Intratumoral Injection of Large Surface Area Microparticle Taxanes in Carcinomas Increases Immune Effector Cell Concentrations, Checkpoint Expression, and Synergy with Checkpoint Inhibitors: A Review of Preclinical and Clinical Studies.

This review summarizes development of large surface area microparticle paclitaxel (LSAM-PTX) and docetaxel (LSAM-DTX) for local treatment of primary carcinomas with emphasis on immunomodulation. Intratumoral (IT) delivery of LSAM-PTX and LSAM-DTX provides continuous, therapeutic drug levels for several weeks. Preclinical studies and clinical trials reported a reduction in tumor volume (TV) and immunomodulation in primary tumor and peripheral blood with increases in innate and adaptive immune cells and decreases in suppressor cells.

Intratumoral Treatment of Melanoma Tumors with Large Surface Area Microparticle Paclitaxel and Synergy with Immune Checkpoint Inhibition.

The effects of intratumoral (IT) large surface area microparticle paclitaxel (LSAM-PTX) alone and in combination with systemic administration of the programmed cell death protein antibody (anti-mPD-1) were evaluated in a syngeneic murine model of melanoma. Groups of mice with subcutaneously implanted Clone M3 (Cloudman S91) tumors were treated with single and combination therapies. Tumor volume (TV) measurements, body weights, and clinical observations were followed in-life.

Phase 1/2 Trial Results of a Large Surface Area Microparticle Docetaxel for the Treatment of High-Risk Nonmuscle-Invasive Bladder Cancer.

Purpose: We investigated the safety, preliminary efficacy, and immune effects of large surface area microparticle docetaxel (LSAM-DTX) administered by direct injection after transurethral resection of bladder tumor (TURBT), and by intravesical instillation in high-risk nonmuscle-invasive bladder cancer.

Materials And Methods: The trial followed an open-label 3+3 dose escalation with additional enrollment at the high dose. After TURBT, subjects received direct injection LSAM-DTX into the resection site and intravesical LSAM-DTX, followed by 6-week induction and 3-week maintenance intravesical LSAM-DTX courses.

Intratumoral submicron particle docetaxel inhibits syngeneic Renca renal cancer growth and increases CD4+, CD8+, and Treg levels in peripheral blood.

Administration of chemotherapeutics as direct injections into tumors offers increased anti-tumor activity and reduced systemic toxicity. In this study, the Renca syngeneic murine xenograft model of renal cancer was used to evaluate the effects of intratumoral (IT) submicron particle docetaxel (NanoDoce®) on tumor growth and immunomodulation. Tumor volume (TV) was compared to controls, including intravenous (IV) chemotherapy.

Local Injection of Submicron Particle Docetaxel is Associated with Tumor Eradication, Reduced Systemic Toxicity and an Immunologic Response in Uro-Oncologic Xenografts.

Intratumoral (IT) administration of submicron particle docetaxel (NanoDoce, NanOlogy LLC, Fort Worth, TX, USA) and its efficacy against genitourinary-oncologic xenografts in rats and mice, xenograft-site docetaxel concentrations and immune-cell infiltration were studied. IT-NanoDoce, IV-docetaxel and IT-vehicle were administered to clear cell renal carcinoma (786-O: rats), transitional cell bladder carcinoma (UM-UC-3: mice) and prostate carcinoma (PC-3: mice). Treatments were given every 7 days with 1, 2, or 3 doses administered.

Development of a guinea pig cutaneous radiation injury model using low penetrating X-rays.

Purpose: A guinea pig skin model was developed to determine the dose-dependent response to soft X-ray radiation into the dermis.

Materials And Methods: X-ray exposure (50 kVp) was defined to a 4.0 × 4.

NorLeu3A(1-7) Accelerates Clear Corneal Full Thickness Wound Healing.

Purpose: We evaluated the effect of the renin angiotensin system (RAS) peptide NorLeu3-Angiotensin (1-7) (NLE) formulated in a viscoelastic gel (USB004) on the healing of full-thickness corneal injuries.

Methods: Dutch pigmented rabbits received conjunctival administration of 0.3% USB004, 0.

NorLeu-Angiotensin (1-7) [DSC127] as a Therapy for the Healing of Diabetic Foot Ulcers.

Diabetes is a disorder that is well known to delay wound repair resulting in the formation of colonized chronic wounds. Over their lifetime, diabetic patients have a 25% incidence of foot ulcers (DFUs), which contribute to increased risk of morbidity, including osteomyelitis and amputations, and increased burden to the healthcare system. The only active product approved for the treatment of diabetic ulcers, Regranex, is not widely used due to minimal proven efficacy and recent warnings added to the Instructions for Use.

Effect of combined radiation injury on cell death and inflammation in skin.

In the event of a nuclear disaster, the individuals proximal to the source of radiation will be exposed to combined radiation injury. As irradiation delays cutaneous repair, the purpose of this study was to elucidate the effect of combined radiation and burn injury (CRBI) on apoptosis and inflammation at the site of skin injury. Male C57Bl/6 mice were exposed to no injury, thermal injury only, radiation only (1 and 6 Gy) and CRBI (1 and 6 Gy) and euthanized at various times after for skin collection.

Angiotensin 1 - 7 stimulation of platelet recovery.

Introduction: Thrombocytopenia is an abnormally low number of platelets in the blood resulting from either too few platelets being produced or existing platelets being destroyed. Severe thrombocytopenia leads to excessive bleeding and can be the result of numerous medical conditions or a side effect of medications or treatments. Although platelet transfusions are typically administered to correct thrombocytopenia, transfusions represent a temporary and unsustainable solution.

Contribution of the Local RAS to Hematopoietic Function: A Novel Therapeutic Target.

The renin-angiotensin system (RAS) has long been a known endocrine system that is involved in regulation of blood pressure and fluid balance. Over the last two decades, evidence has accrued that shows that there are local RAS that can affect cellular activity, tissue injury, and tissue regeneration. There are locally active ligand peptides, mediators, receptors, and signaling pathways of the RAS in the bone marrow (BM).

Angiotensin-(1-7) synergizes with colony-stimulating factors in hematopoietic recovery.

Purpose: Angiotensin (1-7) [A(1-7)] is a bioactive peptide of the renin angiotensin system that stimulates the number of bone marrow progenitors and hematopoietic recovery after myelosuppression. We evaluated the combination of A(1-7) with colony-stimulating factors, Neupogen and Epogen, on bone marrow progenitors and the recovery of circulating formed elements following chemotherapy.

Methods: Mice were injected with gemcitabine followed 2 days later with A(1-7).

Reduction of Leg Pain by Oxiplex Gel After Lumbar Discectomy in Patients With Predominant Leg Pain and Elevated Levels of Lower Back Pain: A Prospective, Randomized, Blinded, Multicenter Clinical Study.

Study Design: A prospective, randomized, blinded, multicenter clinical study.

Objective: To evaluate carboxymethylcellulose/polyethylene oxide gel (Oxiplex) in improving clinical outcomes in subjects having predominant leg pain and elevated low back pain undergoing first-time lumbar discectomy for disk herniation.

Summary Of Background Data: Clinical studies in the United States and Italy found that Oxiplex reduced leg pain after decompression surgery.

Pharmacodynamic stimulation of thrombogenesis by angiotensin (1-7) in recurrent ovarian cancer patients receiving gemcitabine and platinum-based chemotherapy.

Purpose: This randomized, double-blind, placebo-controlled Phase 2 study evaluated safety and efficacy of A(1-7) for reduction in Grade 3-4 thrombocytopenia in patients receiving myelosuppressive chemotherapy. Pharmacodynamic activity of A(1-7) in platelet production and retention of scheduled dose intensity were also determined.

Methods: Thirty-four patients with ovarian, Fallopian tube, or peritoneal carcinoma receiving gemcitabine and carboplatin or cisplatin were evaluated.

Effects of combined radiation and burn injury on the renin-angiotensin system.

The renin-angiotensin system (RAS) plays an important role in wound repair; however, little is known pertaining to RAS expression in response to thermal injury and the combination of radiation plus burn injury (CRBI). The purpose of this study was to test the hypothesis that thermal injury modifies expression of RAS components and CRBI delayed this up-regulation of RAS. Skin from uninjured mice was compared with mice receiving local thermal injury or CRBI (injury site).

NorLeu3-A(1-7) stimulation of diabetic foot ulcer healing: results of a randomized, parallel-group, double-blind, placebo-controlled phase 2 clinical trial.

This randomized, double-blind, placebo-controlled Phase 2 clinical trial explored NorLeu(3)-A(1-7) (DSC127) safety and healing efficacy in diabetic foot ulcers. Patients with chronic, noninfected, neuropathic, or neuroischemic plantar Wagner Grade 1 or 2 foot ulcers (n = 172) were screened for nonhealing. Subjects were randomized to receive 4 weeks' once-daily topical treatment with 0.

Accelerated hematopoietic recovery with angiotensin-(1-7) after total body radiation.

Purpose: Angiotensin (1-7) [A(1-7)] is a component of the renin angiotensin system (RAS) that stimulates hematopoietic recovery after myelosuppression. In a Phase I/IIa clinical trial, thrombocytopenia after chemotherapy was reduced by A(1-7). In this study, the ability of A(1-7) to improve recovery after total body irradiation (TBI) is shown with specific attention to radiation-induced hematopoietic injury.

Oxiplex reduces leg pain, back pain, and associated symptoms after lumbar discectomy.

Study Design: Prospective, randomized, blinded clinical trial.

Objective: To evaluate effectiveness of Oxiplex gel for reduction of pain and associated symptoms after lumbar discectomy.

Summary Of Background Data: Oxiplex gel (carboxymethylcellulose, polyethylene oxide, and calcium) is used during discectomy to coat the surgical site for reduction of pain and symptoms after lumbar discectomy.

Toxicological and toxicokinetic analysis of angiotensin (1-7) in two species.

The objectives of this study were to determine the potential systemic and local toxicity, as well as evaluate the toxicokinetic (TK) profile of angiotensin (1-7) [A(1-7)] when administered daily via subcutaneous injection for 28 days to Sprague-Dawley rats and Beagle dogs. A(1-7) is a member of the renin-angiotensin system and has undergone clinical evaluation for the treatment of chemotherapy-induced myelosuppression. In this present study, A(1-7) was given at 10 mg/(kg day) for 28 days to rats and canines.

Prevention of intra-abdominal adhesions in gynaecological surgery.

Important progress has been made in the field of post-surgical adhesion prevention with the development of consensus statements in gynaecology from the United Kingdom, Germany, the European Society of Gynaecological Endoscopy, Call for Action in Colorectal Surgery and a recent Technical Bulletin from The Practice Committee of the American Society of Reproductive Medicine. These reports suggest that the application of adhesion reduction devices together with the use of microsurgical principles reduces the formation of post-operative adhesions. This commentary provides additional information to assist gynaecologists in making surgical decisions.

Tranilast: a pharmaceutical candidate for reduction of adhesions using a novel approach.

Postsurgical adhesion formation has numerous deleterious side effects in a wide variety of surgical settings. Physical barriers used together with laparoscopy were developed in hopes of reducing the tissue trauma seen with open procedures and separating tissues during the critical time of healing to reduce adhesion formation. Despite meticulous techniques by surgeons and the availability of barriers, adhesion formation remains a serious problem, with more than $1 billion spent annually on complications arising from adhesions.

Reduction of post-surgical adhesion formation with tranilast.

Background: Preclinical studies using the rabbit sidewall and double uterine horn models were used to assess time and dose response of tranilast delivered via subcutaneous pump, p.o., or as an intraperitoneal bolus in viscoelastic gels as well as an intraperitoneal biodegradable poly(p-dioxanone) fiber in reducing adhesions compared to vehicle controls.

Adept (icodextrin 4% solution) reduces adhesions after laparoscopic surgery for adhesiolysis: a double-blind, randomized, controlled study.

Objective: To evaluate the efficacy and safety of Adept (4% icodextrin solution) in reducing adhesions after laparoscopic gynecological surgery involving adhesiolysis.

Design: Multicenter, prospective, randomized, double-blind study comparing Adept with lactated Ringer's solution (LRS).

Patient(s): Four hundred two patients randomized intraoperatively to Adept (n = 203) or LRS (n = 199) returned for second laparoscopy within 4-8 weeks.

The Lumbar Spine Outcomes Questionnaire: its development and psychometric properties.

Background Content: There are currently a number of generic and disease-specific instruments for assessing complaints of low back pain (LBP). None provide the comprehensive coverage of the wide range of factors that are considered essential in evaluating treatment outcomes.

Purpose: To develop and evaluate the psychometric properties of a comprehensive, disease-specific questionnaire for characterizing complaints of LBP and evaluating the outcomes of treatments for these complaints.