KMT2D deficiency drives lung squamous cell carcinoma and hypersensitivity to RTK-RAS inhibition.

Lung squamous cell carcinoma (LUSC) represents a major subtype of lung cancer with limited treatment options. KMT2D is one of the most frequently mutated genes in LUSC (>20%), and yet its role in LUSC oncogenesis remains unknown. Here, we identify KMT2D as a key regulator of LUSC tumorigenesis wherein Kmt2d deletion transforms lung basal cell organoids to LUSC. Kmt2d loss increases activation of receptor tyrosine kinases (RTKs), EGFR and ERBB2, partly through reprogramming the chromatin landscape to repress the expression of protein tyrosine phosphatases. These events provoke a robust elevation in the oncogenic RTK-RAS signaling. Combining SHP2 inhibitor SHP099 and pan-ERBB inhibitor afatinib inhibits lung tumor growth in Kmt2d-deficient LUSC murine models and in patient-derived xenografts (PDXs) harboring KMT2D mutations. Our study identifies KMT2D as a pivotal epigenetic modulator for LUSC oncogenesis and suggests that KMT2D loss renders LUSC therapeutically vulnerable to RTK-RAS inhibition.

Nemvaleukin alfa, a novel engineered IL-2 fusion protein, drives antitumor immunity and inhibits tumor growth in small cell lung cancer.

BACKGROUND: Small cell lung cancer (SCLC) is a deadly disease with a 5-year survival of less than 7%. The addition of immunotherapy to chemotherapy was recently approved as first-line treatment; however, the improved clinical benefit is modest, highlighting an urgent need for new treatment strategies. Nemvaleukin alfa, a novel engineered interleukin-2 fusion protein currently in phase I-III studies, is designed to selectively expand cytotoxic natural killer (NK) cells and CD8+ T cells. Here, using a novel SCLC murine model, we investigated the effects of a mouse version of nemvaleukin (mNemvaleukin) on tumor growth and antitumor immunity. METHODS: A novel Rb1 -/- p53 -/- p130 -/- SCLC model that mimics human disease was generated. After confirming tumor burden by MRI, mice were randomized into four treatment groups: vehicle, mNemvaleukin alone, chemotherapy (cisplatin+etoposide) alone, or the combination of mNemvaleukin and chemotherapy. Tumor growth was measured by MRI and survival was recorded. Tumor-infiltrating lymphocytes and peripheral blood immune cells were analyzed by flow cytometry. Cytokine and chemokine secretion were quantified and transcriptomic analysis was performed to characterize the immune gene signatures. RESULTS: mNemvaleukin significantly inhibited SCLC tumor growth, which was further enhanced by the addition of chemotherapy. Combining mNemvaleukin with chemotherapy provided the most significant survival benefit. Profiling of tumor-infiltrating lymphocytes revealed mNemvaleukin expanded the total number of tumor-infiltrating NK and CD8+ T cells. Furthermore, mNemvaleukin increased the frequencies of activated and proliferating NK and CD8+ T cells in tumors. Similar immune alterations were observed in the peripheral blood of mNemvaleukin-treated mice. Of note, combining mNemvaleukin with chemotherapy had the strongest effects in activating effector and cytotoxic CD8+ T cells. mNemvaleukin alone, and in combination with chemotherapy, promoted proinflammatory cytokine and chemokine production, which was further confirmed by transcriptomic analysis. CONCLUSIONS: mNemvaleukin, a novel cytokine-based immunotherapy, significantly inhibited murine SCLC tumor growth and prolonged survival, which was further enhanced by the addition of chemotherapy. mNemvaleukin alone, and in combination with chemotherapy, drove a strong antitumor immune program elicited by cytotoxic immune cells. Our findings support the evaluation of nemvaleukin alone or in combination with chemotherapy in clinical trials for the treatment of SCLC.

Phase I Study of High-Dose L-methylfolate in Combination with Temozolomide and Bevacizumab in Recurrent IDH wild-type High-Grade Glioma.

Purpose: IDH mutations in low-grade gliomas (LGGs) results in improved survival and DNA hypermethylation compared to IDH wild-type LGGs. IDH-mutant LGGs become hypomethylated during progression. It's uncertain if methylation changes occur during IDH wild-type GBM progression and if the methylome can be reprogrammed. This phase I study evaluated the safety, tolerability, efficacy and methylome changes after L-methylfolate (LMF) treatment, in combination with temozolomide and bevacizumab in patients with recurrent high-grade glioma. Patients and Methods: Fourteen patients total, 13 with GBM, one with anaplastic astrocytoma, all IDH wild-type were enrolled in the study. All patients received LMF at either 15, 30, 60, or 90 mg daily plus temozolomide (75mg/m2 5 days per month) and bevacizumab (10mg/kg every two weeks). Results: No MTD was identified. LMF treated had mOS of 9.5 months (95% CI, 9.1-35.4) comparable to bevacizumab historical control 8.6 months (95% CI, 6.8-10.8). Six patients treated with LMF survived more than 650 days. Across all treatment doses the most adverse events were diarrhea (7%, 1 patient, grade 2), reflux (7%, 1 patient, grade 2), and dysgeusia (7%, 1 patient, grade 2). In the six brains donated at death, there was a 25% increase in DNA methylated CpGs compared to the paired initial tumor. Conclusions: LMF in combination with temozolomide and bevacizumab was well tolerated in patients with recurrent IDH wild-type high-grade glioma. This small study did not establish a superior efficacy with addition of LMF compared to standard bevacizumab therapy, however, this study did show methylome reprogramming in high-grade glioma.

Impact of Neoadjuvant Chemotherapy and Pretreatment Biliary Drainage for Pancreatic Head Ductal Adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related deaths in the USA. Although management strategies have evolved, there are continued controversies about the use of neoadjuvant chemotherapy (NAC) and pretreatment biliary drainage (PBD) in patients with resectable and potentially resectable disease. AIMS: We aimed to characterize the practice trends and outcomes for NAC and PBD. METHODS: A single-center cohort study was performed. Electronic medical records were reviewed between 2011 and 2019, and 140 patients who had pancreaticoduodenectomy for PDAC were included. Diagnosis, treatment, and outcome data were captured. RESULTS: There were no statistically significant temporal trends relating to the use of chemotherapy and PBD. Overall, 41% of patients received NAC and had improved survival, independent of other factors. Of the 71% who received PBD, only 40% had appropriate indications; 30% experienced postprocedure complications, and 34% required reintervention. Factors associated with the application of PBD included preoperative jaundice (OR 70.5, 95% CI 21.4-306.6) and evaluation by non-tertiary therapeutic endoscopists (OR 3.9, 95% CI 1.3-13.6). PBD was associated with a 12-day delay in surgery among those who did not receive NAC (p = 0.005), but there were no differences in surgical complications or mortality. CONCLUSIONS: Our findings suggest that (1) NAC may confer a survival benefit and (2) PBD should be reserved for individuals with jaundice requiring NAC. Implementation of guidelines by North American gastroenterology societies, multidisciplinary treatment models, and delivery of care at high-volume tertiary centers may help optimize management.

Targeting HER2 Exon 20 Insertion-Mutant Lung Adenocarcinoma with a Novel Tyrosine Kinase Inhibitor Mobocertinib.

No targeted treatments are currently approved for HER2 exon 20 insertion-mutant lung adenocarcinoma patients. Mobocertinib (TAK-788) is a potent irreversible tyrosine kinase inhibitor (TKI) designed to target human epidermal growth factor receptor 2 (HER2/ERBB2) exon 20 insertion mutations. However, the function of mobocertinib on HER2 exon 20 insertion-mutant lung cancer is still unclear. Here we conducted systematic characterization of preclinical models to understand the activity profile of mobocertinib against HER2 exon 20 insertions. In HER2 exon 20 insertion-mutant cell lines, the IC50 of mobocertinib was higher than poziotinib and comparable with or slightly lower than afatinib, neratinib, and pyrotinib. Mobocertinib had the lowest HER2 exon 20 insertion IC50/wild-type (WT) EGFR IC50 ratio, indicating that mobocertinib displayed the best selectivity profile in these models. Also, mobocertinib showed strong inhibitory activity in HER2 exon 20YVMA allograft and patient-derived xenograft models. In genetically engineered mouse models, HER2 exon 20G776>VC lung tumors exhibited a sustained complete response to mobocertinib, whereas HER2 exon 20YVMA tumors showed only partial and transient response. Combined treatment with a second antibody-drug conjugate (ADC) against HER2, ado-trastuzumab emtansine (T-DM1), synergized with mobocertinib in HER2 exon 20YVMA tumors. In addition to the tumor cell autonomous effect, sustained tumor growth control derived from M1 macrophage infiltration and CD4+ T-cell activation. These findings support the ongoing clinical development of mobocertinib (NCT02716116) and provide a rationale for future clinical evaluation of T-DM1 combinational therapy in HER2 exon 20YVMA insertion-mutant lung adenocarcinoma patients. SIGNIFICANCE: This study elucidates the potent inhibitory activity of mobocertinib against HER2 exon 20 insertion-mutant lung cancer and the synergic effect of combined mobocertinib and T-DM1, providing a strong rationale for clinical investigation.

Efficient Spin-Orbit Torque Generation in Semiconducting WTe2 with Hopping Transport.

Spin-orbit torques (SOTs) from transition metal dichalcogenide systems (TMDs) in conjunction with ferromagnetic materials are recently found to be attractive in spintronics for their versatile features. However, most of the previously studied crystalline TMDs are prepared by mechanical exfoliation, which limits their potentials for industrial applications. Here, we show that amorphous WTe2 heterostructures deposited by magnetron sputtering possess a sizable damping-like SOT efficiency of ξDLWTe2 ≈ 0.20 and low damping constant of α = 0.009 ± 0.001. Only an extremely low critical switching current density of Jc≈ 7.05 × 109 A/m2 is required to achieve SOT-driven magnetization switching. The SOT efficiency is further proved to depend on the W and Te relative compositions in the co-sputtered W100-xTex samples, from which a sign change of ξDLWTe2 is observed. In addition, the electronic transport in amorphous WTe2 is found to be semiconducting and is governed by a hopping mechanism. With the above advantages and rich tunability, amorphous and semiconducting WTe2 serves as a unique SOT source for future spintronics applications.

Advances in the pharmacotherapeutic management of esophageal squamous cell carcinoma.

INTRODUCTION: Esophageal squamous cancer remains an important cause of mortality worldwide with two new immunotherapy drugs recently approved for metastatic disease. AREAS COVERED: The authors review the epidemiology and genomics of esophageal squamous cell carcinoma. They also examine prior trials involving targeted agents under investigation as well immunotherapies that have been approved and novel combinations. EXPERT OPINION: Great advances have been made in characterizing the molecular changes in esophageal carcinoma. However, relatively few drugs have shown benefit in this disease. Targeted therapies have not shown to improve survival although many of these trials did not explore potential biomarkers. Pembrolizumab and nivolumab are now approved for esophageal squamous carcinoma but much more data are needed to understand how these agents may be used in non-metastatic settings. Novel treatments are still required as overall prognosis remains poor.

Circ_0005075 targeting miR-151a-3p promotes neuropathic pain in CCI rats via inducing NOTCH2 expression.

Neuropathic pain is a most challenging diseases worldwide, caused by the injury of nerve system. CircularRNAs (circRNAs) are revealed to be involved in various diseases, includingneuropathic pain. However, the waycircRNAsparticipate in the progress ofneuropathic painstill needs further study. Identifyingthe possible circRNAexpression patterns of neuropathic painis of great significance to understand its underlying mechanism. Previously, circ_0005075 has been regarded as an important oncogene in multiple cancers and it has been characterized as an inflammation­associated circRNA in various processes. Nevertheless, the functional role of circ_0005075 in neuropathic pain development is still poorly known. In our present study, we observed circ_0005075 was obviously increased in CCI rat models. Knockdown of circ_0005075 repressed thebehaviors of neuropathic pain including mechanical and thermal hyperalgesia. Moreover, loss of circ_0005075 could repress the neuroinflammation via targeting COX-2, IL-6 and TNF-α whereas inducing IL-10 in vivo. Additionally, we predicted miR-151a-3p as the potential target of circ_0005075 using bioinformatics analysis. We displayed that miR-151a-3p was greatly reduced in CCI rats and circ_0005075 reversed the repressive effect of miR-151a-3p on neuropathic pain. For another, NOTCH2 has been shown to induce a variety of intracellular responses correlated withneuropathic pain. Here, we found NOTCH2 expression was strongly induced in CCI rats and miR-151a-3p. In addition, circ_0005075 significantly rescued NOTCH2 expression, which could be repressed by miR-151a-3p. To sum up, we indicated that loss ofcirc_0005075relieved neuropathic pain progression by inducement of miR-151a-3p and inactivation of NOTCH2 signaling.

Cost Effective Mobile Mapping System for Color Point Cloud Reconstruction.

Survey-grade Lidar brands have commercialized Lidar-based mobile mapping systems (MMSs) for several years now. With this high-end equipment, the high-level accuracy quality of point clouds can be ensured, but unfortunately, their high cost has prevented practical implementation in autonomous driving from being affordable. As an attempt to solve this problem, we present a cost-effective MMS to generate an accurate 3D color point cloud for autonomous vehicles. Among the major processes for color point cloud reconstruction, we first synchronize the timestamps of each sensor. The calibration process between camera and Lidar is developed to obtain the translation and rotation matrices, based on which color attributes can be composed into the corresponding Lidar points. We also employ control points to adjust the point cloud for fine tuning the absolute position. To overcome the limitation of Global Navigation Satellite System/Inertial Measurement Unit (GNSS/IMU) positioning system, we utilize Normal Distribution Transform (NDT) localization to refine the trajectory to solve the multi-scan dispersion issue. Experimental results show that the color point cloud reconstructed by the proposed MMS has a position error in centimeter-level accuracy, meeting the requirement of high definition (HD) maps for autonomous driving usage.

Efficient Spin-Orbit Torque Switching with Nonepitaxial Chalcogenide Heterostructures.

The spin-orbit torques (SOTs) generated from topological insulators (TIs) have gained increasing attention in recent years. These TIs, which are typically formed by epitaxially grown chalcogenides, possess extremely high SOT efficiencies and have great potential to be employed in next-generation spintronics devices. However, epitaxy of these chalcogenides is required to ensure the existence of the topologically protected surface state (TSS), which limits the feasibility of using these materials in industry. In this work, we show that nonepitaxial BixTe1-x/ferromagnet heterostructures prepared by conventional magnetron sputtering possess giant SOT efficiencies even without TSS. Through harmonic voltage measurement and hysteresis loop shift measurement, we find that the damping-like SOT efficiencies originated from the bulk spin-orbit interactions of such nonepitaxial heterostructures can reach values greater than 100% at room temperature. We further demonstrate current-induced SOT switching in these BixTe1-x-based heterostructures with thermally stable ferromagnetic layers, which indicates that such nonepitaxial chalcogenide materials can be potential efficient SOT sources in future SOT magnetic memory devices.

Graft-Versus-Host Disease After Pancreatic Transplantation.

Graft-versus-host disease (GVHD) is a common complication of hematopoietic stem cell transplantation but can rarely occur after solid organ transplants. Small bowel and liver transplants are typically implicated, but solid organ transplant-associated GVHD has also been associated with other organs. We present a 40-year-old diabetic woman who underwent renal followed by pancreatic transplantation over a span of 21 months and ultimately developed acute classic GVHD. The diagnosis proved to be challenging in the context of confounding infections and inconclusive bone marrow and skin biopsy findings. She had multiorgan failure at the time of endoscopic confirmation and died after having minimal response to aggressive immunosuppression.

DGCR5 attenuates neuropathic pain through sponging miR-330-3p and regulating PDCD4 in CCI rat models.

Neuropathic pain caused by somatosensory nervous system dysfunction is a serious public health problem. Some long noncoding RNAs (lncRNAs) can participate in physiological processes involved in neuropathic pain. However, the effects of lncRNA DGCR5 in neuropathic pain have not been explored. Therefore, in our current study, we concentrated on the biological roles of DGCR5 in neuropathic pain. Here, it was observed that DGCR5 was significantly decreased in chronic sciatic nerve injury (CCI) rat models. DGCR5 overexpression was able to alleviate neuropathic pain development including mechanical and thermal hyperalgesia. In addition, the current understanding of miR-330-3p function in neuropathic pain remains largely incomplete. Here, we found that miR-330-3p was greatly increased in CCI rats and DGCR5 can modulate miR-330-3p expression negatively. Upregulation of DGCR5 repressed inflammation-correlated biomarkers including interleukin 6 (IL-6), tumor necrosis factor α, and IL-1ß in CCI rats by sponging miR-330-3p. The negative correlation between DGCR5 and miR-330-3p was confirmed in our current study. Inhibition of miR-330-3p suppressed neuropathic pain progression by restraining neuroinflammation in vivo. In addition, PDCD4 was predicted as a downstream target of miR-330-3p. Furthermore, PDCD4 was significantly increased in CCI rats and DGCR5 regulated PDCD4 expression through sponging miR-330-3p in CCI rat models. Taken these together, it was implied that DGCR5/miR-330-3p/PDCD4 axis participated in neuropathic pain treatment.

[Health Risk Evaluation of Organochlorine and Organophosphorous Pesticides in Groundwater in Beijing].

Pollution from organochlorine (OCP) and organophosphorus (OPP) pesticides in groundwater is a key issue for water resource protection. Sixteen kinds of OCP and six kinds of OPP pesticides were detected in 18 groundwater samples determined by GC-MS. Results showed that seven kinds of OPCs and two kinds of OPPs were found in the groundwater in Beijing. Among the OCPs, there were mainly hexachlorobenzene (HCB), hemochromatosis (HCH), and dichlorodiphenyltrichloroethane (DDT), with maximum values of, respectively, 82.4, 193, and 158 ng·L-1. Among the OPPs, there were o, o-dimethyl-o-2,2-dichlorovinylphosphate and o,o-dimethyl methylcarbamoylmethyl phosphorodithioate, with maximum values of 7.1 ng·L-1 and 17.7 ng·L-1, respectively. The OCPs and OPPs were found in the sewage irrigation areas. The results of a probabilistic risk assessment showed that the non-carcinogenic and carcinogenic risks of OCPs and OPPs within the drinking water in Beijing had been controlled, that risks from OCPs were higher, and that women were more sensitive to the toxicity of the pesticides. The monitoring of HCH and DDT in the groundwater should be implemented.

Preparation of thermo-responsive drug-loaded nanofibrous films created by electrospinning.

We prepared thermosensitive and biocompatible drug-loaded nanofibrous films by an electrospinning technique using a block copolymer, poly(N-isopropylacrylamide)-b-poly(l-lactide) (PNLA), and poly(l-lactide) (PLLA). The copolymer PNLA was synthesized by the radical polymerization of N-isopropylacrylamide (NIPAAm), followed by the ring-opening polymerization of l-lactide. The properties of PNIPAAm and PNLA were selectively discussed based on the results of NMR, FT-IR, GPC, and CA analyses. Because of the low molecular weight of PNIPAAm and PNLA and the hydrolysis of PNLA resulting from its hydrophilicity, these copolymers were inappropriate for electrospinning separately. Hence, a mixture of PNLA and PLLA was used to prepare electrospun nanofibrous films. SEM images of the PNLA/PLLA electrospun films showed that homogeneous fibres with smooth surfaces were obtained. In vitro release studies indicated that the drug-release rate of the PNLA/PLLA electrospun nanofibrous films can be adjusted by the content and molecular weight of PNLA and by the environmental temperature. The results demonstrate that electrospinning is a promising way to create stimuli-responsive fibrous films with potential applications in the design of controllable drug delivery systems.

Dependence On Glycolysis Sensitizes BRAF-mutated Melanomas For Increased Response To Targeted BRAF Inhibition.

Dysregulated metabolism can broadly affect therapy resistance by influencing compensatory signaling and expanding proliferation. Given many BRAF-mutated melanoma patients experience disease progression with targeted BRAF inhibitors, we hypothesized therapeutic response is related to tumor metabolic phenotype, and that altering tumor metabolism could change therapeutic outcome. We demonstrated the proliferative kinetics of BRAF-mutated melanoma cells treated with the BRAF inhibitor PLX4720 fall along a spectrum of sensitivity, providing a model system to study the interplay of metabolism and drug sensitivity. We discovered an inverse relationship between glucose availability and sensitivity to BRAF inhibition through characterization of metabolic phenotypes using nearly a dozen metabolic parameters in Principle Component Analysis. Subsequently, we generated rho0 variants that lacked functional mitochondrial respiration and increased glycolytic metabolism. The rho0 cell lines exhibited increased sensitivity to PLX4720 compared to the respiration-competent parental lines. Finally, we utilized the FDA-approved antiretroviral drug zalcitabine to suppress mitochondrial respiration and to force glycolysis in our cell line panel, resulting in increased PLX4720 sensitivity via shifts in EC50 and Hill slope metrics. Our data suggest that forcing tumor glycolysis in melanoma using zalcitabine or other similar approaches may be an adjunct to increase the efficacy of targeted BRAF therapy.

[Distribution Characteristics and Risk Analysis of Antibiotic in the Groundwater in Beijing].

Based on the GC-MS technique, we conducted a survey to investigate the concentration, distributions, and emission sources of sulfonamides (SAs), fluoroquinolones (FQs), tetracycline (TCs), ß-lactam, and macrolides in groundwater in Beijing. Results indicated that SAs, FQs, and TCs were the main types of antibiotic in groundwater, and the detection ratios of trimethoprim, ciprofloxacin, and norfloxacin were above 70%. Concentration of antibiotics in sites from sewage irrigation areas were significantly higher than those from the drinking source area or the south-to-north water recharge areas. The highest concentration of sulfadimidine (236 ng·L-1) and sulfadiazine (96.8 ng·L-1) in groundwater were both found in the sewage irrigation area. An ecological risk analysis showed a low risk for antibiotic in groundwater at drinking source sites, while groundwater at sewage irrigation sites fell into the high risk group. It is important to strengthen the ciprofloxacin monitoring and ensure underground water safety.

Prolonged Benefit from Ipilimumab Correlates with Improved Outcomes from Subsequent Pembrolizumab.

Patients with metastatic melanoma whose disease progresses on ipilimumab can clearly derive benefit from subsequent anti-programmed death-1 (PD-1). However, patients experience heterogeneous outcomes with ipilimumab, including rapid or delayed progression, and it is unclear whether patterns of ipilimumab progression influence subsequent clinical responses to anti-PD-1. We retrospectively reviewed data from 116 patients with metastatic melanoma who progressed on ipilimumab and were subsequently treated with pembrolizumab. The study objectives were to determine whether progression-free survival (PFS) with ipilimumab was associated with PFS, objective response rate (ORR), and clinical benefit rate (CBR; ORR + stable disease) with pembrolizumab. Patients with PFS ≥90 days after treatment with ipilimumab generally had superior outcomes with subsequent pembrolizumab treatment compared with patients with PFS <90 days (ORR, 49% vs. 35%, P = 0.12; CBR, 66% vs. 46%, P = 0.03). Patients with prolonged ipilimumab benefit (PFS ≥ 180 days) had excellent outcomes with pembrolizumab compared with rapid progressors (PFS < 45 days; ORR, 55% vs. 25%; CBR, 80% vs. 25%; median PFS, 249 vs. 50 days). Using logistic regression models, PFS with ipilimumab was independently correlated with response to pembrolizumab (odds ratio, 1.22; 95% CI, 1.02-1.51). This study shows that prolonged PFS with ipilimumab predicts excellent outcomes with subsequent pembrolizumab treatment, offering valuable prognostic information for clinicians. Cancer Immunol Res; 4(7); 569-73. ©2016 AACR.

Valganciclovir and bevacizumab for recurrent glioblastoma: A single-institution experience.

Prolonged treatment with adjuvant valganciclovir has been shown in one retrospective study to exert a significant effect on overall survival (OS) in newly diagnosed patients with glioblastoma multiforme (GBM). However, studies evaluating the effectiveness of valganciclovir in the treatment of recurrent GBM have not been performed. We evaluated the effect of valganciclovir in the recurrent setting in combination with bevacizumab therapy. A retrospective analysis was performed on patients treated for recurrent GBM with off-label valganciclovir and bevacizumab at Vanderbilt University. We identified 13 patients who received valganciclovir plus bevacizumab at some point during their treatment, 8 of whom were started on valganciclovir and bevacizumab concurrently upon first recurrence, whereas 5 had valganciclovir added to their bevacizumab regimen prior to a second recurrence. of these patients, 12 were pathologically confirmed to have GBM, and 1 patient was diagnosed with gliosarcoma. We also identified an institutional cohort of 50 patients who had not been exposed to valganciclovir, but were treated with bevacizumab for first recurrence. The progression-free survival (PFS) at 6 months (PF6) and median OS (mOS) in the valganciclovir plus bevacizumab group was 62% and 13.1 months, respectively, for all 13 patients, and 50% and 11.3 months, respectively, for the 8 concurrently treated patients. In the institutional bevacizumab cohort, the PF6 and mOS were 34% and 8.7 months, respectively. In this retrospective analysis, valganciclovir in combination with bevacizumab exhibited a trend toward improved survival in patients with recurrent GBM. However, given the small sample size and the retrospective nature of this study, a larger prospective study is required to confirm these results.

Clinical Activity of Ipilimumab in Acral Melanoma: A Retrospective Review.

BACKGROUND: Ipilimumab improves overall survival (OS) in advanced melanoma. Acral melanoma is an uncommon clinical subtype of this disease associated with poor prognosis. The clinical activity of ipilimumab has not been well-defined in advanced acral melanoma. METHODS: We retrospectively reviewed the demographics, treatment history, and clinical outcomes for all patients with acral melanoma treated with ipilimumab from two academic centers between February 2006 and June 2013. Using Cox proportional hazards models, we assessed for factors that correlated with OS. RESULTS: A total of 35 patients with acral melanoma received ipilimumab. Melanomas arose on volar surfaces (n = 28) and subungual sites (n = 7); stage M1c disease was present in 54%, and 45% had elevated serum lactate dehydrogenase (LDH). Best response by RECIST 1.1 criteria was complete response in 1 patient, partial response in 3, and stable disease (SD) in 4 for an objective response rate (ORR) of 11.4% and a clinical benefit rate (ORR + SD) at 24 weeks of 22.9%. Median progression-free survival was 2.5 months (95% confidence interval [CI]: 2.3-2.7 months); median OS was 16.7 months (95% CI: 10.9-22.5 months). Normal LDH and absolute lymphocyte count ≥1,000 at 7 weeks predicted longer OS. Immune-related adverse events (irAEs) were noted in 16 patients including 7 with grade 3/4 irAEs (20%). CONCLUSION: Ipilimumab is clinically active in acral melanoma with similar ORR and OS compared with unselected melanoma populations. Ipilimumab remains a viable therapeutic option for patients with advanced acral melanoma. IMPLICATIONS FOR PRACTICE: Ipilimumab is a commonly used immune therapy that improves survival in metastatic melanoma. The clinical activity of ipilimumab in certain rare melanoma subtypes, such as uveal or mucosal melanomas, is suboptimal. Acral melanoma is another unusual subtype of this disease that arises on the palms, soles, and nailbeds. In this study of 35 patients with acral melanoma from 2 centers, ipilimumab was found to have activity that appears equivalent to unselected melanoma (response rate of 11.4%, median overall survival of 16.7 months). Ipilimumab remains a viable treatment option for this melanoma subpopulation.

Nivolumab in melanoma: latest evidence and clinical potential.

Melanoma has historically been considered a refractory disease with few if any options in the advanced/metastatic setting. Advances in both immune and genetically targeted treatment approaches have revolutionized the spectrum of treatment options for melanoma patients over the last several years. Recently, checkpoint inhibition has become a major focus in the immune-based therapy of cancer, especially melanoma. This concept involves inhibition of regulatory cell surface molecules which act normally to dampen or modulate T-cell activation. Cancer, including melanoma, takes advantage of this physiologic mechanism to turn off T-cell activation and prevent effective T-cell antitumor responses. Checkpoint inhibitors such as anti cytotoxic T-lymphocyte antigen 4 (anti-CTLA-4) and anti programmed death-1 (PD-1) can reverse this immune suppression and release T-cell activation. Nivolumab, a monoclonal antibody to the PD-1 receptor, promotes antitumor immunity by removing this key negative regulator of T-cell activation. In phase I/II studies, promising activity and safety have been observed and ongoing phase III trials are comparing nivolumab with other standard of care therapies (chemotherapy, ipilimumab). Efficacy may be even further increased when used in combination with ipilimumab (albeit with increased toxicity). In contrast to typical short-lived responses with cancer therapy in metastatic solid tumors, many responses induced by nivolumab appear durable. In this review, we discuss the evolution of immune therapy in melanoma leading to the development of nivolumab, the clinical experience with this agent, and its future development and clinical potential.