A patient-driven clinicogenomic partnership for metastatic prostate cancer.

Molecular profiling studies have enabled discoveries for metastatic prostate cancer (MPC) but have predominantly occurred in academic medical institutions and involved non-representative patient populations. We established the Metastatic Prostate Cancer Project (MPCproject, mpcproject.org), a patient-partnered initiative to involve patients with MPC living anywhere in the US and Canada in molecular research. Here, we present results from our partnership with the first 706 MPCproject participants. While 41% of patient partners live in rural, physician-shortage, or medically underserved areas, the MPCproject has not yet achieved racial diversity, a disparity that demands new initiatives detailed herein. Among molecular data from 333 patient partners (572 samples), exome sequencing of 63 tumor and 19 cell-free DNA (cfDNA) samples recapitulated known findings in MPC, while inexpensive ultra-low-coverage sequencing of 318 cfDNA samples revealed clinically relevant AR amplifications. This study illustrates the power of a growing, longitudinal partnership with patients to generate a more representative understanding of MPC.

Temporomandibular joint alloplastic reconstruction of post-traumatic joint degeneration with Sawhney Type I ankylosis using 3D-custom GD-condylar cap prosthesis to restore condylar form and function.

Temporomandibular Joint (TMJ) ankylosis as a sequelae following hemarthrosis from trauma, middle ear infection and progressive debilitating arthritis of various etiologies has been well understood, but challenges always arise in terms of choosing least morbid procedure with maximum functional outcome. Total joint replacement (TJR) is the common final stage correction mandating extensive surgical exposure with good technical expertise with its limitations of risk of failure and complications. A case of post-traumatic TMJ degeneration with ankylosis reconstructed using a customised GD-condylar cap prosthesis is described. The patient had an uneventful post-operative period with an acceptable functional outcome. CONCLUSION: The condylar cap prosthesis is a bio-compatible and biomechanically designed in such a way that it can be used for indicated cases by performing minimally invasive surgical technique to achieve an optimal functional and aesthetic outcome.

The Angiosarcoma Project: enabling genomic and clinical discoveries in a rare cancer through patient-partnered research.

Despite rare cancers accounting for 25% of adult tumors1, they are difficult to study due to the low disease incidence and geographically dispersed patient populations, which has resulted in significant unmet clinical needs for patients with rare cancers. We assessed whether a patient-partnered research approach using online engagement can overcome these challenges, focusing on angiosarcoma, a sarcoma with an annual incidence of 300 cases in the United States. Here we describe the development of the Angiosarcoma Project (ASCproject), an initiative enabling US and Canadian patients to remotely share their clinical information and biospecimens for research. The project generates and publicly releases clinically annotated genomic data on tumor and germline specimens on an ongoing basis. Over 18 months, 338 patients registered for the ASCproject, which comprises a large proportion of all patients with angiosarcoma. Whole-exome sequencing (WES) of 47 tumors revealed recurrently mutated genes that included KDR, TP53, and PIK3CA. PIK3CA-activating mutations were observed predominantly in primary breast angiosarcoma, which suggested a therapeutic rationale. Angiosarcoma of the head, neck, face and scalp (HNFS) was associated with a high tumor mutation burden (TMB) and a dominant ultraviolet damage mutational signature, which suggested that for the subset of patients with angiosarcoma of HNFS, ultraviolet damage may be a causative factor and that immune checkpoint inhibition may be beneficial. Medical record review revealed that two patients with HNFS angiosarcoma had received off-label therapeutic use of antibody to the programmed death-1 protein (anti-PD-1) and had experienced exceptional responses, which highlights immune checkpoint inhibition as a therapeutic avenue for HNFS angiosarcoma. This patient-partnered approach has catalyzed an opportunity to discover the etiology and potential therapies for patients with angiosarcoma. Collectively, this proof-of-concept study demonstrates that empowering patients to directly participate in research can overcome barriers in rare diseases and can enable discoveries.

Predictability and Feasibility of Total Alloplastic Temporomandibular Joint Reconstruction using DARSN TM Joint Prosthesis for patients in Indian subcontinent-A prospective clinical study.

PURPOSE: The aim of this study was to investigate the feasibility of a custom made alloplastic Temporomandibular Joint (TMJ) device design in patients undergoing temporomandibular (TM) Total Joint Reconstruction (TJR). OBJECTIVE: TMJ disease with functional and anatomic distortion dictates the need for TJR. There are various materials to reconstruct a TMJ. However, various factors, such as cost, availability of prosthetic joint, limit its use to tertiary health care center. Hence, we have investigated the feasibility and efficacy of the custom made alloplastic TMJ prosthesis (DARSN TM Joint Prosthesis) with the advantage of being acceptable financially and the overall Quality of life (QoL) diagnosed with TMJ ankylosis and End Stage Joint Disease (ESJD) selected from the study population. MATERIALS AND METHODS: The study group comprised of 20 patients with TMJ ankylosis or End Stage Joint Disease (ESJD) who needed TM TJR of which few subjects in the study population had history of failed previous surgery to the TMJ region. The patients underwent resection of the joint followed by TJR using the custom made alloplastic TMJ prosthesis. Various subjective and objective variables were evaluated such as the Jaw Function (JF), Inter-incisal opening (IO), Diet intake (DI), Quality of Life (QoL) using a Psychometric Modified Likert Scale and nutritional status of the patient using the Mid-Upper Arm Circumference (MUAC) as reference. RESULTS: All the subjective and objective variables showed significant improvement in the postoperative period as compared to the preoperative period. The JF score increased with a mean score of 6.25 (P<0.00001). Postoperative mean DI score was 3.15 (P<0.00001) and IO increased up to 29-38mm in 95% of the study population. The study population exhibited an improved overall QoL and nutritional status post-operatively. Follow up period of 1 year showed significant functional improvement among the study population. CONCLUSION: The results shows that the custom made alloplastic joint replacement is safe and effective and reliable alternative to treat patients with TMJ disease which restricts the normal function to a greater degree requiring TM TJR.

Comparison of latency and efficacy of twin mix and modified twin mix in impacted mandibular third molar surgery - A Preliminary Randomized Triple Blind Split Mouth Clinical Study.

INTRODUCTION: Intra-space drug administration have recently gained popularity in the clinical practice posing several advantages over the conventional routes of drug administration. A preliminary prospective randomized triple blind clinical study was conducted to compare the latency and duration of anesthesia with twin mix (1.8ml 2% lignocaine with 1:200,000 epinephrine and 1ml/4mg dexamethasone) and modified twin mix (1.7ml of 4% articaine with 1:100,000 epinephrine and 1ml/4mg dexamethasone) to two conventional local anesthesia solutions along with co-relation of clinical effects in the postoperative phase in patients undergoing extraction of impacted mandibular third molars in terms of patients comfort post-surgery. MATERIALS AND METHODS: The study was conducted among 20 patients with bilateral impacted mandibular third molars who were randomly allotted to two groups, Group A and B. Each patients in both the groups was allotted with study and control site. Among Group A, patients were further divided into Sub-group L (Control) and Sub-group TM (Twin Mix). Group B patients were divided as Sub-group A (Control) and sub-group MTM (Modified Twin Mix). Sub-group L patients received 1.8ml of 2% lignocaine with 1:200,000 adrenaline and sub-group TM received twin mix. Sub-group A received 1.7ml of 4% articaine with 1:100,000 adrenaline and sub-group MTM received modified twin mix solution. All the procedure was performed by a single operator with a gap of 1 month between the two interventions among both the groups. Various subjective and objective parameters were measured pre-operatively and postoperatively to assess the latency and efficacy of various anesthesia solutions used in this study for third molar removal. RESULTS: Mean (±SD) VAS scores for sting on injection and pain were found to be less in TM and MTM sub-group with a score of 2.3 (±0.768) and 2.7 (±0.065) respectively. The anesthetic latency was significantly less in sub-group TM, with a mean (±SD) of 52.4 (±28.3) seconds. Sub-groups A and MTM had longer latency of anesthesia when compared with L and TM sub-groups. The duration of soft tissue anesthesia was maximum in sub-group MTM as compared to the other sub-groups. Patients from control sub-groups among both the groups had increased swelling, post-surgical pain and trismus postoperatively. DISCUSSION: Intra-space administration of twin mix and modified twin mix is clinically efficacious in impacted mandibular third molars surgery with better clinical outcomes postoperatively. We observed one significant difference between TM and MTM that the latter solution provided a prolonged duration of anesthesia increasing the patient's comfort postoperatively after surgical removal of mandibular third molars.

A three dimensional (3D) musculoskeletal finite element analysis of DARSN temporomandibular joint (TMJ) prosthesis for total unilateral alloplastic joint replacement.

PURPOSE: The purpose of this study was to evaluate the strain and stress distribution for DARSN alloplastic unilateral temporomandibular joint (TMJ) prosthesis and the effects on contralateral natural joint using a finite element analysis (FEA). METHODS: The replacement of the TMJ may have complications like infection, failure of hardware, facial paralysis and perforation. The understanding of the mechanical forces exerted by muscles of mastication and jaw movement on the joint helps in identifying the regions on alloplastic TMJ with various maximum forces, which makes that area more prone for failure of hardware. A three dimensional structural FEA was applied using a validated finite element model (FEM) where the areas of stress and strain were evaluated in the alloplastic joint and the contralateral natural joint. As the pattern of stress and strain can be influenced by the materials used for alloplastic joint and geometry of the design, mechanical property of bone and the attached musculature were also considered while construction the FEM analysis. RESULTS: The forces of the muscles of mastication has a vital role on the amount of stress and strain present across the alloplastic joint. Masseter and temporalis exhibited the greatest resultant force on the alloplastic as well as the natural condyle with a magnitude of 272 N and 329 N. This study assessed the maximum stress and strain on the condyle-ramus unit and fossa. CONCLUSION: FEA shows that alloplastic DARSN TMJ prosthesis distributes stress and strain equally between the alloplastic joint site and the contralateral natural joint causing minimal adverse effects to the natural joint. FEA also evaluated the stress and strain on alloplastic component and resulted in drawing clinical implications for operating surgical team.

Partial thickness temporalis rotation for alloplastic temporomandibular joint - how I do it.

With increasing clinical evidence, the replacement of the temporomandibular joint with alloplastic joints is being increasingly accepted in severe degenerative diseases. There remains a risk of infection and a possibility of a failure of not just these prostheses but any alloplastic joint prosthesis post-operatively. Therefore, an extra precaution and additional coverage to the joint using partial thickness myo-temporalis rotation flap could be a useful option to minimize post-operative joint failure.

Plasma cell leukemia: a retrospective study of 10 cases.

BACKGROUND: Plasma cell leukemia (PCL) is a rare aggressive variant of multiple myeloma (MM) characterized by a fulminant course and poor prognosis. Flow cytometry (FCM) is very useful in the diagnosis of the plasma cell leukemia. Herein, we present 10 cases of PCL. MATERIALS AND METHODS: We retrospectively studied immunophenotypic profile of 10 cases of PCL from Jan 2009 to Dec 2013 using 5 parameters, 6 color flow cytometric analysis. We also studied their clinical presentation and other laboratory findings. RESULTS: Common clinical features at presentation were weakness, bone pain, anemia, thrombocytopenia and osteolytic lesions. Plasma cell population were identified by strong expression of CD38 and co-expression of CD38 and CD138. CD56 was expressed in 20% cases. CD19 and CD117 were negative in all cases. CONCLUSIONS: Immunophenotyping is highly useful to differentiate PCL from other chronic lymphoproliferative disorders with plasmacytoid morphology as well as from non-neoplastic reactive plasma cells. Co-expression of CD38 and CD138 is a best combination to identify the plasma cells by using FCM.

Garcina cambogia leaf and seawater for tannase production by marine Aspergillus awamori BTMFW032 under slurry state fermentation.

Garcinia gummi-gutta (syn. G. cambogia, G. quaesita), known to have medicinal properties, was evaluated as a substrate and inducer for tannase production by a marine Aspergillus awamori BTMFW032, under slurry state fermentation using Czapekdox-minimal medium and sea water as the cultivation medium. Among the various natural tannin substrates evaluated, Garcinia leaf supported maximal tannase production. The cultivation conditions and components of the cultivation medium were optimized employing response surface methodology. The experimental results were fitted to a second-order polynomial model at a 92.2% level of significance (p < 0.0001). The maximal tannase activity was obtained in a slurry state medium containing 26.6%, w/v, Garcinia leaf, supplemented with 0.1% tannic acid as inducer. The optimum values of pH, temperature and inoculum concentration obtained were 5.0, 40 degrees C and 3%, respectively. A Box-Behnken model study of the fermentation conditions was carried out, and the best production of tannase was registered at 40 degrees C without agitation. Optimization strategy employing response surface methodology led to nearly 3-fold increase in the enzyme production from 26.2 U/mL obtained in unoptimized medium to 75.2 Units/mL in Box Behnken design, within 18 h of fermentation. It was observed that sea water could support maximal tannase production by A. awamori compared with other media suggesting that the sea water salts could have played an inducer role in expression of tannase encoding genes. To the best of our knowledge, this is the first report on production of tannase, an industrially important enzyme, utilizing Garcinia leaf as substrate under slurry state fermentation by marine A. awamori and sea water as the cultivation medium.

Sensible approaches for reducing clinical trial costs.

BACKGROUND: Over the past decade, annual funding for biomedical research has more than doubled while new molecular entity approvals have declined by one third. OBJECTIVE: To assess the value of practices commonly employed in the conduct of large-scale clinical trials, and to identify areas where costs could be reduced without compromising scientific validity. METHODS: In the qualitative phase of the study, an expert panel recommended potential modifications of mega-trial designs and operations in order to maximize their value (cost versus scientific benefit tradeoff). In the quantitative phase, a mega-trial economic model was used to assess the financial implications of these recommendations. Our initial chronic disease trial design included 20,000 patients randomized at 1000 sites. Each site was assigned 24 monitoring visits and a $10,000 per patient site payment. The case report form (CRF) was 60 pages long, and trial duration was assumed to be 48 months. RESULTS: The total costs of the initial trial design were $421 million ($US 2007). Following the expert panel's recommendations, we varied study duration, CRF length, number of sites, electronic data capture (EDC), and site management components to determine their individual and combined effects upon total trial costs. The use of EDC and modified site management practices were associated with significant reductions in total trial costs. When reductions in all five trial components were combined in a streamlined pharmaceutical industry design, a 59% reduction in total trial costs resulted. When we assumed an even more streamlined trial design than has typically been considered for regulatory submissions in the past, there was a 90% reduction in total trial costs. CONCLUSION: Our results suggest that it is possible to reduce substantially the cost of large-scale clinical trials without compromising the scientific validity of their results. If implemented, our recommendations could free billions of dollars annually for additional clinical studies. Research in the setting of clinical trials should be conducted to refine these findings.

Comparative evaluation of efficacy and safety profile of three anti-tuberculous regimens in Mangalore.

The aim of our study was to evaluate and compare the therapeutic efficacy & safety profile of three different antituberculous regimens for pulmonary tuberculosis. The study sample size included 90 newly diagnosed, sputum positive patients of pulmonary. tuberculosis. 30 each from different groups. The parameters studied were, therapeutic efficacy included weight gain, cough, sputum examination and safety profile: nausea, vomiting, anorexia, gastritis, hepatitis, jaundice diarrhoea, rashes, dizziness, tingling & numbness, flu like symptoms & joint aches. Group-I showed statistically significant weight gain when compared to Group-II. Improvement in cough and conversion to smear negative were seen in 100% of patients in Group-I, 83.3% of patients in Group-II and 93.3% of patients in Group-III. Therapeutic efficacy was highest with Group I regimen, followed by Group III and Group II which was least efficacious. Group II also registered; the maximum cost and highest incidence of adverse effects.