Pulmonary lesion after surgery for renal cancer: progression or new primary?

PURPOSE: To investigate clinical and radiological differences between kidney metastases to the lung (RCCM +) and metachronous lung cancer (LC) detected during follow-up in patients surgically treated for Renal Cell Carcinoma (RCC). METHODS: cM0 surgically-treated RCC who harbored a pulmonary mass during follow-up were retrospectively scrutinized. Univariate logistic regression assessed predictive features for differentiating between LC and RCCM + . Multivariable analyses (MVA) were fitted to predict factors that could influence time between detection and histological diagnosis of the pulmonary mass, and how this interval could impact on survivals. RESULTS: 87% had RCCM + and 13% had LC. LC were more likely to have smoking history (75% vs. 29%, p < 0.001) and less aggressive RCC features (cT1-2: 94% vs. 65%, p = 0.01; pT1-2: 88% vs. 41%, p = 0.02; G1-2: 88% vs. 37%, p < 0.001). The median interval between RCC surgery and lung mass detection was longer between LC (55 months [32.8-107.2] vs. 20 months [9.0-45.0], p = 0.01). RCCM + had a higher likelihood of multiple (3[1-4] vs. 1[1-1], p < 0.001) and bilateral (51% vs. 6%, p = 0.002) pulmonary nodules, whereas LC usually presented with a solitary pulmonary nodule, less than 20 mm. Univariate analyses revealed that smoking history (OR:0.79; 95% CI 0.70-0.89; p < 0.001) and interval between RCC surgery and lung mass detection (OR:0.99; 95% CI 0.97-1.00; p = 0.002) predicted a higher risk of LC. Conversely, size (OR:1.02; 95% CI 1.01-1.04; p = 0.003), clinical stage (OR:1.14; 95% CI 1.06-1.23; p < 0.001), pathological stage (OR:1.14; 95% CI 1.07-1.22; p < 0.001), grade (OR:1.15; 95% CI 1.07-1.23; p < 0.001), presence of necrosis (OR:1.17; 95% CI 1.04-1.32; p = 0.01), and lymphovascular invasion (OR:1.18; 95% CI 1.01-1.37; p = 0.03) of primary RCC predicted a higher risk of RCCM + . Furthermore, number (OR:1.08; 95% CI 1.04-1.12; p < 0.001) and bilaterality (OR:1.23; 95% CI 1.09-1.38; p < 0.001) of pulmonary lesions predicted a higher risk of RCCM + . Survival analysis showed a median second PFS of 10.9 years (95% CI 3.3-not reached) for LC and a 3.8 years (95% CI 3.2-8.4) for RCCM + . The median OS time was 6.5 years (95% CI 4.4-not reached) for LC and 6 years (95% CI 4.3-11.6) for RCCM + . CONCLUSIONS: Smoking history, primary grade and stage of RCC, interval between RCC surgery and lung mass detection, and number of pulmonary lesions appear to be the most valuable predictors for differentiating new primary lung cancer from RCC progression.

[68Ga]Ga-PSMA and [68Ga]Ga-RM2 PET/MRI vs. Histopathological Images in Prostate Cancer: A New Workflow for Spatial Co-Registration.

This study proposed a new workflow for co-registering prostate PET images from a dual-tracer PET/MRI study with histopathological images of resected prostate specimens. The method aims to establish an accurate correspondence between PET/MRI findings and histology, facilitating a deeper understanding of PET tracer distribution and enabling advanced analyses like radiomics. To achieve this, images derived by three patients who underwent both [68Ga]Ga-PSMA and [68Ga]Ga-RM2 PET/MRI before radical prostatectomy were selected. After surgery, in the resected fresh specimens, fiducial markers visible on both histology and MR images were inserted. An ex vivo MRI of the prostate served as an intermediate step for co-registration between histological specimens and in vivo MRI examinations. The co-registration workflow involved five steps, ensuring alignment between histopathological images and PET/MRI data. The target registration error (TRE) was calculated to assess the precision of the co-registration. Furthermore, the DICE score was computed between the dominant intraprostatic tumor lesions delineated by the pathologist and the nuclear medicine physician. The TRE for the co-registration of histopathology and in vivo images was 1.59 mm, while the DICE score related to the site of increased intraprostatic uptake on [68Ga]Ga-PSMA and [68Ga]Ga-RM2 PET images was 0.54 and 0.75, respectively. This work shows an accurate co-registration method for histopathological and in vivo PET/MRI prostate examinations that allows the quantitative assessment of dual-tracer PET/MRI diagnostic accuracy at a millimetric scale. This approach may unveil radiotracer uptake mechanisms and identify new PET/MRI biomarkers, thus establishing the basis for precision medicine and future analyses, such as radiomics.

Role of [68Ga]Ga-PSMA-11 PET radiomics to predict post-surgical ISUP grade in primary prostate cancer.

PURPOSE: The aim of this study is to investigate the role of [68Ga]Ga-PSMA-11 PET radiomics for the prediction of post-surgical International Society of Urological Pathology (PSISUP) grade in primary prostate cancer (PCa). METHODS: This retrospective study included 47 PCa patients who underwent [68Ga]Ga-PSMA-11 PET at IRCCS San Raffaele Scientific Institute before radical prostatectomy. The whole prostate was manually contoured on PET images and 103 image biomarker standardization initiative (IBSI)-compliant radiomic features (RFs) were extracted. Features were then selected using the minimum redundancy maximum relevance algorithm and a combination of the 4 most relevant RFs was used to train 12 radiomics machine learning models for the prediction of PSISUP grade: ISUP ≥ 4 vs ISUP < 4. Machine learning models were validated by means of fivefold repeated cross-validation, and two control models were generated to assess that our findings were not surrogates of spurious associations. Balanced accuracy (bACC) was collected for all generated models and compared with Kruskal-Wallis and Mann-Whitney tests. Sensitivity, specificity, and positive and negative predictive values were also reported to provide a complete overview of models' performance. The predictions of the best performing model were compared against ISUP grade at biopsy. RESULTS: ISUP grade at biopsy was upgraded in 9/47 patients after prostatectomy, resulting in a bACC = 85.9%, SN = 71.9%, SP = 100%, PPV = 100%, and NPV = 62.5%, while the best-performing radiomic model yielded a bACC = 87.6%, SN = 88.6%, SP = 86.7%, PPV = 94%, and NPV = 82.5%. All radiomic models trained with at least 2 RFs (GLSZM-Zone Entropy and Shape-Least Axis Length) outperformed the control models. Conversely, no significant differences were found for radiomic models trained with 2 or more RFs (Mann-Whitney p > 0.05). CONCLUSION: These findings support the role of [68Ga]Ga-PSMA-11 PET radiomics for the accurate and non-invasive prediction of PSISUP grade.

Radiomic and gEnomic approaches for the enhanced DIagnosis of clear cell REnal Cancer (REDIRECt): a translational pilot methodological study.

Background: The combination of radiomic and transcriptomic approaches for patients diagnosed with small clear-cell renal cell carcinoma (ccRCC) might improve decision making. In this pilot and methodological study, we investigate whether imaging features obtained from computed tomography (CT) may correlate with gene expression patterns in ccRCC patients. Methods: Samples from 6 patients who underwent partial nephrectomy for unilateral non-metastatic ccRCC were included in this pilot cohort. Transcriptomic analysis was conducted through RNA-sequencing on tumor samples, while radiologic features were obtained from pre-operative 4-phase contrast-enhanced CT. To evaluate the heterogeneity of the transcriptome, after a 1,000 re-sampling via bootstrapping, a first Principal Component Analyses (PCA) were fitted with all transcripts and a second ones with transcripts deriving from a list of 369 genes known to be associated with ccRCC from The Cancer Genome Atlas (TCGA). Significant pathways in each Principal Components for the 50 genes with the highest loadings absolute values were assessed with pathways enrichment analysis. In addition, Pearson's correlation coefficients among radiomic features themselves and between radiomic features and transcripts expression values were computed. Results: The transcriptomes of the analysed samples showed a high grade of heterogeneity. However, we found four radiogenomic patterns, in which the correlation between radiomic features and transcripts were statistically significant. Conclusions: We showed that radiogenomic approach is feasible, however its clinical meaning should be further investigated.

Preliminary Results of an Ongoing Prospective Clinical Trial on the Use of 68Ga-PSMA and 68Ga-DOTA-RM2 PET/MRI in Staging of High-Risk Prostate Cancer Patients.

The aim of the present study is to investigate the synergic role of 68Ga-PSMA PET/MRI and 68Ga-DOTA-RM2 PET/MRI in prostate cancer (PCa) staging. We present pilot data on twenty-two patients with biopsy-proven PCa that underwent 68Ga-PSMA PET/MRI for staging purposes, with 19/22 also undergoing 68Gaa-DOTA-RM2 PET/MRI. TNM classification based on image findings was performed and quantitative imaging parameters were collected for each scan. Furthermore, twelve patients underwent radical prostatectomy with the availability of histological data that were used as the gold standard to validate intraprostatic findings. A DICE score between regions of interest manually segmented on the primary tumour on 68Ga-PSMA PET, 68Ga-DOTA-RM2 PET and on T2 MRI was computed. All imaging modalities detected the primary PCa in 18/19 patients, with 68Ga-DOTA-RM2 PET not detecting any lesion in 1/19 patients. In the remaining patients, 68Ga-PSMA and MRI were concordant. Seven patients presented seminal vesicles involvement on MRI, with two of these being also detected by 68Ga-PSMA, and 68Ga-DOTA-RM2 PET being negative. Regarding extraprostatic disease, 68Ga-PSMA PET, 68Ga-DOTA-RM2 PET and MRI resulted positive in seven, four and five patients at lymph-nodal level, respectively, and at a bone level in three, zero and one patients, respectively. These preliminary results suggest the potential complementary role of 68Ga-PSMA PET, 68Ga-DOTA-RM2 PET and MRI in PCa characterization during the staging phase.

Perioperative and oncologic outcomes of open radical nephrectomy and inferior vena cava thrombectomy with liver mobilization and Pringle maneuver for Mayo III level tumor thrombus: single institution experience.

BACKGROUND: Scarce data are available regarding the technique and outcomes for patients with RCC and Mayo III caval thrombi. The aim of this study was to report surgical and oncological outcomes of RCC patients with Mayo III thrombi treated with radical nephrectomy and thrombectomy after liver mobilization (LM) and Pringle maneuver (PM). METHODS: Retrospective analysis of surgical technique, outcomes and cancer control in 19 patients undergoing LM and PM in a single tertiary care institution were analyzed. RESULTS: Overall, 78% of the patients had performance status ECOG 1 and 58% had a Comorbidity Index >2. Median surgical time was 305 minutes (IQR 264-440). Intraoperative complications were reported for 39% of patients and postoperative complications for 58% (only grade 1 and 2). Intensive Care Unit support was necessary in 16% of the cases. Median length of hospital stay was 9 days (IQR: 7-11). Thirty- and 90-day mortality were 5% and 15%. Two-year overall survival and cancer-specific survival were 60% and 62%, respectively. CONCLUSIONS: We reported surgical techniques, intra- and perioperative complications and follow-up in the largest cohort of RCC patients requiring LM and PM.

Galectin-3 in Prostate Cancer Stem-Like Cells Is Immunosuppressive and Drives Early Metastasis.

Galectin-3 (Gal-3) is an extracellular matrix glycan-binding protein with several immunosuppressive and pro-tumor functions. The role of Galectin-3 in cancer stem-like cells (CSCs) is poorly investigated. Here, we show that prostate CSCs also colonizing prostate-draining lymph nodes of transgenic adenocarcinoma of the mouse prostate (TRAMP) mice overexpress Gal-3. Gal-3 contributes to prostate CSC-mediated immune suppression because either Gal-3 silencing in CSCs, or co-culture of CSCs and T cells in the presence of the Gal-3 inhibitor N-Acetyl-D-lactosamine rescued T cell proliferation. N-Acetyl-D-lactosamine also rescued the proliferation of T cells in prostate-draining lymph nodes of TRAMP mice affected by prostate intraepithelial neoplasia. Additionally, Gal-3 impacted prostate CSC tumorigenic and metastatic potential in vivo, as Gal-3 silencing in prostate CSCs reduced both primary tumor growth and secondary invasion. Gal-3 was also found expressed in more differentiated prostate cancer cells, but with different intracellular distribution as compared to CSCs, which suggests different functions of Gal-3 in the two cell populations. In fact, the prevalent nuclear and cytoplasmic distribution of Gal-3 in prostate CSCs made them less susceptible to apoptosis, when compared to more differentiated prostate cancer cells, in which Gal-3 was predominantly intra-cytoplasmic. Finally, we found Gal-3 expressed in human and mouse prostate intraepithelial neoplasia lesions and in metastatic lymph nodes. All together, these findings identify Gal-3 as a key molecule and a potential therapeutic target already in the early phases of prostate cancer progression and metastasis.

ProstaTrend-A Multivariable Prognostic RNA Expression Score for Aggressive Prostate Cancer.

BACKGROUND: Prostate cancer (PCa) is the most prevalent solid cancer among men in Western Countries. The clinical behavior of localized PCa is highly variable. Some cancers are aggressive leading to death, while others can even be monitored safely. Hence, there is a high clinical need for precise biomarkers for identification of aggressive disease in addition to established clinical parameters. OBJECTIVE: To develop an RNA expression-based score for the prediction of PCa prognosis that facilitates clinical decision making. DESIGN, SETTING, AND PARTICIPANTS: We assessed 233 tissue specimens of PCa patients with long-term follow-up data from fresh-frozen radical prostatectomies (RPs), from formalin-fixed and paraffin-embedded RP specimens and biopsies by transcriptome-wide next-generation sequencing and customized expression microarrays. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We applied Cox proportional hazard models to the cohorts from different platforms and specimen types. Evidence from these models was combined by fixed-effect meta-analysis to identify genes predictive of the time to death of disease (DoD). Genes were combined by a weighted median approach into a prognostic score called ProstaTrend and transferred for the prediction of biochemical recurrence (BCR) after RP in an independent cohort of The Cancer Genome Atlas (TCGA). RESULTS AND LIMITATIONS: ProstaTrend comprising ∼1400 genes was significantly associated with DoD in the training cohort of PCa patients treated by RP (leave-one-out cross-validation, Cox regression: p=2e-09) and with BCR in the TCGA validation cohort (Cox regression: p=3e-06). The prognostic impact persisted after multivariable Cox regression analysis adjusting for Gleason grading group (GG) ≥3 and resection status (p=0.001; DoD, training cohort) and for GG≥3, pathological stage ≥T3, and resection state (p=0.037; BCR, validation cohort). CONCLUSIONS: ProstaTrend is a transcriptome-based score that predicts DoD and BCR in cohorts of PCa patients treated with RP. PATIENT SUMMARY: ProstaTrend provides molecular patient risk stratification after radical prostatectomy.

Relative Contribution of Sampling and Grading to the Quality of Prostate Biopsy: Results from a Single High-volume Institution.

BACKGROUND: The quality of prostate biopsy is affected by sampling (does the urologist take cores from the right place?) and the histological evaluation (does the pathologist grade correctly?). OBJECTIVE: To evaluate the relative contribution of sampling and histological evaluation to the reliability of prostate biopsy in terms of concordance with grading of the surgical specimen. DESIGN, SETTING, AND PARTICIPANTS: We identified 848 prostate cancer patients who underwent radical prostatectomy between 2015 and 2017 at our institution with external or internal biopsies. Since 2016, a dedicated uropathologist has reviewed all the biopsies sampled externally. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We considered the discordance between biopsy and final pathology as a proxy for the quality of prostate biopsy, and calculated the corresponding discordance rate for each biopsy setting. RESULTS AND LIMITATIONS: We observed the highest rate of grade discordance for patients who had an external biopsy without internal review (66%). Biopsies both sampled and reviewed internally had the lowest discrepancy rate (39%; p<0.0001 compared to external biopsies). Biopsies sampled outside our institution and reviewed internally had an intermediate discordance rate (51%; p=0.003). CONCLUSIONS: The quality of prostate biopsy is influenced by both sampling and evaluation. Highly experienced pathological evaluation of needle biopsies is crucial, but biopsy quality also strongly depends on the quality of the sampled material. Future studies should investigate the mechanism underlying discordance in sampling. Consideration should be given to regionalization of prostate biopsy. PATIENT SUMMARY: The quality of prostate biopsy varies between specialist and community centers. We found that this variation is affected by both sampling (does the urologist take cores from the right place?) and histological evaluation (does the pathologist grade correctly?).

Boosting Interleukin-12 Antitumor Activity and Synergism with Immunotherapy by Targeted Delivery with isoDGR-Tagged Nanogold.

The clinical use of interleukin-12 (IL12), a cytokine endowed with potent immunotherapeutic anticancer activity, is limited by systemic toxicity. The hypothesis is addressed that gold nanoparticles tagged with a tumor-homing peptide containing isoDGR, an αvß3-integrin binding motif, can be exploited for delivering IL12 to tumors and improving its therapeutic index. To this aim, gold nanospheres are functionalized with the head-to-tail cyclized-peptide CGisoDGRG (Iso1) and murine IL12. The resulting nanodrug (Iso1/Au/IL12) is monodispersed, stable, and bifunctional in terms of αvß3 and IL12-receptor recognition. Low-dose Iso1/Au/IL12, equivalent to 18-75 pg of IL12, induces antitumor effects in murine models of fibrosarcomas and mammary adenocarcinomas, with no evidence of toxicity. Equivalent doses of Au/IL12 (a nanodrug lacking Iso1) fail to delay tumor growth, whereas 15 000 pg of free IL12 is necessary to achieve similar effects. Iso1/Au/IL12 significantly increases tumor infiltration by innate immune cells, such as NK and iNKT cells, monocytes, and neutrophils. NK cell depletion completely inhibits its antitumor effects. Low-dose Iso1/Au/IL12 can also increase the therapeutic efficacy of adoptive T-cell therapy in mice with autochthonous prostate cancer. These findings indicate that coupling IL12 to isoDGR-tagged nanogold is a valid strategy for enhancing its therapeutic index and sustaining adoptive T-cell therapy.

Can DCE-MRI reduce the number of PI-RADS v.2 false positive findings? Role of quantitative pharmacokinetic parameters in prostate lesions characterization.

PURPOSE: To test the potential impact of pharmacokinetic parameters, derived from DCE-MRI analysis, on the diagnostic performance of PI-RADSv.2 classification in prostate lesions characterization. METHOD: Among patients who underwent multiparametric prostate MRI (mpMRI) (January 2016-March 2018) followed by histological evaluation (targeted biopsies/prostatectomy), 103 men were retrospectively selected. For each patient the index lesion was identified and pharmacokinetic parameters (Ktrans, Kep, Ve, Vp) were assessed. MRI diagnostic performance in the detection of significant tumors [Gleason Score (GS)≥7] was assessed, considering PI-RADS≥3 as positive. RESULTS: GS ≥ 7 (n = 59) showed higher Ktrans (p < 0.01) and Kep (p = 0.01) compared to GS < 7. At ROC curve analysis, a Ktrans cut-off of 191 × 10-3/min was identified to predict the presence of GS ≥ 7 (AUC:0.75; sensitivity:95%; specificity:61%). Sensitivity and PPV of mpMRI using PI-RADSv.2 were 98% and 61%. Reclassifying PI-RADS≥3 lesions according to Ktrans cut-off, 22 false positives were shifted to true negatives with 3 false negative findings; PPV raised to 79%. Appling Ktrans cut-off to PI-RADS 3 lesions of peripheral zone (n = 18), 12 true negatives, 4 true positives, 2 false positives were identified. CONCLUSIONS: Despite its high sensitivity prostate mpMRI generates many false positive cases: Ktrans in addition to PIRADS v.2 seems to improve MRI-PPV and may help in avoiding redundant biopsies.

Radical Cystectomy in Pathological T4a and T4b Bladder Cancer Patients: Is There Any Space for Sub Stratification?

INTRODUCTION: According to TNM staging, pathological T4ab are comprehensive of the invasion of prostate, seminal vesicles, uterus or vagina and pelvic or abdominal wall. However, few data are available on the perioperative and oncological outcomes of specific organ invasion. MATERIALS AND METHODS: A total of 917 consecutive bladder cancer (BCa) patients treated with radical cystectomy (RC) at a single institution between 1990 and 2015 were studies. Cox regression analyses were used to stratify pT4ab according to the site of invasion and survival. RESULTS: Overall, 176 (19.2%) and 40 (4.4%) patients harbored pT4a or pT4b disease. Specifically, 84 (9.2%) patients reported prostate and/or SVI invasion, 62 (6.8%) prostate only, 16 (1.7%) uterus, 14 (1.5%) vaginal, 24 (2.6%) pelvic wall, and 16 (1.7%) abdominal wall invasion. The median follow-up in pT4 patients was 48 months. The 1-year cancer-specific mortality (CSM) rates were 71, 65, 24, 50, 50, and 72%, for vaginal, uterus, prostate only, prostate and/or seminal vesicles, pelvic wall, and abdominal wall invasions, respectively. At multivariable Cox regression, the invasion of prostate only (hazard ratio [HR] 3.53), prostate and/or SVI (HR 4.98), uterus (HR 7.16), vagina (HR 6.12), pelvic (HR 11.81), abdominal (8.36) were associated with adverse CSM. CONCLUSIONS: Our study described the differences in survival related to invasion site in pT4 patients, confirming poor survival expectancies in this subgroup. Patients with prostate invasion only seem to be associated with better survival than those affected by concomitant invasion of seminal vesicles. Uterus and vaginal invasions were associated with poor survival outcomes. Patients Summary: In this study, we looked at the outcome of locally advanced invasive BCa (stage pT4) in patients treated with RC at a tertiary referral hospital. We analyzed the differences in survival related to the specific organ invasion. We confirmed poor survival in this subgroup of patients. Only patients who had prostate invasion only seem to have a better survival.

PD-L1 Expression and CD8+ T-cell Infiltrate are Associated with Clinical Progression in Patients with Node-positive Prostate Cancer.

Prostate cancer (PCa) patients with lymph node invasion at radical prostatectomy are at higher risk of tumor recurrence and receive immediate androgen deprivation therapy (ADT). While approximately 30% of these patients do not experience recurrence, others experience disease recurrence despite ADT, and currently no biomarkers can accurately identify them. We analyzed tumors from 51 patients with node-positive prostate cancer using immunohistochemistry to investigate whether expression of the immune checkpoint ligand PD-L1 by tumor cells or the density of CD8+ or CD20+ cells are associated with clinical progression. Patients with at least 1% PD-L1+ tumor cells had shorter metastasis-free survival than those with PD-L1- tumors (p=0.008, log-rank test). Univariate Cox regression showed that patients with PD-L1+ tumors had almost four times the risk of experiencing distant metastases than those with PD-L1- tumors (hazard ratio 3.90). In addition, we found that PD-L1 expression was significantly associated with CD8+ T-cell density, but not with CD20+ B-cell density. While these results need to be confirmed in larger studies, they show that PD-L1 and CD8 may be used as biomarkers for node-positive patients at high risk of progression. The study also provides a rationale for selecting patients with node-positive PCa who might benefit the most from adjuvant immunotherapies. PATIENT SUMMARY: None of the available biomarkers can identify node-positive prostate cancer that will recur after surgery. We found that expression of PD-L1 by tumor cells and a high density of CD8+ T cells in tumor are associated with a higher risk of clinical progression in men with node-positive prostate cancer.

Pathological High-risk Renal Cell Carcinoma: Trends in Clinical Characteristics Over 25 Years.

BACKGROUND/AIM: The incidence of renal cell carcinoma (RCC) has been increasing mainly due to the increase in the incidental detection of small renal masses. The aim of this study was to verify whether the trend towards early diagnosis changed the clinical characteristics of pathologically-defined high-risk RCC patients over the last decades. PATIENTS AND METHODS: A total of 741 patients with pathologically-confirmed high-risk RCC (pT1-4, and/or pN1 and/or Fuhrman grade 3-4 and/or all M1 patients) treated with radical (RN) or partial nephrectomy (PN) at a single tertiary referral center between 1987 and 2011 were included in the study. The temporal trends of pre-operative clinical and tumor characteristics were assessed relying on the lowess smoother weighted function with corresponding 95% confidence interval. Estimated annual percentage changes (EAPC) were evaluated using a log linear regression model. RESULTS: The median age of patients increased from 57.5 to 67.3 years between 1987 and 2011 (EAPC 4.9%, p=0.002). Body mass index and gender rates remained stable during the study period. A constant trend towards patients with one or more comorbidity was observed. Moreover, the proportion of asymptomatic patients at diagnosis and of clinical T1 increased by 41.1 and 19.8%, respectively (all p≤0.007). The clinical tumor size dropped from 8.4 to 6.2 cm (EAPC -1.2%, p=0.001). This trend was accompanied by a clinically-relevant increase by 15.3% in the rate of patients without clinical metastases (p=0.07). Conversely, the rate of clinical lymphadenopathies remained stable over time. Finally, the rate of PNs performed increased by 23.3% (p<0.001). CONCLUSION: Over the years, pathologically-confirmed high-risk RCC patients are older, mostly asymptomatic, with smaller cancers, with a higher rate of tumors localized to the kidney and with a decreased rate of metastatic disease at diagnosis. These trends can explain the increasing number of PNs performed despite the presence of a high-risk cancer profile.

Clinical and pathological characteristics of a series of patients with newly diagnosed primary renal liposarcoma: natural history and effect on survival.

OBJECTIVES: Primary renal liposarcoma is an unusual malignant mesenchymal tumor. In this context, all the previous reports were based on cases with insufficient data regarding the natural history of the disease. We decided to fill this gap, reporting the largest single institution series of patients with primary RL and a review of the already available literature. METHODS: We describe 3 cases with radiologically and histologically-confirmed RL out of 3,224 surgeries performed for primary kidney cancers over 28 years (1987-2015, 0.09%) at a single tertiary care center. RESULTS: Patients underwent open radical nephrectomy with an anterior transperitoneal access with complete resection of the retroperitoneal mass and retroperitoneal lymph node dissection; all patients died from tumor progression after a mean time of 45 months. CONCLUSIONS: In conclusion, RL is a very rare mesenchymal renal tumor, with sporadic cases reported. We reported the largest case series of primary RL. The most appropriate approach for RL is nephrectomy with complete resection of all the neoplastic tissue. Stringent follow-up scheme is required due to a high rate of disease recurrence and progression. The role of adjuvant and salvage therapy remains to be investigated.

Targeting Tumor Vasculature with TNF Leads Effector T Cells to the Tumor and Enhances Therapeutic Efficacy of Immune Checkpoint Blockers in Combination with Adoptive Cell Therapy.

Purpose: Irregular blood flow and endothelial cell anergy, which characterize many solid tumors, hinder tumor infiltration by cytotoxic T lymphocytes (CTL). This confers resistance to cancer immunotherapy with monoclonal antibodies directed against regulatory pathways in T lymphocytes (i.e., immune checkpoint blockade, ICB). We investigated whether NGR-TNF, a TNF derivative capable of targeting the tumor vasculature, and improving intratumor infiltration by activated CTLs, could sensitize tumors to ICB with antibodies specific for the PD-1 and CTLA-4 receptors.Experimental Design: Transgenic adenocarcinoma of the mouse prostate (TRAMP) mice with autochthonous prostate cancer and C57BL/6 mice with orthotopic B16 melanoma were treated with NGR-TNF, adoptive T-cell therapy (ACT), and ICB, and monitored for immune surveillance and disease progression.Results: The combination of ACT, NGR-TNF, and ICB was the most effective in delaying disease progression, and in improving overall survival of mice bearing ICB-resistant prostate cancer or melanoma. Mechanistically, the therapeutic effects were associated with potent tumor infiltration, especially by endogenous but also by adoptively transferred PD-1+, granzyme B+, and interferon-γ+ CTLs. The therapeutic effects were also associated with favorable T-effector/regulatory T cell ratios.Conclusions: Targeting the tumor vasculature with low-dose TNF in association with ACT may represent a novel strategy for enhancing T-cell infiltration in tumors and overcoming resistance to immune checkpoint blockers. Clin Cancer Res; 24(9); 2171-81. ©2018 AACR.

Perioperative and Oncologic Outcomes of Nephrectomy and Caval Thrombectomy Using Extracorporeal Circulation and Deep Hypothermic Circulatory Arrest for Renal Cell Carcinoma Invading the Supradiaphragmatic Inferior Vena Cava and/or Right Atrium.

BACKGROUND: Radical nephrectomy (RN) and caval thrombectomy (CT) for renal cell carcinoma, with extracorporeal circulation (ECC) and deep hypothermic circulatory arrest (DHCA) is a challenging surgical approach. OBJECTIVE: To assess peri-operative and oncologic outcomes of renal cell carcinoma patients treated with RN and CT, using ECC and DHCA. DESIGN, SETTING, AND PARTICIPANTS: We retrospectively evaluated 46 patients who underwent RN and CT using ECC and DHCA. SURGICAL PROCEDURE: After retroperitoneal nodal dissection and RN, a cardiopulmonary bypass was placed and DHCA achieved. A combined approach through the abdomen and the thorax was described. MEASUREMENTS: Perioperative and long-term survival outcomes were reported. RESULTS AND LIMITATIONS: Median operative time and length of hospital stay were 545min and 22 d. Overall, 33 patients (72%) did not require any additional interventional or surgical treatment. Thirty-day and 90-d mortality were 11% (5/46) and 15% (7/46). The 1-yr, 2-yr, and 3-yr cancer specific mortality (CSM)-free survival rates were 77%, 62%, and 56%, respectively. After stratification, according to metastatic status at diagnosis, CSM-free survival rates were significantly lower for cM1 patients compared with cM0 patients (1-yr 46% vs 93%, 2-yr 23% vs 81%, 3-yr 23% vs 73%, p<0.01). Our study is limited by its retrospective and uncomparative nature. CONCLUSIONS: RN with CT using ECC and DHCA is a challenging procedure which requires a dedicated multidisciplinary working team to minimise complications and maximise patients' outcomes. PATIENT SUMMARY: Patients with kidney cancer and a thrombus within the inferior vena cava, which reaches above the diaphragm, can be treated with surgery. However, this kind of surgical treatment is challenging and requires a dedicated multidisciplinary team in order to accomplish the task.

Feasibility and Clinical Roles of Different Substaging Systems at First and Second Transurethral Resection in Patients with T1 High-Grade Bladder Cancer.

BACKGROUND: Decision making in T1 high-grade bladder cancer patients remains a challenging issue in urologic practice. OBJECTIVE: To assess the feasibility and potential prognostic role of three different substaging systems in specimens from both primary and second transurethral resection (TUR) of the bladder in T1 high-grade bladder cancer patients. DESIGN, SETTING, AND PARTICIPANTS: A total of 250 consecutive, confirmed pure transitional T1 high-grade bladder tumors submitted to second TUR entered the retrospective study. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Feasibility of two already clinically tested microstaging systems (anatomy-based T1a/T1b/T1c and micrometric T1m/T1e with 0.5-mm thresholds of invasion) and that of a micrometric substage designed by the authors and based on a 1-mm threshold of invasion (Rete Oncologica Lombarda [ROL] system) was assessed by five independent uropathologists on both first and second TUR specimens. Univariable Cox proportional hazards models were attempted to identify significant independent predictors of recurrence and progression after TUR. Kaplan-Meier curves were plotted to compare different substaging methods analyzing recurrence and progression. RESULTS AND LIMITATIONS: The ROL system proved to be feasible in nearly all cases at both first and second TUR. Median follow-up was 60 mo. The univariate Cox regression analysis documented the ROL substage (ROL2 vs ROL1) to be the only statistically significant predictor of progression (hazard ratio: 2.01; 95% CI, 1.03-3.79; p<0.03). For the first time to our knowledge, the substage was investigated and used to assess T1 tumors found at second TUR, registering a high rate of feasibility. CONCLUSIONS: T1 microstaging using different procedures is feasible on both primary- and second-TUR specimens. A high rate of feasibility may be expected for T1m/T1e and ROL systems. The clinical role of microstaging on second TUR remains to be defined. PATIENT SUMMARY: The Rete Oncologica Lombarda system showed feasible results in T1 high-grade bladder tumors. Our substratification was predictive of progression of disease.

Identifying candidates for super-extended staging pelvic lymph node dissection among patients with high-risk prostate cancer.

OBJECTIVES: To assess if the preoperative lymph node invasion (LNI) risk could be used to tailor the extent of pelvic lymph node dissection (PLND) according to individual profile in patients with prostate cancer (PCa) undergoing radical prostatectomy (RP), and to identify those who would benefit from the removal of the common iliac and pre-sacral nodes. PATIENTS AND METHODS: A total of 471 patients with high-risk PCa treated with RP and a super-extended PLND that included the removal of the pre-sacral and common iliac nodes between 2006 and 2016 were identified. The risk of LNI was calculated according to the Briganti nomogram. Multivariable logistic regression analyses assessed the association between LNI risk and involvement of the common iliac and pre-sacral regions. The risk of positive common iliac and pre-sacral nodes was plotted over the LNI risk using the LOWESS-smoothed fit curve. RESULTS: The median preoperative LNI risk was 25.5%. The median number of nodes removed was 23, and 171 (36.3%) patients had LNI. Overall, 61 (13.0%) and 28 patients (5.9%), respectively, had positive common iliac and pre-sacral nodes alone or in combination with other sites. The LNI risk was associated with the involvement of the common iliac and pre-sacral regions (all P < 0.001). The proportion of patients with positive common iliac and pre-sacral nodes progressively increased according to the LNI risk. The adoption of a 30% threshold would result in avoiding the removal of the common iliac and pre-sacral nodes in >60% cases, with a risk of missing LNI in these regions of <5%. CONCLUSIONS: Fewer than 5% of patients with an LNI risk of <30% harbour positive common iliac and pre-sacral nodes. A super-extended PLND that includes the dissection of these regions should be considered exclusively in patients with an LNI risk ≥30%.