A New and Effective Procedure for Advanced Oral Cancer Therapy: The Potential of a Cancer Stem Cell Assay in Guiding Chemotherapy.

Introduction: Ineffective anticancer therapy can result in unnecessary toxicity and the development of resistant clones. Many types of solid tumors, including head and neck squamous cell carcinoma, have been found to contain a small population of cancer stem cells (CSCs) that contribute to tumor propagation, maintenance, and treatment resistance. Materials and methods: Selectively enriched CSCs from primary cancer cell cultures can be used in a chemosensitivity assay for a functional test (ChemoID) that uses patients' live tumor cells to indicate which chemotherapy agent (or "combinations") will kill not only the bulk of tumor cells but also the CSCs that are known to cause cancer to recur. This study aimed to show the potential of testing the sensitivity of CSCs enriched from oral cancer patients' biopsies to conventional chemotherapies. A case series of eleven patients affected by advanced oral squamous cell carcinoma (OSCC) have been included in this study. We compared the results of the CSC assay among all the patients and found that there was variability in the chemotherapy response predicted by the assay. Results: Variability in chemotherapy response was found by the CSC assay in advanced OSCC patients suggesting more precise and personalized therapies to the Oncologist. Conclusions: Variability in chemosensitivity for OSCC warrants the need to investigate further the use of the assay in larger cohorts to gain a broader understanding of the utility of the clinical test.

Treatment of unmethylated MGMT-promoter recurrent glioblastoma with cancer stem cell assay-guided chemotherapy and the impact on patients' healthcare costs.

Background: Glioblastoma (GBM) is a lethal disease. At least in part, the recurrence of GBM is caused by cancer stem cells (CSCs), which are resistant to chemotherapy. Personalized anticancer therapy against CSCs can improve treatment outcomes. We present a prospective cohort study of 40 real-world unmethylated Methyl-guanine-methyl-transferase-promoter GBM patients treated utilizing a CSC chemotherapeutics assay-guided report (ChemoID). Methods: Eligible patients who underwent surgical resection for recurrent GBM were included in the study. Most effective chemotherapy treatments were chosen based on the ChemoID assay report from a panel of FDA-approved chemotherapies. A retrospective chart review was conducted to determine OS, progression-free survival, and the cost of healthcare costs. The median age of our patient cohort was 53 years (24-76). Results: Patients treated prospectively with high-response ChemoID-directed therapy, had a median overall survival (OS) of 22.4 months (12.0-38.4) with a log-rank P = .011, compared to patients who could be treated with low-response drugs who had instead an OS of 12.5 months (3.0-27.4 months). Patients with recurrent poor-prognosis GBM treated with high-response therapy had a 63% probability to survive at 12 months, compared to 27% of patients who were treated with low-response CSC drugs. We also found that patients treated with high-response drugs on average had an incremental cost-effectiveness ratio (ICER) of $48,893 per life-year saved compared to $53,109 of patients who were treated with low-response CSC drugs. Conclusions: The results presented here suggest that the ChemoID Assay can be used to individualize chemotherapy choices to improve poor-prognosis recurrent GBM patient survival and to decrease the healthcare cost that impacts these patients.

Cancer stem cell assay-guided chemotherapy improves survival of patients with recurrent glioblastoma in a randomized trial.

Therapy-resistant cancer stem cells (CSCs) contribute to the poor clinical outcomes of patients with recurrent glioblastoma (rGBM) who fail standard of care (SOC) therapy. ChemoID is a clinically validated assay for identifying CSC-targeted cytotoxic therapies in solid tumors. In a randomized clinical trial (NCT03632135), the ChemoID assay, a personalized approach for selecting the most effective treatment from FDA-approved chemotherapies, improves the survival of patients with rGBM (2016 WHO classification) over physician-chosen chemotherapy. In the ChemoID assay-guided group, median survival is 12.5 months (95% confidence interval [CI], 10.2-14.7) compared with 9 months (95% CI, 4.2-13.8) in the physician-choice group (p = 0.010) as per interim efficacy analysis. The ChemoID assay-guided group has a significantly lower risk of death (hazard ratio [HR] = 0.44; 95% CI, 0.24-0.81; p = 0.008). Results of this study offer a promising way to provide more affordable treatment for patients with rGBM in lower socioeconomic groups in the US and around the world.

Enhancing Targeted Therapy in Breast Cancer by Ultrasound-Responsive Nanocarriers.

Currently, the response to cancer treatments is highly variable, and severe side effects and toxicity are experienced by patients receiving high doses of chemotherapy, such as those diagnosed with triple-negative breast cancer. The main goal of researchers and clinicians is to develop new effective treatments that will be able to specifically target and kill tumor cells by employing the minimum doses of drugs exerting a therapeutic effect. Despite the development of new formulations that overall can increase the drugs' pharmacokinetics, and that are specifically designed to bind overexpressed molecules on cancer cells and achieve active targeting of the tumor, the desired clinical outcome has not been reached yet. In this review, we will discuss the current classification and standard of care for breast cancer, the application of nanomedicine, and ultrasound-responsive biocompatible carriers (micro/nanobubbles, liposomes, micelles, polymeric nanoparticles, and nanodroplets/nanoemulsions) employed in preclinical studies to target and enhance the delivery of drugs and genes to breast cancer.

Virus-Based Immuno-Oncology Models.

Immunotherapy has been extensively explored in recent years with encouraging results in selected types of cancer. Such success aroused interest in the expansion of such indications, requiring a deep understanding of the complex role of the immune system in carcinogenesis. The definition of hot vs. cold tumors and the role of the tumor microenvironment enlightened the once obscure understanding of low response rates of solid tumors to immune check point inhibitors. Although the major scope found in the literature focuses on the T cell modulation, the innate immune system is also a promising oncolytic tool. The unveiling of the tumor immunosuppressive pathways, lead to the development of combined targeted therapies in an attempt to increase immune infiltration capability. Oncolytic viruses have been explored in different scenarios, in combination with various chemotherapeutic drugs and, more recently, with immune check point inhibitors. Moreover, oncolytic viruses may be engineered to express tumor specific pro-inflammatory cytokines, antibodies, and antigens to enhance immunologic response or block immunosuppressive mechanisms. Development of preclinical models capable to replicate the human immunologic response is one of the major challenges faced by these studies. A thorough understanding of immunotherapy and oncolytic viruses' mechanics is paramount to develop reliable preclinical models with higher chances of successful clinical therapy application. Thus, in this article, we review current concepts in cancer immunotherapy including the inherent and synthetic mechanisms of immunologic enhancement utilizing oncolytic viruses, immune targeting, and available preclinical animal models, their advantages, and limitations.

New Minimally Invasive Intraoral Procedure for Condylar Fractures: Clinical Presentation and Considerations on Current Techniques.

ABSTRACT: Mandibular fractures are the third most prevalent maxillofacial traumatic events. Surgical approaches to the condyle are a debated topic. This study describes a mini-invasive technique for condylar fracture reduction. The patient of this study suffered multiple traumatic injuries including a carotid artery dissecting aneurysm, which contraindicated the standard open reduction and internal fixation technique. The novel minimally invasive technique involves intraoral access and fracture fragment realignment using a periosteal elevator, a molar occlusal splint, and intermaxillary fixation after intraoperative radiologic imaging confirmation of condyle reposition.The approach avoids skin incisions and tissue dissection, with good aesthetic outcomes and facial nerve preservation. This technique proved to be safe and simple to be less demanding for the patient, with a shorter recovery time than experienced with other techniques.The results suggest this technique is a good option for the surgical treatment of condylar neck fractures showing favorable rim morphology with primary stability after reduction.

Cancer Stem Cell Assay for the Treatment of Platinum-Resistant Recurrent Ovarian Cancer.

BACKGROUND: Disease recurrence and progression of ovarian cancer is a common event, which is accompanied by the development of platinum-resistant or refractory disease. The presence of chemo-resistant Cancer Stem Cells (CSCs) contribute to tumor propagation, maintenance, and treatment resistance of this difficult to treat disease. We have developed ChemoID, a cytotoxic synergy assay against CSCs that identifies the most effective chemotherapy treatment from a panel of FDA-approved chemotherapies using fresh cancer biopsies. PATIENTS AND METHODS: Ascites or interventional radiology biopsies were collected under physician order from 78 consecutive patients affected by 3rd relapsed ovarian cancer. Test results from the assay were used when possible to treat patients with the highest cell kill drugs, taking into consideration their health status and using dose reductions, if needed. A chart analysis and review of CT and PET scans were performed to determine patients' outcomes for tumor response, Progression-Free Survival (PFS), and Overall Survival (OS). RESULTS: We observed that recurrent ovarian cancer patients treated with high-cell kill chemotherapy agents guided by the CSCs drug response assay had an improvement in their median PFS and OS when compared to historical median PFS and OS and/or when compared to patients who could not receive high cell kill chemotherapies (PFS low cell kill 3.5 months vs. high cell kill 12.0 months; OS low cell kill 6.0 months vs. high cell kill 15.0 months). CONCLUSION: This data indicates that the drug cytotoxicity assay aimed at targeting CSCs may be a useful tool for optimizing treatment selection when first-line therapy fails, and when there are multiple clinically-acceptable and -equivalent treatments available.

Applications of Ultrasound-Mediated Drug Delivery and Gene Therapy.

Gene therapy has continuously evolved throughout the years since its first proposal to develop more specific and effective transfection, capable of treating a myriad of health conditions. Viral vectors are some of the most common and most efficient vehicles for gene transfer. However, the safe and effective delivery of gene therapy remains a major obstacle. Ultrasound contrast agents in the form of microbubbles have provided a unique solution to fulfill the need to shield the vectors from the host immune system and the need for site specific targeted therapy. Since the discovery of the biophysical and biological effects of microbubble sonification, multiple developments have been made to enhance its applicability in targeted drug delivery. The concurrent development of viral vectors and recent research on dual vector strategies have shown promising results. This review will explore the mechanisms and recent advancements in the knowledge of ultrasound-mediated microbubbles in targeting gene and drug therapy.

Epi-Mucosa Fixation and Autologous Platelet-Rich Fibrin Treatment in Medication-Related Osteonecrosis of the Jaw.

Medication-related osteonecrosis of the jaw (MRONJ) frequently affects patients after treatments with bisphosphonates or denosumab, especially with high doses in patients with bone osteoporosis, neoplastic metastases, or possibly anti-angiogenic treatment for cancer. The aim of this article was to show a new treatment planning for stage 2 and stage 3 MRONJ using platelet-rich fibrin (PRF) at the surgical field to enhance healing in association with a new epi-mucosal fixation technique to prevent or treat mandibular fracture. Two cases were treated by epi-mucosa fixation and autologous PRF use for prevention of mandibular fracture risks related to necrotic bone resection or a narrow fracture reduction. Both cases were successfully treated by this new technique of epi-mucosa fixation combined with autologous PRF and achieved good results and good quality of life. Ability to wear prosthesis with good mastication in the absence of side effect such as infection, plate and screw mobilization, pain, and other disabilities or extension of necrosis was reported. After surgical removal of necrotic bone, no infection was detected without any extension of the necrosis.

Left ventricular pseudoaneurysm: An unexpected finding.

A left ventricle pseudoaneurysm (LV PSA) is defined as a free wall rupture of the left ventricle contained by the adjacent pericardial tissue. This rare complication is most commonly encountered following myocardial infarction, trauma, or infection. Surgery is typically warranted to avoid progression to spontaneous rupture, which may potentially lead to cardiac tamponade and death. Cardiac magnetic resonance imaging is the modality of choice to characterize left ventricle morphology and function. Accurate distinction between a pseudoaneurysm and a true aneurysm is crucial, since management and prognosis are significantly different between these 2 entities. We present a case of a 63-year-old male heart transplant recipient, admitted for suspicion of acute cellular rejection, with an unexpected finding of a LV PSA.

Clinical relevance of cancer stem cell chemotherapeutic assay for recurrent ovarian cancer.

INTRODUCTION: Disease recurrence and progression of ovarian cancer is common with the development of platinum-resistant or refractory disease. This is due in large part to the presence of chemo-resistant cancer stem cells (CSCs) that contribute to tumor propagation, maintenance, and treatment resistance. We developed a CSCs drug cytotoxicity assay (ChemoID) to identify the most effective chemotherapy treatment from a panel of FDA approved chemotherapies. METHODS: Ascites and pleural fluid samples were collected under physician order from 45 consecutive patients affected by 3rd-5th relapsed ovarian cancer. Test results from the assay were used to treat patients with the highest cell kill drugs, taking into consideration their health status and using dose reductions, as needed. A retrospective chart review of CT and PET scans was used to determine patients' outcomes for tumor response, time to recurrence, progression-free survival (PFS), and overall survival (OS). RESULTS: We observed that recurrent ovarian cancer patients treated with high-cell kill chemotherapy agents guided by the CSCs drug response assay had an improvement in the median PFS corresponding to 5.4 months (3rd relapse), 3.6 months (4th relapse), and 3.9 months (5th relapse) when compared to historical data. Additionally, we observed that ovarian cancer patients identified as non-responders by the CSC drug response assay had 30 times the hazard of death compared to those women that were identified as responders with respective median survivals of 6 months vs. 13 months. We also found that ChemoID treated patients on average had an incremental cost-effectiveness ratio (ICER) between -$18,421 and $7,241 per life-year saved (LYS). CONCLUSIONS: This study demonstrated improved PFS and OS for recurrent ovarian cancer patients treated with assay-guided chemotherapies while decreasing the cost of treatment.

Cancer Stem Cell Chemotherapeutics Assay for Prospective Treatment of Recurrent Glioblastoma and Progressive Anaplastic Glioma: A Single-Institution Case Series.

BACKGROUND: Chemotherapy-resistant cancer stem cells (CSC) may lead to tumor recurrence in glioblastoma (GBM). The poor prognosis of this disease emphasizes the critical need for developing a treatment stratification system to improve outcomes through personalized medicine. METHODS: We present a case series of 12 GBM and 2 progressive anaplastic glioma cases from a single Institution prospectively treated utilizing a CSC chemotherapeutics assay (ChemoID) guided report. All patients were eligible to receive a stereotactic biopsy and thus undergo ChemoID testing. We selected one of the most effective treatments based on the ChemoID assay report from a panel of FDA approved chemotherapy as monotherapy or their combinations for our patients. Patients were evaluated by MRI scans and response was assessed according to RANO 1.1 criteria. RESULTS: Of the 14 cases reviewed, the median age of our patient cohort was 49 years (21-63). We observed 6 complete responses (CR) 43%, 6 partial responses (PR) 43%, and 2 progressive diseases (PD) 14%. Patients treated with ChemoID assay-directed therapy, in combination with other modality of treatment (RT, LITT), had a longer median overall survival (OS) of 13.3 months (5.4-NA), compared to the historical median OS of 9.0 months (8.0-10.8 months) previously reported. Notably, patients with recurrent GBM or progressive high-grade glioma treated with assay-guided therapy had a 57% probability to survive at 12 months, compared to the 27% historical probability of survival observed in previous studies. CONCLUSIONS: The results presented here suggest that the ChemoID Assay has the potential to stratify individualized chemotherapy choices to improve recurrent and progressive high-grade glioma patient survival. IMPORTANCE OF THE STUDY: Glioblastoma (GBM) and progressive anaplastic glioma are the most aggressive brain tumor in adults and their prognosis is very poor even if treated with the standard of care chemoradiation Stupp's protocol. Recent knowledge pointed out that current treatments often fail to successfully target cancer stem cells (CSCs) that are responsible for therapy resistance and recurrence of these malignant tumors. ChemoID is the first and only CLIA (clinical laboratory improvements amendment) -certified and CAP (College of American Pathologists) -accredited chemotherapeutic assay currently available in oncology clinics that examines patient's derived CSCs susceptibility to conventional FDA (Food and Drugs Administration) -approved drugs. In this study we observed that although the majority of our patients (71.5%) presented with unfavorable prognostic predictors (wild type IDH-1/2 and unmethylated MGMT promoter), patients treated with ChemoID assay-directed therapy had an overall response rate of 86% and increased median OS of 13.3 months compared to the historical median OS of 9.1 months (8.1-10.1 months) previously reported [1] suggesting that the ChemoID assay may be beneficial in personalizing treatment strategies.

Microbubble-mediated delivery of human adenoviruses does not elicit innate and adaptive immunity response in an immunocompetent mouse model of prostate cancer.

BACKGROUND: Gene transfer to malignant sites using human adenoviruses (hAds) has been limited because of their immunogenic nature and host specificity. Murine cells often lack some of the receptors needed for hAds attachment, thus murine cells are generally non-permissive for human adenoviral infection and replication, which limits translational studies. METHODS: We have developed a gene transfer method that uses a combination of lipid-encapsulated perfluorocarbon microbubbles and ultrasound to protect and deliver hAds to a target tissue, bypassing the requirement of specific receptors. RESULTS: In an in vitro model, we showed that murine TRAMP-C2 and human DU145 prostate cancer cells display a comparable expression pattern of receptors involved in hAds adhesion and internalization. We also demonstrated that murine and human cells showed a dose-dependent increase in the percentage of cells transduced by hAd-GFP (green fluorescent protein) after 24 h and that GFP transgene was efficiently expressed at 48 and 72 h post-transduction. To assess if our image-guided delivery system could effectively protect the hAds from the immune system in vivo, we injected healthy immunocompetent mice (C57BL/6) or mice bearing a syngeneic prostate tumor (TRAMP-C2) with hAd-GFP/MB complexes. Notably, we did not observe activation of innate (TNF-α and IL-6 cytokines), or adaptive immune response (neutralizing antibodies, INF-γ+ CD8+ T cells). CONCLUSIONS: This study brings us a step closer to demonstrating the feasibility of murine cancer models to investigate the clinical translation of image guided site-specific adenoviral gene therapy mediated by ultrasound-targeted microbubble destruction.

Multiparametric Magnetic Resonance Imaging in the Assessment of Primary Brain Tumors Through Radiomic Features: A Metric for Guided Radiation Treatment Planning.

Purpose The definition of radiotherapy target volume is a critical step in treatment planning for all tumor sites. Conventional magnetic resonance imaging (MRI) pulse sequences are used for the definition of the gross target volume (GTV) and the contouring of glioblastoma multiforme (GBM) and meningioma. We propose the use of multiparametric MRI combined with radiomic features to improve the texture-based differentiation of tumor from edema for GTV definition and to differentiate vasogenic from tumor cell infiltration edema. Methods Twenty-five patients with brain tumor and peritumoral edema (PTE) were assessed. Of the enrolled patients, 17 (63 ± 10 years old, six female and 11 male patients) were diagnosed with GBM and eight (64 ± 14 years old, five female and three male patients) with meningioma. A 3 Tesla (3T) MRI scanner was used to scan patients using a 3D multi-echo Gradient Echo (GRE) sequence. After the acquisition process, two experienced neuroradiologists independently used an in-house semiautomatic algorithm to conduct a segmentation of two regions of interest (ROI; edema and tumor) in all patients using functional MRI sequences, apparent diffusion coefficient (ADC), and dynamic contrast-enhanced MRI (DCE-MRI), as well as anatomical MRI sequences-T1-weighted, T2-weighted and fluid-attenuated inversion recovery (FLAIR). Radiomic (computer-extracted texture) features were extracted from all ROIs through different approaches, including first-, second-, and higher-order statistics, both with and without normalization, leading to the calculation of around 300 different texture parameters for each ROI. Based on the extracted parameters, a least absolute shrinkage and selection operator (LASSO) analysis was used to isolate the parameters that best differentiated edema from tumors while irrelevant parameters were discarded. Results and conclusions The parameters chosen by LASSO were used to perform statistical analyses which allowed identification of the variables with the best discriminant ability in all scenarios. Receiver operating characteristic results showcase both the best single discriminator and the discriminant capacity of the model using all variables selected by LASSO. Excellent results were obtained for patients with GBM with all MRI sequences, with and without normalization; a T1-weighted sequence postcontrast (T1W+C) with normalization offered the best tumor classification (area under the curve, AUC > 0.97). For patients with meningioma, a good model of tumor classification was obtained through the T1-weighted sequence (T1W) without normalization (AUC > 0.71). However, there was no agreement between the results of both radiologists for some MRI sequences analyzed for patients with GBM and meningioma. In conclusion, a small subset of radiomic features showed an excellent ability to distinguish edema from tumor tissue through its most discriminating features.

Assessment of Treatment Response Following Yttrium-90 Transarterial Radioembolization of Liver Malignancies.

Transarterial radioembolization using yttrium-90 microspheres is an established and effective treatment for liver malignancies. Determining response to this treatment is difficult due to the radical changes that occur in tissue as a response to radiation. Though accurate assessment of treatment response is paramount for proper patient disposition, there is currently no standardized assessment protocol. Current methods of assessment often consider changes in size, necrosis, vascularity, fluorodeoxyglucose-positron emission tomography FDG-PET metabolic activity, and diffusion using diffusion-weighted magnetic resonance imaging (DWI). Current methods of assessment require a lag time of one to two months post-treatment to determine treatment effectiveness. This delay is a hindrance to obtaining better patient outcomes, giving rise to a need to identify markers for faster determination of treatment efficacy.

Eating Green: Shining Light on the Use of Dietary Phytochemicals as a Modern Approach in the Prevention and Treatment of Head and Neck Cancers.

Enthusiasm for the use of dietary bioactive compounds as chemopreventive agents and adjuvants for current therapies has increased laboratory research conducted on several types of cancers including Head and Neck Squamous Cell Carcinoma (HNSCC). The green chemoprevention movement is a modern approach to highlight healthy lifestyle changes that aim to decrease the incidence of HNSCC. A healthy diet can be an effective way to prevent the development of oral cancers. Discovery of the naturally occurring plant based compounds called phytochemicals has facilitated the development of new treatment strategies for patients that are at risk for, or have developed HNSCC. Many of these compounds have been shown to elicit very potent anti-carcinogenic properties. While there are many compounds that have been studied, the compounds from two specific categories of phytochemicals, phenolics (resveratrol, EGCG, curcumin, quercetin, and honokiol) and glucosinolates (sulforaphane, PEITC and BITC), are emerging as potent and effective inhibitors of oral carcinogenesis. These compounds have been shown to inhibit HNSCC growth through a variety of mechanisms. Research has demonstrated that these compounds can regulate cancer cell proliferation through the regulation of multiple cell signaling pathways. They can impede cell cycle progression, induce differentiation and apoptosis, prevent angiogenesis, and inhibit cancer cell invasive and metastatic properties. They can protect normal cells during treatment and reduce the damage caused by chemotherapy and radiotherapy. This review aims to provide an overview of some of the most effective phytochemicals that have the potential to successfully prevent and treat head and neck squamous cell carcinoma.

Emergence of Radiomics: Novel Methodology Identifying Imaging Biomarkers of Disease in Diagnosis, Response, and Progression.

Radiomics is an emerging area within clinical radiology research. It seeks to take full advantage of all the information contained in multiple medical imaging modalities. With a radiomics approach, medical images are not limited to providing only a qualitative assessment but can also provide quantitative data by parameterizing image features. These parameters can be used to identify regions and volumes of interest and discriminate normal healthy tissue from abnormal or diseased tissue. Radiomics is an interlinked sequence of processes of vital importance that begins with the acquisition and selection of medical images that involve standardization of acquisition protocols and inter-equipment normalization. This is followed by the identification and segmentation of regions or volumes of interest by expert radiologists through the use of computational tools that offer speed while reducing variability and bias. The segmentation process is the most critical stage in radiomics. This sometimes requires the incorporation of a pre-processing stage consisting of advanced techniques (reconstruction processes, filtering, etc.). Thereafter, representative characteristics of the region or volume of interest are extracted by approaches based on statistics, morphological features, and transform-based variables. Next, a statistical selection of the parameters that provide a high association and correlation with the clinical condition of interest is performed. Finally, processes such as data integration, standardization, classification, and mining processes can be applied as needed for particular applications. Ongoing research in radiomics aims to reduce the time and costs involved in interpreting medical images while simultaneously increasing the quality of diagnoses and monitoring of as well as the selection of treatment strategies. The results of many studies combining radiomics with standard medical techniques are highly encouraging, and these new approaches are increasingly used. This review article details the components of radiomics and discusses its applications, challenges, and future directions for this exciting new field of study.

Platelet-Rich Fibrin (PRF) in Implants Dentistry in Combination with New Bone Regenerative Flapless Technique: Evolution of the Technique and Final Results.

Most common techniques for alveolar bone augmentation are guided bone regeneration (GBR) and autologous bone grafting. GBR studies demonstrated long-term reabsorption using heterologous bone graft. A general consensus has been achieved in implant surgery for a minimal amount of 2 mm of healthy bone around the implant. A current height loss of about 3-4 mm will result in proper deeper implant insertion when alveolar bone expansion is not planned because of the dome shape of the alveolar crest. To manage this situation a split crest technique has been proposed for alveolar bone expansion and the implants' insertion in one stage surgery. Platelet-rich fibrin (PRF) is a healing biomaterial with a great potential for bone and soft tissue regeneration without inflammatory reactions, and may be used alone or in combination with bone grafts, promoting hemostasis, bone growth, and maturation. AIM: The aim of this study was to demonstrate the clinical effectiveness of PRF combined with a new split crest flapless modified technique in 5 patients vs. 5 control patients. MATERIALS AND METHODS: Ten patients with horizontal alveolar crests deficiency were treated in this study, divided into 2 groups: Group 1 (test) of 5 patients treated by the flapless split crest new procedure; Group 2 (control) of 5 patients treated by traditional technique with deeper insertion of smaller implants without split crest. The follow-up was performed with x-ray orthopantomography and intraoral radiographs at T0 (before surgery), T1 (operation time), T2 (3 months) and T3 (6 months) post-operation. RESULTS: All cases were successful; there were no problems at surgery and post-operative times. All implants succeeded osteointegration and all patients underwent uneventful prosthetic rehabilitation. Mean height bone loss was 1 mm, measured as bone-implant most coronal contact (Δ-BIC), and occurred at immediate T2 post-operative time (3 months). No alveolar bone height loss was detected at implant insertion time, which was instead identified in the control group because of deeper implant insertion. CONCLUSION: This modified split crest technique combined with PRF appears to be reliable, safe, and to improve the clinical outcome of patients with horizontal alveolar crests deficiency compared to traditional implanting techniques by avoiding alveolar height-loss related to deeper insertion of smaller implants.

Analysis of Chemopredictive Assay for Targeting Cancer Stem Cells in Glioblastoma Patients.

INTRODUCTION: The prognosis of glioblastoma (GBM) treated with standard-of-care maximal surgical resection and concurrent adjuvant temozolomide (TMZ)/radiotherapy remains very poor (less than 15 months). GBMs have been found to contain a small population of cancer stem cells (CSCs) that contribute to tumor propagation, maintenance, and treatment resistance. The highly invasive nature of high-grade gliomas and their inherent resistance to therapy lead to very high rates of recurrence. For these reasons, not all patients with similar diagnoses respond to the same chemotherapy, schedule, or dose. Administration of ineffective anticancer therapy is not only costly but more importantly burdens the patient with unnecessary toxicity and selects for the development of resistant cancer cell clones. We have developed a drug response assay (ChemoID) that identifies the most effective chemotherapy against CSCs and bulk of tumor cells from of a panel of potential treatments, offering great promise for individualized cancer management. Providing the treating physician with drug response information on a panel of approved drugs will aid in personalized therapy selections of the most effective chemotherapy for individual patients, thereby improving outcomes. A prospective study was conducted evaluating the use of the ChemoID drug response assay in GBM patients treated with standard of care. METHODS: Forty-one GBM patients (mean age 54 years, 59% male), all eligible for a surgical biopsy, were enrolled in an Institutional Review Board-approved protocol, and fresh tissue samples were collected for drug sensitivity testing. Patients were all treated with standard-of-care TMZ plus radiation with or without maximal surgery, depending on the status of the disease. Patients were prospectively monitored for tumor response, time to recurrence, progression-free survival (PFS), and overall survival (OS). Odds ratio (OR) associations of 12-month recurrence, PFS, and OS outcomes were estimated for CSC, bulk tumor, and combined assay responses for the standard-of-care TMZ treatment; sensitivities/specificities, areas under the curve (AUCs), and risk reclassification components were examined. RESULTS: Median follow-up was 8 months (range 3-49 months). For every 5% increase in in vitro CSC cell kill by TMZ, 12-month patient response (nonrecurrence of cancer) increased two-fold, OR=2.2 (P=.016). Similar but somewhat less supported associations with the bulk tumor test were seen, OR=2.75 (P=.07) for each 5% bulk tumor cell kill by TMZ. Combining CSC and bulk tumor assay results in a single model yielded a statistically supported CSC association, OR=2.36 (P=.036), but a much attenuated remaining bulk tumor association, OR=1.46 (P=.472). AUCs and [sensitivity/specificity] at optimal outpoints (>40% CSC cell kill and >55% bulk tumor cell kill) were AUC=0.989 [sensitivity=100/specificity=97], 0.972 [100/89], and 0.989 [100/97] for the CSC only, bulk tumor only, and combined models, respectively. Risk categorization of patients was improved by 11% when using the CSC test in conjunction with the bulk test (risk reclassification nonevent net reclassification improvement [NRI] and overall NRI=0.111, P=.030). Median recurrence time was 20 months for patients with a positive (>40% cell kill) CSC test versus only 3 months for those with a negative CSC test, whereas median recurrence time was 13 months versus 4 months for patients with a positive (>55% cell kill) bulk test versus negative. Similar favorable results for the CSC test were observed for PFS and OS outcomes. Panel results across 14 potential other treatments indicated that 34/41 (83%) potentially more optimal alternative therapies may have been chosen using CSC results, whereas 27/41 (66%) alternative therapies may have been chosen using bulk tumor results. CONCLUSIONS: The ChemoID CSC drug response assay has the potential to increase the accuracy of bulk tumor assays to help guide individualized chemotherapy choices. GBM cancer recurrence may occur quickly if the CSC test has a low in vitro cell kill rate even if the bulk tumor test cell kill rate is high.