Jimmy Tam Huy Pham

A 79-year-old woman presented to the emergency department with abrupt onset of dark-colored emesis. Her medical history included hypertension and cecal carcinoma. Physical examination and laboratory findings were normal. A radiographic image of the chest from an anterior/posterior view showed a retrocardiac air bubble (image, arrows), indicating a massive incarcerated paraesophageal hiatal hernia. The patient underwent an open-suture cruroplasty and had an unremarkable recovery.

A 71-year-old woman with a history of hypothyroidism presented to the emergency department with dyspnea. Physical examination revealed massive lower eyelid edema bilaterally (image) and dry, flaky skin on her lower extremities. Vital signs were normal. Further investigation revealed that the patient had been noncompliant with her prescribed levothyroxine for more than a year. The results of biochemical tests revealed a thyroid-stimulating hormone level of 220 mIU/L and a free thyroxine level of 0.15 µg/dL. The patient was admitted to the hospital, where a 0.1-mg intravenous dose of levothyroxine was administered daily for 3 days.

Oral cavity and oropharyngeal cancers are considered the eighth most common cancer worldwide, with relatively poor prognosis (62% of patients surviving 5 years, after diagnosis). The aim of this study was to develop a proof-of-concept mucoadhesive lozenge/buccal tablet, as a potential platform for direct sustained delivery of therapeutic antimitotic nanomedicines. Our system would serve as an adjuvant therapy for oral cancer patients undergoing full-scale diagnostic and operative treatment plans. We utilized lipid-based nanocarriers, namely nanoemulsions (NEs), containing mixed-polyethoxylated emulsifiers and a tocopheryl moiety–enriched oil phase. Prototype NEs, loaded with the proapoptotic lipophilic drug genistein (Gen), were further processed into buccal tablet formulations. The chitosan polyelectrolyte solution overcoat rendered NE droplets cationic, by acting as a mucoadhesive interfacial NE layer. With approximate size of 110 nm, the positively charged chitosan-layered NE (+25 mV) vs negatively charged chitosan-free/primary aqueous NE (-28 mV) exhibited a controlled-release profile and effective mucoadhesion for liquid oral spray prototypes. When punch-pressed, porous NE-based buccal tablets were physically evaluated for hardness, friability, and swelling in addition to ex vivo tissue mucoadhesion force and retention time measurements. Chitosan-containing NE tablets were found equivalent to primary NE and placebo tablets in compression tests, yet significantly superior in all ex vivo adhesion and in vitro release assays (P≤0.05). Following biocompatibility screening of prototype chitosan-layered NEs, substantial anticancer activity of selected cationic Gen-loaded NE formulations, against two oropahryngeal carcinomas, was observed. The data strongly indicate the potential of such nanomucoadhesive systems as maintenance therapy for oral cancer patients awaiting surgical removal, or postresection of identified cancerous lesions.

Genistein (Gen), a major soy isoflavone, produces extensive pro-apoptotic anticancer effects, mediated predominantly via induction of mitochondrial damage. Based on several biophysical model criteria, our rational assumptions for the native mitochondrial selectivity of Gen allowed its design as a cationic lipid-based nanocarrier (NC) system. Proof-of-concept nano-formulations, lipidic micelles (Mic), and nanoemulsions (NEs) incorporated Gen, which serves as therapeutic and targeting moieties, specific for mitochondria. Our in vitro experimental data demonstrated superior physicochemical properties and significant cytotoxicity of Gen-NCs (five- to tenfolds lower EC₅₀) compared to all drug controls, in hepatic and colon carcinomas. The established mitochondria-specific accumulation of the various Gen-NCs positively correlated with marked mitochondrial depolarization effects. Within first 24 h, Gen-NC treatments ultimately lead to distinct activation of intrinsic apoptotic pathway markers, such as cytosolic cytochrome c and specific caspase-9 vs. nonspecific caspases-3, 7, and 8. Such mechanistic evidence of the mitochondriotropic activity of our Gen-NC platforms favors their prospective as intracellularly targeted delivery nano-vehicles, to enhance anticancer efficacy of different co-formulated chemotherapeutic agents.

The potent anti-proliferative and pro-apoptotic actions of tocotrienols (T3) against cancer, but not normal tissues, have been hampered by their limited systemic bioavailabilty. Recent expansive development of diverse nanoemulsion (NE) vehicles emphasized their vast potential to improve the effective dosing of different clinical and experimental drugs of lipophilic nature, such as T3. The emphasis of the present work is to develop a pharmaceutically scalable, low-energy nano-emulsification approach for optimized incorporation of T3-rich palm oil (Tocomin®), possessing anticancer activity as a potential cutaneous delivery platform for adjunctive therapy of skin carcinomas, either alone or in combination with other chemotherapeutic agents. Different Tocomin®-NEs, obtained with different homogenization strategies, were screened based on physicochemical uniformity (droplet size, charge and polydispersity) and subjected to stress physical stability testing, along with chemical content analysis (≥90% Tocomin® - incorporation efficiency). Adopted hybrid nano-emulsification of Tocomin®, correlated with highest preservation of DPPH-radical scavenging capacity of active T3 in prototype formulation, Tocomin®-NE, which effectively permeated diffusion cell membranes 4-folds higher than propyleneglycol (PG)-admixed Tocomin® control. Against two different cell models of human cutaneous carcinoma, Tocomin®-hybrid NE demonstrated significantly stronger cytotoxic profiles (p ≤ 0.01), visible in both concentration- and time- dependent manners, with at least 5-folds lower IC50 values, compared to those estimated for the closest Tocomin®-control. The proposed hybrid nano-emulsified formulation of Tocomin® provides simple and stable delivery platform, for effective topical application against keratinocyte tumors.

Genistein (Gen) soy isoflavone produces extensive pro-apoptotic anticancer effects, mediated predominantly via induction of mitochondrial damages. Rationalization of the native mitochondrial selectivity of Gen, utilizing biophysical model assumptions, led to our design of cationic lipid-based nanocarriers (NC) of Gen. Prototype nanoformulations, lipidic micelles (Mic) and nanoemulsions (NEs) incorporated Gen to serve as both therapeutic and targeting moieties, specific for mitochondria. Both Gen-NCs, showing superior physicochemical properties, produced significant cytotoxicity (5–10-fold lower EC₅₀), compared to all drug controls, in hepatic and colon carcinomas. Owing to the mitochondria-specific accumulation of Gen-NCs, their mitochondrial depolarization effect was most evident, leading to marked activation of intrinsic apoptotic pathway markers—cytosolic cytochrme c and specific caspase-9—thus, confirming the direct mitochondrial action of Gen-NCs. This mechanistic evidence of the mitochondria specificity of our Gen-NE and Gen-Mic strongly indicates their potential as targeted delivery nanosystems to augment anticancer efficacy of many lipophilic chemotherapeutics.

Gliomas are invasive cancers that resist all forms of attempted therapy. Immunotherapy using Ag-pulsed dendritic cells has improved survival in some patients. We present evidence that another level of complexity may also contribute to lack of responses by the lymphocytes toward gliomas. Atomic force microscopy of four different glioma types—human U251 and rat T9 and F98 glioma cells, including freshly isolated human glioblastoma multiforme neurosphere cultures (containing “stem cell-like cells”)—revealed a complex surface topography with numerous microvilli and filopodia. These structures were not found on other cell types. Electron microscopy and immunofluorescence microscopy of glioma cells confirmed that microvilli are present. U251 cells with microvilli resisted the cytolytic actions of different human effector cells, (lymphokine-activated killer cells, γδ T cells, conventional CTLs, and chimeric Ag-receptor–redirected T cells) better than their nonmicrovilli-expressing counterparts. Killer lymphocytes released perforin, which was detected within the glioma’s microvilli/filopodia, indicating these structures can receive the cytolytic effector molecules, but cytotoxicity is suboptimal. Air-dried gliomas revealed nodes within the microvilli/filopodia. The microvilli that penetrated 0.4-μm transwell chamber’s pores resisted the actions of CTLs and physical damage. Those nodelike structures may represent a compartmentalization that resists physical damage. These microvilli may play multiple roles in glioma biology, such as invasion and resistance to lymphocyte-mediated killing.