Immune Checkpoint Molecule TIGIT Regulates Kidney T Cell Functions and Contributes to AKI.

SIGNIFICANCE STATEMENT: T cells mediate pathogenic and reparative processes during AKI, but the exact mechanisms regulating kidney T cell functions are unclear. This study identified upregulation of the novel immune checkpoint molecule, TIGIT, on mouse and human kidney T cells after AKI. TIGIT-expressing kidney T cells produced proinflammatory cytokines and had effector (EM) and central memory (CM) phenotypes. TIGIT-deficient mice had protection from both ischemic and nephrotoxic AKI. Single-cell RNA sequencing led to the discovery of possible downstream targets of TIGIT. TIGIT mediates AKI pathophysiology, is a promising novel target for AKI therapy, and is being increasingly studied in human cancer therapy trials. BACKGROUND: T cells play pathogenic and reparative roles during AKI. However, mechanisms regulating T cell responses are relatively unknown. We investigated the roles of the novel immune checkpoint molecule T cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) in kidney T cells and AKI outcomes. METHODS: TIGIT expression and functional effects were evaluated in mouse kidney T cells using RNA sequencing (RNA-Seq) and flow cytometry. TIGIT effect on AKI outcomes was studied with TIGIT knockout (TIGIT-KO) mice in ischemia reperfusion (IR) and cisplatin AKI models. Human kidney T cells from nephrectomy samples and single cell RNA sequencing (scRNA-Seq) data from the Kidney Precision Medicine Project were used to assess TIGIT's role in humans. RESULTS: RNA-Seq and flow cytometry analysis of mouse kidney CD4+ T cells revealed increased expression of TIGIT after IR injury. Ischemic injury also increased TIGIT expression in human kidney T cells, and TIGIT expression was restricted to T/natural killer cell subsets in patients with AKI. TIGIT-expressing kidney T cells in wild type (WT) mice had an effector/central memory phenotype and proinflammatory profile at baseline and post-IR. Kidney regulatory T cells were predominantly TIGIT+ and significantly reduced post-IR. TIGIT-KO mice had significantly reduced kidney injury after IR and nephrotoxic injury compared with WT mice. scRNA-Seq analysis showed enrichment of genes related to oxidative phosphorylation and mTORC1 signaling in Th17 cells from TIGIT-KO mice. CONCLUSIONS: TIGIT expression increases in mouse and human kidney T cells during AKI, worsens AKI outcomes, and is a novel therapeutic target for AKI.

Predictive model for systemic recurrence following cisplatin-based neoadjuvant chemotherapy and radical nephroureterectomy for high risk upper tract urothelial carcinoma.

INTRODUCTION: Neoadjuvant chemotherapy (NAC) is increasingly used prior to radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC). Systemic recurrence (SR) carries a dismal prognosis. We sought to determine risk factors associated with SR in this setting. METHODS: We evaluated a multi-center database of patients with UTUC who received cisplatin-based NAC before RNU. Final pathology at RNU was dichotomized into ypT<2 vs ypT≥2. Univariable and multivariable analyses were performed to identify risk factors associated with SR. Three groups were defined based on the number of significant risk factors (groups 1, 2, 3 for 0-1, 2, 3 risk factors, respectively) and evaluated for recurrence-free survival (RFS) using the Kaplan-Meier method. RESULTS: 106 patients were identified between 2004 and 2018. Median age was 67.0 years [IQR = 61-73.3]; 57 (54%) and 49 (46 %) patients received MVAC and GC, respectively. Final pathological stage was ypT<2 in 57 (54%); 23% (24/106) had SR. On univariable analysis, pathological variables on final specimen including ypT≥2, lymphovascular invasion (ypLVI), and nodal involvement were associated with SR. On multivariable analysis, ypLVI OR = 4.1 (95% CI 1.2-13.6; P = 0.024) and pathological nodal involvement OR = 4.5 (95% CI 1.3-15.7; P = 0.017) were predictive of recurrence. Stratifying by the number of risk factors, the 2-year RFS was 95%, 55%, and 18% for groups 1, 2, and 3 respectively (log-rank <0.001). CONCLUSION: This model evaluates the risk of SR following NAC and RNU to guide counseling and decision-making after surgery. Adverse pathological variable including ypLVI and nodal involvement, in combination with ypT-stage, are strongly associated with SR.

Improved identification of patients with oligometastatic clear cell renal cell carcinoma with PSMA-targeted 18F-DCFPyL PET/CT.

OBJECTIVE: Complete surgical resection of metastatic sites has been shown to prolong survival in select patients with oligometastatic RCC. This treatment strategy is dependent upon the accurate characterization of a patient's extent of disease. The objective of this study was to explore the utility of PSMA-targeted 18F-DCFPyL PET/CT in patients with presumed oligometastatic clear cell RCC. METHODS: This is a subset analysis of a prospective study in which patients with RCC were imaged with 18F-DCFPyL PET/CT (ClinicalTrials.gov identifier NCT02687139). In the present analysis, patients with oligometastatic clear cell RCC, defined as ≤ 3 metastatic lesions on conventional imaging, were evaluated. 18F-DCFPyL PET/CT scans were reviewed for sites of disease and compared to conventional imaging. RESULTS: The final cohort included 14 patients with oligometastatic clear cell RCC. Conventional imaging revealed 21 metastatic lesions and 3 primary tumors. 18F-DCFPyL PET/CT detected 29 sites of metastatic disease and 3 primary tumors. Of the 21 metastatic lesions detected on conventional imaging, 17 (81.0%) had radiotracer uptake. Additionally, all 3 primary tumors had radiotracer uptake. In 4 (28.6%) patients a total of 12 more lesions were identified on 18F-DCFPyL PET/CT than conventional imaging. Notably, 3 (21.4%) patients were no longer considered oligometastatic. The detection rates of conventional imaging and 18F-DCFPyL PET/CT for identifying sites of disease were 66.7% and 88.9%, respectively. CONCLUSIONS: PSMA-targeted PET/CT appears to aid in the identification of patients with oligometastatic clear cell RCC. If borne out in future studies, this suggests that PSMA-targeted imaging has the potential to help select candidates for metastasis-directed therapy.

Clinical and Radiographic Predictors of Great Vessel Resection or Reconstruction During Retroperitoneal Lymph Node Dissection for Testicular Cancer.

OBJECTIVE: To evaluate whether specific clinical or radiographic factors predict inferior vena cava (IVC) or abdominal aortic (AA) resection or reconstruction (RoR) at the time of postchemotherapy retroperitoneal lymph node dissection (RPLND) for germ cell tumors of the testicle. MATERIALS AND METHODS: Two hundred seventy-seven patients undergoing postchemotherapy RPLND at two institutions between 2005 and 2015 were identified. Preoperative imaging was reviewed with radiologists blinded to operative details. Univariable and multivariable logistic regressions were performed, and a model was created to predict the need for great vessel RoR using radiographic and clinical factors. RESULTS: Of 97 patients with preoperative imaging and clinical data available, 16 (17%) underwent RoR at RPLND. On univariable analysis dominant mass size, degree of circumferential vessel involvement, and vessel deformity were associated with RoR (all P <.05). No patients with clinical stage IIA or IIB disease at diagnosis required RoR. In the multivariable model, mass involvement of the IVC >135° (odds ratio 65.5, 7.8-548, P <.01) and involvement of the AA >330° (odds ratio 29.0, 3.44-245, P <.01) were predictive for RoR. These thresholds yielded a PPV of 48% and 50% and a NPV of 92% and 97% for IVC and AA RoR, respectively. CONCLUSION: Degree of circumferential involvement of the great vessels is an independent predictor for resection or reconstruction of the IVC or AA at postchemotherapy RPLND. Patients at high risk of great vessel reconstruction should be informed accordingly and have the proper teams available for complex vascular reconstruction.

Inconsistent Detection of Sites of Metastatic Non-Clear Cell Renal Cell Carcinoma with PSMA-Targeted [18F]DCFPyL PET/CT.

PURPOSE: To investigate the utility of prostate-specific membrane antigen (PSMA)-targeted [18F]DCFPyL positron emission tomography (PET)/X-ray computed tomography (CT) imaging for the detection of sites of disease in patients with metastatic non-clear cell renal cell carcinoma (RCC). PROCEDURES: Eight patients with metastatic non-clear cell RCC underwent imaging with PSMA-targeted [18F]DCFPyL PET/CT. Imaged RCC histologic subtypes included papillary RCC (n = 3), chromophobe RCC (n = 2), unclassified RCC (n = 2), and Xp11 translocation RCC (n = 1). Using comparison to conventional CT and/or magnetic resonance imaging as reference, two radiologists with expertise in nuclear medicine identified putative sites of disease on [18F]DCFPyL PET/CT and classified each lesion as having no radiotracer uptake, equivocal uptake, or definitive uptake. RESUTS: In total, 73 metastatic sites and 3 primary tumors compatible with sites of non-clear cell RCC were identified on conventional imaging. Metastatic sites of disease included lymph nodes (n = 40), venous thrombi (n = 3), pulmonary nodules (n = 10), bone lesions (n = 15), brain lesions (n = 3), and retroperitoneal masses (n = 2). Only 10 of the 73 lesions (13.7 %) were classified as having definitive radiotracer uptake (median SUVmax = 3.25, range = 1.2-9.5), 14 lesions (19.2 %) had equivocal uptake (median SUVmax = 2.85, range = 0.5-6.5), and 49 lesions (67.1 %) had no definitive uptake above background (median SUVmax = 1.7, range = 0.2-3.0). The three primary renal tumors demonstrated lower radiotracer avidity relative to surrounding normal renal parenchyma. CONCLUSIONS: A small proportion of sites of non-clear cell RCC showed uptake of the PSMA-targeted radiotracer [18F]DCFPyL. Unlike for clear cell RCC, the results of this study indicate that PSMA-based PET is not appropriate for imaging other RCC subtypes.

Margin Assessment in Renal Surgery Using a Handheld Optical Coherence Tomography Probe.

OBJECTIVE: To assess the use of a handheld optical coherence tomography (OCT) probe for the evaluation of intraoperative surgical margins during partial nephrectomy (PN). METHODS: In an initial feasibility study, a radical nephrectomy specimen with a 9-cm tumor was cut into 19 sections, exposing 0 mm (n = 8), 1 mm (n = 6), and 2 mm (n = 5) gross margins. OCT was used to determine the margin width in each specimen. Second, a prospective ex vivo assessment of 15 PN tumor specimens was performed with OCT to determine margin status and to measure the attenuation coefficient of tumor and renal parenchyma. RESULTS: Median OCT margin width measurements for sectioned samples were 0 mm, 0.9 mm (range 0.7-2.9 mm), and 2.7 (range 1.65-2.8 mm) for grossly 0 mm (positive), 1 mm, and 2 mm margins, respectively. The difference between measurements from all margin groups was statistically significant (P <.04). The sensitivity and specificity for identifying positive margins were both 100%. In the PN specimens, OCT correctly found that all specimens had negative margins (within <.0001). CONCLUSION: We have demonstrated the feasibility of using a handheld OCT probe to assess margins ex vivo during PN. OCT may reduce the need for intraoperative frozen section and aid in minimizing parenchymal excision.

Renal Mass and Localized Renal Cancer: AUA Guideline.

PURPOSE: This AUA Guideline focuses on evaluation/counseling and management of adult patients with clinically localized renal masses suspicious for cancer, including solid-enhancing tumors and Bosniak 3/4 complex-cystic lesions. MATERIALS AND METHODS: Systematic review utilized research from the Agency for Healthcare Research and Quality and additional supplementation by the authors and consultant methodologists. Evidence-based statements were based on body of evidence strength Grade A/B/C (Strong/Moderate/Conditional Recommendations, respectively) with additional statements presented as Clinical Principles or Expert Opinions. RESULTS: Great progress has been made since the previous guidelines on management of localized renal masses were released (2009). The current guidelines provide updated, evidence-based recommendations regarding evaluation/counseling of patients with clinically localized renal masses, including the evolving role of renal mass biopsy. Given great variability of clinical, oncologic and functional characteristics, index patients are not utilized and the panel advocates individualized counseling/management. Management options (partial nephrectomy/radical nephrectomy/thermal ablation/active surveillance) are reviewed including recent data about comparative effectiveness and potential morbidities. Oncologic issues are prioritized while recognizing that functional outcomes are of great importance for survivorship for most patients with localized kidney cancer. A more restricted role for radical nephrectomy is recommended following well-defined selection criteria. Priority for partial nephrectomy is recommended for clinical T1a lesions, along with selective use of thermal ablation, particularly for tumors ≤3.0 cm. Important considerations for shared decision-making about active surveillance are explicitly defined. CONCLUSIONS: Several factors should be considered during counseling/management of patients with clinically localized renal masses, including general health/comorbidities, oncologic potential of the mass, pertinent functional issues and relative efficacy/potential morbidities of various management strategies.

Comparison of biochemical recurrence-free survival between periprostatic and pelvic lymph node metastases of prostate cancer.

OBJECTIVE: To assess the pathologic characteristics and prognostic significance of periprostatic lymph node (LN) metastasis of prostate cancer. The latter was performed by comparing biochemical recurrence (BCR)-free survival in cases of periprostatic LN metastasis versus matched patients showing pelvic LN metastasis. METHODS AND MATERIALS: We identified 15 patients who underwent radical prostatectomy in our institution (1984-2011) showing positive periprostatic and negative pelvic LN with available follow-up information (group 1). These patients were matched 1:2 to patients with positive pelvic LN (group 2) for pertinent clinicopathologic parameters. RESULTS: Main locations of positive periprostatic LN were posterior base and mid posterolateral. Overall higher rate of positive margins, smaller LN, and metastasis size were encountered in group 1 compared with group 2. At 5 years postprostatectomy, 69% of patients in group 1 were free of BCR, whereas 26% of those in group 2 remained BCR free, suggesting that patients with periprostatic node metastasis appeared to have a lower risk of BCR. However, the difference was not statistically significant (P = .072). The same was true when adjusted for the effect of prostate-specific antigen, surgical margin status, size of LNs, size of metastasis, age, and year of surgery. CONCLUSION: Patients with periprostatic node metastasis may have a lower risk of BCR compared with those with metastasis to pelvic LN. Future analysis of larger cohorts will help establish the biologic significance of prostate cancer metastasis to periprostatic LN.

A comparative cost analysis of robot-assisted versus traditional laparoscopic partial nephrectomy.

BACKGROUND AND PURPOSE: Robot-assisted laparoscopic partial nephrectomy (RALPN) is supplanting traditional laparoscopic partial nephrectomy (LPN) as the technique of choice for minimally invasive nephron-sparing surgery. This evolution has resulted from potential clinical benefits, as well as proliferation of robotic systems and patient demand for robot-assisted surgery. We sought to quantify the costs associated with the use of robotics for minimally invasive partial nephrectomy. METHODS: A cost analysis was performed for 20 consecutive robot-assisted partial nephrectomy (RPN) and LPN patients at our institution from 2009 to 2010. Data included actual perioperative and hospitalization costs as well as professional fees. Capital costs were estimated using purchase costs and amortization of two robotic systems from 2001 to 2009, as well as maintenance contract costs. The estimated cost/case was obtained using total robotic surgical volume during this period. Total estimated costs were compared between groups. A separate analysis was performed assuming "ideal" robotic utilization during a comparable period. RESULTS: RALPN had a cost premium of +$1066/case compared with LPN, assuming actual robot utilization from 2001 to 2009. Assuming "ideal" utilization during a comparable period, this premium decreased to +$334; capital costs per case decreased from $1907 to $1175. Tumor size, operative time, and length of stay were comparable between groups. CONCLUSIONS: RALPN is associated with a small to moderate cost premium depending on assumptions regarding robotic surgical volume. Saturated utilization of robotic systems decreases attributable capital costs and makes comparison with laparoscopy more favorable. Purported clinical benefits of RPN (eg, decreased warm ischemia time, increased utilization of nephron-sparing surgery) need further study, because these may have cost implications.

Laparoscopic resection of local recurrence after previous radical nephrectomy for clinically localized renal-cell carcinoma: perioperative outcomes and initial observations.

BACKGROUND AND PURPOSE: Local recurrence is rare after radical nephrectomy for clinically localized renal-cell carcinoma (RCC). Aggressive open surgical resection of isolated local recurrence has been shown to offer durable local control and potential improvement in cancer-specific survival. The objective of this study is to assess early outcomes on a select group of patients who underwent laparoscopic resection of isolated local recurrence after radical nephrectomy for clinically localized RCC. PATIENTS AND METHODS: The perioperative and clinical outcomes of four patients who underwent laparoscopic resection of local recurrence between 2007 and 2009 by a single surgeon were reviewed. RESULTS: Two patients underwent resection of ipsilateral adrenal recurrence while the remaining two underwent resection of recurrence in retroperitoneal lymph nodes. The mean age of patients was 57 years (44-66 y), all had primary tumors with clear-cell histology, and Eastern Cooperative Oncology Group performance status was 0. The mean recurrence size was 5 cm (3-7 cm). All surgical margins were negative. Mean operative time was 195 minutes (170-210 min), and mean estimated blood loss was 187 mL (100-250 mL). No patient needed blood transfusion. Mean length of stay was 2.5 days (2-3 d). At a mean follow-up of 12 months (2-26 mos), 1 patient experienced further recurrence. All patients are alive, and three have no evidence of disease. CONCLUSIONS: Aggressive surgical resection of isolated local recurrence of RCC after radical nephrectomy with curative intent may be beneficial and has traditionally been performed using open surgery. In our limited experience, a laparoscopic approach may be used in selected patients with small well-circumscribed recurrences with low morbidity and excellent short-term outcomes.