Continuous liquid interface production of 3D printed drug-loaded spacers to improve prostate cancer brachytherapy treatment.

Brachytherapy, which is the placement of radioactive seeds directly into tissue such as the prostate, is an important curative treatment for prostate cancer. By delivering a high dose of radiation from within the prostate gland, brachytherapy is an effective method of killing prostate cancer cells while limiting radiation dose to normal tissue. The main shortcomings of this treatment are: less efficacy against high grade tumor cells, acute urinary retention, and sub-acute urinary frequency and urgency. One strategy to improve brachytherapy is to incorporate therapeutics into brachytherapy. Drugs, such as docetaxel, can improve therapeutic efficacy, and dexamethasone is known to decrease urinary side effects. However, both therapeutics have high systemic side effects. To overcome this challenge, we hypothesized that we can incorporate therapeutics into the inert polymer spacers that are used to correctly space brachytherapy seeds during brachytherapy to enable local drug delivery. To accomplish this, we engineered 3D printed drug-loaded brachytherapy spacers using continuous liquid interface production (CLIP) with different surface patterns to control drug release. These devices have the same physical size as existing spacers, allowing them to easily replace commercial spacers. We examined these drug-loaded spacers using docetaxel and dexamethasone as model drugs in a murine model of prostate cancer. We found that drug-loaded spacers led to higher therapeutic efficacy for brachytherapy, and there was no discernable systemic toxicity from the drug-loaded spacers. STATEMENT OF SIGNIFICANCE: There has been high interest in the application of 3D printing to engineer novel medical devices. However, such efforts have been limited by the lack of technologies that can fabricate devices suitable for real world medical applications. In this study, we demonstrate a unique application for 3D printing to enhance brachytherapy for cancer treatment. We engineered drug-loaded brachytherapy spacers that can be fabricated using Continuous Liquid Interface Production (CLIP) 3D printing, allowing tunable printing of drug-loaded devices, and implanted intraoperatively with brachytherapy seeds. In combined chemotherapy and brachytherapy we are able to achieve greater therapeutic efficacy through local drug delivery and without systemic toxicities. We believe our work will facilitate further investigation in medical applications of 3D printing.

3D printed drug-loaded implantable devices for intraoperative treatment of cancer.

Surgery is an important treatment for cancer; however, local recurrence following macroscopically-complete resection is common and a significant cause of morbidity and mortality. Systemic chemotherapy is often employed as an adjuvant therapy to prevent recurrence of residual disease, but has limited efficacy due to poor penetration and dose-limiting off-target toxicities. Selective delivery of chemotherapeutics to the surgical bed may eliminate residual tumor cells while avoiding systemic toxicity. While this is challenging for traditional drug delivery technologies, we utilized advances in 3D printing and drug delivery science to engineer a drug-loaded arrowhead array device (AAD) to overcome these challenges. We demonstrated that such a device can be designed, fabricated, and implanted intraoperatively and provide extended release of chemotherapeutics directly to the resection area. Using paclitaxel and cisplatin as model drugs and murine models of cancer, we showed AADs significantly decreased local recurrence post-surgery and improved survival. We further demonstrated the potential for fabricating personalized AADs for intraoperative application in the clinical setting.

Co-delivery of etoposide and cisplatin in dual-drug loaded nanoparticles synergistically improves chemoradiotherapy in non-small cell lung cancer models.

Chemoradiotherapy with cisplatin and etoposide is a curative management regimen for both small and non-small cell lung cancers. While the treatment regimen is effective, it also has a high toxicity profile. One potential strategy to improve the therapeutic ratio of chemoradiation is to utilize nanotherapeutics. Nanoparticle formulation of cisplatin and etoposide, however, is challenging due to the significant mismatch in chemical properties of cisplatin and etoposide. Herein we report the formulation of a polymeric nanoparticle formulation of cisplatin and etoposide using a prodrug approach. We synthesized a hydrophobic platinum prodrug, which was then co-delivered with etoposide using a nanoparticle. Using mouse models of lung cancer, we demonstrated that dual-drug loaded nanoparticles are significantly more effective than small molecule chemotherapy in chemoradiotherapy. These results support further investigation of nanoparticle-based drug formulations of combination chemotherapies and the use of nanotherapeutics in chemoradiotherapy. STATEMENT OF SIGNIFICANCE: The treatment of lung cancer often involves a combination of chemotherapy and radiation. While it can be effective, it also has a high toxicity profile. Preferential delivery of chemotherapeutics to the tumor while avoiding normal tissue would improve efficacy and lower toxicity. While this is challenging with conventional drug delivery technologies, nanotechnology offers a unique opportunity. In this study, we have engineered nanoparticles that are loaded with combination chemotherapeutics and showed such nanotherapeutics are more effective and less toxic than free chemotherapeutics in chemoradiotherapy. Our work highlights the importance and potential of nanoformulations of combination chemotherapy in chemoradiotherapy and cancer treatment. This approach can be translated clinically and it can have a significant impact on cancer treatment.

Enhancing Combined Immunotherapy and Radiotherapy through Nanomedicine.

Radiotherapy and immunotherapy are two key treatments for cancer. There is growing evidence that they are also synergistic, and combination treatments are being studied extensively in the clinical setting. In addition, there is emerging evidence that nanotechnology-enabled therapeutics can potentiate both radiotherapy and immunotherapy, in turn improving both treatments. This is an exciting new area of interdisciplinary science and has significant potential for major clinical impact. Some of the approaches in this area have already reached the clinical stage. In this review, we will discuss recent advances in the interface between radiotherapy, immunotherapy, and nanomedicine. We plan to review the many approaches to combine these three fields for cancer treatment.

Nanotechnology in Radiation Oncology.

Nanotechnology has made remarkable contributions to clinical oncology. Nanotherapeutics and diagnostic tools have distinctive characteristics which allow them superior abilities to deliver therapeutics and imaging agents for radiation oncology. Compared to solid biopsies and imaging, the analysis of circulating tumor cells (CTCs) offers a more rapid, real-time, and less invasive method to monitor the dynamic molecular profiles of tumors. The potential of CTCs to be translated as a novel cancer biomarker has been demonstrated in numerous clinical studies. This review will discuss clinical applications of nanomaterials in radiation oncology and the implication of CTCs in cancer detection and monitoring.

Emerging Nano-/Microapproaches for Cancer Immunotherapy.

Cancer immunotherapy has achieved remarkable clinical efficacy through recent advances such as chimeric antigen receptor-T cell (CAR-T) therapy, immune checkpoint blockade (ICB) therapy, and neoantigen vaccines. However, application of immunotherapy in a clinical setting has been limited by low durable response rates and immune-related adverse events. The rapid development of nano-/microtechnologies in the past decade provides potential strategies to improve cancer immunotherapy. Advances of nano-/microparticles such as virus-like size, high surface to volume ratio, and modifiable surfaces for precise targeting of specific cell types can be exploited in the design of cancer vaccines and delivery of immunomodulators. Here, the emerging nano-/microapproaches in the field of cancer vaccines, immune checkpoint blockade, and adoptive or indirect immunotherapies are summarized. How nano-/microparticles improve the efficacy of these therapies, relevant immunological mechanisms, and how nano-/microparticle methods are able to accelerate the clinical translation of cancer immunotherapy are explored.

Nanotechnology Approaches to Improving Cancer Immunotherapy.

Cancer immunotherapy is a powerful, growing treatment approach to cancer that can be combined with chemotherapy, radiotherapy, and oncosurgery. Modulating the immune system to enhance anticancer response by several strategies has yielded improved cancer survival. Despite this progress, the success rate for immunotherapy has been below expectations due to unpredictable efficacy and off-target side effects from systemic dosing. Nanotechnology offers numerous different materials and targeting properties to overcome many of these challenges in immunotherapy. In this chapter, we review current immunotherapy and its challenges as well as the latest nanotechnology applications in cancer immunotherapy.

Nanoparticle co-delivery of wortmannin and cisplatin synergistically enhances chemoradiotherapy and reverses platinum resistance in ovarian cancer models.

Most ovarian cancer patients respond well to initial platinum-based chemotherapy. However, within a year, many patients experience disease recurrence with a platinum resistant phenotype that responds poorly to second line chemotherapies. As a result, new strategies to address platinum resistant ovarian cancer (PROC) are needed. Herein, we report that NP co-delivery of cisplatin (CP) and wortmannin (Wtmn), a DNA repair inhibitor, synergistically enhances chemoradiotherapy (CRT) and reverses CP resistance in PROC. We encapsulated this regimen in FDA approved poly(lactic-co-glycolic acid)-poly(ethylene glycol) (PLGA-PEG) NPs to reduce systemic side effects, enhance cellular CP uptake, improve Wtmn stability, and increase therapeutic efficacy. Treatment of platinum-sensitive ovarian cancer (PSOC) and PROC murine models with these dual-drug loaded NPs (DNPs) significantly reduced tumor burden versus treatment with combinations of free drugs or single-drug loaded NPs (SNPs). These results support further investigation of this NP-based, synergistic drug regimen as a means to combat PROC in the clinic.

Co-delivery of paclitaxel and cisplatin with biocompatible PLGA-PEG nanoparticles enhances chemoradiotherapy in non-small cell lung cancer models.

Chemoradiotherapy (CRT) with paclitaxel (PTX) and cisplatin (CP) is part of the standard of care for patients with locally advanced non-small cell lung cancer (NSCLC). Despite the high treatment intensity, many patients still develop local recurrence after treatment. Thus, there is a strong need to further improve CRT for lung cancer. One strategy is to co-deliver cytotoxic chemotherapy agents using biocompatible nanoparticles (NPs) which can limit off-target tissue toxicity and improve therapeutic efficacy. Herein, we report the development of dual-drug loaded nanoformulations that improve the efficacy of CRT for NSCLC by co-encapsulation of cisplatin (CP) and PTX in PLGA-PEG NPs. Mice bearing NSCLC xenografts given the dual-drug loaded NPs during CRT showed greater inhibition of tumor growth than free drug combinations or combinations of single-drug loaded NPs. These results indicate that using a NP co-delivery strategy for this common CRT regimen may improve clinical responses in NSCLC patients.

Is confirmation of ureteric stent placement in laparoscopic pyeloplasty necessary?

PURPOSE: Placement of an antegrade double-J (JJ) ureteric stent is an important component of pyeloplasty. Correct siting of distal end of the stent in the bladder is essential for ease of removal. To date, no studies have compared methods for confirming stent position. This study aims to address that void in the literature. METHODS: Eligible patients underwent laparoscopic pyeloplasty with antegrade stent placement at our institution from 2007 to 2015 inclusive. Methods to verify distal stent position of rigid cystoscopy, artificial bladder filling or no confirmation were compared. Effectiveness was determined by the proportion of malpositioned stents detected intra-operatively compared to the total found malpositioned, both intra-operatively and during follow-up. RESULTS: A total of 75 patients underwent laparoscopic pyeloplasty. Forty-six (61.3%) patients had distal stent position assessed intra-operatively, comprising 27 by cystoscopy and 19 by artificial bladder filling, while for 29 (38.7%) patients no verification method was used. Cystoscopy, artificial bladder filling and no confirmation detected intra-operatively 2, 1 and 0 malpositioned stents, from malpositioned stent totals of 2, 2 and 1, respectively. CONCLUSION: Malposition of JJ ureteric stent is uncommon, and omitting intra-operative position verification appears reasonable in select cases. Artificial bladder filling can help detect malpositioned JJ stents without repositioning the patient for cystoscopy. However, our results suggest both may be unreliable. If stent malposition is suspected, certainty is desired or extended operative duration is less critical, then the surgeon should proceed with cystoscopy.

Prospective, randomized, controlled trial of thoracic epidural or patient-controlled opiate analgesia on perioperative quality of life.

BACKGROUND: Perioperative epidural analgesia provides continuous pain control and may have advantages over parenteral opiate administration. This study assessed the impact of epidural analgesia on quality of life (QOL) of patients undergoing major surgery. METHODS: Sixty patients undergoing thoracic or thoraco-abdominal surgery were studied prospectively. Patients were randomly assigned to receive either thoracic epidural analgesia or patient-controlled i.v. opiate analgesia (PCA) after operation. Visual analogue pain and sedation scores were recorded for the period of the study. QOL health surveys at 24 h (SF-8 acute form) and at 1 week (SF-36) were recorded. Results were examined by uni- and multivariate analyses corrected for the effect of multiple comparisons. RESULTS: Mean pain scores were significantly lower in the epidural group at most time points. Physical and mental scores in the epidural group were significantly better than the PCA group for both SF-8 and SF-36 QOL health surveys (P<0.001). CONCLUSIONS: Epidural analgesia with local anaesthetic and opioid improves QOL and delivers better analgesia compared with PCA in patients undergoing major thoraco-abdominal surgery.

Hyperbaric oxygen therapy and the eye.

Hyperbaric oxygen therapy (HBOT) is a primary or adjunctive therapy for a variety of medical disorders including some involving the eye. This paper is the first comprehensive review of HBOT for ocular indications. The authors recommend the following as ocular indications for HBOT: decompression sickness or arterial gas embolism with visual signs or symptoms, central retinal artery occlusion, ocular and periocular gas gangrene, cerebro-rhino-orbital mucormycosis, periocular necrotizing fasciitis, carbon monoxide poisoning with visual sequelae, radiation optic neuropathy, radiation or mitomycin C-induced scleral necrosis, and periorbital reconstructive surgery. Other ocular disorders that may benefit from HBOT include selected cases of ischemic optic neuropathy, ischemic central retinal vein occlusion, branch retinal artery occlusion with central vision loss, ischemic branch retinal vein occlusion, cystoid macular edema associated with retinal venous occlusion, post-surgical inflammation, or intrinsic inflammatory disorders, periocular brown recluse spider envenomation, ocular quinine toxicity, Purtscher's retinopathy, radiation retinopathy, anterior segment ischemia, retinal detachment in sickle cell disease, refractory actinomycotiC lacrimal canaliculitis, pyoderma gangrenosum of the orbit and refractory pseudomonas keratitis. Visual function should be monitored as clinically indicated before, during, and after therapy when HBOT is undertaken to treat vision loss. Visual acuity alone is not an adequate measure of visual function to monitor the efficacy of HBOT in this setting. Ocular examinations should also include automated perimetry to evaluate the central 30 degrees of visual field at appropriate intervals. Interpretation of the literature on the efficacy of HBOT in treating ocular disorders is complicated by several factors: frequent failure to include visual field examination as an outcome measure, failure to adequately address the interval from symptom onset to initiation of HBOT, and lack of evidence for optimal treatment regimens for essentially all ocular indications. Because some ocular disorders require rapid administration of HBOT to restore vision, patients with acute vision loss should be considered emergent when they present. Visual acuity should be checked immediately, including vision with pinhole correction. If the patient meets the criteria for emergent HBOT outlined in the paper, normobaric oxygen should be started at the highest inspired oxygen fraction possible until arrangements can be made for HBOT.

The effects of acetabular cup temperature and duration of cement pressurization on cement porosity in a canine total hip replacement model.

OBJECTIVE: To determine the effect of acetabular cup temperature and duration of cement pressurization on porosity of the acetabular cement mantel. STUDY DESIGN: In vitro study. METHODS: Twenty-four polyurethane foam blocks prepared for acetabular prosthetic implantation were implanted with polyethylene acetabular cups using four combinations and variations of temperature and pressure: (1) high temperature/short-term pressurization; (2) high temperature/long-term pressurization; (3) low temperature/long-term pressurization; and (4) low temperature short-term pressurization. Five 1-mm-thick slices were taken from the center of each block using a tissue processing system. The slices were scanned into a personal computer using a photo slide scanner. Imaging software was used to determine cement surface area and size, number, and distribution of pores. The quality of the cement-implant interface was subjectively evaluated. Statistical analysis of relative cement porosity was performed by a Kruskal-Wallis analysis of variance comparing the four groups individually and combining the short-term pressurization groups versus the long-term pressurization groups. RESULTS: There were no significant differences in cement porosity between the four test groups (P =.11). There were no significant differences in porosity between the combined groups (P =.48). CONCLUSIONS: There is no benefit in prewarming acetabular cups before implantation. There are no deleterious effects of short-term pressurization of the cement during implantation.

The peripheral lymphoid compartment is disrupted in flaky skin mice.

Flaky skin (fsn) is an autosomal recessive mutation on mouse chromosome 17 that causes severe anaemia, forestomach papillomatosis and a papulosquamous skin disease that resembles psoriasis in humans. In the present paper, it is reported that fsn causes peripheral lymphadenopathy, CD4/CD8 imbalance and hyperresponsiveness to T cell growth factors. Peripheral lymph nodes (PLN) of adult mutant (fsn/fsn) mice were found to contain almost 10-fold more leucocytes than PLN from phenotypically normal littermates (+/fsn or +/+, hereafter referred to as +/?). Analysis of PLN cells using mAbs and flow cytometry revealed that this predominantly lymphoid hyperplasia was characterized by approximately equivalent increases in the numbers of CD3+ T cells and CD19+ B cells. However, expansion within the T cell compartment was non-random, because fsn/fsn PLN had a considerably reduced ratio of CD4+ to CD8+ T cells (1.08 +/- 0.37) compared to +/? PLN (2.47 +/- 0.44, P < 0.0001). In vitro assays of cellular proliferation in response to T and B cell growth factors showed that fsn/fsn PLN cells were hyperresponsive to IL-2, IL-4 and IL-7 when compared with PLN cells from +/? mice. Studies using mesenteric lymph node and peripheral blood cells showed that hyperresponsive cells are widely distributed in fsn/fsn mice. Experiments in newborn mice showed that the lymphoid disturbances caused by fsn are established at least as early as 2 weeks of age, a time that precedes the onset of the earliest clinical skin lesions. These data implicate a role for the fsn gene product in regulating the size and content of the peripheral lymphoid compartment.

Common but curable. Responding to symptoms of testicular cancer.

Testicular cancer is one of the most common cancers in men between the ages of 15 and 34. Symptoms of testicular cancer vary but can include scrotal nodules or swelling and a sensation of fullness or heaviness of the scrotum, which may be interpreted as pain. Four treatment options are available for testicular cancer: surgery to remove the cancer, radiation therapy, chemotherapy and bone marrow transplantation. No matter what a patient's treatment course, follow-up studies and office visits are imperative.

Human in vitro immune responses to Mycobacterium tuberculosis.

SETTING: T helper cells can be divided into 2 subsets on the basis of their cytokine generation. T helper 1 cells secreting gamma interferon and interleukin 2 appear to be more prominent in patients with limited tuberculous disease. OBJECTIVE: The purpose of this study was to evaluate human T helper cell immune responses to mycobacterial antigens in vitro and correlate these with the clinical features of patients with tuberculous infection or disease. DESIGN: We studied 51 subjects and 11 controls who were grouped according to disease involvement as follows: 1) Mantoux negative, BCG negative, no disease; 2) Mantoux positive, no disease; 3) localized extrapulmonary; 4) healed pulmonary; 5) active pulmonary; and 6) miliary/disseminated. Peripheral blood mononuclear cells were cultured with PHA, PPD or Tetanus Toxoid, proliferation assessed and the supernatant analysed using an ELISA for IFN gamma. ELISA was also used to measure M. tuberculosis specific antibodies in the serum. RESULTS: Mantoux size correlated with PPD proliferation r = 0.5, P = 0.005 and gamma IFN production r = 0.36, P < 0.01. All groups produced abundant gamma IFN although there was a trend toward higher production in groups 3 and 4. M. tuberculosis specific IgA (P = 0.003) and IgG1 (P = 0.002) was higher in groups 5 and 6. Those patients with limited disease (groups 2-4) had significantly lower levels of IgG4 than patients with severe disease (groups 5 & 6) (P < 0.02). CONCLUSION: In conclusion patients with healed or extrapulmonary disease have immune responses in vitro suggestive of a TH1 (cell mediated immune) response, whereas patients with miliary/disseminated disease have antibody production suggestive of a TH2 response, together with high gamma IFN production. Both TH1 and TH2 responses may be necessary for host protection if there is a high bacillary load.

Putative markers for the detection of breast carcinoma cells in blood.

The aim of this study was to investigate certain genes for their suitability as molecular markers for detection of breast carcinoma cells using the reverse transcriptase-polymerase chain reaction (RT-PCR). RNA was prepared from MCF-7 breast carcinoma cells and peripheral blood leucocytes of healthy female volunteers. This RNA was screened for mRNA of MUC1, cytokeratin 19 (CK19) and CD44 (exons 8-11) by RT-PCR and the results validated by Southern blots. Variable degrees of expression of MUC1 and CD44 (exons 8-11) were detected in normal peripheral blood, rendering these genes non-specific for epithelial cells and therefore unsuitable for use as markers to detect breast carcinoma cells. Although CK19 mRNA was apparently specific, it was deemed unsuitable for use as a marker of breast cancer cells in light of its limited sensitivity. Furthermore, an attempt at using nested primers to increase sensitivity resulted in CK19 mRNA being detected after two amplification rounds in blood from healthy volunteers.

Cytokine production by oral and peripheral blood neutrophils in adult periodontitis.

Proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) and interleukin 1 beta (IL-1 beta) also possess bone-resorptive properties, and are generally considered to play a role in the pathogenesis of periodontal disease. In the present study, TNF-alpha and IL-1 beta production by oral and peripheral blood polymorphonuclear leukocytes (PMN) was examined in 40 patients with adult periodontitis and 40 orally healthy matched controls. Oral PMN released considerable amounts of both cytokines in unstimulated culture, and there was no difference between patients and controls when the cytokine levels were corrected for cell number. However, when the effect of disease activity was examined, cytokine release by oral PMN was found to be greatest in patients with advanced periodontitis. Within the healthy control group, IL-1 beta production by oral PMN was significantly higher in males (Mann-Whitney test, P = 0.0008). Examination of IL-1 beta production by peripheral blood PMN exposed to recombinant human granulocyte-macrophage colony stimulating factor revealed no difference between the patient and control groups. In contrast, IL-1 beta production by peripheral blood PMN was significantly reduced in patients with advanced disease (Mann-Whitney test, P = 0.02), and peripheral PMN IL-1 beta synthesis was greater in female controls (Mann-Whitney test, P = 0.054). No effect of race on cytokine production could be discerned in patients or controls. These results indicate that several factors influence cytokine production in oral health and disease, and that a dichotomy in cytokine gene expression exists between oral and peripheral blood PMN in adult periodontitis.

Pericardial angiosarcoma simulating pericardial effusion by echocardiography.

A fast-growing angiosarcoma caused incapacitation of a boy and death in a period of three months. The growth of the tumor was well documented by a series of echocardiograms. The heart was well encased by a thick layer of purplish vascular neoplasm enveloped mostly by thin pericardium, with some additional few foci of extracardiac metastasis. The heart weighed 2,000 gm. It is worthy to note that another cause of an echo-free space may be the presence of a pericardial tumor, rather than pericardial effusion.