Adequate Reserve Research Articles

O-275 Is there a case for ovarian tissue cryopreservation in young girls and Turner syndrome patients?

Abstract The development of new cancer drugs and drug combinations has led to a dramatic increase in the survival rates of prepubertal and postpubertal girls undergoing myeloablative treatment for malignant or non-malignant diseases. This includes girls who will receive high doses of alkylating agents, total body irradiation, or high radiation doses to the craniospinal, abdominal or pelvic area. Chemotherapy is also used as a conditioning regimen before hematopoietic stem cell transplantation for treatment of, for example, beta thalassaemia or homozygous sickle-cell anaemia. The corollary of improved treatment outcomes of childhood diseases is that many survivors are now at risk of multi-faceted, chronic morbidity, impaired quality-of-life and psychosocial problems. Depending on the nature and duration of their treatment some, but not all, young patients facing fertility threatening diagnosis and treatments will have an increased risk of adverse pregnancy outcomes and premature ovarian insufficiency (POI) as their future fertile potential will be defined by the number of follicles remaining in their ovaries following completion of their chemotherapy/radiotherapy. While a fully functioning hypothalamic-pituitary-ovarian axis and uterus are vital to the reproductive potential of adult females, Ovarian tissue cryopreservation (OTC) is now being used to safeguard the future fertility of prepubertal and adolescent girls and young women undergoing treatments that have a high risk of causing POI. OTC is increasingly advocated for young girls receiving an early diagnosis of the most common sex chromosome abnormality- Turner Syndrome (TS) who have a high risk of POI. In theory the ovaries of girls, including TS patients with an adequate ovarian reserve, are well suited to OTC as their ovaries contain high numbers primordial follicles which can be used to preserve future fertility. Ovarian tissue can be removed laparoscopically and early staged follicles cryopreserved in situ within slices of cortex. The operative approaches used for tissue removal from paediatric and adolescent patients are variable and invasive and are dependent on patient age, health and ovarian reserve at the time of tissue recovery. Extensive research has shown that ovarian cryopreservation techniques are robust and that experienced practitioners can achieve high levels of survival of both the ovarian stroma and follicle compartments post thaw. Cryobanked ovarian cortex collected from prepubertal and postpubertal girls has been shown to function normally and support fertility, pregnancy to term and the birth of healthy babies following orthotopic autografting in adulthood. Regardless of patient age at tissue preservation, autografting of frozen-thawed ovarian cortex at either the site of the retained ovary or into the peritoneal cavity results in an immediate and significant follicle loss due to ischaemia and accelerated apoptosis. Those primordial follicles that survive graft revascularization have been shown to have the capacity to grow to preovulatory stages, to reinstate hormonal function and to undergo ovulation and restore natural fertility. Alternatively, follicle growth can be induced in autografted tissue by controlled ovarian stimulation before oocyte harvest for insemination in vitro using assisted reproductive technologies. Graft functional longevity remains variable between patients and may extend from months to years. Alternative methods for fertility restoration such as the complete in vitro growth and maturation of oocytes and the construction of artificial ovaries remain unproven in humans. While OTC can be recommended for young girls at high risk of developing ovarian insufficiency for genetic reasons or following high dose chemotherapy and/or irradiation, to date very few young patients with stored ovarian tissue have used their tissue for fertility restoration. OTC therefore remains experimental and further research is needed to establish the risks, benefits, efficacy, safety and ethical and clinical frameworks for offering fertility preservation to girls during childhood and adolescence and to girls with TS.

ACCRU-GI-2008: A phase II randomized study of atezolizumab (Atezo) plus a multi-kinase inhibitor (MKI) versus MKI alone in patients with unresectable advanced hepatocellular carcinoma (aHCC) who previously received atezolizumab plus bevacizumab (Bev).

TPS4170 Background: IMbrave150 is the first study demonstrating the benefit of anti-PDL1 in the frontline treatment of aHCC, and established Atezo/Bev as a new 1st line standard for aHCC. There is currently limited evidence to guide subsequent therapy for aHCC patients progressing on Atezo/Bev. ACCRU-GI-2008 is designed to determine the benefit of continuing Atezo into 2nd line and the safety of Atezo plus a MKI in patients with aHCC who previously received Atezo/Bev. The study is being conducted across 12 centers in the United States (ClincalTrials.gov#: NCT05168163). Methods: This study utilizes a 2:1 randomized phase II design where eligible patients will receive either Atezo/MKI (experimental arm) or MKI alone (control). Patients will be stratified according to the MKI choice (cabozantinib or lenvatinib, per physician’s decision), etiology of HCC (viral vs. non-viral) and alpha-fetoprotein level ( < 400 vs. > = 400 ng/mL). The major eligibility criteria are histological/cytological diagnosis or clinical diagnosis of HCC per the AASLD or WASL 2018 guidelines, has advanced disease not amendable to curative treatment, previously received and progressed on Atezo/Bev, has received only 1 previous line of systemic therapy (2nd line only), ECOG PS 0-1, Child Pugh Class A, adequate organ reserves and RECIST v1.1 measurable disease; previous MKI for advanced disease is excluded. The primary endpoints are overall survival (OS) and progression free survival (PFS). A total sample size of 122, with 89 PFS events, we will have 80% power to detect an improvement in median PFS from 4 to 7 months, assuming a one-sided significance level of 0.05. With approximately 84 deaths, we will have 80% power to detect an improvement in median OS from 10 to 18 months, assuming a one-sided significance level of 0.05. The overall one-sided significance level, for the study, is 0.1. An OS interim analysis will be conducted at 89 PFS events. Secondary endpoints include objective response, duration of response, and adverse events. Archival tumor and serial blood samples will be collected to evaluate for potential prediction biomarkers and mechanisms of sensitivity/resistance. Baseline and on-treatment tumor biopsy specimens will also be collected from the initial 10 patients of each arm. The study is approved by the ethics committee and enrollment to the study will be underway by Q2/3 2022. Clinical trial information: NCT05168163.

ARTISTRY-7: A phase 3, multicenter study of nemvaleukin alfa in combination with pembrolizumab versus chemotherapy in patients (pts) with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer.

TPS5609 Background: ARTISTRY-7 will evaluate the novel engineered cytokine nemvaleukin alfa (nemvaleukin, ALKS 4230) in pts with gynecologic cancers. Epithelial ovarian cancer (OC) is the 7th most common cause of cancer mortality in women. OC is an area of high unmet need, as many pts become resistant or refractory to frontline platinum-based chemotherapy. Nemvaleukin was designed to selectively bind to the intermediate-affinity interleukin-2 (IL-2) receptor, preferentially activating and expanding antitumor CD8+ T and NK cells with minimal expansion of Tregs. This selectivity may provide enhanced tumor killing and improved safety/tolerability compared with high-dose IL-2. In clinical studies, nemvaleukin, as monotherapy and in combination with pembrolizumab, has shown evidence of clinical benefit in multiple tumor types, including OC. In ARTISTRY-1, 4 responses were observed in pts with OC, including 2 complete responses, 1 in a pt with platinum-resistant OC and 5 prior lines of therapy, and 2 partial responses. Methods: ARTISTRY-7 is a phase 3, multicenter, open-label randomized study of nemvaleukin and/or pembrolizumab vs chemotherapy. Eligible pts are women (≥18 y) with histologically confirmed epithelial OC (high-grade serous, endometrioid, clear cell), fallopian tube cancer, or primary peritoneal cancer. Pts must have received ≥1 prior line of systemic therapy in the platinum-sensitive setting, ≤5 prior lines in the platinum-resistant setting, and prior bevacizumab, with radiographic progression on most recent therapy. Primary platinum-refractory disease (progression on first-line platinum therapy) or primary platinum resistance (progression < 3 months after completion of first-line platinum therapy) is exclusionary. Pts must have ECOG performance status of 0 or 1, estimated life expectancy of ≥3 months, and adequate hematologic reserve and hepatic and renal function. Approximately 376 pts will be randomized (3:1:1:3) to receive nemvaleukin 6 μg/kg IV on days 1-5 and pembrolizumab 200 mg IV on day 1 of each 21-day cycle, pembrolizumab monotherapy, nemvaleukin monotherapy, or chemotherapy (pegylated liposomal doxorubicin, paclitaxel, topotecan, or gemcitabine) and stratified according to PD-L1 status, histologic subtype (high-grade vs non–high-grade serous), and chemotherapy (paclitaxel vs other). Pts will continue treatment until disease progression or intolerable toxicity (maximum 35 cycles for pembrolizumab; nemvaleukin can be continued). The primary endpoint is investigator-assessed PFS (RECIST v1.1) in the nemvaleukin/pembrolizumab vs chemotherapy group. Secondary/exploratory endpoints include overall survival, other antitumor measures, safety, health-related quality of life, and pharmacokinetic/pharmacodynamic effects. Clinical trial information: NCT05092360.

ARTISTRY-3: Effect of nemvaleukin alfa with a less frequent IV dosing schedule as monotherapy and in combination with pembrolizumab and impact on the tumor microenvironment (TME) in patients (pts) with advanced solid tumors.

TPS2684 Background: Nemvaleukin alfa (nemvaleukin, ALKS 4230) is a novel engineered cytokine that selectively binds the intermediate-affinity interleukin-2 (IL-2) receptor, preferentially activating and expanding antitumor CD8+ T cells and NK effector cells, with minimal effect on regulatory T cells. Nemvaleukin was designed to leverage antitumor effects of the IL-2 pathway while limiting typical IL-2‒associated toxicity. In ARTISTRY-1, the recommended phase 2 dose (RP2D) for nemvaleukin monotherapy of 6 µg/kg IV on days 1 to 5 of a 21-day cycle elicited durable and deep responses in pts with advanced melanoma and renal cell carcinoma (Boni et al. ASCO 2021:abstr 2513). Responses with nemvaleukin plus pembrolizumab were also observed in platinum-resistant ovarian, breast, cervical, gastrointestinal, and genitourinary cancers. ARTISTRY-3 will investigate the effects of nemvaleukin as monotherapy and in combination with pembrolizumab on the TME in pts with advanced solid tumors, and in an additional cohort (Cohort 2), to further assess a less frequent IV dosing schedule for nemvaleukin. Methods: The phase 1/2, open-label ARTISTRY-3 (NCT04592653) study will enroll adults (≥18 years) with select advanced solid tumors, ≥1 accessible lesion for biopsy, ≥1 target lesion (per RECIST v1.1), ECOG PS of 0 or 1, estimated life expectancy of ≥3 months, adequate hematologic reserve, and adequate hepatic and renal function. Primary objectives: to evaluate effects of nemvaleukin monotherapy on the TME (Cohort 1) and to determine RP2D for less frequent dosing schedule (Cohort 2). Additional objectives are to evaluate: efficacy, safety, immunogenicity, and pharmacokinetics of nemvaleukin monotherapy; effects of nemvaleukin plus pembrolizumab on the TME; and correlative biomarkers of nemvaleukin as monotherapy and combination. Following the protocol amendment, additional pts enrolled in Cohort 1 will receive lead-in monotherapy at a dose selected based on results from Cohort 2, and pre- and on-treatment biopsies will be collected for TME assessments. Subsequent cycles will be administered in combination with pembrolizumab, and a biopsy may be collected at cycle 4 or 5. Tumor types eligible for Cohort 2 are selected based on activity observed in the ARTISTRY-1 study. A quantitative system pharmacology model was applied to identify a less frequent schedule for nemvaleukin monotherapy and combination. Cohort 2 will initially assess safety and tolerability of nemvaleukin at 1 dose per 21-day cycle. Two doses per 21-day cycle may be implemented to achieve optimal PK/PD parameters. Bayesian optimal interval design methodology with open enrollment will be applied to facilitate dose escalation decisions. Clinical trial information: NCT04592653.

ARTISTRY-6: Nemvaleukin alfa monotherapy in patients with advanced mucosal and cutaneous melanoma.

TPS9609 Background: Despite improved outcomes for melanoma patients with the introduction of checkpoint inhibitors (CPIs), ̃50% of patients do not respond. A subset of responders ultimately progress and have limited treatment options, underscoring a high unmet need for novel treatments with durable benefit. Patients with mucosal melanoma exhibit response rates and progression-free survival times ̃2 times lower than those with cutaneous melanoma. Nemvaleukin alfa (nemvaleukin, ALKS 4230) is a novel, engineered cytokine that selectively binds the intermediate-affinity interleukin-2 receptor complex to preferentially activate CD8+ T and NK cells with minimal expansion of regulatory T cells. Nemvaleukin has been granted Orphan Drug designation for the treatment of mucosal melanoma by the FDA. In ARTISTRY-1, the intravenous (IV) recommended phase 2 dose (RP2D) of 6 µg/kg nemvaleukin monotherapy demonstrated durable antitumor activity in patients with advanced melanoma, including mucosal melanoma, previously treated with a CPI. In ARTISTRY-2, the subcutaneous (SC) RP2D of 3 mg q7d was identified demonstrating pharmacodynamic effects consistent with IV delivery. Data support further evaluation of nemvaleukin monotherapy among patients with advanced mucosal and cutaneous melanoma. Methods: ARTISTRY-6 is a phase 2, global, multicenter, open-label study. Eligible patients have had prior treatment with an anti–PD-(L)1 therapy with or without anti–CTLA-4 therapy and have an ECOG performance status of 0 or 1 and adequate hematologic reserve and hepatic and renal function. Patients with advanced cutaneous (Cohort 1) and mucosal (Cohort 2) melanoma will receive nemvaleukin at the SC and IV RP2D, respectively. Patients will receive nemvaleukin until progression or intolerable toxicity. The primary objective is to evaluate the antitumor activity of nemvaleukin monotherapy defined by overall response rate. Additional objectives include the evaluation of safety, health-related quality of life, predictive biomarkers, pharmacokinetics, immunogenicity, and pharmacodynamic effects. Clinical trial information: NCT04830124.

Evaluation of a perioperative steroid coverage after pituitary surgery

IntroductionSerum cortisol levels within the first days after pituitary surgery have been shown to be a predictor of post-surgical adrenal insufficiency. However, the indication of empirical glucocorticoids to avoid this complication remains controversial.The objective is to assess the role of cortisol in the early postoperative period as a predictor of long-term corticotropic function according to the pituitary perisurgical protocol with corticosteroid replacement followed in our center. MethodsOne hundred eighteen patients who underwent surgery in a single center between December 2012 and January 2020 for a pituitary adenoma were included. Of these, 54 patients with previous adrenal insufficiency (AI), Cushing's disease, or tumors that required treatment with high-dose glucocorticoids (GC) were excluded. A treatment protocol with glucocorticoids was established, consisting of its empirical administration at rapidly decreasing doses, and serum cortisol was determined on the third day after surgery. Subsequent adrenal status was assessed through follow-up biochemical and clinical evaluations. ResultsOut of the 64 patients treated, there were 56 macroadenomas and 8 microadenomas. The incidence of adrenal insufficiency after pituitary surgery was 4.7%. The optimal cut-off value that predicted an adequate corticotropic reserve, taking into account the best relationship of specificity and sensitivity, was ≥4.1 μg/dl for serum cortisol on the third day (sensitivity 95.1%, specificity 100%). ConclusionSerum cortisol on the third day predicts the development of adrenal insufficiency. We suggest a cortisol cut-off point of ≥4.1 μg/dl on postoperative on the third day after surgery as a predictor of the adrenal reserve in the long-term.

Multi-stage resilience scheduling of electricity-gas integrated energy system with multi-level decentralized reserve

Extreme events pose threats to secure and consistent supply of electricity-gas integrated energy system (EGIES), and adequate resilience is essential for improving risk defense abilities. Considering the constraints of power distribution network (PDN) and natural gas system (NGS), a multi-stage strategy integrating multi-level decentralized reserve is proposed for resilience enhancement in EGIES. Storages of multi-area community integrated energy systems (CIESs) serve as the secondary reserve while the primary reserve, i.e., independent electric power/natural gas system, fails to meet reserve requirements. Furthermore, the thermal storage of building air on the consumption side is taken as the tertiary reserve, so as to obtain a better emergency response effect. The scheduling framework consists of reserve calculation, economic scheduling, and fault restoration. On the basis of multi-area reserve calculation, day-ahead economic scheduling is conducted, maintaining adequate reserve with consideration of decentralized reserve constraints; thus, high-priority demands can be recovered in case of supply disruptions. In addition, the flexible topology of PDN is utilized to facilitate the restored loads by optimal islanding partition. Via conic relaxation conversion, the original nonconvex model is tracked into a unified mixed-integer second-order cone programming (MISOCP) formulation, which can be effectively and accurately solved. Finally, numerical study on a modified IEEE 33-bus test system and a modified 7-node gas system connecting multiple community integrated energy systems shows the effectiveness of the proposed resilience strategy.

Regional Logistics in Improving the Defense Economy in the Region

Covid-19 has had an impact not only on health but also on the resilience of the national economy. Learning from the history of war, if we have weapons without food reserves, it will be messy as well as increasing food security to anticipate the impact of disease outbreaks such as Covid-19 which could happen again in the future. The Ministry of Defense is serious about developing the Food Estate Program by reviewing several potential land locations for planting strategic commodities. The plan to develop the "Food Estate" area in Central Kalimantan launched by the President of the Republic of Indonesia Joko Widodo is a collaboration between the Ministry of Defense, the Ministry of PUPR, the Ministry of Agriculture, the Ministry of Environment and Forestry and the Ministry of SOEs. The research method uses descriptive qualitative. The results of the study show that the strength of food security is no less important than the strength of weapons, especially in dealing with the current situation such as the impact of the Covid-19 pandemic. For this reason, Indonesia must have adequate food reserves.

Understanding Dyspnea in a Patient with Pulmonary Vein Stenosis

<h3>Introduction</h3> 53-year-old female with a medical history of familial dilated cardiomyopathy, status post atrial fibrillation ablation in 2014 complicated by left pulmonary vein stenosis (PVS) requiring stenting, presents with dyspnea post surgical valve repair for tricuspid regurgitation. <h3>Case Report</h3> The patient presented with dyspnea and orthopnea for 1 month post cardiac surgery which did not improve with diuresis. Right heart catheterization confirmed euvolemia and preserved cardiac output. Given the history of PVS, lung perfusion scan was obtained which revealed left lung perfusion of 6% and right lung perfusion of 94% (1A). CTA confirmed occluded left sided pulmonary vein (1B). Further review of records confirmed that lung perfusion scan demonstrated similar results 4 years ago, and thus PVS did not adequately explain her acute dyspnea. Pulmonary function testing was obtained revealing FEV1 39% predicted, FVC 37% of predicted, FEV1/FVC 106% predicted, suggestive of new restrictive physiology. There was no significant parenchymal lung disease on chest CT to explain this finding, so chest fluoroscopy was performed. This confirmed right hemidiaphragm paralysis (1C), most likely secondary to phrenic nerve injury during cardiac surgery. Home noninvasive positive pressure ventilation at night was instituted, and over time her symptoms improved. <h3>Summary</h3> Patients with chronic unilateral PVS may be asymptomatic if there is adequate contralateral pulmonary reserve. Additional etiologies of dyspnea should be excluded in such patients. Unilateral hemidiaphragm paralysis is frequently asymptomatic. However, in rare circumstances, these two syndromes can occur on contralateral sides resulting in debilitating symptoms.

Spatial variation of vegetation changes in Sokoto region from 2000 to 2018

Previous researchers reported that vegetation is one of the natural resources that are constantly changing. These changes are mostly found in an area affected by human activities. Those researchers study vegetation using holistic approach without identifying the locations affected and species of plant that withstand the prevailing conditions. The aim of this research was to find out the locations where these changes are mostly affected. This was achieved using Coefficient of Variation analysis on MODIS-EVI dataset, supported by the field observation. The result shows that high CV areas are mostly around farmlands and around the nomadic routes, while low CV areas are around the floodplains of Rivers Sokoto and Rima. The identified plant species that can survive in the high CV areas are Gueira senegalensis (Sabara), Combretum micranthum (Geza) and Piliostigma thonningii (Kalgo). It was recommended that the dominant plant species in the area should be domesticated and used for afforestation programme in the region. Government should provide adequate grazing reserves and animal routes to avoid indiscriminate grazing activities in the area.

The impact of non-structural carbohydrates (NSC) concentration on yield in Prunus dulcis, Pistacia vera, and Juglans regia

Successful yield in orchards is the culmination of a series of events that start with plants entering dormancy with adequate energy reserves (non-structural carbohydrates; NSC). These NSC are responsible for the maintenance of activities during dormancy and extending onto the period of activeness. Using multi-year yield information and monthly NSC content in twigs, we show that high levels of carbohydrate in Prunus dulcis, Pistachio vera, and Juglans regia during the winter months are indeed associated with high yield, while high levels of the NSC in late summer often correlate with low yield. An evaluation of monthly NSC level importance on yield revealed that for P. dulcis high levels in February were a good predictor of yield and that low levels throughout summer were associated with high yield. In P. vera, high levels of NSC in December were best predictors of yield. J. regia exhibited peculiar patterns; while high pre-budbreak reserves were associated with high yields they only played a minor role in explaining crop, the most important months for predicting yields were June and July. Results suggest that NSC levels can serve as good predictors of orchard yield potential and should be monitored to inform orchard management.

Surgical revascularization for moyamoya angiopathy: Clinical and radiological outcomes of direct and indirect bypasses in 86 affected hemispheres

Moyamoya is a progressive cerebral angiopathy that entails a formidable natural history of repeated ischemic or haemorrhagic insults if not intervened. The potential advantages of direct/combined bypass can be harvested only if they are not outweighed by perioperative morbidity. Direct bypasses for the paediatric group have been less utilized because of small vessel calibres and an inherently more robust angioplasticity. This study was undertaken to examine the clinical and perfusion imaging outcomes of operated moyamoya disease or syndrome patients in Hong Kong’s Southeast Asian population. Comparison was made between direct/combined and indirect bypass cohorts. Subgroup analysis of the paediatric cohort was conducted to determine outcomes of a direct-bypass-first strategy. From November 2000 to September 2020, 86 hemispheres underwent revascularization at a tertiary neurosurgical unit with a mean clinical follow-up time of 70.0 months. 70.9% of the procedures involved direct bypasses. Direct/combined revascularization demonstrated superiority in restoring adequate cerebrovascular reserve capacity (CVRC) (63.2% vs 27.3%, p = 0.015), and freedom from transient ischemic attacks in the first 5 years post-operation by Kaplan-Meier plot with log-rank test (p = 0.038). Follow-up imaging revealed 96.5% of the bypass grafts remained patent. Direct/combined procedures significantly predicted restoration of adequate CVRC on follow-up perfusions scans by binary logistic regression (OR 4.57, p = 0.009). Compared to the adult cohort, direct bypasses in children carried no excessive perioperative morbidity. These results support a liberal bypass-first paradigm in both adult and paediatric cohorts.

Development a New Flexibility Index Suitable for Power System Operational Planning

Power system flexibility is an important characteristic in both power system planning and operation, which should be evaluated and maintained in the desired value. On the other hand, more renewable energy integration leads to increasing uncertainty and variability in the power system. Therefore, the power system should have the sufficient ability to overcome the adverse effects of uncertainty and variability named as flexibility, which should be improved by suitable tools such as adequate reserve, fast ramp up/down generation sources and suitable energy storage capacity. Power system flexibility evaluation is the main task that needs suitable indices to indicate the level of system flexibility correctly. In the current paper, a well-known system flexibility index named normalized flexibility index, which is used for power system planning horizon is modified to use for the operational planning time zone. In this concept, the flexibility index is separated into two components, each of them indicating the ability of the power system to withstand upward/downward net-load uncertainty and variability. In the further, this is shown these two components are the same as the upward/downward system reserve and can be converted to economic value simply. So, this concept facilitates the economic trade-off between operation cost and system flexibility, improving cost to achieve the best level of system flexibility.

A phase I study of pharmacokinetic (PK)-driven sequential dosing of rucaparib (RUB) with irinotecan liposome (nal-IRI) and fluorouracil (5FU) in metastatic gastrointestinal (mGI) and pancreas (PANC) cancers.

563 Background: RUB is an oral PARP1,2,3 inhibitor that demonstrated efficacy in patients (pts) with ovarian and prostate cancers harboring deleterious BRCA mutations. RUB exerts synergistic anti-tumor effect with IRI preclinically though the combination has overlapping toxicities. We previously published on the population PK of nal-IRI (Adiwijaya, Ma et al, Clin Pharm Ther 2017). We conducted a phase I study to evaluate a novel sequential dosing of RUB with nal-IRI/5FU in mGI cancer pts. Methods: Eligible pts had incurable mGI cancer previously received &gt; 1 line of therapy (rx), ECOG PS 0-1, had RECIST measurable disease, adequate organ reserves and not received IRI for metastatic disease. Previous PARPi rx was excluded. The endpoints included dose limiting toxicity (DLT), maximum tolerated dose (MTD) and toxicity profile. The dose escalation utilized the 3+3 design. RUB was given oral bid on Day 4 to 13 and 18 to 27 with nal-IRI i.v. and 5FU i.v. 2400 mg/m2 over 46 hr on Day 1 and 15, every 28 day. Planned dose levels were RUB 400 mg/nal-IRI 50 mg/m2 (DL1), 400 mg/70 mg/m2 (DL2) and 600 mg/70 mg/m2 (DL3). Adverse events (AEs) were scored per CTCAE v4.03. Molecular profile was evaluated by CLIA-certified NGS testing. Results: Eighteen pts including 11 colorectal (CRC), 6 PANC, 1 gastroesophageal (GE) were enrolled and 12 were evaluable for DLTs. DL2 was not tolerable (DLT: G3 diarrhea, nausea and vomiting) and DL2A was added (RUB 600 mg/nal-IRI 50 mg/m2). DL2A enrolled 6 pts with no DLT and was determined as the MTD. Of DLT-evaluable pts, G3 and worse treatment-related AEs from all cycles were diarrhea (33%), fatigue (25%), leukopenia (25%), neutropenia (25%), anemia (8%) and nausea (8%). Four of 12 response evaluable pts had partial response: 2 CRC (1 had ATM mut), 1 PANC ( ATM mut), 1 GE ( BRCA2 mut) whilst 3 responders previously had platinum (PLA). Five pts had stable disease beyond 16 weeks (range 18.9 to 100.7 weeks), and all had prior PLA. Conclusions: The study successfully determined the MTD of RUB in combination with nal-IRI and 5FU. Encouraging efficacy was observed in PLA-treated mGI cancers including responses in those harboring ATM and BRCA alterations. The study is proceeding to evaluate the efficacy of the combination in metastatic pancreas cancer pts with and without BRCA1/2 or PALB2 alterations. Clinical trial information: NCT03337087.

Structural Safety Assessment and Traffic Control Strategies of Widened Highway Bridges under Maintenance Works Requiring Partial Lane Closure

An increasing number of existing bridges need to be widened due to the rapid growth of road transport. Owing to the discontinuities in design specifications for the new and old structures in the widened bridges, it is expected that the old bridge might fail to meet the new design standard, leading to a potential need for vastly retrofit or even totally reconstruction. However, the new and old bridges carry slow and fast traffic lanes respectively, resulting in an uneven distribution of traffic loads between them. A previous study indicated that most components of the old bridge possessed adequate security reserves under normal traffic conditions of all lanes open. However, there are occasional scenarios that the new bridge requires closing traffic lanes to perform maintenance works. Under such circumstances, the traffic is completely diverted from the new bridge to the old bridge, and the safety of the old bridge becomes a critical issue. This study proposes a numerical approach to investigate the structural safety of widened bridges under maintenance works requiring partial lane closure on the new bridge and recommends traffic control measures to ensure bridge safety. The results show that several old slabs are unsafe under the maintenance works requiring lane closure. The weight restriction with a limit value not exceeding 35 t can ensure the safety of the widened bridge, whereas speed control is not effective. The hybrid uses of weight restriction and speed control further enhance the safety of the bridge. When the speed limit is 60 km/h, the weight limits should be not greater than 50 t and 45 t for the one-lane and two-lane closure scenarios, respectively. The research findings are of benefit to bridge engineers when maintenance works requiring lane closures are planned on widened bridges.

A Probabilistic Methodology for Estimating Reserve Requirement and Optimizing Its Components in Systems With High Wind Penetration

The growing penetration of wind generation comes with implicit challenges for power system operators, one of which is the effect that additional shares have on the sufficient magnitude of reserve capacity needed. The determination of adequate reserves would enhance the efficiency and flexibility of the power system. The probabilistic methodology suggested in this paper estimates the reserve requirements as a function of historical data and estimates the incremental increase in reserve requirements as the penetration level increases. Also, the paper estimates the optimal mix of spinning reserve and standing reserve to decrease the number of part-loaded power plants and accommodate more wind power, where a synchronized plant operates less efficiently when partially loaded to provide a reserve. The adopted methodology is applied to real data collected from aggregated wind farms in the period from 2015 to 2020.

Long-Term Follow-Up of Multilevel Thoracic Ossification of the Posterior Longitudinal Ligament Following Circumferential Decompression via Posterior Approach: A Retrospective Study.

ObjectiveTo examine the postoperative progression of multilevel thoracic posterior longitudinal ligament (OPLL) at circumferential decompression (CD) levels and evaluate the long‐term results after CD via the posterior approach.MethodsClinical data from 16 patients with thoracic myelopathy secondary to OPLL who underwent CD at a single center were evaluated retrospectively from 2007 to 2014 and were followed up for more than 60 months. Patients of all sexes and ages were included in the study. Thin‐slice computed tomography scans obtained at the time of surgery and the most recent follow‐up were analyzed. The ossified area was measured on the axial reconstructed scan of the most obvious protrusion of ossification at the CD level. The neurological outcomes were evaluated using modified Japanese Orthopaedic Association (JOA) scores and Hirabayashi recovery rates (HRRs). Continuous variables were presented as the mean ± standard deviation and were analyzed using the Student's t‐test, while categorical variables were tested using Fisher's exact test.ResultsAmong all patients, the most predominant type was the mixed type (9/16, 56.3%), while the circumscribed type was only found in two patients (12.5%), and the continuous type was found in five patients (31.2%). Six cases were associated with ossification of the ligamentum flavum, and two cases were combined with cervical OPLL. The OPLL area at the CD level increased in all patients. The mean follow‐up period was 5.5 ± 0.92 years (range 5–8 years). The mean area of ossification increased from 35.63 ± 39.23 mm2 at the time of surgery to 99.94 ± 65.39 mm2 at the last follow‐up visit (P < 0.01). There was no internal fixation disorder on any computed tomography scan after the operation. The average JOA score of all patients improved from 4.2 ± 2.2 points before surgery to 8.4 ± 2.6 points at the final follow‐up (P < 0.01). The overall HRR was 61.8%. None of the patients exhibited any neurological deterioration due to OPLL progression. One patient developed a severe gait disturbance due to worsening lumbar canal stenosis, an unrelated cause, but the other 15 experienced gait disturbance improvements.ConclusionsAccording to the long‐term follow‐up results, although OPLL progression did not decrease or stop after removing the OPLL mass, CD is a safe and effective procedure that can provide adequate reserve ventral space to cope with postoperative OPLL progression.

Central bank digital currency, loan supply, and bank failure risk: a microeconomic approach

Central bank digital currencies (CBDCs), which are legal tenders in digital form, are expected to reduce currency issuance and circulation costs and broaden the scope of monetary policy. In addition, these currencies may also reduce consumers’ need for conventional demand deposits, which, in turn, increases banks’ loan provision costs because deposits require higher rates of return. We use a microeconomic banking model to investigate the effects of introducing an economy-wide, account-type CBDC on a bank’s loan supply and its failure risk. Given that a CBDC is expected to lower the cost of liquidity circulation and become a strong substitute for demand deposits, both the loan supply and the bank failure risk increase. These increases are countered by subsequent increases in the rates of return on term deposits and loans, which, in turn, reduce the loan supply and thus bank failure risk. These offsetting forces lead to no significant change in banking, as long as the rate of return on loans is below a certain threshold. However, once the rate is above the threshold, bank failure risk increases, thereby undermining banking stability. The problem is more pronounced when the degree of pass-through of funding costs to the loan rate is high and the profitability of a successful project is low. Our results imply that central banks wishing to introduce an economy-wide, account-type CBDC should first monitor yields on bank loans and consider policy measures that induce banks to maintain adequate liquidity reserve levels.

Scenario-based Planning of State Material Reserves: Case Study of Latvia

The article deals with the issue of identifying required material reserves, also referred to as strategic or emergency reserves. These reserves are managed by state authority as part of national crisis preparedness. The article explores how scenarios can be used as a method for planning, i.e. determining adequate, realistic, and affordable material reserves. A scenario-based analysis, well proven in the defence planning domain, is identified as a method offering a high degree of analytical rigor and traceability of resulting requirements. Selected planning scenarios clearly must reflect national threat/hazard and risk assessments. They also have to reflect other important national policies, such as those governing economy, industry, health care, or environment. The illustrative conduct of the initial steps of the proposed method is demonstrated using Latvia’s security policy circumstances.

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. DisclosuresKumar: 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.