Enfortumab Vedotin-Induced Febrile Neutropenia and Hyperglycemia Successfully Treated with Multidisciplinary Treatment Including Continuous Hemodialysis Filtration and Insulin Injection in a Patient with Chemo-Resistant Metastatic Urothelial Carcinoma: A Case Report.

Introduction: Enfortumab vedotin (EV) is an antibody-drug conjugate combining a monoclonal antibody targeting nectin-4 with a highly potent microtubule disrupting agent. EV is expected to be a candidate for the third-line treatment for urothelial carcinoma previously treated with platinum-based chemotherapy and PD-1/PD-L1 inhibitors. Very few cases of patients experienced hyperglycemia of unknown cause.

A novel diagnostic examination for dropped head syndrome (DHS) (Prone position cervical extension test; DHS test).

Background: Dropped head syndrome (DHS) is followed by severe cervical extension muscle weakness that results in chin-on chest deformity. However, maintaining a neutral cervical position can be temporarily possible, and the diagnosis of DHS might sometimes be difficult. The purpose of the present study is to examine a novel clinical test (DHS test) as the diagnostic utility for objective evaluation that focuses on cervical extension condition in the prone position.

Clinical trials of self-replicating RNA-based cancer vaccines.

Therapeutic cancer vaccines, designed to activate immune effectors against tumor antigens, utilize a number of different platforms for antigen delivery. Among these are messenger RNAs (mRNA), successfully deployed in some prophylactic SARS-CoV2 vaccines. To enhance the immunogenicity of mRNA-delivered epitopes, self-replicating RNAs (srRNA) that markedly increase epitope expression have been developed.

A Non-Invasive Deep Photoablation Technique to Inhibit DCIS Progression and Induce Antitumor Immunity.

Ductal carcinoma in situ (DCIS) of the breast is often managed by lumpectomy and radiation or mastectomy, despite its indolent features. Effective non-invasive treatment strategies could reduce the morbidity of DCIS treatment. We have exploited the high heat shock protein 90 (HSP90) activity in premalignant and malignant breast disease to non-invasively detect and selectively ablate tumors using photodynamic therapy (PDT).

Combination of a novel heat shock protein 90-targeted photodynamic therapy with PD-1/PD-L1 blockade induces potent systemic antitumor efficacy and abscopal effect against breast cancers.

Background: We previously demonstrated potent antitumor activity against human breast cancer xenografts using photodynamic therapy (PDT) targeting a novel tumor-specific photosensitizer (HS201), which binds heat shock protein 90 (HS201-PDT). However, induction of systemic antitumor immunity by HS201-PDT alone or by the combination strategy with immune checkpoint blockade has yet to be determined.

Methods: Using unilateral and bilateral implantation models of syngeneic breast tumors (E0771, MM3MG-HER2, and JC-HER3) in mice, we assessed whether HS201-PDT could induce local and systemic antitumor immunity.

Sensitizing immune unresponsive colorectal cancers to immune checkpoint inhibitors through MAVS overexpression.

Background: The majority of colorectal carcinomas (CRCs) are insensitive to programmed death protein-1/programmed death-ligand 1 (anti-PD-1/PD-L1) immune checkpoint inhibitor (ICI) antibodies. While there are many causes for ICI insensitivity, recent studies suggest that suppression of innate immune gene expression in tumor cells could be a root cause of this insensitivity and an important factor in the evolution of tumor immunosuppression.

Methods: We first assessed the reduction of mitochondrial antiviral signaling gene (MAVS) and related RIG-I pathway gene expression in several patient RNA expression datasets.

Combination of ultrasound-based mechanical disruption of tumor with immune checkpoint blockade modifies tumor microenvironment and augments systemic antitumor immunity.

Background: Despite multimodal adjuvant management with radiotherapy, chemotherapy and hormonal therapies, most surgically resected primary breast cancers relapse or metastasize. A potential solution to late and distant recurrence is to augment systemic antitumor immunity, in part by appropriately presenting tumor antigens, but also by modulating the immunosuppressive tumor microenvironment (TME). We previously validated this concept in models of murine carcinoma treated with a novel predominately microcavitating version of high-intensity focused ultrasound (HIFU), mechanical high-intensity focused ultrasound (M-HIFU).

HSP90-Specific nIR Probe Identifies Aggressive Prostate Cancers: Translation from Preclinical Models to a Human Phase I Study.

A noninvasive test to discriminate indolent prostate cancers from lethal ones would focus treatment where necessary while reducing overtreatment. We exploited the known activity of heat shock protein 90 (Hsp90) as a chaperone critical for the function of numerous oncogenic drivers, including the androgen receptor and its variants, to detect aggressive prostate cancer. We linked a near-infrared fluorescing molecule to an HSP90 binding drug and demonstrated that this probe (designated HS196) was highly sensitive and specific for detecting implanted prostate cancer cell lines with greater uptake by more aggressive subtypes.

Intratumoral Plasmid IL12 Expands CD8 T Cells and Induces a CXCR3 Gene Signature in Triple-negative Breast Tumors that Sensitizes Patients to Anti-PD-1 Therapy.

Purpose: Triple-negative breast cancer (TNBC) is an aggressive disease with limited therapeutic options. Antibodies targeting programmed cell death protein 1 (PD-1)/PD-1 ligand 1 (PD-L1) have entered the therapeutic landscape in TNBC, but only a minority of patients benefit. A way to reliably enhance immunogenicity, T-cell infiltration, and predict responsiveness is critically needed.

Long-term survival of patients with stage III colon cancer treated with VRP-CEA(6D), an alphavirus vector that increases the CD8+ effector memory T cell to Treg ratio.

Background: There remains a significant need to eliminate the risk of recurrence of resected cancers. Cancer vaccines are well tolerated and activate tumor-specific immune effectors and lead to long-term survival in some patients. We hypothesized that vaccination with alphaviral replicon particles encoding tumor associated antigens would generate clinically significant antitumor immunity to enable prolonged overall survival (OS) in patients with both metastatic and resected cancer.

Heat shock protein 90-targeted photodynamic therapy enables treatment of subcutaneous and visceral tumors.

Photodynamic therapy (PDT) ablates malignancies by applying focused near-infrared (nIR) light onto a lesion of interest after systemic administration of a photosensitizer (PS); however, the accumulation of existing PS is not tumor-exclusive. We developed a tumor-localizing strategy for PDT, exploiting the high expression of heat shock protein 90 (Hsp90) in cancer cells to retain high concentrations of PS by tethering a small molecule Hsp90 inhibitor to a PS (verteporfin, VP) to create an Hsp90-targeted PS (HS201). HS201 accumulates to a greater extent than VP in breast cancer cells both in vitro and in vivo, resulting in increased treatment efficacy of HS201-PDT in various human breast cancer xenografts regardless of molecular and clinical subtypes.

Impact of synchronized anti-PD-1 with Ad-CEA vaccination on inhibition of colon cancer growth.

The purpose of this study was to determine whether addition of anti-PD-1 antibody increased the immunogenicity and anti-tumor activity of Ad-CEA vaccination in a murine model of colon cancer. Ad-CEA was administered prior to implantation of MC-38-CEA cells followed by administration of anti-PD-1 antibody. CEA-specific T-cell responses were measured by flow cytometry and ELISPOT.

Evaluation of Yanagihara facial nerve grading system based on a muscle fiber analysis of human facial muscles.

Purpose: We morphometrically analyzed human facial muscles, and evaluated the Yanagihara facial nerve grading system using our data.

Methods: We used 15 types of human facial muscle, 2 types of masticatory muscle and 2 types of skeletal muscle. The materials were obtained from 11 Japanese male cadavers aged 43-86 years.

Niclosamide-induced Wnt signaling inhibition in colorectal cancer is mediated by autophagy.

The Wnt signaling pathway, known for regulating genes critical to normal embryonic development and tissue homeostasis, is dysregulated in many types of cancer. Previously, we identified that the anthelmintic drug niclosamide inhibited Wnt signaling by promoting internalization of Wnt receptor Frizzled 1 and degradation of Wnt signaling pathway proteins, Dishevelled 2 and β-catenin, contributing to suppression of colorectal cancer growth and Here, we provide evidence that niclosamide-mediated inhibition of Wnt signaling is mediated through autophagosomes induced by niclosamide. Specifically, niclosamide promotes the co-localization of Frizzled 1 or β-catenin with LC3, an autophagosome marker.

Vaccine-Induced Memory CD8 T Cells Provide Clinical Benefit in HER2 Expressing Breast Cancer: A Mouse to Human Translational Study.

Purpose: Immune-based therapy for metastatic breast cancer has had limited success, particularly in molecular subtypes with low somatic mutations rates. Strategies to augment T-cell infiltration of tumors include vaccines targeting established oncogenic drivers such as the genomic amplification of HER2. We constructed a vaccine based on a novel alphaviral vector encoding a portion of HER2 (VRP-HER2).

Right Time and Place for IL12: Targeted Delivery Stimulates Immune Therapy.

Systemic IL12 therapy has potent antitumor effects, but clinical delivery of this potent cytokine has been complicated by systemic toxicity. A novel strategy to deliver IL12 to the tumor microenvironment appears promising in a first-in-human study, appearing to stimulate tumor-specific adaptive immune responses with minimal systemic toxicity..

Effects of Aerobic Cycling Training on O Dynamics in Several Leg Muscles in Early Post-myocardial Infarction.

The aim of this study was to test the effects of aerobic cycling training on O dynamics in several leg muscles in early post-myocardial infarction (post-MI). Fifteen post-MI patients were divided into a 12-week training group (TR, n = 9) or a control/non-training group (CON, n = 6). All participants performed ramp bicycle exercise until exhaustion at two times: within 12-35 days of their MI and then again 12 weeks later.

Polyfunctional anti-human epidermal growth factor receptor 3 (anti-HER3) antibodies induced by HER3 vaccines have multiple mechanisms of antitumor activity against therapy resistant and triple negative breast cancers.

Background: Upregulation of human epidermal growth factor receptor 3 (HER3) is a major mechanism of acquired resistance to therapies targeting its heterodimerization partners epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2), but also exposes HER3 as a target for immune attack. We generated an adenovirus encoding full length human HER3 (Ad-HER3) to serve as a cancer vaccine. Previously we reported the anti-tumor efficacy and function of the T cell response to this vaccine.

Detection of HSP90 Identifies Breast Cancers with Aggressive Behavior.

Hsp90, a chaperone to numerous molecular pathways in malignant cells, is elevated in aggressive breast cancers. We hypothesized that identifying breast cells with elevated Hsp90 activity in situ could result in early detection of aggressive breast cancers. We exploited the uptake of an Hsp90 inhibitor by malignant cells to create an imaging probe (HS131) of Hsp90 activity by linking it to a near-infrared (nIR) dye.

Multi-site Measurements of Muscle O Dynamics During Cycling Exercise in Early Post-myocardial Infarction.

The aim of this study was to compare the muscle oxygen dynamics between early post-myocardial infarction (n = 12; MI) and age-matched elderly subjects without MI (n = 12; CON) in several leg muscles during ramp cycling exercise. Muscle oxygen saturation (SmO), deoxygenated-hemoglobin concentration (∆deoxy-Hb), and total-hemoglobin concentration (∆total-Hb) were monitored continuously at the distal site of vastus lateralis (VLd), proximal site of the vastus lateralis (VLp), rectus femoris (RF), vastus medialis (VM), gastrocnemius medialis (GM), and tibialis anterior (TA) muscles by near infrared spatial resolved spectroscopy. At given absolute workloads, higher SmO was observed at VLd, VLp, RF, and VM in MI, compared to CON.

Vaccination targeting human HER3 alters the phenotype of infiltrating T cells and responses to immune checkpoint inhibition.

Expression of human epidermal growth factor family member 3 (HER3), a critical heterodimerization partner with EGFR and HER2, promotes more aggressive biology in breast and other epithelial malignancies. As such, inhibiting HER3 could have broad applicability to the treatment of EGFR- and HER2-driven tumors. Although lack of a functional kinase domain limits the use of receptor tyrosine kinase inhibitors, HER3 contains antigenic targets for T cells and antibodies.