Radiation and Checkpoint Inhibitor Immunotherapy Lead to Long Term Disease Control in a Metastatic RCC patient With Brain Metastases.

Renal cell carcinoma (RCC) comprises 4.2% of all new cancer cases in the United States and 30% of cases are metastatic (mRCC) at diagnosis. Brain metastatic RCC historically has poor prognosis, but the development of immune checkpoint inhibitors has revolutionized their care and may be successfully combined with SBRT to improve prognosis. Here, we present a case of a patient with mRCC who had brain metastases treated with concurrent immune checkpoint inhibitors and SBRT. He continues to survive with good functional status years following his initial diagnosis. We discuss the relevant history regarding treatment approach in patients with brain metastatic RCC, ongoing trials focusing on the combination of immunotherapy and radiation, and the potential and promise of the abscopal effect.

Chemerin Reactivates PTEN and Suppresses PD-L1 in Tumor Cells via Modulation of a Novel CMKLR1-mediated Signaling Cascade.

PURPOSE: Chemerin (retinoic acid receptor responder 2, RARRES2) is an endogenous leukocyte chemoattractant that recruits innate immune cells through its receptor, ChemR23. RARRES2 is widely expressed in nonhematopoietic tissues and often downregulated across multiple tumor types compared with normal tissue. Recent studies show that augmenting chemerin in the tumor microenvironment significantly suppresses tumor growth, in part, by immune effector cells recruitment. However, as tumor cells express functional chemokine/chemoattractant receptors that impact their phenotype, we hypothesized that chemerin may have additional, tumor-intrinsic effects. EXPERIMENTAL DESIGN: We investigated the effect of exogenous chemerin on human prostate and sarcoma tumor lines. Key signaling pathway components were elucidated using qPCR, Western blotting, siRNA knockdown, and specific inhibitors. Functional consequences of chemerin treatment were evaluated using in vitro and in vivo studies. RESULTS: We show for the first time that human tumors exposed to exogenous chemerin significantly upregulate PTEN expression/activity, and concomitantly suppress programmed death ligand-1 (PD-L1) expression. CMKLR1 knockdown abrogated chemerin-induced PTEN and PD-L1 modulation, exposing a novel CMKLR1/PTEN/PD-L1 signaling cascade. Targeted inhibitors suggested signaling was occurring through the PI3K/AKT/mTOR pathway. Chemerin treatment significantly reduced tumor migration, while significantly increasing T-cell-mediated cytotoxicity. Chemerin treatment was as effective as both PD-L1 knockdown and the anti-PD-L1 antibody, atezolizumab, in augmenting T-cell-mediated tumor lysis. Forced expression of chemerin in human DU145 tumors significantly suppressed in vivo tumor growth, and significantly increased PTEN and decreased PD-L1 expression. CONCLUSIONS: Collectively, our data show a novel link between chemerin, PTEN, and PD-L1 in human tumor lines, which may have a role in improving T-cell-mediated immunotherapies.

Chemerin Suppresses Breast Cancer Growth by Recruiting Immune Effector Cells Into the Tumor Microenvironment.

Infiltration of immune cells into the tumor microenvironment (TME) can regulate growth and survival of neoplastic cells, impacting tumorigenesis and tumor progression. Correlations between the number of effector immune cells present in a tumor and clinical outcomes in many human tumors, including breast, have been widely described. Current immunotherapies utilizing checkpoint inhibitors or co-stimulatory molecule agonists aim to activate effector immune cells. However, tumors often lack adequate effector cell numbers within the TME, resulting in suboptimal responses to these agents. Chemerin (RARRES2) is a leukocyte chemoattractant widely expressed in many tissues and is known to recruit innate leukocytes. CMKLR1 is a chemotactic cellular receptor for chemerin and is expressed on subsets of dendritic cells, NK cells, and macrophages. We have previously shown that chemerin acts as a tumor suppressive cytokine in mouse melanoma models by recruiting innate immune defenses into the TME. Chemerin/RARRES2 is down-regulated in many tumors, including breast, compared to normal tissue counterparts. Here, using a syngeneic orthotopic EMT6 breast carcinoma model, we show that forced overexpression of chemerin by tumor cells results in significant recruitment of NK cells and T cells within the TME. While chemerin secretion by EMT6 cells did not alter their phenotypic behavior in vitro, it did significantly suppress tumor growth in vivo. To define the cellular effectors required for this anti-tumor phenotype, we depleted NK cells or CD8+ T cells and found that either cell type is required for chemerin-dependent suppression of EMT6 tumor growth. Finally, we show significantly reduced levels of RARRES2 mRNA in human breast cancer samples compared to matched normal tissues. Thus, for the first time we have shown that increasing chemerin expression within the breast carcinoma TME can suppress growth by recruitment of NK and T cells, thereby supporting this approach as a promising immunotherapeutic strategy.

Mechanisms and Functions of Chemerin in Cancer: Potential Roles in Therapeutic Intervention.

Chemerin [RARRES2 [retinoic acid receptor responder 2], TIG2 [tazarotene induced gene 2 (TIG2)]] is a multifunctional cytokine initially described in skin cultures upon exposure to the synthetic retinoid tazarotene. Its secreted pro-form, prochemerin, is widely expressed, found systemically, and is readily converted into active chemerin by various proteases. Subsequent studies elucidated major roles of chemerin as both a leukocyte chemoattractant as well as an adipokine. Chemerin's main chemotactic receptor, the G-protein coupled receptor CMKLR1, is expressed on macrophages, dendritic, and NK cells. With respect to its role in immunology, chemerin mediates trafficking of these cells to sites of inflammation along its concentration gradient, and likely helps coordinate early responses, as it has been shown to have antimicrobial and angiogenic properties, as well. Recently, there has been mounting evidence that chemerin is an important factor in various cancers. As with its role in immune responses-where it can act as both a pro- and anti-inflammatory mediator-the potential functions or correlations chemerin has in or with cancer appears to be context dependent. Most studies, however, suggest a downregulation or loss of chemerin/RARRES2 in malignancies compared to the normal tissue counterparts. Here, we perform a comprehensive review of the literature to date and summarize relevant findings in order to better define the roles of chemerin in the setting of the tumor microenvironment and tumor immune responses, with an ultimate focus on the potential for therapeutic intervention.

Chemerin modulation of tumor growth: potential clinical applications in cancer.

Chemerin is a relatively newly described, yet increasingly studied multifunctional protein that mediates a variety of important biological functions. With significant roles in immune trafficking and adipo/angiogenesis, chemerin has gained traction in recent years for its potential functions in cancer, tumorigenesis, and immune surveillance. Chemerin's main chemotactic cellular receptor, CMKLR1, is expressed on both immune cells and malignant tumor cells, while a second non-signaling receptor, CCRL2, may act to help concentrate chemerin along activated endothelial cells and at sites of inflammation. With recent findings that chemerin expression is altered in a multitude of cancer types, there is evidence that chemerin may play significant roles in suppressing -- or potentially promoting -- tumor growth, depending on the context. Several studies suggest a key role for chemerin in recruiting innate immune defenses to sites of inflammation via its concentration gradient, with additional studies identifying chemerin as a tumor suppressive cytokine. Thus, therapeutically targeting the chemerin/CMKLR1 axis may have the potential to favorably modulate tumor growth. Here, we conduct a brief review of chemerin's various roles in cancer, compiling the most recent data regarding its expression and function, with an emphasis on its potential for future prognostic and clinical applications.

Macular hole as a risk factor of choroidal detachment in rhegmatogenous retinal detachment.

PURPOSE: Choroidal detachment (CD) associated with rhegmatogenous retinal detachment (RRD) is a rare, but serious condition, which makes the prognosis worse. Previously reported risk factors for CD in RRD patients include high myopia, aphakia, pseudophakia, and advanced age. However, macular hole has not been discussed as an important factor in increasing the risk of CD in RRD patients. The purpose of this study was to evaluate macular hole as a risk factor for CD in eyes evidencing RRD. METHODS: The medical records of 480 patients with primary RRD were reviewed. We compared the CD incidence among the RRD patients in accordance with the presence or absence of macular holes. The relationship between gender, age, presence of systemic disease, refractive errors, lens status, intraocular pressure and the development of CD were also analyzed. RESULTS: The incidence (4/21 eyes, 19.0%) of CD in the RRD with macular hole was significantly higher than that (7/459 eyes, 1.5%) observed in the RRD without macular hole (p=0.010). The preoperative intraocular pressure (mean+/-SD; 2.5+/-1.3 mmHg) in the RRD with CD and macular hole was significantly lower than that (7.4+/-4.4 mmHg) observed in the cases of RRD with CD without macular hole (p=0.035). The eyes complicated by CD evidenced a higher prevalence of diabetes mellitus (p=0.024) than was observed in the eyes without CD. CONCLUSIONS: The retinal detachment combined with macular hole creates a predisposition toward the development of profound hypotony and CD.

Subretinal fluid bleb after successful scleral buckling and cryotherapy for retinal detachment.

PURPOSE: To determine the characteristics of subretinal fluid (SRF) blebs after successful scleral buckling with cryotherapy as a treatment for rhegmatogenous retinal detachment (RD) and to investigate their possible origin. DESIGN: Retrospective case series. METHODS: The incidence of SRF bleb and the temporary aspects associated with the appearance and disappearance of the lesion were analyzed. Optical coherence tomography (OCT) was used to confirm SRF and indocyanine green angiography (ICGA) was carried out to evaluate choroidal circulation in some of the cases. RESULTS: SRF bleb was observed in 11 (9.3%) of 118 cases with the history of successful scleral buckling and cryotherapy. The lesions were detected 8.7 +/- 5.5 (mean +/- standard deviation [SD]) weeks after complete retinal reattachment, and the mean +/- SD period required for the disappearance of the lesion was 4.7 +/- 3.4 months. SRFs were verified by OCT in five cases of macular involvement. ICGA revealed choroidal vascular congestion and hyperpermeability near the lesion in three of four cases, and these vascular abnormalities remained unchanged after the removal of the scleral explant. CONCLUSIONS: SRF bleb after successful RD surgery disappears spontaneously within one year. The origin of the lesion may be associated with choroidal vascular changes resulting from cryotherapy.

Clinical results of a scleral fixation of the posterior chamber intraocular lens, through sclerotomies, 1 mm posterior to the limbus.

The aim of this study was to evaluate the clinical outcomes of scleral fixation of a posterior chamber intraocular lens and an anterior vitrectomy through sclerotomies, 1 mm posterior to the limbus. The study comprised of seven eyes that required a scleral fixation. Sclerotomies, 1 mm posterior to the limbus, were performed using a 20G sclerotome at the 2 and 8 o'clock positions. Group 1 was defined as four eyes requiring scleral fixation of the secondary IOL (Intraocular lens), and group 2 as three eyes where dislocated IOLs were repositioned and fixed to the sclera via sclerotomy sites. In all the eyes, the knot of string (10-0 prolene, W1713, Ethicon, USA) was buried. Postoperatively, the visual acuity was greatly improved, by more than 4 lines in the Snellen visual acuity chart, with the exception of one case of macular degeneration. The scleral fixation of the IOL through sclerotomies, 1 mm posterior to the limbus, had advantages in that the scleral fixation of the IOL could be achieved through sclerotomy sites, and the anterior vitrectomy parallel to the iris plane.

Junctional scotoma in giant cerebral aneurysm.

A brain lesion located at the lateral side of the sella turcica can produce a junctional scotoma by compressing the ipsilateral optic nerve and the contralateral inferonasal nerve fiber. This study reports a female patient with a junctional scotoma caused by a cerebral aneurysm. At the initial visit, she complained of visual disturbance in both eyes and the right optic disc was atrophied. The visual field showed right blindness and left superotemporal quadrantopsia. A brain CT indicated an approximately 3 cm sized brain mass located superolateral to the sella turcica. The brain MRI showed the lesion to be more like an aneurysm than a pituitary adenoma. Therefore, 4 vessels angiography was done, and this lesion was confirmed to be a sellar variant of an aneurysm located at the right carotid siphon. Like a tumor of the optic chiasm, a cerebral aneurysm can cause visual disturbance and visual field defects. Therefore, an early differential diagnosis is important because the prognosis and treatment of an aneurysm differ.