Automatic Radiotherapy Planning for Glioblastoma Radiotherapy With Sparing of the Hippocampus and nTMS-Defined Motor Cortex

BackgroundNavigated transcranial magnetic stimulation (nTMS) of the motor cortex has been successfully implemented into radiotherapy planning by a number of studies. Furthermore, the hippocampus has been identified as a radiation-sensitive structure meriting particular sparing in radiotherapy. This study assesses the joint protection of these two eloquent brain regions for the treatment of glioblastoma (GBM), with particular emphasis on the use of automatic planning.Patients and MethodsPatients with motor-eloquent brain glioblastoma who underwent surgical resection after nTMS mapping of the motor cortex and adjuvant radiotherapy were retrospectively evaluated. The radiotherapy treatment plans were retrieved, and the nTMS-defined motor cortex and hippocampus contours were added. Four additional treatment plans were created for each patient: two manual plans aimed to reduce the dose to the motor cortex and hippocampus by manual inverse planning. The second pair of re-optimized plans was created by the Auto-Planning algorithm. The optimized plans were compared with the “Original” plan regarding plan quality, planning target volume (PTV) coverage, and sparing of organs at risk (OAR).ResultsA total of 50 plans were analyzed. All plans were clinically acceptable with no differences in the PTV coverage and plan quality metrics. The OARs were preserved in all plans; however, overall the sparing was significantly improved by Auto-Planning. Motor cortex protection was feasible and significant, amounting to a reduction in the mean dose by >6 Gy. The dose to the motor cortex outside the PTV was reduced by >12 Gy (mean dose) and >5 Gy (maximum dose). The hippocampi were significantly improved (reduction in mean dose: ipsilateral >6 Gy, contralateral >4.6 Gy; reduction in maximum dose: ipsilateral >5 Gy, contralateral >5 Gy). While the dose reduction using Auto-Planning was generally better than by manual optimization, the radiated total monitor units were significantly increased.ConclusionConsiderable dose sparing of the nTMS-motor cortex and hippocampus could be achieved with no disadvantages in plan quality. Auto-Planning could further contribute to better protection of OAR. Whether the improved dosimetric protection of functional areas can translate into improved quality of life and motor or cognitive performance of the patients can only be decided by future studies.

Comparative study of efficacy and safety of parenteral iron sucrose versus ferric carboxymaltose in treatment of postpartum iron deficiency anaemia

Background: Postpartum anaemia often leads to multiple clinical complications in mother as well as infant and iron supplementation with parenteral iron is the preferred treatment modality. The present study was planned to compare the efficacy and tolerability of IV iron sucrose and IV ferric carboxymaltose in treatment of postpartum iron deficiency anaemia.Methods: This randomized, parallel, open label, prospective 4-weeks study was conducted from June 2019 to December 2020 in women with postpartum anaemia admitted to obstetrics and gynaecology inpatient department of a tertiary care hospital. Women with postpartum iron deficiency anaemia (N=60) were randomly divided into two groups; receiving Injection iron sucrose (N=30, maximum dose 500 mg) or Injection ferric carboxymaltose (N=30, maximum dose 500 mg). Change in haemoglobin and serum ferritin levels from baseline to the end of 2 and 4 weeks of treatment were evaluated.Results: The results showed early, sustained and significant increase in the haemoglobin levels in both the groups. However, the difference was not significant between groups (p=0.2). Evaluation of replenishment of iron stores (serum ferritin) showed improvement in both the groups, however in FCM group the rise was found to be significant (p<0.05).Conclusions: FCM in a lower dose of 500mg was found to be safe and effective in significantly improving haemoglobin concentration as well as in replenishing iron stores in patients with postpartum anaemia.

DOSIMETRIC ANALYSIS OF ADAPTIVE RADIOTHERAPY(ART) IN LOCALLY ADVANCED HEAD AND NECK CANCER

PURPOSE/OBJECTIVE: The objective of this study is to evaluate the dosimetric parameters in adaptive radiotherapy for locally advanced head and neck cancers METHODS AND MATERIALS: This is a Hospital-based Prospective study conducted in the period from Dec 2020 to March 2021. Histologically proven Head and Neck Carcinoma patients with Stage III to IV (locally advanced) were selected for the study. A total of 10 patients receiving denitive, conformal radiation therapy to the head and neck region were evaluated for the study. After the acquisition of CT images, target volumes, OARs were contoured in the planning CT. Images were again acquired midway during the planned course of radiation therapy. Body contours, target volumes, and organs at risk were redrawn on the new set of images. Two sets of additional treatment plans were generated: 1) a non-optimized plan (plan 2), which is an overlay of the original plan (plan 1) on the new set of contours, and 2) an optimized plan(plan 3) with the new set of contours. These 3 sets of plans were then compared for dosimetric differences. RESULTS: Four patients had locally advanced nasopharyngeal cancers, 4 patients had locally advanced oropharyngeal cancers, 2 patients had locally advanced hypopharyngeal cancer. The average reduction in gross tumour volume was 37.1 ml. The average changes in right and left parotid volume were 5.94 and 5.49 ml, respectively. With the non-optimized plan, the average increase in the maximum dose to the spinal cord was 9.8% (58.96-68.76; p= 0.156). With reoptimization, the maximum dose to the spinal cord decreased from 68.76% to 54.97% (mean difference, -13.79%, p=0.03). The average D99 for the planning target volume( dose received by 99% of the target volume) was 98.68% and 98.65% with the original and reoptimized plans, respectively. Most of the patients during radiation had Grade 2 skin toxicity and Grade 2 mucositis which was managed conservatively. CONCLUSIONS: This study demonstrates that during radiation there is gross changes of volumes in locally advanced head and neck cancers and thus adaptive radiation therapy plays a pivotal role in locally advanced head and neck cancer

Effects of immunoglobulin plus prednisolone in reducing coronary artery lesions in patients with Kawasaki disease: study protocol for a phase III multicenter, open-label, blinded-endpoints randomized controlled trial

Background Kawasaki disease (KD) is an acute systemic vasculitis of unclear etiology that mainly affects infants and young children. Strategies to reduce the incidence and severity of coronary artery lesions (CALs), the determinant factor in the long-term prognosis of KD, are currently a focus of studies on KD. Corticosteroids, preferred in the treatment of the majority of vasculitides, are controversial in the treatment of acute KD. In this trial, we will evaluate whether the addition of prednisolone to standard intravenous immunoglobulin (IVIG) plus aspirin therapy can reduce the occurrence of CAL in Chinese patients with KD. Methods This is a multicenter, prospective, open-label, randomized controlled trial, which is expected to be conducted in more than 20 hospitals in China and aims to assess the efficacy and safety of IVIG + prednisolone treatment versus standard treatment. Patients with KD who fulfill the inclusion and exclusion criteria will be recruited and randomized (1:1) to receive either a large dose of IVIG (2 g/kg over 12–24 h with a maximum dose of 60 g) + aspirin 30 mg/kg/d or IVIG (2 g/kg over 12–24 h) + aspirin 30 mg/kg/d + prednisolone (2 mg/kg/d with a maximum dose of 60 mg tapered over 15 days after normalization of C-reactive protein concentration). The primary outcome will be the occurrence of CAL at 1 month of illness. The follow-up duration for each participant will be set as 1 year. Patients and treating physicians will be unmasked to group allocation. Discussion This will be the first multicenter randomized controlled trial to evaluate the efficacy of IVIG + aspirin + prednisolone in Chinese pediatric patients with KD, which may provide high-level evidence for improving the initial treatment for acute KD. Trial registration ClinicalTrials.govNCT04078568. Registered on 16 August 2018.

Trial in Progress: Phase I Open-Label Study of Metformin and Nelfinavir in Combination with Bortezomib in Patients with Relapsed and/or Refractory Multiple Myeloma

Background: GLUT4 inhibition is an attractive therapeutic option in multiple myeloma (MM) given the dependence of MM cells on glucose transport. Furthermore, combining a GLUT4 inhibitor with an oxidative phosphorylation inhibitor in MM cells to counter the possibility of therapeutic resistance to GLUT4 inhibition has demonstrated synergistic promise (Dalva-Aydemir et al, Clin Can Res 2015). Using a GLUT4 inhibitor such as the HIV protease inhibitor nelfinavir is an attractive choice since it not only inhibits the transport function of GLUT4, but it also lowers the cytotoxicity resistance of MM cells against proteasome inhibitors such as bortezomib (Driessen et al, Blood 2018). Thus, in summary the FDA-approved oral HIV-PI nelfinavir, long used for the treatment of HIV disease, can bind to glucose transporters (GLUT4) on MM cells and reversibly inhibit glucose uptake, thus disrupting the Warburg effect. Nelfinavir can also enhance the activity of PIs such as bortezomib overcome its resistance in MM cells. Metformin, an oral FDA-approved drug for the treatment of Type II Diabetes has the ability to disrupt the electron transport chain of defective mitochondria within MM cells, thus blocking the ability of such mitochondria to generate energy and anabolic substrates as compensatory mechanisms required for proliferation in the setting of GLUT4 inhibition. Thus, this study will look at the safety and tolerability of repurposing the existing FDA-approved drugs for Type II diabetes and HIV in combination with bortezomib for the treatment of relapsed and/or refractory myeloma. Methods: This study is a phase 1 clinical trial of metformin and nelfinavir in combination with bortezomib for patients with relapsed and/or refractory myeloma. Part A of this trial is a 3+3 dose escalation design with 3 dose levels planned. Part B is a dose expansion cohort at the Maximal Tolerated Dose (MTD) determined in Part A. Up to a maximum of 36 patients will be enrolled and treated for a maximum of six 21-day cycles. Bortezomib is administered in its usual weekly subcutaneous dosing schedule of days 1, 8 and 15 of a 21-day cycle at a dose level of 1.3 mg/m2. Metformin will be administered for 14 days of a 21-day cycle and started at a dose level of 500 mg twice daily and will be investigated to a maximum dose of 1000 mg twice daily. Nelfinavir will also be administered for 14 days of a 21-day cycle and started at a dose level of 1250 mg twice daily and will be investigated to a maximum dose of 2500 mg twice daily. Key inclusion criteria include having relapsed/refractory myeloma with at least 2 prior lines of therapy and prior exposure to PIs, immunomodulators and Anti-CD38 monoclonal antibodies, adequate hematologic reserve, kidney function and liver function. This trial especially allows patients with non-secretory disease yet measurable by bone marrow assessments or cross-sectional imaging of plasmacytomas to be enrolled which constitutes an unmet need in the real-world MM population. Finally, this allows patients to be treated with a dexamethasone-free regimen. The primary objective of this trial is to determine the MTD of metformin and nelfinavir in combination with bortezomib. The secondary objective is to evaluate the safety and tolerability as well as the overall response rate (ORR) associated with this combination. Potential predictive biomarkers as well as resistance mechanisms using genomic RNA, immunohistochemistry and metabolomics-based assessment platforms will be evaluated in this study. Recruitment is ongoing with no safety concerns. This trial is registered on clinicaltrials.gov: NCT03829020. This investigator-initiated trial was funded by the generous gift of the Helen Diller Family Foundation. Disclosures Kumar: Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bluebird Bio: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Consultancy; Antengene: Consultancy, Honoraria; Novartis: Research Funding; Carsgen: Research Funding; Roche-Genentech: Consultancy, Research Funding; Beigene: Consultancy; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Merck: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tenebio: Research Funding; BMS: Consultancy, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. Ailawadhi: Karyopharm: Consultancy; AbbVie: Consultancy; Genentech: Consultancy; Takeda: Consultancy; GSK: Consultancy, Research Funding; Xencor: Research Funding; Cellectar: Research Funding; Medimmune: Research Funding; Ascentage: Research Funding; Pharmacyclics: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; BeiGene, Ltd.: Consultancy; Sanofi: Consultancy; Oncopeptides: Consultancy.

Preventing Accidental Overdoses by Innovating a Restrictive Prescription Pill Dispenser Vial (RPPDV)

Rather than attempting to prevent all overdoses, the Prescription Pill Dispenser Vial (RPPDV) aims to prevent accidental overdoses by controlling how many pills a user can access within a twenty-four hour period. The RPPDV is much like a traditional pill vial. The body is similar to a conventional pill vial; however, it is modified to prevent the cap's opening without a special screw. The cap is heavily modified and uses a CR2032 or CR2025 coin cell battery to power a gate and the unlocking of the pill cap. The RPPDV works first when the user clicks the red button on the cap of the RPPDV, which opens the pill gate and opens space into a pill container section. This section is large enough for only one pill (or two if multiple pills are required simultaneously). Once a tablet has entered the pill container section, the button must be pressed again to close the pill gate. The user cannot open the lid to the pill container section until the pill gate is closed (see Fig 1.4.1). The RPPDV is similar to an escrow service, with the pill holder section acting as a middleman. The size of the pill holder container prevents access to multiple pills at the same time. The number of times the user presses the button is recorded and timed with a 555 timer set for twenty-four hours. For example, if a drug has a maximum dose of three pills per day, the button could be capped at four cycles or eight total pushes (to allow a grace cycle if a tablet is broken or stuck). Similarly, the gate cannot be opened unless the lid to the pill container section is closed. The production price of the RPPDV is significantly higher than a traditional pill vial and can get higher depending on the additional features added to the RPPDV. The necessary components to function include CR2032 or CR2025 lithium batteries, a 555 timer, and a coin battery holder, along with plastic and metal molds. The base model alone produces an estimated average cost per unit of $1.33 USD (see Fig 4.2.1). Additional features include adding a Bluetooth Low Energy (Bluetooth LE) component to customize the number of unlocks per day and RFIDs for storage and tracking. Prices vary depending on the specifications of the RPPDV.

Principles of dose-setting in toxicology studies: the importance of kinetics for ensuring human safety

Regulatory toxicology seeks to ensure that exposures to chemicals encountered in the environment, in the workplace, or in products pose no significant hazards and produce no harm to humans or other organisms, i.e., that chemicals are used safely. The most practical and direct means of ensuring that hazards and harms are avoided is to identify the doses and conditions under which chemical toxicity does not occur so that chemical concentrations and exposures can be appropriately limited. Modern advancements in pharmacology and toxicology have revealed that the rates and mechanisms by which organisms absorb, distribute, metabolize and eliminate chemicals—i.e., the field of kinetics—often determine the doses and conditions under which hazard, and harm, are absent, i.e., the safe dose range. Since kinetics, like chemical hazard and toxicity, are extensive properties that depend on the amount of the chemical encountered, it is possible to identify the maximum dose under which organisms can efficiently metabolize and eliminate the chemicals to which they are exposed, a dose that has been referred to as the kinetic maximum dose, or KMD. This review explains the rationale that compels regulatory toxicology to embrace the advancements made possible by kinetics, why understanding the kinetic relationship between the blood level produced and the administered dose of a chemical is essential for identifying the safe dose range, and why dose-setting in regulatory toxicology studies should be informed by estimates of the KMD rather than rely on the flawed concept of maximum-tolerated toxic dose, or MTD.

Effect of Prenatal Administration of Retinoic Acid on Developing Spinal Cord of Albino Rats

Background Vitamin A and its derivatives (Retinoids) are essential for both normal embryonic development and maintenance of differentiation.Retinoids is a well-known teratogen when administered to embryos Aim to investigate the structural changes induced by prenatal administration of vitamin A on the developing spinal cord of albino rats. Material and methods forty pregnant albino rats were exposed to variable doses of vitamin A (retinylpalmitate) on gd 10.The pregnant albino rats were divided into three groups: Group I (control): rats received sesame oil by oral gavagedaily, till date of delivery. Group II (minimum therapeutic dose): rats were given retinylpalmitate 50 mg/kg daily. Group III (maximum therapeutic dose): rats were givenretinylpalmitate 100 mg/kg daily. The viable offspring of all groups were evaluated for changes in developing spinal cord at PND10. At the end of the experiment, rats offspring were sacrificed, the spinal cord were dissected out, and subjected to histological examination followed by computer image analysis. Results PDN10 neonates of mothers received minimum dose of vitamin A (subgroup II) revealed few immature irregular dorsal horn neurons with relatively decreased cellular density in anterior horn neurons. Meanwhile, the PDN10 neonates of mothers received daily maximum therapeutic dose of vitamin A (subgroup III) exhibited dark,pyknotic nucleiand packed dorsal horn cells while anterior horn cells were shrunkenandkaryoliticnuclei. Conclusion minimum and maximum doses of vitamin A in pregnant rats attributed to morphological changes in spinal cord of their young neonates and in long term follow up which was more obvious in maximum dose than low intake. Therefore, it might be assumed that neither minimum nor maximum dose could be used as a safe drug for their serious side effects on spinal cord morphology and consequently its functions.

Oral mini-pulse steroid therapy in severe chronic urticaria

Background: Treatment of chronic urticaria can be difficult at times. The present study aimed to evaluate the efficacy of oral mini-pulse (OMP) therapy with methylprednisolone in management of severe chronic urticaria (CU). Methods and material: 100 patients with severe chronic urticaria, not controlled with maximum dose of a second generation antihistamine, were enrolled in the study after an informed written consent. All patients were treated with methylprednisolone 16 mg tablet on two consecutive days of a week for 2 months along with levocetirizine 5 mg tablet once daily. All patients were reviewed at 0, 2, 4, and 8 weeks with urticaria activity score (UAS). Results: The study comprised of 100 patients (33 males and 67 females) with severe chronic urticaria. 29 patients (29%) had raised TSH levels while Autologous Serum Skin Test was positive in 37 patients. Mean UAS in patients treated with OMP was 5.76 at baseline which reduced to 0.6 at the end of treatment period. Conclusion: Mean UAS showed a significant decline following OMP therapy with methylprednisolone. Most of the patients maintained the benefits of therapy at the end of follow up period of 4 months.