Preliminary evaluation of urinary soluble Met as a biomarker for urothelial carcinoma of the bladder.

BACKGROUND: Among genitourinary malignancies, bladder cancer (BCa) ranks second in both prevalence and cause of death. Biomarkers of BCa for diagnosis, prognosis and disease surveillance could potentially help prevent progression, improve survival rates and reduce health care costs. Among several oncogenic signaling pathways implicated in BCa progression is that of hepatocyte growth factor (HGF) and its cell surface receptor, Met, now targeted by 25 experimental anti-cancer agents in human clinical trials. The involvement of this pathway in several cancers is likely to preclude the use of urinary soluble Met (sMet), which has been correlated with malignancy, for initial BCa screening. However, its potential utility as an aid to disease surveillance and to identify patients likely to benefit from HGF/Met-targeted therapies provide the rationale for this preliminary retrospective study comparing sMet levels between benign conditions and primary BCa, and in BCa cases, between different disease stages. METHODS: Normally voided urine samples were collected from patients with BCa (Total: 183; pTa: 55, pTis: 62, pT1: 24, pT2: 42) and without BCa (Total: 83) on tissue-procurement protocols at three institutions and sMet was measured and normalized to urinary creatinine. Normalized sMet values grouped by pathologic stage were compared using non-parametric tests for correlation and significant difference. ROC analyses were used to derive classification models for patients with or without BCa and patients with or without muscle-invasive BCa (MIBCa or NMIBCa). RESULTS: Urinary sMet levels accurately distinguished patients with BCa from those without (p<0.0001, area under the curve (AUC): 0.7008) with limited sensitivity (61%) and moderate specificity (76%), and patients with MIBCa (n=42) from those with NMIBCa (n=141; p<0.0001, AUC: 0.8002) with moderate sensitivity and specificity (76% and 77%, respectively) and low false negative rate (8%). CONCLUSIONS: Urinary sMet levels distinguish patients with BCa from those without, and patients with or without MIBCa, suggesting the potential utility of urinary sMet as a BCa biomarker for surveillance following initial treatment. Further studies are warranted to determine its potential value for prognosis in advanced disease, predicting treatment response, or identifying patients likely to benefit from Met-targeted therapies.

Chronic diarrhoea and ichthyosis vulgaris: a rare presentation of Hodgkin's lymphoma.

A man in his 30s presented with several months of non-bloody diarrhoea and nausea along with conjunctivitis, diffuse ichthyosis and cellulitis in the setting of progressive neck swelling. He was ultimately diagnosed with nodular sclerosing Hodgkin's lymphoma after undergoing a broad infectious, rheumatological and neoplastic workup. This represents a rare presentation of classic Hodgkin's lymphoma and demonstrates the known alteration of cellular immunity in Hodgkin's lymphoma alongside manifestations of the profound inflammatory state associated with the disease. The patient was initiated on chemotherapy and many of his symptoms resolved. Hodgkin's lymphoma may present as a multisystemic cascade of symptoms and should be high on the differential diagnosis for a patient with lymphadenopathy and associated infectious, gastrointestinal and cutaneous symptoms.

Safety and patient experience with at-home infusion of ocrelizumab for multiple sclerosis.

OBJECTIVE: This study aimed to evaluate safety (infusion-related reactions [IRRs]) and patient satisfaction (patient-reported outcomes [PROs]) for at-home ocrelizumab administration for patients with multiple sclerosis (MS). METHODS: This open-label study included adult patients with an MS diagnosis who had completed a ≥ 600-mg ocrelizumab dose, had a patient-determined disease steps score of 0 to 6 and had completed PROs. Eligible patients received a 600-mg ocrelizumab home-based infusion over 2 h, followed by 24-h and 2-week post-infusion follow-up calls. IRRs and adverse events (AEs) were documented during infusions and follow-up calls. PROs were completed before and 2 weeks post infusion. RESULTS: Overall, 99 of 100 expected patients were included (mean [SD] age, 42.3 [7.7] years; 72.7% female; 91.9% White). The mean (SD) infusion time was 2.5 (0.6) hours, and 75.8% of patients completed their ocrelizumab infusion between 2 to 2.5 h. The IRR incidence rate was 25.3% (95% CI: 16.7%, 33.8%)-similar to other shorter ocrelizumab infusion studies-and all AEs were mild/moderate. In total, 66.7% of patients experienced AEs, including itch, fatigue, and grogginess. Patients reported significantly increased satisfaction with the at-home infusion process and confidence in the care provided. Patients also reported a significant preference for at-home infusion compared with prior infusion center experiences. INTERPRETATION: IRRs and AEs occurred at acceptable rates during in-home infusions of ocrelizumab over a shorter infusion time. Patients reported increased confidence and comfort with the home infusion process. Findings from this study provide evidence of the safety and feasibility of home-based ocrelizumab infusion over a shorter infusion period.

Toxicity of organic fluorophores used in molecular imaging: literature review.

Fluorophores are potentially useful for in vivo cancer diagnosis. Using relatively inexpensive and portable equipment, optical imaging with fluorophores permits real-time detection of cancer. However, fluorophores can be toxic and must be investigated before they can be administered safely to patients. A review of published literature on the toxicity of 19 widely used fluorophores was conducted by searching 26 comprehensive biomedical and chemical literature databases and analyzing the retrieved material. These fluorophores included Alexa Fluor 488 and 514, BODIPY FL, BODIPY R6G, Cy 5.5, Cy 7, cypate, fluorescein, indocyanine green, Oregon green, 8-phenyl BODIPY, rhodamine 110, rhodamine 6G, rhodamine X, rhodol, TAMRA, Texas red, and Tokyo green. Information regarding cytotoxicity, tissue toxicity, in vivo toxicity, and mutagenicity was included. Considerable toxicity-related information was available for the Food and Drug Administration (FDA)-approved compounds indocyanine green and fluorescein, but published information on many of the non-FDA-approved fluorophores was limited. The information located was encouraging because the amounts of fluorophore used in molecular imaging probes are typically much lower than the toxic doses described in the literature. Ultimately, the most effective and appropriate probes for use in patients will be determined by their fluorescent characteristics and the safety of the conjugates.

Eomesodermin Increases Survival and IL-2 Responsiveness of Tumor-specific CD8+ T Cells in an Adoptive Transfer Model of Cancer Immunotherapy.

Tumor-specific CD8 T cells often fail to elicit effective antitumor immune responses due to an inability to expand into a substantial effector population and persist long-term in vivo. Using an adoptive transfer model of cancer immunotherapy, we demonstrate that constitutive eomesodermin (Eomes) expression in tumor-specific CD8 T cells improves tumor rejection and survival. The increase in tumor rejection was associated with an increased number and persistence of CD8 T cells in lymphoid tissues during acute tumor rejection, tumor regrowth, and in mice that remained tumor-free. Constitutive Eomes expression increased expression of CD25, and this was associated with enhanced interleukin-2 responsiveness and tumor-specific CD8 T-cell proliferation. Moreover, constitutive Eomes expression improved cell survival. Taken together, our data suggest that constitutive Eomes expression enhances CD8 T-cell proliferation and survival, in part through the enhancement of interleukin-2 responsiveness through CD25 induction.

STAT5 inhibition induces TRAIL/DR4 dependent apoptosis in peripheral T-cell lymphoma.

Peripheral T-cell lymphoma (PTCL) is a rare, aggressive, heterogeneous, Non-Hodgkin's lymphoma with poor prognosis and inadequate response to current therapies. Recent sequencing studies indicate a prevalence of activating mutations in the JAK/STAT signaling pathway. Oncogenic mutations in STAT5B, observed in approximately one third of cases of multiple different PTCL subtypes, correlate with inferior patient outcomes. Therefore, interest in the development of therapeutic strategies for targeting STAT5 in PTCL is warranted. In this study, we show that the drug pimozide inhibits STAT5 in PTCL, leading to apoptotic cell death by means of the TRAIL/DR4 dependent extrinsic apoptotic pathway. Pimozide induced PTCL cell death is caspase 8 dependent, increases the expression of the TRAIL receptor, DR4, on the surface of pre-apoptotic PTCL cells, and enhances TRAIL induced apoptosis in a TRAIL dependent manner. In parallel, we show that mRNA and protein levels of intrinsic pathway BCL-2 family members and mitochondrial membrane potential remain unaffected by STAT5 knockdown and/or inhibition. In primary PTCL patient samples, pimozide inhibits STAT5 activation and induces apoptosis. Our data support a role for STAT5 inhibition in PTCL and implicate potential utility for inhibition of STAT5 and activation of the extrinsic apoptotic pathway as combination therapy in PTCL.

Concurrent Mutations in ATM and Genes Associated with Common γ Chain Signaling in Peripheral T Cell Lymphoma.

Peripheral T cell lymphoma (PTCL) is a heterogeneous malignancy with poor response to current therapeutic strategies and incompletely characterized genetics. We conducted whole exome sequencing of matched PTCL and non-malignant samples from 12 patients, spanning 8 subtypes, to identify potential oncogenic mutations in PTCL. Analysis of the mutations identified using computational algorithms, CHASM, PolyPhen2, PROVEAN, and MutationAssessor to predict the impact of these mutations on protein function and PTCL tumorigenesis, revealed 104 somatic mutations that were selected as high impact by all four algorithms. Our analysis identified recurrent somatic missense or nonsense mutations in 70 genes, 9 of which contained mutations predicted significant by all 4 algorithms: ATM, RUNX1T1, WDR17, NTRK3, TP53, TRMT12, CACNA2D1, INTS8, and KCNH8. We observed somatic mutations in ATM (ataxia telangiectasia-mutated) in 5 out of the 12 samples and mutations in the common gamma chain (γc) signaling pathway (JAK3, IL2RG, STAT5B) in 3 samples, all of which also harbored mutations in ATM. Our findings contribute insights into the genetics of PTCL and suggest a relationship between γc signaling and ATM in T cell malignancy.

Bone disease from monoclonal gammopathy of undetermined significance to multiple myeloma: pathogenesis, interventions, and future opportunities.

Manifestations of bone disease-osteopenia, osteolytic lesions, and fractures-are the hallmark of multiple myeloma (MM) and occur clinically in the vast majority of patients. These abnormalities can have devastating clinical effects by increasing both the morbidity and mortality of patients. Bone disease is usually found when patients are diagnosed with active MM; however, recent data suggest that it is present in early myelomagenesis, including patients with myeloma precursor disease, monoclonal gammopathy of undetermined significance (MGUS). The primary mechanisms of abnormal bone remodeling are increased osteoclastic activity, which occurs in close proximity to active myeloma cells, and decreased activity of the surrounding osteoblasts. Better understanding of the pathogenesis of bone disease in MM will allow us to enhance our current therapeutic options in the treatment of bone disease. In patients with active MM and at least one lytic lesion, intravenous bisphosphonates have been shown to decrease skeletal-related events and pain, improve performance status, and maintain quality of life. Emerging evidence suggests that intervention at earlier stages of disease may prevent skeletal-related events at time of progression, but there is no evidence that bisphosphonates in this setting change the natural history of the disease.