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      Predictive role of PD-L1 expression in the response of renal Medullary carcinoma to PD-1 inhibition

      case-report

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          Abstract

          Background

          Renal medullary carcinoma is one of the rarest malignancies arising from the kidney. Despite various aggressive therapeutic regimens, mortality remains significantly high (95%) with a median overall survival of 5 months. Furthermore, the scarcity of this malignancy renders randomized clinical trials impossible. We examined the expression of programmed death ligand 1 (PD-L1) in two new renal medullary carcinoma cases, investigated their responses to the PD-L1 inhibitor nivolumab and explored the predictive role of the rate of PD-L1 expression in such response.

          Case presentation

          Two African-American patients (male and female) with sickle cell trait who presented to our center with hematuria and flank pain were diagnosed with metastatic renal medullary carcinoma. PD-L1 was expressed at rate of 25% and 60% in patient 1 and 2 respectively. Following nephrectomy, they were started on nivolumab. Patient 1 initially responded to the treatment with regression of metastatic lesions. However, following this early response, patient 1 who has been receiving nivolumab for more than 15 months, was noted to have a disease progression. Patient 2 had disease progression after 3 months of nivolumab therapy.

          Conclusions

          Although PD-L1 is expressed in these patients with renal medullary carcinoma, response to nivolumab was only observed in patient 1 whose tumor has the lowest rate of PD-L1 expression. This may suggest that in RMC, response to PD-L1 inhibition therapy may not correlate with the rate of PD-L1 expression.

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          Most cited references13

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          Costimulatory B7-H1 in renal cell carcinoma patients: Indicator of tumor aggressiveness and potential therapeutic target.

          Expression of B7-H1, a costimulating glycoprotein in the B7 family, is normally restricted to macrophage-lineage cells, providing a potential costimulatory signal source for regulation of T cell activation. In contrast, aberrant expression of B7-H1 by tumor cells has been implicated in impairment of T cell function and survival, resulting in defective host antitumoral immunity. The relationship between tumor-associated B7-H1 and clinical cancer progression is unknown. Herein, we report B7-H1 expression by both renal cell carcinoma (RCC) tumors of the kidney and RCC tumor-infiltrating lymphocytes. In addition, our analysis of 196 clinical specimens reveals that patients harboring high intratumoral expression levels of B7-H1, contributed by tumor cells alone, lymphocytes alone, or tumor and/or lymphocytes combined, exhibit aggressive tumors and are at markedly increased risk of death from RCC. In fact, patients with high tumor and/or lymphocyte B7-H1 levels are 4.5 times more likely to die from their cancer than patients exhibiting low levels of B7-H1 expression (risk ratio 4.53; 95% confidence interval 1.94-10.56; P < 0.001.) Thus, our study suggests a previously undescribed mechanism whereby RCC may impair host immunity to foster tumor progression. B7-H1 may prove useful as a prognostic variable for RCC patients both pre- and posttreatment. In addition, B7-H1 may represent a promising target to facilitate more favorable responses in patients who require immunotherapy for treatment of advanced RCC.
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            Balanced Translocations Disrupting SMARCB1 Are Hallmark Recurrent Genetic Alterations in Renal Medullary Carcinomas.

            Renal medullary carcinoma (RMC) is a rare and highly aggressive neoplasm that most often occurs in the setting of sickle cell trait or sickle cell disease (SCD). Most patients present with metastatic disease resistant to conventional chemotherapy, and therefore there is an urgent need for molecular insight to propose new therapies.
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              Renal medullary carcinoma. The seventh sickle cell nephropathy.

              Over the last 22 years, we have encountered 34 examples of a highly aggressive neoplasm with a microscopic morphology that is highly predictive of finding sickled erythrocytes in the tissue. With the exception of one patient, all are believed to have had sickle cell trait or, in one case, hemoglobin SC disease. These 33 patients are the subject of this report and, where their race was known, they were all blacks between the ages of 11 and 39 years. Between the ages of 11 and 24 years, males predominated by 3 to 1. Beyond age 24, however, the tumors occurred equally in men and women. The dominant tumor mass was in the medulla and ranged from 4 to 12 cm in diameter. Mean size was 7 cm; median, 6 cm. Peripheral satellites in the renal cortex and pelvic soft tissues, as well as venous and lymphatic invasion, were usually present. The lesions exhibited a reticular, yolk sac-like, or adenoid cystic appearance, often with poorly differentiated areas in a highly desmoplastic stroma admixed with neutrophils and usually marginated by lymphocytes. The tumors had usually metastasized when first discovered, and none was confined to the kidney at the time of nephrectomy. The mean duration of life after surgery was 15 weeks. These tumors probably arise in the calyceal epithelium in or near the renal papillae, the same site that produces the more familiar picture of unilateral hematuria in patients with sickle cell trait. We have concluded that renal medullary carcinoma represents another example of renal disease associated with sickle cell disorders. The other six are unilateral hematuria, papillary necrosis, nephrotic syndrome, renal infarction, inability to concentrate urine, and pyelonephritis.
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                Author and article information

                Contributors
                qsodji@augusta.edu
                kklein@augusta.edu
                skavuri@augusta.edu
                jparikh@augusta.edu
                Journal
                J Immunother Cancer
                J Immunother Cancer
                Journal for Immunotherapy of Cancer
                BioMed Central (London )
                2051-1426
                15 August 2017
                15 August 2017
                2017
                : 5
                : 62
                Affiliations
                [1 ]ISNI 0000 0001 2284 9329, GRID grid.410427.4, Department of Medicine, , Augusta University, ; 1120 15th St, Augusta, GA 30912 USA
                [2 ]ISNI 0000 0001 2284 9329, GRID grid.410427.4, Department of Radiology, , Augusta University, ; 1120 15th St, Augusta, GA 30912 USA
                [3 ]ISNI 0000 0001 2284 9329, GRID grid.410427.4, Department of Pathology, , Augusta University, ; 1120 15th St, Augusta, GA 30912 USA
                [4 ]ISNI 0000 0001 2284 9329, GRID grid.410427.4, Hematology oncology section, , Augusta University, ; 1120 15th St, Augusta, GA 30912 USA
                Author information
                http://orcid.org/0000-0002-1450-087X
                Article
                267
                10.1186/s40425-017-0267-9
                5557570
                28807004
                6785cec5-3327-4f04-b42c-e546694c5763
                © The Author(s). 2017

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 23 February 2017
                : 13 July 2017
                Categories
                Case Report
                Custom metadata
                © The Author(s) 2017

                renal medullary carcinoma,sickle cell trait,immunotherapy,pd-l1,nivolumab

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