Wilbur B. Bowne

Hyaluronidase Embedded in Nanocarrier PEG Shell for Enhanced Tumor Penetration and Highly Efficient Antitumor Efficacy.

One of the major challenges in applying nanomedicines to cancer therapy is their low interstitial diffusion in solid tumors. Although the modification of nanocarrier surfaces with enzymes that degrade extracellular matrix is a promising strategy to improve nanocarrier diffusion in tumors, it remains challenging to apply this strategy in vivo via systemic administration of nanocarriers due to biological barriers, such as reduced blood circulation time of enzyme-modified nanocarriers, loss of enzyme function in vivo, and life-threatening side effects. Here, we report the conjugation of recombinant human hyaluronidase PH20 (rHuPH20), which degrades hyaluronic acid, on the surfaces of poly(lactic-co-glycolic acid)-b-polyethylene glycol (PLGA-PEG) nanoparticles followed by anchoring a relatively low density layer of PEG, which reduces the exposure of rHuPH20 for circumventing rHuPH20-mediated clearance. Despite the extremely short serum half-life of rHuPH20, our unique design maintains the function of rHuPH20 and avoids its effect on shortening nanocarrier blood circulation. We also show that rHuPH20 conjugated on nanoparticles is more efficient than free rHuPH20 in facilitating nanoparticle diffusion. The facile surface modification quadruples the accumulation of conventional PLGA-PEG nanoparticles in 4T1 syngeneic mouse breast tumors and enable their uniform tumor distribution. The rHuPH20-modified nanoparticles encapsulating doxorubicin efficiently inhibit the growth of aggressive 4T1 tumors under a low drug dose. Thus, our platform technology may be valuable to enhance the clinical efficacy of a broad range of drug nanocarriers. This study also provides a general strategy to modify nanoparticles with enzymes that otherwise may reduce nanoparticle circulation or lose function in the blood.

Palliative Surgery for Advanced Cancer: Identifying Evidence-Based Criteria for Patient Selection: Case Report and Review of Literature.

BACKGROUND Criteria for selecting patients with advanced cancer for palliative surgery (PS) remains poorly defined. Decision making for PS requires realistic treatment goals with well-defined criteria. Here we discuss a 71-year-old Jehovahs Witness with advanced stage renal cell carcinoma (RCC) who presented with profound anemia due to intractable bleeding from gastric metastasis. After repeated attempts with endoscopic and angiographic management, she underwent surgical palliation. Through this case, we developed 10-item evidence-based criteria for selecting patients for PS. OBJECTIVE The study objective was to provide a review of pertinent literature for PS and identify evidence-based criteria for patient selection. These criteria were relevant for selecting this patient with metastatic RCC and may prove beneficial for selecting advanced cancer patients for PS. METHODS A MEDLINE search revealed 175 publications relevant to PS. Among these, 17 articles defining patient selection criteria (PSC) were reviewed. A frequency-based analysis of each criterion was performed. Another search returned 30 cases of RCC gastric metastases from 25 published reports. Outcome analysis was determined by the Kaplan-Meier actuarial method. RESULTS Ten criteria were identified: symptom control, prognosis, preoperative performance status, quality of life (QoL), tumor burden amenable to palliation, procedure-related morbidity and mortality, feasibility of nonsurgical therapies, anticipated hospitalization, requirement for additional palliation, and cost. This patient met all inclusion criteria and underwent a successful gastrectomy. Median survival for patients with RCC gastric metastasis was 20 months. CONCLUSIONS This report illustrates an example of implementation of evidence-based criteria for selecting advanced cancer patients for PS. Validation of these criteria is warranted.

Retroperitoneal Castleman's disease: advocating a multidisciplinary approach for a rare clinical entity

BackgroundCastleman’s disease is a rare and poorly understood disease entity that may resemble more common conditions and represents a clinical challenge to the treating surgeon.Case presentationIn this report, we describe a case of a 61-year-old Caucasian woman with a symptomatic retroperitoneal mass. The specimen obtained from her resection contained a protuberant encapsulated mass, exhibiting microscopic features consistent with localized, unicentric Castleman’s disease. These characteristics included architectural features and immunohistochemical findings consistent with the hyaline vascular variant of Castleman’s disease.ConclusionWe report a very rare case of a retroperitoneal hyaline vascular type of Castleman’s disease. We discuss the diagnostic dilemma Castleman’s disease may present to the surgeon, with an emphasis on multidisciplinary management of these patients. We also review current data on pathogenesis, treatment and outcomes.

Pancreatic mucinous cystic neoplasm in a transgender patient.

BackgroundCystic pancreatic lesions are increasingly more frequent detected clinical entities. Mucinous cystic neoplasm (MCN) is a hormone-related pancreatic tumor (HRTP) with a strong predominance in young and middle-aged females.Case presentationHere, we present the case of a 31-year-old surgically transgendered female-to-male patient with a history of alcoholic pancreatitis, on chronic testosterone therapy. He was found to have a pancreatic MCN and underwent distal pancreatectomy and splenectomy.ConclusionTo our knowledge, this is the first reported case of a transgender patient with a history of hormone replacement therapy (HRT) and pancreatic MCN. We consider possible mechanisms for the pathogenesis to explain this patient’s neoplasm.

Clinical Trials in CRS and HIPEC: Ongoing Trials and Future Directives

Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have gained momentum as a viable treatment option for primary or recurrent malignancies with peritoneal metastasis (PM). Despite significant progress over the last 30 years, this field has lacked in high-quality randomized, controlled trials, with most data supporting the use of CRS and HIPEC coming from smaller retrospective and prospective trials. Ultimately, validation of treatment efficacy and outcomes will require large, collaborative, well-organized, outcomes-based studies. Thus far, the use of CRS and HIPEC in metastatic gastric, ovarian, pancreatic, and other gastrointestinal malignancies has spurred further development of a growing number of prospective clinical trials to study outcomes and survival benefit. This chapter summarizes some of the notable, completed clinical trials and current trials being conducted.

Clinical studies in CRS and HIPEC: Trials, tribulations, and future directions-A systematic review

The field of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has suffered from a lack of clinical trials to validate its expanding use.

Dense and Dynamic Polyethylene Glycol Shells Cloak Nanoparticles from Uptake by Liver Endothelial Cells for Long Blood Circulation

Research into long-circulating nanoparticles has in the past focused on reducing their clearance by macrophages. By engineering a hierarchical polyethylene glycol (PEG) structure on nanoparticle surfaces, we revealed an alternative mechanism to enhance nanoparticle blood circulation. The conjugation of a second PEG layer at a density close to but lower than the mushroom-to-brush transition regime on conventional PEGylated nanoparticles dramatically prolongs their blood circulation via reduced nanoparticle uptake by non-Kupffer cells in the liver, especially liver sinusoidal endothelial cells. Our study also disclosed that the dynamic outer PEG layer reduces protein binding affinity to nanoparticles, although not the total number of adsorbed proteins. These effects of the outer PEG layer diminish in the higher density regime. Therefore, our results suggest that the dynamic topographical structure of nanoparticles is an important factor in governing their fate in vivo. Taken together, this study advances our understanding of nanoparticle blood circulation and provides a facile approach for generating long circulating nanoparticles.

Incidentally discovered low-grade appendiceal mucinous neoplasm: a precursor to pseudomyxoma peritonei

Appendiceal mucoceles (AMs) infrequently arise from an underlying malignancy. Treatment has progressed toward a less aggressive approach over time; they can be managed by appendectomy‐only unless pathology reveals malignancy. The ultimate goal of management is to prevent AM rupture, avoiding the syndrome of pseudomyxoma peritonei.