with extensive morphologic, immunohistochemical, and molecular characterization, performed a systematic review of the literature (that identified 9 papers), and used a Bayesian data analysis to understand the characteristics of this disease. Our study collectively described 16 cases. This neoplasm is mainly found in adults (mean age about 40 years) and often has a size of about 3 cm. By morphology, the tumor can infiltrate testicular tubules and is composed of spindle cells; few mitoses can be seen (usually 2/10 HPF). Neoplastic cells are diffusely positive with α-smooth muscle actin with a tram-track staining pattern. S100 protein, FOXL2, and SF1 are also characteristically positive. Moreover, this neoplasm can display epithelial differentiation, in about half of the cases. In conclusion, we foresee the use of this statistical approach in pathology: our analysis allowed a more precise description of this rare entity.
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http://dx.doi.org/10.1007/s00428-020-02957-8DOI Listing
April 2021

[18F]Fluoro-Deoxy-Glucose positron emission tomography to evaluate lymph node involvement in patients with muscle-invasive bladder cancer receiving neoadjuvant pembrolizumab.

Urol Oncol 2021 04 16;39(4):235.e15-235.e21. Epub 2020 Oct 16.

Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Background: Data regarding the role of positron emission tomography/computed tomography (PET/CT) to stage lymph nodes in patients receiving neoadjuvant immunotherapy before radical cystectomy are lacking. The aim of this study is to evaluate the role of PET/CT to predict the pathologic lymph node involvement (LNI) in patients with MIBC receiving neoadjuvant pembrolizumab within the PURE-01 trial (NCT02736266).

Material And Methods: Three courses of pembrolizumab were administered before radical cystectomy and extended pelvic lymph node dissection in clinical T2-4aN0M0 MIBC based on contrast-enhanced CT scan. LNI was also assessed with PET/CT before and after treatment. PET/CT results were compared with histopathological findings. The ability of baseline and post-therapy PET/CT to evaluate LNI was assessed, and univariate logistic regression analyses were performed.

Results: From February 2017 to August 2019, a total of 108 patients and 105 patients had evaluable baseline and post-pembrolizumab scans, respectively. The sensitivity to detect LNI was 27% and 37.5% for pre- and post-pembrolizumab PET/CT, and specificity was 97% and 98%, respectively. In total, 4 of 7 patients (57%) showing baseline FDG-uptake had LNI vs. 11 of 101 (11%) with no baseline uptake. All but 1 of the 7 patients did not respond to pembrolizumab. Both pre- and post-pembrolizumab PET/CT significantly predicted LNI (P = 0.004 and P < 0.001) at univariate analyses. Our results warrant further validation in larger datasets.

Conclusions: PET/CT performance does not justify its use in routine practice for cN0 MIBC. However, our preliminary data revealed opportunities for the use of baseline PET/CT, within clinical trials, to optimally select patients with MIBC who are best suited for neoadjuvant immunotherapy strategies. Validation in larger datasets, as well as a cost analysis, are needed.
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http://dx.doi.org/10.1016/j.urolonc.2020.09.035DOI Listing
April 2021

Prognostic Role of Early Interim Fluorodeoxyglucose Positron Emission Tomography in Patients With Advanced Seminoma Undergoing Standard Treatment.

Clin Genitourin Cancer 2021 06 13;19(3):237-245.e2. Epub 2020 Aug 13.

Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. Electronic address:

Background: Patients with advanced seminoma have an exceedingly favorable prognosis. Studies aiming to reduce the total treatment burden and side effects in patients with well-defined disease and very good prognosis are warranted.

Patients And Methods: In a prospective observational study, patients with advanced stage seminoma were treated with bleomycin, etoposide, and cisplatin (BEP) or EP according to guidelines. Fluorodeoxyglucose with positron emission tomography and computed tomography (FDG-PET/CT) examinations were performed at baseline, after 2 cycles (PET/CT2) in all patients, and after chemotherapy at the physician's discretion. Disease response to treatment assessed by PET/CT was qualitatively evaluated by 2 independent nuclear medicine physicians. Contrast-enhanced CT scans were also performed according to guidelines (at baseline, after treatment, during follow-up). The study's primary endpoint was to evaluate the association between PET/CT2 findings and relapse-free survival.

Results: From January 2009 to January 2017, a total of 75 consecutive patients were enrolled, of whom 70 were included for analysis. The clinical disease stage was IIA-B and IIC-III in 40% and 60%, respectively. By local assessment, 46 PET/CT2 scans (65.7%) were reported as negative, and 46% of these patients had stage IIC-III disease. Five-year relapse-free survival of PET/CT2-positive patients was 75% (95% confidence interval, 60-95) compared to 97.8% (95% confidence interval, 93.7-100) of PET/CT2-negative patients (P = .002). In univariate analyses, PET/CT2 was significantly associated with relapse-free survival (P = .02).

Conclusions: No residual FDG uptake after 2 cycles of conventional chemotherapy is prognostic in advanced seminoma, but it may be useful to optimize the standard prognostic risk groups and may be tested within larger prospective clinical trials of chemotherapy deescalation.
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http://dx.doi.org/10.1016/j.clgc.2020.08.007DOI Listing
June 2021

Practice patterns related to prostate cancer grading: results of a 2019 Genitourinary Pathology Society clinician survey.

Urol Oncol 2021 05 15;39(5):295.e1-295.e8. Epub 2020 Sep 15.

Departments of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD.

Purpose: To survey urologic clinicians regarding interpretation of and practice patterns in relation to emerging aspects of prostate cancer grading, including quantification of high-grade disease, cribriform/intraductal carcinoma, and impact of magnetic resonance imaging-targeted needle biopsy.

Materials And Methods: The Genitourinary Pathology Society distributed a survey to urology and urologic oncology-focused societies and hospital departments. Eight hundred and thirty four responses were collected and analyzed using descriptive statistics.

Results: Eighty percent of survey participants use quantity of Gleason pattern 4 on needle biopsy for clinical decisions, less frequently with higher Grade Groups. Fifty percent interpret "tertiary" grade as a minor/<5% component. Seventy percent of respondents would prefer per core grading as well as a global/overall score per set of biopsies, but 70% would consider highest Gleason score in any single core as the grade for management. Seventy five percent utilize Grade Group terminology in patient discussions. For 45%, cribriform pattern would affect management, while for 70% the presence of intraductal carcinoma would preclude active surveillance.

Conclusion: This survey of practice patterns in relationship to prostate cancer grading highlights similarities and differences between contemporary pathology reporting and its clinical application. As utilization of Gleason pattern 4 quantification, minor tertiary pattern, cribriform/intraductal carcinoma, and the incorporation of magnetic resonance imaging-based strategies evolve, these findings may serve as a basis for more nuanced communication and guide research efforts involving pathologists and clinicians.
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http://dx.doi.org/10.1016/j.urolonc.2020.08.027DOI Listing
May 2021

The Leydig cell tumour Scaled Score (LeSS): a method to distinguish benign from malignant cases, with additional correlation with MDM2 and CDK4 amplification.

Histopathology 2021 Jan 24;78(2):290-299. Epub 2020 Sep 24.

Department of Diagnostic Pathology and Laboratory Medicine, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy.

Aims: To investigate the morphological and molecular characteristics of Leydig cell tumours (LCTs) of the testis for the identification of cases that may metastasise.

Methods And Results: Six parameters for a predictive model of the metastatic risk were evaluated in 37 benign and 14 malignant LCTs of the testis [LCT Scaled Score (LeSS)]. The tumour size (benign LCTs, mean 13.3 mm; malignant LCTs, mean 44 mm) (P < 0.001) and five other parameters (infiltrative margins, necrosis, vascular invasion, mitotic count, and nuclear atypia) showed significant differences (Wilcoxon's test, P < 0.001). Eight metastatic LCTs and one benign LCT had infiltrative margins. Foci of coagulative necrosis occurred in 10 metastatic LCTs, whereas vascular invasion was identified in nine of 14 metastatic LCTs and none of 37 benign LCTs. Benign LCTs showed <2 mitoses/10 high-power fields (HPFs), whereas a high mitotic count (range, 3-50 mitoses/10 HPFs) was a feature of malignant LCTs. These parameters were selected by use of an inferential analysis based on univariate logistic regression models to develop a score. A LeSS of <4 correctly identified all histologically and clinically benign LCTs. A LeSS of ≥4 correctly identified all malignant LCTs. MDM2 and CDK4 immunostains were applied in all 51 cases: benign LCTs were negative; three of 11 malignant LCTs (27%) showed strong and diffuse immunopositivity and high levels of MDM2 and CDK4 amplification as determined with fluorescence in-situ hybridisation analysis and next-generation sequencing.

Conclusion: We provide a new tool, the LeSS, for the prediction of malignant behaviour in LCTs.
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http://dx.doi.org/10.1111/his.14225DOI Listing
January 2021

The Value of Multiparametric Magnetic Resonance Imaging Sequences to Assist in the Decision Making of Muscle-invasive Bladder Cancer.

Eur Urol Oncol 2021 10 27;4(5):829-833. Epub 2020 Jun 27.

Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy. Electronic address:

Interim data from the PURE-01 study, using pembrolizumab before radical cystectomy in muscle-invasive bladder cancer (MIBC), suggested that multiparametric magnetic resonance imaging (mpMRI) was able to predict the pathologic response. Owing to the availability of novel effective therapies in MIBC, the possibility to assess tumor response easily has become exceedingly important. The primary objective of the present study was to evaluate the association between individual and combined MRI sequences, and the pathologic response in the final PURE-01 population. Images were internally evaluated and the diagnostic performance was analyzed for separate sequences, along with their combination. From February 2017 to December 2019, 143 patients were enrolled in PURE-01, and 123 with suitable paired imaging assessments before and after pembrolizumab tests (N = 246 mpMRI in total) were analyzed in relation to the pathologic response. The area under the curve (AUC) of the combination of all sequences to predict ypT0ypN0 response was 0.74. By excluding dynamic contrast enhancement (DCE) assessment, the AUC was 0.74. When looking at ypT ypN0 response, the AUC was 0.87 in both cases. Without DCE, 95% of patients with no evidence of disease resulted in ypT ypN0 and 65% ypT0ypN0 responders. In conclusion, the final results confirmed the reliability of mpMRI and suggested the opportunity to avoid intravenous gadolinium contrast to personalize bladder-sparing strategies in radiologically complete responders. PATIENT SUMMARY: We evaluated the reliability of multiparametric bladder magnetic resonance imaging to predict the pathologic response to pembrolizumab administered before radical cystectomy in muscle-invasive bladder cancer. We observed that this radiologic examination is promising in the attempt to identify opportunities to spare the bladder in selected, radiologically defined complete responders. We also observed that the use of intravenous gadolinium contrast can be avoided in future studies. ClinicalTrials.gov, number NCT02736266.
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http://dx.doi.org/10.1016/j.euo.2020.06.004DOI Listing
October 2021

The 2019 Genitourinary Pathology Society (GUPS) White Paper on Contemporary Grading of Prostate Cancer.

Arch Pathol Lab Med 2021 04;145(4):461-493

Douglass Hanly Moir Pathology, Faculty of Medicine and Health Sciences Macquarie University, North Ryde, Australia (Maclean).

Context.—: Controversies and uncertainty persist in prostate cancer grading.

Objective.—: To update grading recommendations.

Data Sources.—: Critical review of the literature along with pathology and clinician surveys.

Conclusions.—: Percent Gleason pattern 4 (%GP4) is as follows: (1) report %GP4 in needle biopsy with Grade Groups (GrGp) 2 and 3, and in needle biopsy on other parts (jars) of lower grade in cases with at least 1 part showing Gleason score (GS) 4 + 4 = 8; and (2) report %GP4: less than 5% or less than 10% and 10% increments thereafter. Tertiary grade patterns are as follows: (1) replace "tertiary grade pattern" in radical prostatectomy (RP) with "minor tertiary pattern 5 (TP5)," and only use in RP with GrGp 2 or 3 with less than 5% Gleason pattern 5; and (2) minor TP5 is noted along with the GS, with the GrGp based on the GS. Global score and magnetic resonance imaging (MRI)-targeted biopsies are as follows: (1) when multiple undesignated cores are taken from a single MRI-targeted lesion, an overall grade for that lesion is given as if all the involved cores were one long core; and (2) if providing a global score, when different scores are found in the standard and the MRI-targeted biopsy, give a single global score (factoring both the systematic standard and the MRI-targeted positive cores). Grade Groups are as follows: (1) Grade Groups (GrGp) is the terminology adopted by major world organizations; and (2) retain GS 3 + 5 = 8 in GrGp 4. Cribriform carcinoma is as follows: (1) report the presence or absence of cribriform glands in biopsy and RP with Gleason pattern 4 carcinoma. Intraductal carcinoma (IDC-P) is as follows: (1) report IDC-P in biopsy and RP; (2) use criteria based on dense cribriform glands (>50% of the gland is composed of epithelium relative to luminal spaces) and/or solid nests and/or marked pleomorphism/necrosis; (3) it is not necessary to perform basal cell immunostains on biopsy and RP to identify IDC-P if the results would not change the overall (highest) GS/GrGp part per case; (4) do not include IDC-P in determining the final GS/GrGp on biopsy and/or RP; and (5) "atypical intraductal proliferation (AIP)" is preferred for an intraductal proliferation of prostatic secretory cells which shows a greater degree of architectural complexity and/or cytological atypia than typical high-grade prostatic intraepithelial neoplasia, yet falling short of the strict diagnostic threshold for IDC-P. Molecular testing is as follows: (1) Ki67 is not ready for routine clinical use; (2) additional studies of active surveillance cohorts are needed to establish the utility of PTEN in this setting; and (3) dedicated studies of RNA-based assays in active surveillance populations are needed to substantiate the utility of these expensive tests in this setting. Artificial intelligence and novel grading schema are as follows: (1) incorporating reactive stromal grade, percent GP4, minor tertiary GP5, and cribriform/intraductal carcinoma are not ready for adoption in current practice.
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http://dx.doi.org/10.5858/arpa.2020-0015-RADOI Listing
April 2021

Predicting the Pathologic Complete Response After Neoadjuvant Pembrolizumab in Muscle-Invasive Bladder Cancer.

J Natl Cancer Inst 2021 01;113(1):48-53

Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Background: In the PURE-01 study (NCT02736266), we aimed to evaluate the ability to predict the pathologic complete response (pT0N0) after pembrolizumab by using clinical and tumor biomarkers.

Methods: In an open-label, single-arm, phase 2 study, 3 courses of 200 mg pembrolizumab preceding radical cystectomy were administered in patients with T2-4aN0M0 muscle-invasive bladder cancer. The analyses included a comprehensive genomic profiling and programmed cell-death-ligand-1 (PD-L1)-combined positive score assessment (CPS; Dako 22C3 antibody) of pre- and posttherapy samples. Multivariable logistic regression analyses evaluated baseline clinical T stage and tumor biomarkers in association with pT0N0 response. Corresponding coefficients were used to develop a calculator of pT0N0 response based on the tumor mutational burden (TMB), CPS, and the clinical T stage. Decision-curve analysis was also performed. All statistical tests were 2-sided.

Results: From February 2017 to June 2019, 112 patients with biomarker data were enrolled (105 with complete TMB and CPS data). Increasing TMB and CPS values featured a linear association with logistic pT0N0 probabilities (P = .02 and P = .004, respectively). For low TMB values (≤11 mut/Mb, median value, n = 53), pT0N0 probability was not associated with increasing CPS. Conversely, for high TMB values (>11 mut/Mb, n = 52), pT0N0 was statistically significantly associated with higher CPS (P = .004). The C index of the pT0N0 probability calculator was 0.77. On decision-curve analysis, the net benefit of the model was higher than the "treat-all" option within the clinically meaningful threshold probabilities of 40%-50%.

Conclusions: The study presents a composite biomarker-based pT0N0 probability calculator that reveals the complex interplay between TMB and CPS, added to the clinical T stage.
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http://dx.doi.org/10.1093/jnci/djaa076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781448PMC
January 2021

Can Patients with Muscle-invasive Bladder Cancer and Fibroblast Growth Factor Receptor-3 Alterations Still Be Considered for Neoadjuvant Pembrolizumab? A Comprehensive Assessment from the Updated Results of the PURE-01 Study.

Eur Urol Oncol 2021 12 14;4(6):1001-1005. Epub 2020 May 14.

Decipher Biosciences Inc., Vancouver, British Columbia, Canada.

In the PURE-01 study, patients with muscle-invasive bladder cancer (MIBC) who achieved a pathological complete response (CR; ypT0N0) had tumor features suggesting that pre-existing immunity may promote response. We focused on fibroblast growth factor receptor-3 (FGFR3) genomic alterations (GAs) as potential tumor resistance features. The primary endpoint of our study was CR. FGFR3 GAs were assessed via comprehensive genomic profiling of sequenced DNA (N = 112), a transcriptome-based FGFR3 activity signature, an FGFR3 subtyping model based on long noncoding RNA (lncRNA), and gene expression profiling (N = 84 for all three). We used Wilcoxon rank-sum tests, Fisher's exact test, and logistic regression analyses to analyze the associations between the various FGFR3 alterations and CR. High FGFR3 activity was defined as a signature score that was higher than the median value. Cases that were positive for lncRNA-FGFR3 subtype (lncRNA-FGFR3 active, N = 11) had consistent biology with published data: low epithelial-mesenchymal transition and immune-signature scores, high p53 activity, FGFR3 activity, and sonic hedgehog activity. In total, 17 (15.2%), 42 (50%), and 11 patients (13%) showed FGFR3 GAs or high FGFR3 signature scores, or had lncRNA-FGFR3-active tumors. Despite an association of high FGFR3 gene expression with a lower CR rate (p = 0.01), we did not find a correlation between FGFR3 activity or mutation/fusion and CR (p = 0.2 and p = 0.8). We conclude that the association of FGFR3 expression with pathological response is balanced by multiple factors. Overall, FGFR3-altered tumors should not be excluded from neoadjuvant immunotherapy studies at this time. PATIENT SUMMARY: In patients with muscle-invasive bladder cancer treated within the PURE-01 trial, we analyzed the role of fibroblast growth factor receptor-3 (FGFR3) alterations, at the DNA and RNA levels, in association with the pathological response. We did not find any robust association, mainly when analyzing the landscape of alterations defining tumors with higher biological FGFR activity. Overall, FGFR3 activity and gene alterations did not provide sufficiently robust data to exclude patients whose tumors harbor these alterations from neoadjuvant immunotherapy trials.
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http://dx.doi.org/10.1016/j.euo.2020.04.005DOI Listing
December 2021

Impact of Molecular Subtyping and Immune Infiltration on Pathological Response and Outcome Following Neoadjuvant Pembrolizumab in Muscle-invasive Bladder Cancer.

Eur Urol 2020 06 9;77(6):701-710. Epub 2020 Mar 9.

Decipher Biosciences Inc., Vancouver, British Columbia, Canada. Electronic address:

Background: The PURE-01 study (NCT02736266) evaluated the use of pembrolizumab before radical cystectomy (RC) in muscle-invasive bladder cancer (MIBC).

Objective: To evaluate the ability of molecular signatures to predict the pathological complete response (CR: ypT0N0) and progression-free survival (PFS) after pembrolizumab and RC.

Design, Setting, And Participants: We analyzed the expression data from patients with T2-4aN0M0 MIBC enrolled in the PURE-01 study (N=84) and from patients of a retrospective multicenter cohort treated with cisplatin-based neoadjuvant chemotherapy (NAC; N=140).

Intervention: Neoadjuvant pembrolizumab or NAC and RC.

Outcome Measurements And Statistical Analysis: Immune signatures and molecular subtyping (The Cancer Genome Atlas, consensus model, and genomic subtyping classifier [GSC]) were evaluated in relation to CR and PFS. Multivariable logistic regression analyses for CR were used, adjusting for gender and clinical T stage.

Results And Limitations: The Immune190 signature was significant for CR on multivariable logistic regression analyses (p= 0.02) in PURE-01, but not in the NAC cohort (p= 0.7). Hallmark signatures for interferon gamma (IFNγ; p= 0.004) and IFNα response (p= 0.006) were also associated with CR for PURE-01, but not for NAC (IFNγ: p= 0.9 and IFNα: p= 0.8). In PURE-01, 93% of patients with the highest Immune190 scores (>1st quartile) had 2-yr PFS versus 79% of those with lower scores; no difference was observed in NAC patients, as well as for the other hallmarks in both groups. The neuroendocrine-like subtype had the worst 2-yr PFS in all three subtyping models (33%) and the GSC claudin-low subtype had the best, with no recurrences in 2 yr. Basal subtypes (across classifications) with higher Immune190 scores showed 100% 2-yr PFS after pembrolizumab therapy (p = 0.04, compared with basal-Immune190 low). Statistical analyses are limited by the small number of events and short follow-up.

Conclusions: Higher RNA-based immune signature scores were significantly associated with CR and numerically improved PFS outcomes after pembrolizumab, but not after NAC. These data emphasize that RNA profiling is a potential tool for personalizing neoadjuvant therapy selection.

Patient Summary: We used gene expression profiling to evaluate the association between immune gene expression and response to neoadjuvant immunotherapy, compared with standard chemotherapy, in patients with muscle-invasive bladder cancer (MIBC). We found a significant association between immune gene expression and response to pembrolizumab, but not chemotherapy. We conclude that gene expression profiling has the potential to guide personalized neoadjuvant therapy in MIBC.
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http://dx.doi.org/10.1016/j.eururo.2020.02.028DOI Listing
June 2020

ECCO Essential Requirements for Quality Cancer Care: Prostate cancer.

Crit Rev Oncol Hematol 2020 Apr 7;148:102861. Epub 2020 Jan 7.

European Cancer Organisation (ECCO).

Background: ECCO Essential Requirements for Quality Cancer Care (ERQCC) are written by experts representing all disciplines involved in cancer care in Europe. They give oncology teams, patients, policymakers and managers an overview of essential care throughout the patient journey.

Prostate Cancer: Prostate cancer is the second most common male cancer and has a wide variation in outcomes in Europe. It has complex diagnosis and treatment challenges, and is a major healthcare burden. Care must only be a carried out in prostate/urology cancer units or centres that have a core multidisciplinary team (MDT) and an extended team of health professionals. Such units are far from universal in European countries. To meet European aspirations for comprehensive cancer control, healthcare organisations must consider the requirements in this paper, paying particular attention to multidisciplinarity and patient-centred pathways from diagnosis, to treatment, to survivorship.
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http://dx.doi.org/10.1016/j.critrevonc.2019.102861DOI Listing
April 2020

Multiparametric Magnetic Resonance Imaging as a Noninvasive Assessment of Tumor Response to Neoadjuvant Pembrolizumab in Muscle-invasive Bladder Cancer: Preliminary Findings from the PURE-01 Study.

Eur Urol 2020 05 25;77(5):636-643. Epub 2019 Dec 25.

Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.

Background: In the PURE-01 study, pembrolizumab was given preoperatively before radical cystectomy in clinical T2-4aN0M0 patients. An accurate clinical response assessment may be useful for developing new perioperative strategies in these patients.

Objective: To evaluate the association between bladder multiparametric magnetic resonance imaging (mpMRI) findings after pembrolizumab and the pathological complete response (CR; pT0).

Design, Setting, And Participants: Patients were staged using bladder mpMRI whereby radiologists were asked to characterize the following parameters: residual disease at T1- and T2-weighted images (step 1: yes/no), presence of hyperintense spots within the bladder wall on diffusion-weighted imaging (step 2: yes/no), and presence of pathological contrast enhancement (step 3: yes/no), before and after three cycles of pembrolizumab. Examinations were internally assessed by two senior radiologists and externally evaluated by a third senior radiologist.

Intervention: To evaluate bladder tumor response after neoadjuvant pembrolizumab, mpMRI was used.

Outcome Measurements And Statistical Analysis: The primary objective was to predict the pT0 after neoadjuvant pembrolizumab by relying on the mpMRI findings. Cohen's kappa statistics was used to assess interobserver variability. Univariable analyses for pT0 were performed including internal and external post-therapy mpMRI steps.

Results And Limitations: From February 2017 to October 2018, 82 patients (164 total mpMRI assessments) were analyzed. The agreement between the internal and external mpMRI assessments after therapy was acceptable (κ values ranging from 0.5 to 0.76). Each mpMRI step was significantly associated with pT0 in both internal and external assessments. In patients with CR/no evidence of residual disease (NED) in all internally evaluated mpMRI steps (N = 37), the pT0 was seen in 23 (62%), compared with 19 of 26 externally evaluated NED patients (73%).

Conclusions: In post-pembrolizumab muscle-invasive bladder cancer, mpMRI sequence assessment had acceptable interobserver variability and represented the basis for the proposal of a radiological CR/NED status definition predicting the pT0 response to pembrolizumab. After validation of these findings with external datasets, we propose this tool for developing bladder-sparing immunotherapy maintenance therapies.

Patient Summary: Assessment of the extent of disease in patients with muscle-invasive bladder cancer using conventional imaging yields serious limitations. In the PURE-01 study, we evaluated the potential of bladder multiparametric magnetic resonance imaging (MRI) to predict the pathological complete response to neoadjuvant pembrolizumab. After validation with larger datasets, the proposed stepwise assessment incorporating multiparametric MRI sequences will be used at our center to develop bladder-sparing approaches in future studies.
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http://dx.doi.org/10.1016/j.eururo.2019.12.016DOI Listing
May 2020

Reporting Practices and Resource Utilization in the Era of Intraductal Carcinoma of the Prostate: A Survey of Genitourinary Subspecialists.

Am J Surg Pathol 2020 05;44(5):673-680

Cleveland Clinic, Cleveland, OH.

Intraductal carcinoma of the prostate (IDC-P) has been recently recognized by the World Health Organization classification of prostatic tumors as a distinct entity, most often occurring concurrently with invasive prostatic adenocarcinoma (PCa). Whether documented admixed with PCa or in its rare pure form, numerous studies associate this entity with clinical aggressiveness. Despite increasing clinical experience and requirement of IDC-P documentation in protocols for synoptic reporting, the specifics of its potential contribution to assessment of grade group (GG) and cancer quantitation of PCa in both needle biopsies (NBx) and radical prostatectomy (RP) specimens remain unclear. Moreover, there are no standard guidelines for incorporating basal cell marker immunohistochemistry (IHC) in the diagnosis of IDC-P, either alone or as part of a cocktail with AMACR/racemase. An online survey containing 26 questions regarding diagnosis, reporting practices, and IHC resource utilization, focusing on IDC-P, was undertaken by 42 genitourinary subspecialists from 9 countries. The degree of agreement or disagreement regarding approaches to individual questions was classified as significant majority (>75%), majority (51% to 75%), minority (26% to 50%) and significant minority (≤25%). IDC-P with or without invasive cancer is considered a contraindication for active surveillance by the significant majority (95%) of respondents, although a majority (66%) also agreed that the clinical significance/behavior of IDC-P on NBx or RP with PCa required further study. The majority do not upgrade PCa based on comedonecrosis seen only in the intraductal component in NBx (62%) or RP (69%) specimens. Similarly, recognizable IDC-P with GG1 PCa was not a factor in upgrading in NBx (78%) or RP (71%) specimens. The majority (60%) of respondents include readily recognizable IDC-P in assessment of linear extent of PCa at NBx. A significant majority (78%) would use IHC to confirm or exclude intraductal carcinoma if other biopsies showed no PCa, while 60% would use it to confirm IDC-P with invasive PCa in NBx if it would change the overall GG assignment. Nearly half (48%, a minority) would use IHC to confirm IDC-P for accurate Gleason pattern 4 quantitation. A majority (57%) report the percentage of IDC-P when present, in RP specimens. When obvious Gleason pattern 4 or 5 PCa is present in RP or NBx, IHC is rarely to almost never used to confirm the presence of IDC-P by the significant majority (88% and 90%, respectively). Most genitourinary pathologists consider IDC-P to be an adverse prognostic feature independent of the PCa grade, although recommendations for standardization are needed to guide reporting of IDC-P vis a vis tumor quantitation and final GG assessment. The use of IHC varies widely and is performed for a multitude of indications, although it is used most frequently in scenarios where confirmation of IDC-P would impact the GG assigned. Further study and best practices recommendations are needed to provide guidance with regards to the most appropriate indications for IHC use in scenarios regarding IDC-P.
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http://dx.doi.org/10.1097/PAS.0000000000001417DOI Listing
May 2020

Updated Results of PURE-01 with Preliminary Activity of Neoadjuvant Pembrolizumab in Patients with Muscle-invasive Bladder Carcinoma with Variant Histologies.

Eur Urol 2020 04 8;77(4):439-446. Epub 2019 Nov 8.

San Raffaele Hospital and Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy.

Background: Patients with predominant variant histology (VH) of bladder tumors, defined as involving >50 % of the tumor specimens, are typically excluded from clinical trials, and for these patients, the efficacy of standard chemotherapy is limited.

Objective: To evaluate the activity of preoperative pembrolizumab in patients with muscle-invasive bladder carcinoma (MIBC) and VH, enrolled in PURE-01 study (NCT02736266).

Design, Setting, And Participants: In the open-label, single-arm, phase 2 PURE-01 study, three courses of 200 mg pembrolizumab preceding radical cystectomy (RC) were administered in T2-4aN0M0 MIBC patients. The amended study design included patients with predominant VH.

Intervention: Neoadjuvant pembrolizumab and RC.

Outcome Measurements And Statistical Analysis: Pathological complete response (pT0) in intention-to-treat population was the primary endpoint. Biomarker analyses included programmed cell-death ligand-1 (PD-L1) expression using the combined positive score (CPS; Dako 22C3 antibody) and comprehensive genomic profiling (FoundationOne assay). Multivariable logistic regression analyses (MVAs) evaluated the histological category (predominant VH vs nonpredominant VH vs pure urothelial carcinoma), tumor mutational burden (TMB) and CPS in association with the pathological response.

Results And Limitations: From February 2017 to June 2019, 114 patients were enrolled; 34 (30%) of them presented with VH, including 19 (17%) with predominant VH. In total, the pT0 rate was 37% (95% confidence interval [CI]: 28-46) and the pT ≤ 1 rate was 55% (95% CI: 46-65). The majority of predominant VH patients presented with squamous-cell carcinoma (SCC; N = 7), and six of seven (86%) had downstaging to pT ≤ 1, with one pT0; two of three lymphoepithelioma-like (LEL) variants had a pT0 response. None of the remaining nine predominant VHs had a response. On MVA, TMB and CPS were associated with both the pT0 and the pT ≤ 1 response, regardless of tumor histology.

Conclusions: The updated PURE-01 results confirm the activity of neoadjuvant pembrolizumab in MIBC. Patients with SCC and LEL features may be suitable for neoadjuvant immunotherapy trials. CPS and TMB are the key response predictors irrespective of the histological subtypes.

Patient Summary: In the PURE-01 study, we have preliminarily evaluated the activity of neoadjuvant pembrolizumab in patients with predominant variant histology (VH). Of these patients, those harboring squamous-cell carcinoma or a lymphoepithelioma-like variant feature had major, although preliminary, pathological responses compared with those with other predominant VHs. Expression of programmed cell-death ligand-1 and tumor mutational burden may predict the pathological response to pembrolizumab, and provide a rationale for selecting patients according to these features instead of the histological bladder cancer subtypes.
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http://dx.doi.org/10.1016/j.eururo.2019.10.026DOI Listing
April 2020

EAU-EANM-ESTRO-ESUR-SIOG Prostate Cancer Guideline Panel Consensus Statements for Deferred Treatment with Curative Intent for Localised Prostate Cancer from an International Collaborative Study (DETECTIVE Study).

Eur Urol 2019 Dec 3;76(6):790-813. Epub 2019 Oct 3.

Department of Urology, Netherlands Cancer Institute, Amsterdam, The Netherlands.

Background: There is uncertainty in deferred active treatment (DAT) programmes, regarding patient selection, follow-up and monitoring, reclassification, and which outcome measures should be prioritised.

Objective: To develop consensus statements for all domains of DAT.

Design, Setting, And Participants: A protocol-driven, three phase study was undertaken by the European Association of Urology (EAU)-European Association of Nuclear Medicine (EANM)-European Society for Radiotherapy and Oncology (ESTRO)-European Association of Urology Section of Urological Research (ESUR)-International Society of Geriatric Oncology (SIOG) Prostate Cancer Guideline Panel in conjunction with partner organisations, including the following: (1) a systematic review to describe heterogeneity across all domains; (2) a two-round Delphi survey involving a large, international panel of stakeholders, including healthcare practitioners (HCPs) and patients; and (3) a consensus group meeting attended by stakeholder group representatives. Robust methods regarding what constituted the consensus were strictly followed.

Results And Limitations: A total of 109 HCPs and 16 patients completed both survey rounds. Of 129 statements in the survey, consensus was achieved in 66 (51%); the rest of the statements were discussed and voted on in the consensus meeting by 32 HCPs and three patients, where consensus was achieved in additional 27 statements (43%). Overall, 93 statements (72%) achieved consensus in the project. Some uncertainties remained regarding clinically important thresholds for disease extent on biopsy in low-risk disease, and the role of multiparametric magnetic resonance imaging in determining disease stage and aggressiveness as a criterion for inclusion and exclusion.

Conclusions: Consensus statements and the findings are expected to guide and inform routine clinical practice and research, until higher levels of evidence emerge through prospective comparative studies and clinical trials.

Patient Summary: We undertook a project aimed at standardising the elements of practice in active surveillance programmes for early localised prostate cancer because currently there is great variation and uncertainty regarding how best to conduct them. The project involved large numbers of healthcare practitioners and patients using a survey and face-to-face meeting, in order to achieve agreement (ie, consensus) regarding best practice, which will provide guidance to clinicians and researchers.
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http://dx.doi.org/10.1016/j.eururo.2019.09.020DOI Listing
December 2019
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