Liposomes produced by microfluidics and extrusion: A comparison for scale-up purposes.

Successful liposomal formulations in the clinic are severely limited due to poor translational capability of the traditional bench techniques to clinical production settings. The gold standard for liposome bench manufacturing is a multi-step and parameter dependent extrusion method. Moreover, these parameters need re-optimization for clinical production. The microfluidics technique utilizes vigorous mixing of fluids at a nanoliter scale to produce liposomes in batches from milliliters to a couple liters. The fine control of process parameters results in improved reproducibility between batches. It is inherently scalable; however, the characteristics of liposomes produced by microfluidics both in vitro and in vivo have never been compared to those produced using extrusion. In this manuscript, we describe the comparison between the traditional extrusion method to microfluidics, the new paradigm in liposome production and scale-up.

Adjuvant Radiotherapy in Early-Stage Breast Cancer: Evidence-Based Options.

BACKGROUND: Patients with a diagnosis of early-stage breast cancer are offered the option of either mastectomy or breast-conserving therapy (BCT) secondary to multiple randomized trials demonstrating equivalent long-term outcomes. Traditionally, BCT has used standard whole-breast irradiation (SWBI) after breast-conserving surgery, although several alternatives have emerged during the past few decades. METHODS: This report reviews key studies supporting each radiation technique and its respective eligibility criteria to assist clinicians in deciding which adjuvant radiotherapy options are appropriate for their patients. RESULTS: In the past, completion of SWBI required 5-7 weeks of daily treatments. During the past two decades, alternatives to SWBI have emerged including hypofractionated whole-breast irradiation (3-4 weeks), accelerated partial-breast irradiation (1-3 weeks), and endocrine therapy alone. Multiple randomized trials have established the equivalence of these alternative strategies to SWBI for appropriately selected patients. Additionally, the current guidelines for patient selection demonstrate a large amount of overlap in the selection criteria for each technique. CONCLUSION: Clinicians must evaluate patient and pathologic criteria and engage in informed discussions with patients when determining which adjuvant radiation techniques are appropriate. Future strategies being explored include using tumor genetics to identify low-risk patients and switching from paradigms that omit radiotherapy to those that omit endocrine therapy.

Impact of active smoking on outcomes in HPV+ oropharyngeal cancer.

BACKGROUND: The role of smoking among patients with human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) is unclear. METHODS: A retrospective cohort study of patients with HPV(+) OPSCC from 2001 to 2015 at a tertiary-care institution was conducted. The primary outcome was overall survival (OS). RESULTS: Among 484 included patients, 94 (19.4%) were active smokers, 226 (46.7%) were former smokers, and 164 (33.9%) never smoked. Among active smokers, 82 patients (87.2%) had a ≥10 pack-year and 69 (73.4%) had a ≥20 pack-year smoking history. After adjusting for covariates, active smoking was a significant predictor of inferior OS (HR 2.28, P < .001) and PFS (HR 2.26, P < .001). When including pack-years as the covariate, ≥20 pack-years predicted a decreased effect-size for inferior OS and PFS. CONCLUSIONS: For patients with HPV(+) OPSCC, active smoking at diagnosis is the most powerful covariate capturing smoking history to predict OS and PFS.

Liposomal formulation of hypoxia activated prodrug for the treatment of ovarian cancer.

In this work, a new sphingomyelin-cholesterol liposomal formulation (CPD100Li) for the delivery of a hypoxia activated prodrug of vinblastine, mon-N-oxide (CPD100), is developed. The optimized liposomal formulation uses an ionophore (A23187) mediated pH-gradient method. Optimized CPD100Li is characterized for size, drug loading, and stability. The in vitro toxicity of CPD100Li is assessed on different aspects of cell proliferation and apoptosis of ES2 ovarian cancer under normoxic and hypoxic conditions. The pharmacokinetics of CPD100Li in mice as well as the influence of A23187 on the retention of CPD100 are assessed. The dose limiting toxicity (DLT) and maximum tolerated dose (MTD) for CPD100Li are evaluated in nude mice. CPD100 is loaded in the liposome at 5.5 mg/mL. The sizes of CPD100Li using DLS, qNano and cryo-TEM techniques are 155.4 ±â€¯4.2 nm, 132 nm, and 112.6 ±â€¯19.8 nm, respectively. There is no difference between the in vitro characterization of CPD100Li with and without ionophore. Freshly prepared CPD100Li with ionophore are stable for 48 h at 4 °C, while the freeze-dried formulation is stable for 3 months under argon at 4 °C. The hypoxic cytotoxicity ratios (HCR) of CPD100 and CPD100Li are 0.16 and 0.11, respectively. CPD100Li under hypoxic conditions has a 9.2-fold lower IC50 value as compared to CPD100Li under normoxic conditions, confirming the hypoxia dependent activation of CPD100. CPD100Li treated ES2 cells show a time dependent enhanced cell death, along with caspase production and an increase in the number of cells in G0/G1 and higher cell arrest. The blood concentration profile of CPD100Li in mice without A23187 has a 12.6-fold lower area under the curve (AUC) and 1.6-fold lower circulation time compared to the CPD100Li with A23187. The DLT for both CPD100 and CPD100Li is 45 mg/kg and the MTD is 40 mg/kg in nude mice. Based on the preliminary data obtained, we clearly show that the presence of ionophore affects the in vivo stability of CPD100. CPD100Li presents a unique opportunity to develop a first-in-kind chemotherapy product based on achieving selective drug activation through the hypoxic physiologic microenvironment of solid tumors.

Clinical and dosimetric implications of intensity-modulated radiotherapy for early-stage glottic carcinoma.

Conventional parallel-opposed radiotherapy (PORT) is the established standard technique for early-stage glottic carcinoma. However, case reports have reported the utility of intensity-modulated radiotherapy (IMRT) and volumetric-modulated arc therapy (VMAT) with or without image guidance (image-guided radiotherapy, IGRT) in select patients. The proposed advantages of IMRT/VMAT include sparing of the carotid artery, thyroid gland, and the remaining functional larynx, although these benefits remain unclear. The following case study presents a patient with multiple vascular comorbidities treated with VMAT for early-stage glottic carcinoma. A detailed explanation of the corresponding treatment details, dose-volume histogram (DVH) analysis, and a review of the relevant literature are provided. Conventional PORT remains the standard of care for early-stage glottic carcinoma. IMRT or VMAT may be beneficial for select patients, although great care is necessary to avoid a geographical miss. Clinical data supporting the benefit of CRT are lacking. Therefore, these techniques should be used with caution and only in selected patients.

Isolated Nodal Failure after Stereotactic Body Radiotherapy for Lung Cancer: The Role for Salvage Mediastinal Radiotherapy.

INTRODUCTION: Isolated nodal failure (INF) without synchronous local or distant failure is an uncommon occurrence after stereotactic body radiation therapy (SBRT) for lung cancer. Here we review the natural history and patterns of failure after post-SBRT INF with or without salvage mediastinal radiotherapy (SvRT). METHODS: Patients treated with SBRT for non-small cell lung cancer with definitive intent were identified. Patients who experienced hilar or mediastinal INF without synchronous distant, lobar, or local failure were included and grouped according to the use of SvRT. The rates of subsequent locoregional control, distant metastases, progression-free survival (PFS), and overall survival were assessed. RESULTS: Of 797 patients treated with definitive SBRT, 24 (3%) experienced INF and 15 (63%) received SvRT. The most common SvRT regimen (53%) was 45 Gy in 15 fractions. The median follow-up after INF was 11.3 months for survivors. There were no grade 3 or higher toxicities after SvRT. The 1-year Kaplan-Meier PFS and overall survival estimates were 33% and 56% for patients not receiving radiotherapy and 75% and 73% with SvRT. After SvRT, the rate of locoregional control at 1 year was 84.4%. Crude rates of distant failure were 20.0% with SvRT and 22.2% with no radiotherapy. Of the 13 deaths observed, five (38%) were related to distant progression of lung cancer, four (31%) to comorbidities, three (23%) to mediastinal progression, and one (8%) to an unknown cause. CONCLUSIONS: INF is uncommon after SBRT. Despite the significant comorbidities of this population, intrathoracic progression remains a contributor to morbidity and mortality. SVRT for INF is well tolerated and may improve PFS.

Outcomes for prostate glands >60 cc treated with low-dose-rate brachytherapy.

PURPOSE: We sought to analyze whether outcomes of biochemical relapse-free survival (bRFS), late genitourinary (GU), and late gastrointestinal toxicity are different for prostate cancer patients with small (≤60 cc) vs. large (>60 cc) prostates following low dose-rate brachytherapy. METHODS AND MATERIALS: The bRFS outcomes for 2076 low- or intermediate-risk prostate cancer patients from 1996 to 2012 were determined from a review of a prospectively maintained database. All patients were treated with (125)I monotherapy without androgen deprivation therapy. Biochemical failure was defined per the Phoenix definition. Patient-related factors and dosimetric values were examined in Cox regression analyses for bRFS and late toxicity. Late toxicity was scored according to a modified Common Terminology Criteria for Adverse Events version 4.0 scale. RESULTS: The median followup for all patients was 55 months. The 5-year bRFS rates for all patients, prostates >60 cc, and prostates ≤60 cc were 93.4% (95% confidence interval [CI]: 92.1%, 94.7%), 96.7% (95% CI: 94.4%, 98.9%), and 92.9% (95% CI: 91.4%, 94.3%), respectively. On multivariable analysis, prostate size >60 cc was significantly associated with improved bRFS (p = 0.01), as were initial prostate-specific antigen and biopsy Gleason score (p < 0.0001 and p = 0.0002, respectively). Patients with prostates >60 cc had significantly higher rates of Grade 3-4 late GU toxicity at 5 years than patients with smaller prostates; 7.2% (95% CI: 4.0%, 10.4%) and 3.2% (95% CI: 2.3%, 4.1%), respectively (p = 0.0007). The overall late gastrointestinal toxicity rate for all patients was 0.7% at 5 years with no significant difference between the two groups. CONCLUSIONS: Implantation of large prostates >60 cc results in favorable bRFS outcomes and is associated with increased but acceptable rates of Grade 3 and higher late GU toxicities.

Genome Sequence of Gordonia Phage Yvonnetastic.

Gordonia bacteriophage Yvonnetastic was isolated from soil in Pittsburgh, PA, using Gordonia terrae 3612 as a host. Yvonnetastic has siphoviral morphology and a genome of 98,136 bp, with 198 predicted protein-coding genes and five tRNA genes. Yvonnetastic does not share substantial sequence similarity with other sequenced bacteriophage genomes.