Shen, Steven S.

Pelvicalyceal invasion (PCI) is a relatively novel pT3a staging parameter for renal cell carcinoma (RCC) nephrectomies. While interobserver reproducibility staging studies of sinus/vascular invasion in RCC exist, a similar evaluation for PCI has not been performed. Moreover, in our experience, there is also diagnostic variability in how pathologists interpret PCI. Herein, we explore interobserver reproducibility among genitourinary (GU) pathologists. Twenty hematoxylin and eosin-stained digitized slides from RCCs (all grossly approaching the renal pelvis) were distributed to 31 GU pathologists to classify each as PCI or not PCI based on their respective clinical practices; slides with concomitant sinus/fat/vascular invasion were excluded. Slides were then evaluated for the following 4 morphologic features: tumor abutting renal pelvis, tumor pushing/indenting into the renal pelvis, polypoid configuration of tumor into the renal pelvis, and tumor eroding through renal pelvic urothelium. Interobserver reproducibility was assessed, and the morphologic features were correlated with PCI. Relationships between pathologists’ interpretations, morphologic features, and PCI were evaluated using hierarchical clustering. Although the diagnosis of PCI was relatively uniform with a majority agreement (>67%) reached in 16/20 slides, overall interobserver reproducibility was only moderate (kappa=0.601). While all 4 morphologic features were sensitive for PCI, polypoid configuration of the tumor into the renal pelvis and the tumor eroding through the renal pelvic urothelium were most specific (90%, 100%, respectively). Although we show general consensus among genitourinary pathologists on PCI assessment, clarifying the diagnostic guidelines with specific criteria should be included in pathologic staging systems.

AimsCompared to lymphovascular invasion (LVI), hilar soft tissue invasion (HSTI) is a relatively novel pT2 staging parameter in testicular germ cell tumours (GCT), associated with metastasis at the time of diagnosis and a risk factor for disease relapse. Given diagnostic variability in how pathologists interpret HSTI, herein we explore interobserver reproducibility among genitourinary (GU) pathologists.MethodsTwenty haematoxylin and eosin‐stained digitized slides from testicular GCTs were distributed to 30 GU pathologists to classify each as HSTI or not HSTI based on their respective clinical practices; slides with concomitant LVI were excluded. Slides were then evaluated for the following morphologic features: tumour invasion beyond prominent hilar vessels, tumour invasion beyond the rete, tumour invasion beyond the level parallel to hilar adipose tissue and tumour within (directly touching) hilar adipose tissue. Interobserver reproducibility was assessed, and the morphological features were correlated with HSTI. Relationships between pathologists' interpretations, morphological features and HSTI were evaluated using hierarchical clustering.ResultsAlthough the diagnosis of HSTI was relatively uniform with a majority agreement (>67%) reached in 17/20 slides, overall interobserver reproducibility was only moderate (kappa = 0.50). Morphological features such as invasion beyond the level parallel to hilar adipose tissue and invasion into fat were more sensitive and specific for HSTI, while features such as invasion beyond hilar vessels and invasion beyond rete were less useful.ConclusionsThese findings suggest that more specific defined diagnostic criteria for testicular GCT HSTI are needed.

Background The indoleamine 2,3-dioxygenase (IDO) pathway is a key counter-regulatory mechanism that, in cancer, is exploited by tumors to evade antitumor immunity. Indoximod is a small-molecule IDO pathway inhibitor that reverses the immunosuppressive effects of low tryptophan (Trp) and high kynurenine (Kyn) that result from IDO activity. In this study, indoximod was used in combination with a checkpoint inhibitor (CPI) pembrolizumab for the treatment for advanced melanoma. Methods Patients with advanced melanoma were enrolled in a single-arm phase II clinical trial evaluating the addition of indoximod to standard of care CPI approved for melanoma. Investigators administered their choice of CPI including pembrolizumab (P), nivolumab (N), or ipilimumab (I). Indoximod was administered continuously (1200 mg orally two times per day), with concurrent CPI dosed per US Food and Drug Administration (FDA)-approved label. Results Between July 2014 and July 2017, 131 patients were enrolled. (P) was used more frequently (n=114, 87%) per investigator’s choice. The efficacy evaluable population consisted of 89 patients from the phase II cohort with non-ocular melanoma who received indoximod combined with (P). The objective response rate (ORR) for the evaluable population was 51% with confirmed complete response of 20% and disease control rate of 70%. Median progression-free survival was 12.4 months (95% CI 6.4 to 24.9). The ORR for Programmed Death-Ligand 1 (PD-L1)-positive patients was 70% compared with 46% for PD-L1-negative patients. The combination was well tolerated, and side effects were similar to what was expected from single agent (P). Conclusion In this study, the combination of indoximod and (P) was well tolerated and showed antitumor efficacy that is worth further evaluation in selected patients with advanced melanoma.