A flexible multivariate random effects proportional odds model with application to adverse effects during radiation therapy

Radiation therapy in patients with head and neck cancer has a toxic effect on mucosa, the soft tissue in and around the mouth. Hence mucositis is a serious common side effect and is a condition characterized by pain and inflammation of the surface of the mucosa. Although the mucosa recovers during breaks of and following the radiotherapy course the recovery will depend on the type of tissue involved and on its location. We present a novel flexible multivariate random effects proportional odds model which takes account of the longitudinal course of oral mucositis at different mouth sites and of the radiation dosage (in terms of cumulative dose). The model is an extension of the {\em proportional odds model} which is used for ordinal response variables. Our model includes the ordinal multivariate response of the mucositis score by location, random intercepts for individuals and includes a non-linear function of cumulative radiation dose. The model allows to test whether sensitivity differs by mouth sites after having adjusted for site specific cumulative radiation dose. The model also allows to check whether and how the (non-linear) effect of site specific dose differs by site. We fit the model to longitudinal patient data from a prospective observation and find that after adjusting for cumulative dose, upper, lower lips and mouth floor are associated with the lowest mucositis scores and hard and soft palate are associated with the highest mucositis scores. This implies the possibility that tissues at different mouth locations differ in their sensitivity to the toxic effect of radiation. We also find that cumulative dose followed by mouth site are the strongest predictors of mucositis, and the effects of age and gender are negligible

NASA Light-Emitting Diodes for the Prevention of Oral Mucositis in Pediatric Bone Marrow Transplant Patients

Objective: The purpose of this study was to determine the effects of prophylactic near-infrared light therapy from light-emitting diodes (LEDs) in pediatric bone marrow transplant (BMT) recipients. Background Data: Oral mucositis (OM) is a frequent side effect of chemotherapy that leads to increased morbidity. Near-infrared light has been shown to produce biostimulatory effects in tissues, and previous results using nearinfrared lasers have shown improvement in OM indices. However, LEDs may hold greater potential for clinical applications. Materials and Methods: We recruited 32 consecutive pediatric patients undergoing myeloablative therapy in preparation for BMT. Patients were examined by two of three pediatric dentists trained in assessing the Schubert oral mucositis index (OMI) for left and right buccal and lateral tongue mucosal surfaces, while the patients were asked to rate their current left and right mouth pain, left and right xerostomia, and throat pain. LED therapy consisted of daily treatment at a fluence of 4 J/cm2 using a 670-nm LED array held to the left extraoral epithelium starting on the day of transplant, with a concurrent sham treatment on the right. Patients were assessed before BMT and every 2–3 days through posttransplant day 14. Outcomes included the percentage of patients with ulcerative oral mucositis (UOM) compared to historical epidemiological controls, the comparison of left and right buccal pain to throat pain, and the comparison between sides of the buccal and lateral tongue OMI and buccal pain. Results: The incidence of UOM was 53%, compared to an expected rate of 70–90%. There was also a 48% and 39% reduction of treated left and right buccal pain, respectively, compared to untreated throat pain at about posttransplant day 7 (p \u3c 0.05). There were no significant differences between sides in OMI or pain. Conclusion: Although more studies are needed, LED therapy appears useful in the prevention of OM in pediatric BMT patients

NASA Light Emitting Diode Medical Applications from Deep Space to Deep Sea

This work is supported and managed through the NASA Marshall Space Flight Center-SBIR Program. LED-technology developed for NASA plant growth experiments in space shows promise for delivering light deep into tissues of the body to promote wound healing and human tissue growth. We present the results of LED-treatment of cells grown in culture and the effects of LEDs on patients’ chronic and acute wounds. LED-technology is also biologically optimal for photodynamic therapy of cancer and we discuss our successes using LEDs in conjunction with light-activated chemotherapeutic drugs

A Phase I Study of Abiraterone Acetate Combined with BEZ235, a Dual PI3K/mTOR Inhibitor, in Metastatic Castration Resistant Prostate Cancer.

Lessons learnedThe combination of standard dose abiraterone acetate and BEZ235, a pan-class I PI3K and mTORC1/2 inhibitor, was poorly tolerated in men with progressive mCRPC.Although the clinical development of BEZ235 has been discontinued in prostate cancer, agents that more selectively target PI3K-AKT-mTOR signaling may have a more favorable therapeutic index and should continue to be explored.BackgroundAndrogen receptor (AR) and phosphatidylinositol-3 kinase (PI3K) signaling are two commonly perturbed pathways in prostate cancer. Preclinical data have shown that the two pathways compensate for each other when one is inhibited, and combined inhibition of AR and PI3K signaling may be a viable strategy to prevent or overcome castration resistance.MethodsThis phase I study evaluated the safety and tolerability of abiraterone acetate and prednisone combined with BEZ235, a dual PI3K and mTORC1/2 inhibitor, in men with progressive metastatic castration resistant prostate cancer (mCRPC) who have not received prior chemotherapy.ResultsSix patients (n = 6) were treated at the starting dose level of abiraterone acetate 1,000 mg with prednisone 5 mg twice daily and BEZ235 200 mg twice daily in a 3 + 3 dose escalation design. The study was terminated early because three of the six patients (50%) experienced dose-limiting toxicities: grade 3 mucositis, grade 3 hypotension, and grade 4 dyspnea and pneumonitis. All six patients had previously progressed on abiraterone/prednisone. The median treatment duration was 27 days (range: 3-130 days). No prostate-specific antigen (PSA) decline or objective response were observed.ConclusionThe combination of standard-dose abiraterone/prednisone with BEZ235 200 mg twice daily was poorly tolerated in patients with mCRPC. The on-target and off-target effects of dual PI3K and mTORC inhibition likely contributed to the unacceptable toxicity profile. The Oncologist 2017;22:503-e43

Interventions for preventing oral mucositis for patients with cancer receiving treatment

Background: Treatment of cancer with chemotherapy is becoming increasingly more effective but is associated with short and long-term side effects. Oral side effects remain a major source of illness despite the use of a variety of agents to prevent them. Objectives: To evaluate the effectiveness of oral (and topical) prophylactic agents for oral mucositis and oral candidiasis in patients with cancer (excluding head and neck cancer), compared with placebo or no treatment. Search Strategy: Computerised MEDLINE, EMBASE, CINAHL, CANCERLIT, the Cochrane Controlled Trials Register and the Cochrane Oral Health Group Specialist Register search up to July 1999. Reference lists from relevant articles were scanned and the authors of eligible studies were contacted to identify trials and obtain additional information. Selection Criteria: Studies were selected if they met the following criteria: design - random or quasi-random allocation of participants; participants - anyone with cancer receiving chemotherapy (excluding head and neck cancer); interventions - prophylactic agents prescribed to reduce oral conditions arising from cancer or its treatment; outcomes - mucositis and oral candidiasis. Data Collection and Analysis: Information regarding methods, participants, interventions and outcome measures and results were independently extracted, in duplicate, by two reviewers (JC &amp; HW). Specialist advice was sought to categorise interventions. Authors were contacted for details of randomisation and withdrawals and a quality assessment was carried out using the Jadad criteria (Jadad 1998). The Cochrane Oral Health Group statistical guidelines were followed and relative risk values calculated using random effects models where significant heterogeneity was detected (P &lt; 0.1). Main Results: Thirty-eight reports of trials were initially included. Two were duplicate reports and nine were excluded as there was no useable information. Of the 27 useable studies 14 had data for mucositis comprising 945 randomised patients and 15 included data for oral candidiasis with 1164 randomised patients. Of the eight prophylactic agents used for mucositis only one, ice chips, was effective (Relative risk 0.57, 95% CI 0.43 to 0.77, chi-square for heterogeneity = 0.26 (df = 1), p = 0.61). The NNT to prevent one extra case of mucositis over the baseline incidence using ice chips was 4 (95%CI: 3 to 7). The NNT for when the baseline incidence of mucositis in the population ranges from 50% to 80% are 5 to 4 respectively. There is evidence that antifungal agents which are partially or fully absorbed from the gastrointestinal tract prevent oral candidiasis and that the partially absorbed agents may be more effective than the fully absorbed agents. The RR for partially absorbed agents was 0.13 (95% CI 0.06 to 0.27, chi-square for heterogeneity = 5.3 (df = 3), P = 0. 15). The NNT to prevent one extra case of oral candidiasis over the baseline incidence using partially absorbed drugs was 3 (95% CI: 3 to 5). The NNT for when the baseline incidence of oral candidiasis in the population ranges from 30% to 70% are 4 to 2 respectively. The general reporting of RCT's was poor however the median Jadad score was acceptable and improved further when the authors provided additional information. The sensitivity analysis confirmed the findings for oral candidiasis. Reviewer's Conclusions: There is some evidence that ice chips prevent mucositis. None of the other prophylactic agents included in this review prevented mucositis. There is evidence that prophylactic use of antifungal agents which are absorbed or partially absorbed from the gastrointestinal tract reduce the clinical signs of oral candidiasis, and the partially absorbed drugs may be more effective. Future trials in this area should address the link between oral and general health including outcomes relevant to the patient. Collaboration between medical and dental teams is indicated.</p

Oral platelet gel supernatant plus supportive medical treatment versus supportive medical treatment in the management of radiation-induced oral mucositis: a matched explorative active control trial by propensity analysis

OBJECTIVES:: In this active control trial, the rate of radio-induced WHO grade 3/4 oral mucositis and the change in quality of life, assessed by OMWQ-HN, were measured in subjects with head and neck cancer treated by platelet gel supernatant (PGS) and supportive medical treatment versus subjects treated by supportive medical treatment alone. MATERIALS AND METHODS:: Eighty patients with nonmetastatic head and neck cancer underwent curative or adjuvant radiotherapy. All patients underwent supportive medical treatment and/or PGS at the beginning and during radiotherapy. Sixteen patients received PGS in association with supportive medical treatment. To obtain 2 groups virtually randomized for important clinical characteristics subjects were matched, by propensity analysis, with a group of subjects (64 patients) treated with supportive medical treatment alone. RESULTS:: Subjects treated with standard supportive treatment experienced significant higher WHO grade 3/4 toxicity (55%; 35/64) than subjects treated by PGS (13%; 3/16). The reduced toxicity found in PGS group paralleled with the evidence that they developed later symptoms with respect to controls. The Cox proportional hazard model indicated that patients treated with standard supportive medical treatment experienced 2.7-fold increase (hazard ratio=2.7; 95% confidence interval, 1.3-5.7) in the occurrence of WHO grade 3/4 toxicity. PGS group significantly experienced higher quality of life than control groups as measured by OMWQ-HN. A significant decrease in the opioid analgesics usage was found in the PGS group. CONCLUSIONS:: These preliminary data should be interpreted with caution and could serve as a framework around which to design future trials

A Systematic Review of Recall Regimen and Maintenance Regimen of Patients with Dental Restorations. Part 2: Implant-Borne Restorations

Purpose To evaluate the current scientific evidence on patient recall and maintenance of implant-supported restorations, to standardize patient care regimens and improve maintenance of oral health. An additional purpose was to examine areas of deficiency in the current scientific literature and provide recommendations for future studies. Materials and Methods An electronic search for articles in the English language literature from the past 10 years was performed independently by multiple investigators using a systematic search process. After application of predetermined inclusion and exclusion criteria, the final list of articles was reviewed to meet the objectives of this review. Results The initial electronic search resulted in 2816 titles. The systematic application of inclusion and exclusion criteria resulted in 14 articles that satisfied the study objectives. An additional 6 articles were added through a supplemental search process for a total of 20 studies. Of these, 11 were randomized controlled clinical trials, and 9 were observational studies. The majority of the studies (15 out of 20) were conducted in the past 5 years and most studies were conducted in Europe (15), followed by Asia (2), South America (1), the United States (1), and the Middle East (1). Results from the qualitative data on a combined 1088 patients indicated that outcome improvements in recall and maintenance regimen were related to (1) patient/treatment characteristic (type of prosthesis, type of prosthetic components, and type of restorative materials); (2) specific oral topical agents or oral hygiene aids (electric toothbrush, interdental brush, chlorhexidine, triclosan, water flossers) and (3) professional intervention (oral hygiene maintenance, and maintenance of the prosthesis). Conclusions There is minimal evidence related to recall regimens in patients with implant-borne removable and fixed restorations; however, a considerable body of evidence indicates that patients with implant-borne removable and fixed restorations require lifelong professional recall regimens to provide biological and mechanical maintenance, customized for each patient. Current evidence also demonstrates that the use of specific oral topical agents and oral hygiene aids can improve professional and at-home maintenance of implant-borne restorations. There is evidence to demonstrate differences in mechanical and biological maintenance needs due to differences in prosthetic materials and designs. Deficiencies in existing evidence compel the forethought of creating clinical practice guidelines for recall and maintenance of patients with implant-borne dental restorations

Phase I dose-escalation study of the mTOR inhibitor sirolimus and the HDAC inhibitor vorinostat in patients with advanced malignancy.

Preclinical models suggest that histone deacetylase (HDAC) and mammalian target of rapamycin (mTOR) inhibitors have synergistic anticancer activity. We designed a phase I study to determine the safety, maximum tolerated dose (MTD), recommended phase II dose (RP2D), and dose-limiting toxicities (DLTs) of combined mTOR inhibitor sirolimus (1 mg-5 mg PO daily) and HDAC inhibitor vorinostat (100 mg-400 mg PO daily) in patients with advanced cancer. Seventy patients were enrolled and 46 (66%) were evaluable for DLT assessment since they completed cycle 1 without dose modification unless they had DLT. DLTs comprised grade 4 thrombocytopenia (n = 6) and grade 3 mucositis (n = 1). Sirolimus 4 mg and vorinostat 300 mg was declared RP2D because MTD with sirolimus 5 mg caused significant thrombocytopenia. The grade 3 and 4 drug-related toxic effects (including DLTs) were thrombocytopenia (31%), neutropenia (8%), anemia (7%), fatigue (3%), mucositis (1%), diarrhea (1%), and hyperglycemia (1%). Of the 70 patients, 35 (50%) required dose interruption or modification and 61 were evaluable for response. Partial responses were observed in refractory Hodgkin lymphoma (-78%) and perivascular epithelioid tumor (-54%), and stable disease in hepatocellular carcinoma and fibromyxoid sarcoma. In conclusion, the combination of sirolimus and vorinostat was feasible, with thrombocytopenia as the main DLT. Preliminary anticancer activity was observed in patients with refractory Hodgkin lymphoma, perivascular epithelioid tumor, and hepatocellular carcinoma

Peri-implant diseases and metabolic syndrome components: a systematic review

OBJECTIVE: Metabolic syndrome (MetS) is defined as a spectrum of conditions associated with an increased risk of developing CVD and type 2 diabetes. MetS include: hyperglycemia, hypertension, visceral obesity, dyslipidemia with elevated values of triglycerides (TG) and low levels of HDL. The aim of this review is to provide current knowledge of the relationship between MetS, its components and peri-implant diseases. MATERIALS AND METHODS: An electronic literature search was conducted in the English language in several databases. The Newcastle-Ottawa Scale was used for quality assessment of cohort and cross-sectional studies; while systematic reviews were evaluated through AMSTAR; results were reported according to the PRISMA Statement. RESULTS: A total of 272 records were identified through database searching, six studies were included for qualitative analysis. No study directly related to MetS was found, there was inconsistent and controversial evidence regarding association with cardiovascular disease. A higher risk of peri-implantitis was detected in people with hyperglycemia. CONCLUSIONS: Future research should be orientated in assessing the risk of peri-implant diseases, evaluating patient's therapeutic response, analyzing directionality of the relationship between MetS, its components and biologic implant complications. Few studies have investigated the possible relationship between systemic conditions and peri-implant diseases. The aim of this review is to present, in a systematic manner, current evidence and knowledge regarding possible association between cardiovascular disease and implant biologic complications. Out of the one-hundred-eighty-nine studies screened, just five studies were selected for qualitative analysis: three cohort studies (one prospective and two retrospectives) and two cross-sectional studies. According to their results, there is inconsistent and controversial evidence regarding association of cardiovascular disease and implant biologic complications. Future research should be orientated in conducting longitudinal studies, evaluating patients affected by cardiovascular disease rehabilitated with dental implants