Matteo Santoni

PD-1 blockade therapy in renal cell carcinoma: Current studies and future promises

RCC is considered an immunogenic tumor with a prominent dysfunctional immune cell infiltrate, unable to control tumor growth. Evasion of immune surveillance, a process defined immune-editing, leads to malignant progression. The striking improvement of knowledge in immunology has led to the identification of immune checkpoints (such as CTLA-4 and PD-1), whose blockage enhances the antitumor immunity. The interaction between PD-1, an inducible inhibitory receptor expressed on lymphocytes and DCs, and PD-L1 ligand, expressed by tumor cells, results in a down-regulation of the T-cell response. Therefore, the PD-1/PD-L1 axis inhibition by targeted-antibodies, increasing the T-cell proliferation and cytotoxicity, represents a promising mechanism to stimulate the anti-tumor activity of the immune system, improving the outcomes of cancer patients. Several PD-1 and PD-L1 inhibitors have been evaluated in different tumor types, showing promising results. The interesting correlation between lymphocytes PD-1 expression and RCC advanced stage, grade and prognosis, as well as the selective PD-L1 expression by RCC tumor cells and its potential association with worse clinical outcomes, have led to the development of new anti PD-1/PD-L1 agents, alone or in combination with anti-angiogenic drugs or other immunotherapeutic approaches, for the treatment of RCC. In this review we discuss the role of PD-1/PD-L1 in RCC, focusing on the biological rationale, current clinical studies and promising therapeutic perspectives to target the PD-1 pathway.

BAP1, PBRM1 and SETD2 in clear-cell renal cell carcinoma: molecular diagnostics and possible targets for personalized therapies

Several novel recurrent mutations of histone modifying and chromatin remodeling genes have been identified in renal cell carcinoma. These mutations cause loss of function of several genes located in close proximity to VHL and include PBRM1, BAP1 and SETD2. PBRM1 encodes for BAF180, a component of the SWI/SNF chromatin remodeling complex, and is inactivated in, on average, 36% of clear cell renal cell carcinoma (ccRCC). Mutations of BAP1 encode for the histone deubiquitinase BRCA1 associated protein-1, and are present in 10% of ccRCCs. They are largely mutually exclusive with PBRM1 mutations. Mutations to SETD2, a histone methyltransferase, occur in 10% of ccRCC. BAP1- or SETD2-mutated ccRCCs have been associated with poor overall survival, while PBRM1 mutations seem to identify a favorable group of ccRCC tumors. This review describes the roles of PBRM1, BAP1 and SETD2 in the development and progression of ccRCC and their potential for future personalized approaches.

Does prostate acinar adenocarcinoma with Gleason Score 3 + 3 = 6 have the potential to metastasize?

BackgroundThere is a worldwide debate involving clinicians, uropathologists as well as patients and their families on whether Gleason score 6 adenocarcinoma should be labelled as cancer.Case descriptionWe report a case of man diagnosed with biopsy Gleason score 6 acinar adenocarcinoma and classified as low risk (based on a PSA of 5 ng/mL and stage cT2a) whose radical prostatectomy specimen initially showed organ confined Gleason score 3 + 3 = 6, WHO nuclear grade 3, acinar adenocarcinoma with lymphovascular invasion and secondary deposit in a periprostatic lymph node. When deeper sections were cut to the point that almost all the slice present in the paraffin block was sectioned, a small tumor area (<5% of the whole tumor) of Gleason pattern 4 (poorly formed glands) was found in an extraprostatic position.ConclusionThe epilogue was that the additional finding changed the final Gleason score to 3 + 3 = 6 with tertiary pattern 4 and the stage to pT3a.Virtual SlidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_190

HER family receptor expression and prognosis in pancreatic cancer.

Background HER family receptors play a key role in tumor progression in several malignancies, such as colorectal, lung or breast cancer. The aims of this study were to investigate expression of HER-1, HER-2 and HER-3 in pancreatic cancer (PC) samples and evaluate the association between HER-family receptor expression and patients’ clinical outcomes. Methods Tissue samples from 91 PC patients were subjected to immunohistochemical staining to assess the expression of HER-1, HER-2 and HER-3. Semiquantitative scores of zero (no staining or staining in less than 10% of cancer cells), 1+, 2+ or 3+ were assigned to each sample based on the intensity of staining for HER receptors. Scores of 2+ or 3+ were defined as positive staining. Results HER-1 overexpression was observed in 41 out of 91 samples (45.1%), while HER-2 was not overexpressed in any of the analyzed samples. HER-3 was overexpressed in 37 samples (40.7%) and was found to be associated with advanced TNM stage. In particular, HER-3 was overexpressed in 12 out of 16 stage IV patients (75%) compared with only 33.3% of stage I-III patients (p = 0.02). Among 79 patients with available survival data, the 6 patients with strong HER-3 expression (score 3+) had a shorter survival compared with remaining patients (median overall survival 6.9 months vs. 12.3 months, respectively). Conclusions HER-1 and HER-3 were found to be expressed in a significant proportion of PC patients. Strong HER-3 expression represents an indicator of poor prognosis in PC patients, being associated with advanced stage and shorter survival.

Is there still a role for sorafenib in metastatic renal cell carcinoma? A systematic review and meta-analysis of the effectiveness of sorafenib over other targeted agents

BACKGROUNDnThe treatment of metastatic renal cell carcinoma (mRCC) has largely improved over the last decade, due to the availability of several targeted agents (TAs). Sorafenib was the first TA to report a benefit in terms of PFS in this disease, and it has largely been used as a comparator in randomized trials. We tested its activity compared to other TAs by performing a systematic review and meta-analysis.nnnMETHODSnMEDLINE/PubMed, the Cochrane library, and the ASCO university websites were searched for randomized phase II or III trials that compared other TAs to sorafenib in mRCC. Data extraction was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The measured outcomes were progression free survival (PFS), overall survival (OS), and the overall response rate (ORR). Sub-analyses were performed for MSKCC prognostic groups and lines of therapy.nnnRESULTSnA total of 3094 patients were evaluable for PFS. Other TAs significantly reduce the risk of progression compared to sorafenib (HR=0.78; 95% CI, 0.72-0.85; p<0.001). This difference remains significant in patients in a good prognostic group with respect to both first- (HR=0.61; 95%CI, 0.44-0.85; p=0.003) and second-line therapy (HR=0.58; 95% CI, 0.42-0.79; p<0.001). No significant differences were, however, found in patients with an intermediate prognosis in terms of both first- (HR=0.80; 95% CI, 0.60-1.00; p=0.05) and second-line treatment (HR=0.89; 95% CI, 0.73-1.07; p=0.21). In 2922 patients evaluable for OS, no significant difference was found between other TAs and sorafenib (HR=1.07; 95% CI, 0.97-1.18; p=0.18). A benefit was also not identified when the analysis was limited to patients treated with first or subsequent lines of therapy or in patients previously treated with sunitinib. Significant differences were found in terms of the ORR in the 2963 evaluable patients favoring other TAs (RR=1.48; 95% CI, 1.24-1.76; p<0.001). This difference remain significant when a sub-analysis was performed per line of therapy.nnnCONCLUSIONSnOther TAs improve PFS but not OS when compared to sorafenib. The use of sorafenib in patients with an intermediate prognosis, especially in second-line therapy, does not have a detrimental effect on PFS and might be an option for certain patients.

Pseudocarcinomatous hyperplasia associated with primary lymphoma in the urinary bladder: a case report

A case of pseudocarcinomatous hyperplasia of the urothelium associated with primary extranodal marginal-type lymphoma of the urinary bladder in an 81-year-old man is described. To the best of our knowledge, this is the first report in the literature of a primary lymphoma of the bladder associated with pseudocarcinomatous hyperplasia of the urothelium, closely mimicking the nested variant of urothelial carcinoma. The lesion enters in the differential diagnosis with a collision tumor, which has been described rarely in the bladder.

Handling of the Surgical Specimen and Pathology Reporting of Penile Neoplasms

The pathology report supplies important information to guide the therapeutic approach and predict prognostic expectations in penile neoplastic disease. It provides the histological diagnosis and subtype as well as other factors affecting prognosis such as histological grade, site or sites of growth, size, thickness, anatomical depth of invasion and vascular or perineural infiltration. In circumcision specimen reports, the margins of resection to be examined are the coronal sulcus, the mucosal and cutaneous margin, whereas in penectomy specimens the urethral/periurethral, corporal, and cutaneous margins have to be investigated.

Handling of the Surgical Specimen and Pathology Reporting of Malignant Germ Cell and Sex Cord-Stromal Tumors of the Testis

Testis specimen should be handled in a detailed manner in order to assure gathering of comprehensive and accurate pathological information. Indeed macroscopic and microscopic items included in a pathology report have prognostic implications. Pathological data, together with clinical and biochemical (i.e., tumor markers) information, are useful in decision-making about patients care after orchiectomy, especially to define the need of adjuvant treatment versus surveillance.

Re: Idir Ouzaid and Karim Bensalah. Results of the First Trial Assessing Adjuvant Tyrosine Kinase Inhibitors in Renal Cell Carcinoma Do Not reASSURE. Eur Urol 2015;68:542–3

We read with great interest the contribution by Ouzaid and Bensalah [1]. They analyzed the recent failure of the randomized phase 3 ASSURE trial (NCT00326898) comparing 1-yr treatment with sorafenib (400 mg twice daily), sunitinib (50 mg/day for 4 wk of every 6 wk), or placebo as adjuvant therapies for patients with completely resected renal cell carcinoma (RCC). The authors questioned the study accrual, the 1-yr duration of adjuvant treatment, and the lack of predictive biological biomarkers. However, other concerns seem to merit further investigation.