Maximum Dose Research Articles

Cytotoxicity and apoptosis activities of passion fruit (Passiflora edulis Sims) seed extract on HSC-2, HSC-3, MCF-7, and HaCaT cell lines

Context: Passion fruit (Passiflora edulis Sims) is a well-known plant in the tropical islands, especially in North Sumatra, Indonesia, because of its sweet and refreshing taste. Although the fruit is often used as a syrup and sweetener, the efficacy of P. edulis fruit seed extract for anticancer activity has not been widely studied. Aims: To evaluate the ability of P. edulis fruit seed extract to induce cytotoxicity and apoptosis in HSC-2, HSC-3, MCF-7, and HaCaT cell lines. Methods: P. edulis fruit seed extract was extracted by using 96% ethanol. The cytotoxicity activity was measured by using an MTT assay for 48 hours. Apoptosis was examined using a TUNEL assay, and the morphology of the apoptosis bodies was analyzed using electron microscopy. Results: The IC50 values of P. edulis fruit seed extract were 572.79 µg/mL and 439.54 µg/mL for HSC-3 and MCF-7, respectively. The seed did not show cytotoxic activity on the HSC-2 cell line, but it induced proliferation of the HaCaT cell line in the maximum dose. The P. edulis fruit seed extract induced apoptosis activity in HSC-3, MCF-7, and HaCaT cell lines. Most DNA fragments were found in the cytosol of HSC-3 cells and the nucleus of MCF-7 cells. Conclusions: The P. edulis fruit seed extract has cytotoxicity and apoptosis activities in oral cancer (HSC-3 cells) and breast cancer (MCF-7 cells), as well as being safe in normal human keratinocytes (HaCaT cell line). The P. edulis fruit seed extract can be considered an adjuvant agent in cancer treatment.

Evaluation of Acute and Subacute Oral Toxicity of Erlangea tomentosa (Oliv. & Hiern) S. Moore (Asteraceae) Methanol Leaf Extract in Experimental Wistar Albino Rats

Erlangea tomentosa (Oliv. & Hiern) S. Moore's leaves, which are in the Asteraceae family, were tested for acute and subacute toxicity in experimental Wistar rats. Lorke’s (bi-phasic) method was used to evaluate the acute toxicity profile of the plant extract. In phase 2, twelve rats of both sexes were administered a maximum dosage of 5000 mg/kg of extract. Observations of toxicity signs were made and recorded for 2 hours consecutively, for 24 hours intermittently, as well as for the next 14 days. For the subacute study, rats were orally administered water and plant extract daily for 28 days. Toxicological effects were recorded daily, and body weights were documented weekly. Hematological, biochemical, and histopathological tests as well as relative organ weights were evaluated at the conclusion of the study. In phase 2 of the acute toxicity study, it was found that the plant extract was toxic at doses of 1600, 3100, and 5000 mg/kg, with only one death at the highest dose. In the subacute toxicity study, animals that were administered 800 mg/kg of extract for 28 days showed symptoms of toxicity. The weight of the kidneys increased; urea and ALT levels increased; as well as total protein and albumin levels decreased compared to the control group. At the same dose, histopathology examination revealed alterations of the liver and kidneys, while hematopoietic cells were significantly disrupted compared to the control animals. Based on the findings, the methanol-extracted leaves of E. tomentosa showed a moderate level of acute toxicity. The administration of the extract at a dose of 400 mg/kg was safe, but 800 mg/kg was toxic. This caused damage to their livers and kidneys. This led to an increase in ALT and ALP, changes in blood parameters like Hb, RBC, and PLT, as well as the development of inflammatory cells.

Measurements regarding a combined therapy concept for ophthalmic tumors consisting of brachytherapy and x-rays

Objective. We present a novel concept to treat ophthalmic tumors which combines brachytherapy and low-energy x-ray therapy. Brachytherapy with 106Ru applicators is inadequate for intraocular tumors with a height of 7 mm or more. This results from a steep dose gradient, and it is unfeasible to deliver the required dose at the tumor apex without exceeding the maximum tolerable sclera dose of usually 1000 Gy to 1500 Gy. Other modalities, such as irradiation with charged particles, may be individually contraindicated. A dose boost at the apex provided by a superficial x-ray therapy unit, performed simultaneously with the brachytherapy, results in a more homogeneous dose profile than brachytherapy alone. This avoids damage to organs at risk. The applicator may also serve as a beam stop for x-rays passing through the target volume, which reduces healthy tissue dosage. This study aims to investigate the suitability of the applicator to serve as a beam stop for the x-rays. Approach. A phantom with three detector types comprising a soft x-ray ionization chamber, radiochromic films, and a self-made scintillation detector was constructed to perform dosimetry. Measurements were performed using a conventional x-ray unit for superficial therapy to investigate the uncertainties of the phantom and the ability of the applicator to absorb x-rays. The manufacturer provided a dummy plaque to obtain x-ray dose profiles without noise from 106Ru decays. Results. The phantom is generally feasible to obtain dose profiles with three different detector types. The interaction of x-rays with the silver of the applicator leads to an increased dose rate in front of the applicator. The dose rate of the x-rays is reduced by up to 90% behind a 106Ru applicator. Therefore, a 106Ru applicator can be used as a beam stop in combined x-ray and brachytherapy treatment.

Dosimetric risk factors for radiation esophagitis in patients with breast cancer following regional nodal radiation

BACKGROUND Radiation esophagitis (RE) is one of the most common clinical symptoms of regi-onal lymph node radiotherapy for breast cancer. However, there are fewer studies focusing on RE caused by hypofractionated radiotherapy (HFRT). AIM To analyze the clinical and dosimetric factors that contribute to the development of RE in patients with breast cancer treated with HFRT of regional lymph nodes. METHODS Between January and December 2022, we retrospectively analysed 64 patients with breast cancer who met our inclusion criteria underwent regional nodal intensity-modulated radiotherapy at a radiotherapy dose of 43.5 Gy/15F. RESULTS Of the 64 patients in this study, 24 (37.5%) did not develop RE, 29 (45.3%) developed grade 1 RE (G1RE), 11 (17.2%) developed grade 2 RE (G2RE), and none developed grade 3 RE or higher. Our univariable logistic regression analysis found G2RE to be significantly correlated with the maximum dose, mean dose, relative volume 20-40, and absolute volume (AV) 20-40. Our stepwise linear regression analyses found AV30 and AV35 to be significantly associated with G2RE (P < 0.001). The optimal threshold for AV30 was 2.39 mL [area under the curve (AUC): 0.996; sensitivity: 90.9%; specificity: 91.1%]. The optimal threshold for AV35 was 0.71 mL (AUC: 0.932; sensitivity: 90.9%; specificity: 83.9%). CONCLUSION AV30 and AV35 were significantly associated with G2RE. The thresholds for AV30 and AV35 should be limited to 2.39 mL and 0.71 mL, respectively.

CDC Clinical Guidelines on the Use of Doxycycline Postexposure Prophylaxis for Bacterial Sexually Transmitted Infection Prevention, United States, 2024.

No vaccines and few chemoprophylaxis options exist for the prevention of bacterial sexually transmitted infections (STIs) (specifically syphilis, chlamydia, and gonorrhea). These infections have increased in the United States and disproportionately affect gay, bisexual, and other men who have sex with men (MSM) and transgender women (TGW). In three large randomized controlled trials, 200 mg of doxycycline taken within 72 hours after sex has been shown to reduce syphilis and chlamydia infections by >70% and gonococcal infections by approximately 50%. This report outlines CDC's recommendation for the use of doxycycline postexposure prophylaxis (doxy PEP), a novel, ongoing, patient-managed biomedical STI prevention strategy for a selected population. CDC recommends that MSM and TGW who have had a bacterial STI (specifically syphilis, chlamydia, or gonorrhea) diagnosed in the past 12 months should receive counseling that doxy PEP can be used as postexposure prophylaxis to prevent these infections. Following shared decision-making with their provider, CDC recommends that providers offer persons in this group a prescription for doxy PEP to be self-administered within 72 hours after having oral, vaginal, or anal sex. The recommended dose of doxy PEP is 200 mg and should not exceed a maximum dose of 200 mg every 24 hours.Doxy PEP, when offered, should be implemented in the context of a comprehensive sexual health approach, including risk reduction counseling, STI screening and treatment, recommended vaccination and linkage to HIV PrEP, HIV care, or other services as appropriate. Persons who are prescribed doxy PEP should undergo bacterial STI testing at anatomic sites of exposure at baseline and every 3-6 months thereafter. Ongoing need for doxy PEP should be assessed every 3-6 months as well. HIV screening should be performed for HIV-negative MSM and TGW according to current recommendations.

Analysis of Antipsychotic Dosage in Patients With Tardive Dyskinesia: A Case-Control Study Using the Claims Database of the Corporate Health Insurance Association.

This study aimed to assess the association between antipsychotic doses and the risk of tardive dyskinesia (TD) in clinical practice using a Japanese claims database from 2010 to 2020. The study population included patients 15 years or older with a diagnosis record of schizophrenia, depression, or bipolar disorder who were prescribed antipsychotics. Using a case-control design, we categorized patients newly diagnosed with TD as cases, with corresponding 1:10 matching in the control group. The primary endpoint was the relative risk of TD in the >median dose and ≤median dose groups, as determined using conditional logistic regression analysis adjusted for age. The analysis population included 58,452 patients, and the median daily antipsychotic dose was 75 mg/d of chlorpromazine equivalent (CPZE). Of these, 80 were identified as TD cases, and doses >75 mg/d were associated with a significantly increased risk of TD at the last prescription and the maximum dose, respectively, before the date of the first diagnosis of TD. Post-hoc analysis further showed a significant association between doses ≥300 mg/d and the risk of TD compared to doses ≤75 mg/d and doses >75 to <300 mg/d. Comparing ≥300 mg/d versus >75 to <300 mg/d, the odd ratios at the last prescription and maximum dose before the first diagnosis of TD were 3.40 and 3.50, respectively. In the Japanese medical claims database of patients receiving relatively low doses of antipsychotics, doses >75 mg/d were associated with an increased risk of TD in a dose-dependent manner.

Diversifying the anthracycline class of anti-cancer drugs identifies aclarubicin for superior survival of acute myeloid leukemia patients

The efficacy of anthracycline-based chemotherapeutics, which include doxorubicin and its structural relatives daunorubicin and idarubicin, remains almost unmatched in oncology, despite a side effect profile including cumulative dose-dependent cardiotoxicity, therapy-related malignancies and infertility. Detoxifying anthracyclines while preserving their anti-neoplastic effects is arguably a major unmet need in modern oncology, as cardiovascular complications that limit anti-cancer treatment are a leading cause of morbidity and mortality among the 17 million cancer survivors in the U.S. In this study, we examined different clinically relevant anthracycline drugs for a series of features including mode of action (chromatin and DNA damage), bio-distribution, anti-tumor efficacy and cardiotoxicity in pre-clinical models and patients. The different anthracycline drugs have surprisingly individual efficacy and toxicity profiles. In particular, aclarubicin stands out in pre-clinical models and clinical studies, as it potently kills cancer cells, lacks cardiotoxicity, and can be safely administered even after the maximum cumulative dose of either doxorubicin or idarubicin has been reached. Retrospective analysis of aclarubicin used as second-line treatment for relapsed/refractory AML patients showed survival effects similar to its use in first line, leading to a notable 23% increase in 5-year overall survival compared to other intensive chemotherapies. Considering individual anthracyclines as distinct entities unveils new treatment options, such as the identification of aclarubicin, which significantly improves the survival outcomes of AML patients while mitigating the treatment-limiting side-effects. Building upon these findings, an international multicenter Phase III prospective study is prepared, to integrate aclarubicin into the treatment of relapsed/refractory AML patients.

Evaluating the effectiveness of the maximum permitted dose of midazolam in seizure termination: Insights from New South Wales, Australia.

Out-of-hospital seizures demand rapid management. Midazolam plays a key role in stopping seizures. At times the first dose of midazolam proves insufficient, necessitating additional doses. Within the New South Wales Ambulance (NSWA) service, the upper limit for midazolam administration is set at 15 mg. However, the outcomes and safety of using midazolam at this maximum dosage have not been thoroughly investigated. A retrospective analysis of out of hospital electronic health records from New South Wales, Australia, over the year 2022, was conducted. The study manually reviewed cases where adult patients received the maximum dose of midazolam for seizure management by paramedics. It focused on seizure cessation success rates and the incidence of adverse effects to evaluate the clinical implications of high-dose midazolam administration. Of 818 790 individual attendances by NSWA clinicians, a total of 11 392 (1.4%) adults had seizures noted, of which midazolam was administered in 2565 (22.5%). An algorithm shows that in 2352 (91.7%) instances the midazolam was associated with the apparent termination of seizures. Analysis revealed that 176 (1.5%) proportion of all adult's seizure patients required the maximum dose of midazolam for seizure control. These higher doses successfully terminate seizures in about half of the instances. AEs following the maximum dose of midazolam included hypoxia in 26.7% of patients and respiratory depression in 9.7%, indicating significant side effects at higher dosages. In New South Wales, Australia, administering the maximum dose of midazolam to seizure patients is rare but proves effective in approximately half of the refractory seizure cases. Therefore, assessing the potential for additional doses of midazolam or the use of a second-line agent is advisable.

Fertility-sparing uterine displacement for pelvic malignancies: surgical options and radiotherapy dosimetry on a human cadaver

BackgroundRadio(chemo)therapy is often required in pelvic malignancies (cancer of the anus, rectum, cervix). Direct irradiation adversely affects ovarian and endometrial function, compromising the fertility of women. While ovarian transposition is an established method to move the ovaries away from the radiation field, surgical procedures to displace the uterus are investigational. This study demonstrates the surgical options for uterine displacement in relation to the radiation dose received. MethodsThe uterine displacement techniques were carried out sequentially in a human female cadaver to demonstrate each procedure step by step and assess the uterine positions with dosimetric CT scans in a hybrid operating room. Two treatment plans (anal and rectal cancer) were simulated on each of the four dosimetric scans (1. anatomical position, 2. uterine suspension of the round ligaments to the abdominal wall 3. ventrofixation of the uterine fundus at the umbilical level, 4. uterine transposition). Treatments were planned on Eclipse® System (Varian Medical Systems®,USA) using Volumetric Modulated Arc Therapy. Data about maximum (Dmax) and mean (Dmean) radiation dose received and the volume receiving 14 Gy (V14Gy) were collected.ResultsAll procedures were completed without technical complications. In the rectal cancer simulation with delivery of 50 Gy to the tumor, Dmax, Dmean and V14Gy to the uterus were respectively 52,8 Gy, 34,3 Gy and 30,5cc (1), 31,8 Gy, 20,2 Gy and 22.0cc (2), 24,4 Gy, 6,8 Gy and 5,5cc (3), 1,8 Gy, 0,6 Gy and 0,0cc (4). For anal cancer, delivering 64 Gy to the tumor respectively 46,7 Gy, 34,8 Gy and 31,3cc (1), 34,3 Gy, 20,0 Gy and 21,5cc (2), 21,8 Gy, 5,9 Gy and 2,6cc (3), 1,4 Gy, 0,7 Gy and 0,0cc (4).ConclusionsThe feasibility of several uterine displacement procedures was safely demonstrated. Increasing distance to the radiation field requires more complex surgical interventions to minimize radiation exposure. Surgical strategy needs to be tailored to the multidisciplinary treatment plan, and uterine transposition is the most technically complex with the least dose received.

A Maximum Dose Bioassay to Assess Efficacy of Spinetoram against Cowpea Thrip Megalurothrips usitatus in China.

The bean flower thrip Megalurothrips usitatus (Bagnall) is a severe pest on cowpeas and causes a 20-30% reduction in cowpeas in Hainan, China, with even complete crop failure in severe cases. Spinetoram is currently the most important pesticide against M. usitatus in cowpea production. In the main producing areas of cowpeas in Hainan, however, the efficacy of spinetoram against M. usitatus is not well known. In the present study, we employed the maximum dose bioassay to evaluate the efficacy of the mortality rates of adult thrips at F0 in spinetoram, freshly collected from 212 field populations of M. usitatus collected from 20 villages in the Yazhou District of Hainan. Our results showed that the mortality rates of these thrip populations exposed to spinetoram were from 3.31% to 100%. Among them, the mortality rates of 66.98% (142/212) of the populations exceeded 80%, while that of 33.96% (72/212) of the populations surpassed 90%. Only a small proportion of 0.47% (1/212) the populations exhibited a mortality rate below 10%, and 4.72% (10/212) displayed rates below 50%. Furthermore, significant differences were also observed in the mortality rates of thrips among different villages. Taken together, the maximum dosage bioassay method is a rapid and easily implemented approach providing valuable insights into the field efficacy of insecticides and offers guidance in determining the optimal dosage required in the field. Spinetoram is still effective against M. usitatus in the main producing areas of cowpeas in Hainan, but caution should be exercised in its combined use with other methods to reduce potential resistance.

Complementary use of conduction system pacing techniques for the “pace and ablate” strategy in permanent atrial fibrillation - a case report

Abstract Introduction The feasibility of the conduction system pacing combined with atrioventricular node ablation was demonstrated in patients with atrial fibrillation in whom rate control can’t be achieved with medication and heart failure. Clinical case We present a case of an 82-year-old man with a personal history of permanent atrial fibrillation, admitted with symptoms of heart failure. The resting electrocardiogram showed a very fast ventricular response, and the echocardiography showed a depressed left ventricular function, raising the suspicion of a tachycardia-mediated cardiomyopathy. Since the patient was on maximum doses of atrioventricular nodal-blocking drugs, we opted for a physiological pacing and atrioventricular node ablation strategy. First, the His bundle capture was achieved at low pacing thresholds, and ablation of the atrioventricular node was attempted. Unfortunately, after several failed attempts, an acute increase in the His bundle capture threshold was noted, suggesting inadvertent tissue ablation beneath the pacing lead. In this scenario, we removed the lead from the His bundle area and achieved optimal left bundle branch area pacing. With the lead in this position, atrioventricular node ablation was performed during the first attempt. At the six-month follow-up, there was no recovery of atrioventricular node conduction. Device interrogation revealed stable pacing and sensing parameters, and there was a significant improvement in clinical status and left ventricular function. Conclusions Mastering both His bundle pacing and left bundle branch area pacing offers the potential to overcome intraprocedural challenges, giving alternative strategies to achieve physiological pacing. These approaches can be used interchangeably based on the evolving dynamics of the procedure and the patient’s specific needs.

Phase I trial of chidamide, an oral HDAC inhibitor, in combination with oral etoposide in patients with refractory/recurrent neuroblastoma.

10034 Background: Chidamide, an oral subtype-selective histone deacetylase (HDAC) inhibitor, has been shown to be effective in adult patients with hematological tumors. However, there is no data on its safety and efficacy in pediatric cancer patients. Combination of HDAC inhibitors and etoposide have shown synergistic anti-tumor effects in preclinical studies of neuroblastoma. We conducted a phase I trial in pediatric patients with recurrent or refractory neuroblastoma to determine the maximum tolerable dose (MTD) of chidamide combined with oral etoposide treatment. Methods: Daily oral etoposide 35 mg/m2/dose was administered on days 1–21 in combination with escalating doses of chidamide (14 and 17 mg/m2/d) twice weekly in each 28-day cycle using the standard 3 + 3 design. Patients with response or stable disease after two cycles would maintain treatment until disease progression or unacceptable toxicity occurred. Chidamide pharmacokinetic testing was performed. Results: 31 patients were enrolled in this study. The median age was 7 years (range 3 – 18). 14 patients were included in the dose escalation phase (Ia), 17 patients in the expansion cohort (Ib). The MTD of chidamide was 14 mg/m2/d, with dose limiting neutropenia and thrombocytopenia observed at 17 mg/m2/d. Median number of cycles completed was 2.5 (range 1–11). A total of 19 patients (61.3%) experienced treatment-related grade 3/4 hematologic toxicity, and no grade 3/4 non-hematological toxicity was observed. No objective responses were seen. Conclusions: In children with refractory/recurrent neuroblastoma, chidamide is well-tolerated at 14 mg/m2/d twice weekly when combining with oral etoposide 35 mg/m2/d daily. Prolonged disease stability achieved in patients with minimal residual diseases deserves further investigation. Clinical trial information: NCT05338541 .

Radiological environmental impact assessment for phosphate industry in Korea

NORM is used as a raw material in various industries worldwide. According to the IAEA, radiological effects may occur in the environment due to raw materials and by-products generated from NORM industries. The objective of this study was to assess radiological environmental impact of the phosphate processing industry to identify the radiological effects on the general public. The resident farmer scenario was chosen as the exposure scenario due to the living characteristics of the public around the facility and the conservatism of the assessment. The RESRAD-OFFSITE code was used to evaluate the radiation dose to the public. The maximum radiation dose to the public was 6.13 × 10−3 mSv/y. Main exposure pathways were aquatic food ingestion, radon inhalation, and meat ingestion. The uranium series accounted for about 99 % of the total radiation dose, while the thorium series and K-40 nuclides accounted for less than 1 %. These study results can be used for management of radiological impact to the public around domestic NORM industries.

Does Adjuvant Gamma Knife Stereotactic Radiosurgery Have a Role in Treating Optic Nerve Sheath Meningiomas?

Meningiomas arising from or adjacent to the optic nerve sheath meningioma (ONSM) are management challenges because of their risk of visual loss. Stereotactic radiosurgery (SRS) is a minimally invasive modality that can be added as adjuvant treatment for patients whose tumor has progressed or recurred after initial resection. The authors retrospectively reviewed 2,030 meningioma patients who underwent SRS between 1987 and 2022. In total, 7 patients (4 females; median age = 49) were found with tumors originating from the optic nerve sheath. None of the patients had tumors that engulfed the optic nerve as such tumors typically undergo fractionated radiation therapy (FRT) to preserve vision. The clinical history, visual function, and radiographic and neurological findings were characterized. Outcome measures included visual status, tumor control, and the need for additional management. All patients underwent either initial gross total (n = 1) or partial surgical resection (n = 6) before SRS. Two patients with progressive tumor growth also had SRS after failing additional fractionated radiation after surgery (54 Gy, 30 fractions for both patients). The median time between the date of surgery and the SRS procedure date was 38 months. The Leksell Gamma Knife was used to deliver a margin dose of 12 Gy (range: 8-14 Gy) to a median cumulative tumor volume of 3.3 cc (range: 1.2-18 cc). The median maximal optic nerve radiation dose was 6.5 Gy (range: 1.9-8.1 Gy). After SRS, the median follow-up time was 130 months (range: 26-169 months). Two patients showed local tumor progression at 20 and 55 months after SRS. Four had stable visual function, 2 experienced improved visual acuity, and 1 patient had visual deterioration. Meningiomas arising from (but not engulfing the optic nerve) represent management quandaries after failed initial surgical removal. In this experience, salvage SRS was associated with tumor control and vision preservation in 5 of 7 patients. Additional experience with this strategy may further define the role of SRS both as a salvage and primary option.

Phase I trial of talimogene laherparepvec for the treatment of peritoneal surface malignancies (TEMPO).

2668 Background: Peritoneal surface malignancies (PSM) constitute a group of difficult-to-treat metastatic diseases that respond poorly to standard chemotherapy. Talimogene Laherparepvec (T-VEC), the first FDA-approved oncolytic virus (OV), demonstrates potential in treating various malignancies by effectively initiating crucial immune responses. Yet, the utility of intraperitoneal (ip) T-VEC for unresectable PSM is still unexplored. Methods: TEMPO (NCT03663712) was a nonrandomized, open-label, multicenter phase I trial involving 18 patients with unresectable PSM originating from the appendix (n=14), ovary (n=3), or small bowel (n=1). The trial aimed to determine the recommended Phase 2 dose (RP2D) and maximum tolerated dose (MTD) of ip T-VEC, as well as to evaluate its safety and tolerability. An exploratory endpoint was the Restricted Mean Survival Time (RMST), the estimated non-parametric mean survival time up until the longest patient follow-up time (i.e. maximum of the longest follow-up, and generally an underestimate of the actual mean survival time especially in small samples). Patients received an initial dose of 4x106 plaque-forming units (pfu) of ip T-VEC, followed by their assigned dose every two weeks for up to four additional doses, using a standard ‘3+3’ dose escalation scheme. The doses tested were 4x106, 4x107, and 4x108 pfu of ip T-VEC. Safety assessments were conducted regularly. Results: The RP2D is 4x108 pfu of T-VEC. The trial reported no dose-limiting toxicities, thus the MTD was not reached. Treatment-Related Adverse Events (TRAEs) were recorded and categorized by the maximum dose received (Table).One patient treated with 4x106 pfu had grade 3 abdominal pain and another grade 3 fatigue. No severe TRAEs occurred with 4x107pfu. One patient showed a grade 3 neutrophil count decrease at 4x108 pfu. The RMST, calculated with a truncation time of 5.5 months, varied across the doses. Patients receiving 4x106 pfu had an RMST of 3.1 (95% CI= 1.550-4.733) months, while those treated with 4x107 and 4x108 pfu had RMSTs of 4.2 (95% CI= 2.492-5.884) and 4.6 (95% CI= 3.551-5.722) months, respectively. Conclusions: We conclude that ip T-VEC is safe in patients with unresectable PSM. TEMPO successfully identified 4x108 pfu as the RP2D for TVEC. Notably, the RMST increased with increasing doses of TL. These results are promising, considering the limited benefit of conventional chemotherapy in treating PSM. This study positions T-VEC as a promising candidate for combination immunotherapies for PSM that amplifies the bystander immune response induced by OVs. Clinical trial information: NCT03663712 . [Table: see text]

Neoadjuvant pazopanib with radiation therapy in patients with localized sarcoma: Experience from a sarcoma center.

e23555 Background: Tissue oxygenation is critical to the success of radiation therapy (RT) in any tumor type. However, tumor vasculature is abnormally structured and dysfunctional. Anti-angiogenic molecules have been shown to stabilize the intratumoral vascular structures and improve tissue oxygenation, which may aid in the success of RT. Pazopanib (PAZO) is a multi-kinase inhibitor targeting the Vascular Endothelial Growth Factor Receptor. Here, we report the pathologic outcome and clinical correlates of concurrent use of neoadjuvant PAZO and RT in our cohort of patients with localized soft-tissue sarcoma (STS). Methods: This is a retrospective, single institution study of patients diagnosed with localized STS between January 2019 and October 2023. Patients who received concurrent PAZO and pre-operative external beam RT (50 Gy in 25 fractions) were included. Patients with metastatic disease, unplanned resections, and those requiring excisional biopsy/curettage for diagnosis were excluded. The primary endpoint was the rate of major pathologic response (mPR) defined by &gt; 90% necrosis on surgical pathology specimen. The secondary endpoint was local relapse-free survival (RFS), distant metastasis-free survival (DMFS), and local and distant relapse rate (RR) at 6 months. All-grade toxicities from PAZO were recorded. Results: Ten patients with a median age of 51 years (Interquartile range (IQR): 34-76) were included. Undifferentiated pleomorphic sarcoma was the most common histologic subtype (50% patients). Median follow up was 24.2 months (IQR: 11-36). Six patients tolerated the maximum dose of PAZO until RT completion (800mg PO daily). The dose of PAZO was reduced in 4 patients due to grade 3 GI toxicity and HTN. Nine patients stayed on PAZO until RT completion. The median time to surgery after RT was 42 days (IQR: 37-77). The median largest tumor dimension prior to RT was 11.65 cm (IQR: 3.8 to 18), and 10.6 cm (IQR: 5.4 to 19.7) after RT completion. Nine of 10 patients had R0 resection, and 7 (70%) had mPR. Three of 7 (43%) patients had complete necrosis. All patients with R0 resection have no local recurrence after a median follow-up of 23 months (IQR: 11-36). Median local RFS was 20 months (IQR: 5-32), and DMFS was 6 months (IQR: 1-32). The local RR at 6 months was 10%, and the distant RR at 6 months was 30%. No correlation was observed between mPR and DMFS. Conclusions: Historically, neoadjuvant RT alone induces a mPR in ~30% of patients with localized STS. In our cohort, neoadjuvant PAZO with RT achieved an mPR in 70% of patients. Although dose reduction and grade 3 toxicity were noted in the majority of patients, these were reversible after stopping PAZO. There was no correlation between mPR and DMFS. However, a short course of PAZO with RT may help achieve R0 margins, which is the strongest predictor of better local RFS. A randomized trial is warranted to help understand the true impact of neoadjuvant PAZO with RT.

Type II RAF inhibitor tovorafenib in relapsed/refractory pediatric low-grade glioma (pLGG): Reversible decreases in growth velocity in the phase 2 FIREFLY-1 trial.

10036 Background: Tovorafenib is an investigational, selective, CNS-penetrant, type II RAF inhibitor. Results from the ongoing FIREFLY-1 (NCT04775485) phase 2 study (1) in BRAF-altered pLGG showed clinically meaningful tumor responses and a manageable safety profile with tovorafenib monotherapy. Decreased growth velocity (GV) was observed; this is an update on changes in GV in skeletally immature children receiving tovorafenib. Methods: A planned safety analysis was completed on August 8, 2023 and included 137 patients (Arm 1: 77 &amp; Arm 2: 60) treated with ≥1 dose of tovorafenib in FIREFLY-1. This report provides additional follow-up on all cases of decreased growth velocity (GV), an adverse event of special interest (AESI), reported to the Sponsor’s global safety database (GSDB) as of January 19, 2024. Results: Decreased GV was reported in 40 (29.2%) of 137 patients; 26 (19%) had GV reduction ≥50% from baseline (BL). Of those with decreased GV, 30 (75.0%) had pre-existing neuromuscular or endocrine comorbidities that may affect normal growth, including 6 (15%) with precocious puberty being treated with a gonadotropin-releasing hormone analogue, and 9 (22.5%) with BL heights 2 standard deviations above or below average for age and sex. Nineteen of the 40 patients with this AESI had on-treatment bone age assessments; none showed advancement of bone age from BL or premature closure of growth plates. No osteopenia or abnormal fractures were reported. Of the 35 patients with growth hormone (GH) testing, only 2 had signs of GH deficiency (both had optic pathway tumors; 1 had GH deficiency at BL, the other, a new tumor-associated GH deficiency). Post-treatment heights ≥3 months off treatment were reported for 10 of 40 patients who had interrupted or discontinued treatment for any reason (mean follow up: 5.8 months), including 2 (1.5%) permanent discontinuations and 3 (2.2%) interruptions due to decreased GV. All 10 showed post-treatment recovery in annualized GV (AGV) (average on-treatment AGV 1.1 cm/y vs. average post-treatment AGV 8 cm/y), in some cases exceeding expected average AGV for age. One additional 4-year-old boy with on-treatment AGV of 1.2 cm/y had an off-treatment AGV of 12.3 cm/y after 2 months of off-treatment follow-up. Decreased GV was reported to the GSDB for 5 (11.4%) of 44 patients who received above the maximum dose of tovorafenib used in FIREFLY-1 in an ongoing investigator-initiated study. Four of the 5 patients from this study had ≥3 months of off-treatment follow-up reported; all 4 showed evidence of GV recovery. Conclusions: Decreased GV has been observed in patients treated with tovorafenib. Early follow-up data from patients whose treatment was interrupted show consistent evidence for GV recovery and preservation of growth potential on bone age studies. 1. Kilburn LK, et al. Nat Med.2023. Clinical trial information: NCT04775485 .

Efficacy of 10%,25% and 50% dextrose in the treatment of hypoglycemia in the emergency department – A randomized controlled study

IntroductionDocumented symptomatic hypoglycemia is defined as “event during which typical symptoms of hypoglycemia are accompanied by measured blood glucose of ≤70 mg/dL. Most of the studies and recommendations for the unconscious hypoglycemic adult advocate the use of 25 g of glucose as 50 mL of 50% dextrose solution intravenous or 1 mg of intramuscular glucagon. ObjectiveTo compare the efficacy and safety of 5 g boluses of 10%, 25% and 50% dextrose in the treatment of hypoglycemic patients presenting to our emergency department. MethodsThis was a randomized controlled single blinded study. Hypoglycemic patients in altered mental status were randomized into three treatment arms to be administered 10%, 25% or 50% dextrose. 5 g aliquots of intravenous 10%,25% or 50% dextrose were administered over 1 min. Time taken to achieve a Glasgow Coma Scale (GCS) of 15 and median total doses (g) were the primary outcomes. ResultsData of 204 patients were analysed in the study. There was no difference in the median time to achieve a GCS of 15 in all three treatment arms (6 min). Total median dose administered in the 10% and 25% groups was lower than 50% (10 g vs 15 g). Proportion of patients who received the maximum dose of 25 g was higher in the 50% group as compared to 10% and 25% groups (12%, 3%, 4%). ConclusionThere was no difference in 10% dextrose and 25% dextrose as compared to 50% dextrose in achieving the baseline mental status (or GCS 15) in the treatment of hypoglycemia in the ED.

Phase 1b/2a study evaluating the combination of MN-166 (ibudilast) and temozolomide in patients with newly diagnosed and recurrent glioblastoma (GBM).

2016 Background: Ibudilast is a selective inhibitor of macrophage inhibitory factor (MIF) activity, which is upregulated in GBM and promotes stem cell growth. It also disrupts the interaction between MIF and CD74. When combined with temozolomide (TMZ) in preclinical studies, it attenuates the immunosuppressive properties of myeloid-derived suppressor cells and enhances tumor regression. This is a phase 1b/2a single-center, open-label, dose escalation study evaluating the safety, tolerability, and efficacy of the combination of Ibudilast and TMZ in newly diagnosed (nGBM) and recurrent (rGBM) GBM was initiated (NCT03782415). Methods: We included patients with nGBM who had completed concurrent chemoradiation, and patients with first GBM relapse who had a measurable enhancing disease. Patients were treated with monthly cycles of temozolomide (5 days of a 28-day cycle) and daily ibudilast, with a starting dose of 30 mg twice daily (BID), and escalated to a maximal dose of 50 mg BID. The primary objectives were to evaluate the safety and tolerability of the combination and determine the phase 2 recommended dose (R2PD) for phase 1b, and to evaluate the efficacy of the combination, determined by the 6-month progression-free survival rate (PFS-6) for phase 2a. A standard 3+3 design was used for phase 1b. For the rGBM cohort, a sample size of 30 provided 80% power to discriminate between historical 15% and 35% PFS-6 rates for rGBM patients. The trial would be considered successful if at least 8 patients were progression free at 6 months. Secondary objectives included overall survival (OS). Immunohistochemistry (IHC) studies were performed on archival tumor samples to evaluate factors of the tumor immune microenvironment. Results: 36 patients with nGBM and 26 patients with rGBM were included; 61% were males, with median age of 59 years. Ibudilast 50 mg BID was deemed to be the R2PD. PFS-6 was 44% (16 patients) in nGBM, and 31% (8 patients) in rGBM. The median OS was 21.0 months (17.7, 23.1) for nGBM and 8.6 months (7.8, 10.5) for rGBM. IHC evaluation on the original tumor tissue for patients with rGBM revealed a significantly higher CD3 positive cells infiltration, and elevated CD74 expression in tumors of patients who progressed at 5 months compared to those who did not. Conclusions: This study met its primary endpoint for rGBM, as the combination of ibudilast and TMZ was associated with a higher PFS-6 rate than historical controls. CD3 expression was a good predictor for tumor progression at 5 months in patients with rGBM. Encouraging preclinical studies suggest enhanced efficacy of ibudilast in GBM when combined to immune checkpoint blockade agents. Clinical trial information: NCT03782415 .

Radiation resistant metal–organic frameworks for the production of high specific activity 51Cr by the Szilard-Chalmers effect

Chromium-51 (51Cr) is an attractive radionuclide for diagnosis, which is usually applied for red cells and platelet radiolabeling. However, commercially available 51Cr produced in nuclear reactors via neutron activation requires long irradiation times and complex separation methods. In this work, five metal–organic frameworks (MIL-100 (Cr), MIL-100 (Fe), MIL-100 (Al), MIL-101 (Cr) and aluminium fumarate MOF (FuAl)) were synthesized and the effect of gamma ray irradiation with a high dose rate and a maximum dose of 6 MGy was investigated. The two chromium-based MOFs, MIL-100 (Cr) and MIL-101 (Cr), were selected as radiation targets to produce high specific activity 51Cr by the Szilard-Chalmers effect. A solid–liquid extraction was applied to extract the produced 51Cr under different conditions, including different extractants, extraction times and pH. The most promising results were achieved when using irradiated MIL-101 (Cr) and EDTA as extracting agent, reaching an enrichment factor of 1132 ± 50.