Selecting patients with metastatic clear-cell renal cell carcinoma (m-ccRCC) who might benefit from treatment with targeted tyrosine kinase inhibitors (TKI) is a challenge. Our aim was to identify ...molecular markers associated with outcome in patients with m-ccRCC treated with sunitinib.
We performed global transcriptome analyses on 53 primary resected ccRCC tumors from patients who developed metastatic disease and were treated with first-line sunitinib. We also determined chromosome copy-number aberrations, methylation status, and gene mutations in von Hippel-Lindau and PBRM1. Molecular data were analyzed in relation with response rate (RR), progression-free survival (PFS), and overall survival (OS). Validation was performed in 47 additional ccRCC samples treated in first-line metastatic setting with sunitinib.
Unsupervised transcriptome analysis identified 4 robust ccRCC subtypes (ccrcc1 to 4) related to previous molecular classifications that were associated with different responses to sunitinib treatment. ccrcc1/ccrcc4 tumors had a lower RR (P = 0.005) and a shorter PFS and OS than ccrcc2/ccrcc3 tumors (P = 0.001 and 0.0003, respectively). These subtypes were the only significant covariate in the multivariate Cox model for PFS and OS (P = 0.017 and 0.006, respectively). ccrcc1/ccrcc4 tumors were characterized by a stem-cell polycomb signature and CpG hypermethylation, whereas ccrcc3 tumors, sensitive to sunitinib, did not exhibit cellular response to hypoxia. Moreover, ccrcc4 tumors exhibited sarcomatoid differentiation with a strong inflammatory, Th1-oriented but suppressive immune microenvironment, with high expression of PDCD1 (PD-1) and its ligands.
ccRCC molecular subtypes are predictive of sunitinib response in metastatic patients, and could be used for personalized mRCC treatment with TKIs, demethylating or immunomodulatory drugs.
To optimize the management of patients with chronic hepatitis C virus (HCV) infection, noninvasive tests to determine the degree of hepatic fibrosis have been developed. The aims of this study were ...(1) to validate a simple, inexpensive, noninvasive test called FIB‐4, which combines standard biochemical values (platelets, ALT, AST) and age, in a series of 847 liver biopsies performed in HCV‐monoinfected patients; and (2) to compare the results of 780 FIB‐4 and FibroTests performed the same day in a series of 592 HCV‐infected patients. The FIB‐4 index enabled the correct identification of patients with severe fibrosis (F3‐F4) and cirrhosis with an area under the receiver operating characteristic curve of 0.85 (95% CI 0.82‐0.89) and 0.91 (95% CI 0.86‐0.93), respectively. An FIB‐4 index <1.45 had a negative predictive value of 94.7% to exclude severe fibrosis with a sensitivity of 74.3%. An FIB‐4 index higher than 3.25 had a positive predictive value to confirm the existence of a significant fibrosis (F3‐F4) of 82.1% with a specificity of 98.2%. Using these ranges, 72.8% of the 847 liver biopsies were correctly classified. The FIB‐4 index was strongly correlated to the FibroTest results for a score <1.45 or >3.25 (κ = 0.561, P < 0.01). A FIB‐4 value <1.45 or >3.25 (64.6% of the cases) was concordant with FibroTest results in 92.1% and 76%, respectively. Conclusion: For values outside 1.45‐3.25, the FIB‐4 index is a simple, accurate, and inexpensive method for assessing liver fibrosis and proved to be concordant with FibroTest results. (HEPATOLOGY 2007.)
A distinct pathologic entity characterized by expression of the anaplastic lymphoma kinase (ALK) protein (hence described as ALK lymphoma) has emerged within the heterogeneous group of CD30 ...anaplastic large-cell lymphomas. Central nervous system (CNS) involvement is extremely rare in anaplastic large-cell lymphoma. In children, only isolated cases have been reported, mainly as secondary CNS involvement. We report on a 13-year-old boy presenting with headaches and diplopia. Cerebrospinal fluid was infiltrated with atypical large granular lymphocytes. Magnetic resonance imaging of the brain revealed leptomeningeal enhancement. A frontal lobe biopsy showed a pleomorphic neoplasm diffusely infiltrating the meninges composed of large cells with bizarre nuclei similar to those evidenced in cerebrospinal fluid. Immunohistochemical stains showed diffuse strong positivity for CD8, CD30, anaplastic lymphoma kinase protein: p80 and negative monocyte-macrophage and B cell markers. TCR gamma was clonally rearranged. This finding was confirmed by reverse transcription-polymerase chain reaction analysis of the NPM/ALK fusion protein. Epstein-Barr virus was not detected. No evidence of extra-CNS disease was found by imaging study, cytologic examination, or molecular studies. The patient underwent complete remission with polychemotherapy followed by a CNS irradiation. At +10 months from onset, he suffered a full relapse. After a short-term remission with vinblastine, he underwent nonmyeloablative allogeneic bone marrow transplantation, but unfortunately died from multiple organ failure. This case is the first reported occurrence of a primary meningeal ALK lymphoma in a child.
We previously reported a 35-gene expression classifier identifying four clear-cell renal cell carcinoma groups (ccrcc1 to ccrcc4) with different tumour microenvironments and sensitivities to ...sunitinib in metastatic clear-cell renal cell carcinoma. Efficacy profiles might differ with nivolumab and nivolumab–ipilimumab. We therefore aimed to evaluate treatment efficacy and tolerability of nivolumab, nivolumab–ipilimumab, and VEGFR-tyrosine kinase inhibitors (VEGFR-TKIs) in patients according to tumour molecular groups.
This biomarker-driven, open-label, non-comparative, randomised, phase 2 trial included patients from 15 university hospitals or expert cancer centres in France. Eligible patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status of 0–2, and had previously untreated metastatic clear-cell renal cell carcinoma. Patients were randomly assigned (1:1) using permuted blocks of varying sizes to receive either nivolumab or nivolumab–ipilimumab (ccrcc1 and ccrcc4 groups), or either a VEGFR-TKI or nivolumab–ipilimumab (ccrcc2 and ccrcc3 groups). Patients assigned to nivolumab–ipilimumab received intravenous nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses followed by intravenous nivolumab 240 mg every 2 weeks. Patients assigned to nivolumab received intravenous nivolumab 240 mg every 2 weeks. Patients assigned to VEGFR-TKIs received oral sunitinib (50 mg/day for 4 weeks every 6 weeks) or oral pazopanib (800 mg daily continuously). The primary endpoint was the objective response rate by investigator assessment per Response Evaluation Criteria in Solid Tumors version 1.1. The primary endpoint and safety were assessed in the population who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT02960906, and with the EU Clinical Trials Register, EudraCT 2016-003099-28, and is closed to enrolment.
Between June 28, 2017, and July 18, 2019, 303 patients were screened for eligibility, 202 of whom were randomly assigned to treatment (61 to nivolumab, 101 to nivolumab–ipilimumab, 40 to a VEGFR-TKI). In the nivolumab group, two patients were excluded due to a serious adverse event before the first study dose and one patient was excluded from analyses due to incorrect diagnosis. Median follow-up was 18·0 months (IQR 17·6–18·4). In the ccrcc1 group, objective responses were seen in 12 (29%; 95% CI 16–45) of 42 patients with nivolumab and 16 (39%; 24–55) of 41 patients with nivolumab–ipilimumab (odds ratio OR 0·63 95% CI 0·25–1·56). In the ccrcc4 group, objective responses were seen in seven (44%; 95% CI 20–70) of 16 patients with nivolumab and nine (50% 26–74) of 18 patients with nivolumab–ipilimumab (OR 0·78 95% CI 0·20–3·01). In the ccrcc2 group, objective responses were seen in 18 (50%; 95% CI 33–67) of 36 patients with a VEGFR-TKI and 19 (51%; 34–68) of 37 patients with nivolumab–ipilimumab (OR 0·95 95% CI 0·38–2·37). In the ccrcc3 group, no objective responses were seen in the four patients who received a VEGFR-TKI, and in one (20%; 95% CI 1–72) of five patients who received nivolumab–ipilimumab. The most common treatment-related grade 3–4 adverse events were hepatic failure and lipase increase (two 3% of 58 for both) with nivolumab, lipase increase and hepatobiliary disorders (six 6% of 101 for both) with nivolumab–ipilimumab, and hypertension (six 15% of 40) with a VEGFR-TKI. Serious treatment-related adverse events occurred in two (3%) patients in the nivolumab group, 38 (38%) in the nivolumab–ipilimumab group, and ten (25%) patients in the VEGFR-TKI group. Three deaths were treatment-related: one due to fulminant hepatitis with nivolumab–ipilimumab, one death from heart failure with sunitinib, and one due to thrombotic microangiopathy with sunitinib.
We demonstrate the feasibility and positive effect of a prospective patient selection based on tumour molecular phenotype to choose the most efficacious treatment between nivolumab with or without ipilimumab and a VEGFR-TKI in the first-line treatment of metastatic clear-cell renal cell carcinoma.
Bristol Myers Squibb, ARTIC.
Beyond the 2 classical forms of congenital hyperinsulinism, focal and diffuse, we report our experience on the surgical treatment of atypical forms. We define 2 subtypes among these atypical forms of ...hyperinsulinism: in case of a giant focal form the surgical strategy is the same as in focal forms. In case of hyperinsulinism caused by a mosaic, our experience suggests the benefit of a limited resection from the tail to the body of the pancreas.
Papillary renal cell carcinomas (pRCC) are the most common nonclear cell RCC subtype. Germline mutations of the MET oncogene at 7q31 have been detected in patients with hereditary type I pRCC and in ...13% of sporadic type I pRCC. Recent report of MET inhibition strengthened the role of c-Met inhibition across pRCC.
We collected 220 frozen samples of sporadic pRCC through the French RCC Network and quality controlled for percentage of malignant cells >70%. Gene expression was assessed on 98 pRCC using human whole-genome Agilent 8 × 60K arrays. Copy number alterations were analyzed using Agilent Human 2 × 400K and 4× 180K array for type II pRCC and comparative genomic microarray analysis method for type I pRCC. MET gene sequencing was performed on type I pRCC.
MET expression level was high across all pRCC. We identified copy number alterations (gain) in 46% of type II pRCC and in 81% of type I pRCC. Correlation between DNA copy number alterations and mRNA expression level was highly significant. Eleven somatic mutations of MET gene were identified amongst 51 type I pRCC (21.6%), including 4 new mutations. We validated LRRK2 cokinase as highly correlated to MET expression.
The present report expands the role of MET activation as a potential target across all pRCC subtypes. These data support investigating MET inhibitors in pRCC in correlation with MET activation status.
Enteropathy-associated T cell lymphoma is a severe complication of celiac disease (CD). One mechanism suggested to underlie its development is chronic exposure of intraepithelial lymphocytes (IELs) ...to potent antiapoptotic signals initiated by IL-15, a cytokine overexpressed in the enterocytes of individuals with CD. However, the signaling pathway by which IL-15 transmits these antiapoptotic signals has not been firmly established. Here we show that the survival signals delivered by IL-15 to freshly isolated human IELs and to human IEL cell lines derived from CD patients with type II refractory CD (RCDII) - a clinicopathological entity considered an intermediary step between CD and enteropathy-associated T cell lymphoma - depend on the antiapoptotic factors Bcl-2 and/or Bcl-xL. The signals also required IL-15Rbeta, Jak3, and STAT5, but were independent of PI3K, ERK, and STAT3. Consistent with these data, IELs from patients with active CD and RCDII contained increased amounts of Bcl-xL, phospho-Jak3, and phospho-STAT5. Furthermore, incubation of patient duodenal biopsies with a fully humanized human IL-15-specific Ab effectively blocked Jak3 and STAT5 phosphorylation. In addition, treatment with this Ab induced IEL apoptosis and wiped out the massive IEL accumulation in mice overexpressing human IL-15 in their gut epithelium. Together, our results delineate the IL-15-driven survival pathway in human IELs and demonstrate that IL-15 and its downstream effectors are meaningful therapeutic targets in RCDII.
Clear cell papillary renal cell carcinoma (RCC), an entity with strikingly indolent behavior, recently was added to the World Health Organization classification of renal tumors and represents the ...fourth most common histologic type of renal cell carcinoma. This article aims to describe the imaging features of clear cell papillary RCC along with its clinical and pathologic characteristics.
This retrospective study consisted of 27 patients with 44 clear cell papillary RCC tumors. The inclusion criteria were a pathologically proven clear cell papillary RCC and the availability of preoperative imaging including at least CT or MRI. Two experienced radiologists performed the imaging analysis independently.
Patients (mean age, 62 years old) presented with renal failure in 26% of cases, and four had a tumor-predisposing disease. Multiple clear cell papillary RCC tumors occurred in 5 of the 27 patients. Two imaging patterns were recognizable. Solid clear cell papillary RCC (
= 23, 52%) presented as heterogeneous tumors with minor cystic changes (74%) and rarely exhibited calcifications (10%). All solid tumors showed hyperintensity on T2-weighted images compared with renal cortex and maximal enhancement on corticomedullary phase with a delayed washout. Cystic clear cell papillary RCC (
= 21, 48%) were classified as Bosniak IV (57%), III (33%), or IIF (10%), with a predominant unilocular pattern (76%). Pathologic stage according to TNM classification was mostly pT1a and low grade on nucleolar grade. All patients were alive at the date of last follow-up after treatment with no metastasis or recurrence.
Clear cell papillary RCC exhibits two imaging patterns including cystic and solid in almost equal proportion. Imaging characteristics of solid clear cell papillary RCC including high signal T2 intensity and early arterial enhancement are unexpectedly distinct from papillary RCC and very similar to clear cell RCC.
PDF
