Insulin-like growth factor-1 receptor inhibitor, AMG-479, in cetuximab-refractory head and neck squamous cell carcinoma

Background Recurrent head and neck squamous cell carcinoma (HNSCC) remains a difficult cancer to treat. Here, we describe a patient with HNSCC who had complete response to methotrexate (MTX) after progressing on multiple cytotoxic agents, cetuximab, and AMG-479 (monoclonal antibody against insulin-like growth factor-1 receptor [IGF-1R]). Methods The clinical information was collected by a retrospective medical record review under an Institutional Review Board-approved protocol. From 4 tumors and 2 normal mucosal epithelia, global gene expression, and IGF-1R and dihydrofolate reductase (DHFR) protein levels were determined. Results Effective target inhibition in the tumor was confirmed by the decreased protein levels of total and phospho-IGF-1R after treatment with AMG-479. Decreased level of DHFR and conversion of a gene expression profile associated with cetuximab-resistance to cetuximab-sensitivity were also observed. Conclusion This suggests that the combination of AMG-479 and MTX or cetuximab may be a promising therapeutic approach in refractory HNSCC

Rechallenge patients with immune checkpoint inhibitors following severe immune-related adverse events: review of the literature and suggested prophylactic strategy.

Patients with cancer who developed severe, grade 3 or 4 immune-related adverse events (irAEs) during therapy with immune checkpoint inhibitors are at risk for developing severe toxicities again on rechallenge with checkpoint inhibitors. Consequently, medical oncologists and multidisciplinary teams are hesitant to retreat in this scenario, despite the fact that a number of patients may derive clinical benefit from this approach. Balancing such clinical benefit and treatment-related toxicities for each patient is becoming increasingly challenging as more and more patients with cancer are being treated with checkpoint inhibitors. In this manuscript, we provide an extensive overview of the relevant literature on retreatment after toxicity, and suggest prophylactic approaches to minimize the risk of severe irAE following rechallenge with immune checkpoint blockade, since treatment may be lifesaving in a number of occasions

MECHANICAL PROPERTIES ANISOTROPY RESEARCH OF COLD ROLLED TRANSFORMER STEEL

В настоящей работе было проведено испытание на растяжение образцов сплава Fe-3%Si в состоянии после холодной прокатки. Испытания проводили в трёх направлениях: направление прокатки, поперечное и диагональное (45° относительно направления прокатки). Было обнаружено, что величина временного сопротивления в направлении прокатки на 5 % меньше, чем в поперечном направлении.Tensile tests of Fe-3%Si alloy cold rolled samples were carried out in this paper. There were three orientations of samples for tensile tests: rolling direction, transverse direction and diagonal direction (45° to rolling direction). It was discovered that ultimate strength value in rolling direction is less than transverse direction by 5 %

The Great Debate at "Melanoma Bridge", Naples, December 7th, 2019.

The Great Debate session at the 2019 Melanoma Bridge congress (December 5-7, Naples, Italy) featured counterpoint views from experts on five topical issues in melanoma. These were whether to choose local intratumoral treatment or systemic treatment, whether patients with stage IIIA melanoma require adjuvant therapy or not, whether treatment is better changed at disease progression or during stable disease, whether adoptive cell transfer (ACT) therapy is more appropriate used before or in combination with checkpoint inhibition therapy, and whether treatment can be stopped while the patient is still on response. As was the case for previous meetings, the debates were assigned by meeting Chairs. As such, positions taken by each of the melanoma experts during the debates may not have reflected their respective personal approach

Recombinant interleukin-21 plus sorafenib for metastatic renal cell carcinoma: a phase 1/2 study

Abstract Background Despite the positive impact of targeted therapies on metastatic renal cell carcinoma (mRCC), durable responses are infrequent and an unmet need exists for novel therapies with distinct mechanisms of action. We investigated the combination of recombinant Interleukin 21 (IL-21), a cytokine with unique immunostimulatory properties, plus sorafenib, a VEGFR tyrosine kinase inhibitor. Methods In this phase 1/2 study, 52 mRCC patients received outpatient treatment with oral sorafenib 400 mg twice daily plus intravenous IL-21 (10–50 mcg/kg) on days 1–5 and 15–19 of each 7-week treatment course. The safety, antitumor activity, pharmacokinetic and pharmacodynamic effects of the combination were evaluated. Results In phase 1 (n = 19), the maximum tolerated dose for IL-21 with the standard dose of sorafenib was determined to be 30 mcg/kg/day; grade 3 skin rash was the only dose-limiting toxicity. In phase 2, 33 previously-treated patients tolerated the combination therapy well with appropriate dose reductions; toxicities were mostly grade 1 or 2. The objective response rate was 21% and disease control rate was 82%. Two patients have durable responses that are ongoing, despite cessation of both IL-21 and sorafenib, at 41+ and 30+ months, respectively. The median progression-free survival in phase 2 was 5.6 months. The pharmacokinetic and pharmacodynamic properties of IL-21 appeared to be preserved in the presence of sorafenib. Conclusion IL-21 plus sorafenib has antitumor activity and acceptable safety in previously treated mRCC patients. IL-21 may represent a suitable immunotherapy in further exploration of combination strategies in mRCC. Trial registration ClinicalTrials.gov Identifier: NCT0038928

Continuous Monitoring of Information on Anode Current Distribution as Means of Improving the Process of Controlling and Forecasting Process Disturbances

За последние десятилетия система АСУТП электролиза достигла больших возможностей по улучшению сбора и обработки сигналов, которые обеспечивают основу для регулирования питания, теплового баланса и магнитогидродинамической (МГД) стабильности. Несмотря на значительное развитие, постоянно растут потребности в датчиках контроля, которые могут распознавать и реагировать на возникающие изменения. C 2008 г. на электролизерах опытного участка РА-400, расположенного в опытно-промышленном корпусе электролиза ОАО «РУСАЛ Саяногорск», эксплуатируется система непрерывного мониторинга информации о распределении тока по анодам, интегрированная в АСУТП СААТ-2. На протяжении промышленных испытаний система мониторинга постоянно совершенствовалась в части достоверности информации, обеспечения работоспособности оборудования в условиях агрессивных сред, а также при выполнении технологических и ремонтных операций на электролизере. Полученная информация о распределении тока по анодам позволила разработать алгоритмы, прогнозирующие на ранней стадии отклонения в питании глиноземом электролизера с последующим перераспределением по точкам автоматической подачи глинозема (АПГ), прогнозирование и распознавание технологических нарушений на подошве анодов («конуса»)The aluminum reduction process control system in recent decades has given great opportunities for improving the collection and processing of signals that provide the basis for the adjustment of feeding, thermal balance and magnetohydrodynamic (MHD) stability. Despite considerable development, there is a growing need for control sensors that can detect and respond to emerging changes. Since 2008, the cells operating in the RA-400 pilot area inside the Pilot Potroom at OJSC RUSAL Sayanogorsk have been using a system for continuous monitoring of information on anode current distribution. The system has been integrated in the ‘CAAT-2’ control system. In the course of industrial tests, the monitoring system was continuously improved – in terms of information reliability, and equipment operability in aggressive environments and during pot tending & maintenance operations. The obtained information on anode current distribution allowed for developing algorithms to detect, at an early stage, variations in cell alumina feeding, including further alumina re-distribution between feed points, and forecast and detect anode bottom problems (“spike”

Element Accumulation Patterns of Native Plant Species under the Natural Geochemical Stress

A biogeochemical study of more than 20,000 soil and plant samples from the North Caucasus, Dzungarian Alatau, Kazakh Uplands, and Karatau Mountains revealed features of the chemical element uptake by the local flora. Adaptation of ore prospecting techniques alongside environmental approaches allowed the detection of geochemical changes in ecosystems, and the lessons learned can be embraced for soil phytoremediation. The data on the influence of phytogeochemical stress on the accumulation of more than 20 chemical elements by plants are considered in geochemical provinces, secondary fields of deposits, halos surrounding ore and nonmetallic deposits, zones of regional faults and schist formation, and over lithological contact lines of chemically contrasting rocks overlain by 5-20 m thick soils and unconsolidated cover. We have corroborated the postulate that the element accumulation patterns of native plants under the natural geochemical stress depend not only on the element content in soils and the characteristics of a particular species but also on the values of ionic radii and valences; with an increase in the energy coefficients of a chemical element, its plant accumulation decreases sharply. The contribution of internal factors to element uptake from solutions gives the way to soil phytoremediation over vast contaminated areas. The use of hyperaccumulating species for mining site soil treatment depends on several external factors that can strengthen or weaken the stressful situation, viz., the amount of bedrock exposure and thickness of unconsolidated rocks over ores, the chemical composition of ores and primary halos in ore-containing strata, the landscape and geochemical features of sites, and chemical element migration patterns in the supergene zone

The Great Debate at 'Immunotherapy Bridge', Naples, December 5, 2019

As part of the 2019 Immunotherapy Bridge congress (December 4–5, Naples, Italy), the Great Debate session featured counterpoint views from leading experts on six topical issues in immunotherapy today. These were the use of chimeric antigen receptor T cell therapy in solid tumors, whether the Immunoscore should be more widely used in clinical practice, whether antibody-dependent cellular cytotoxicity is important in the mode of action of anticytotoxic T-lymphocyte-associated protein 4 antibodies, whether the brain is immunologically unique or just another organ, the role of microbiome versus nutrition in affecting responses to immunotherapy, and whether chemotherapy is immunostimulatory or immunosuppressive. Discussion of these important topics are summarized in this report

Patterns of Clinical Response with Talimogene Laherparepvec (T-VEC) in Patients with Melanoma Treated in the OPTiM Phase III Clinical Trial

PURPOSE: Talimogene laherparepvec (T-VEC) is an oncolytic immunotherapy designed to induce tumor regression of injected lesions through direct lytic effects, and of uninjected lesions through induction of systemic antitumor immunity. In this study, we describe the patterns and time course of response to T-VEC from the phase III OPTiM trial of 436 patients with unresected stages IIIB-IV melanoma. METHODS: Lesion-level response analyses were performed based on the type of lesion (injected or uninjected cutaneous, subcutaneous, or nodal lesions; or visceral lesions [uninjected]), and the best percentage change from baseline of the sum of products of the longest diameters was calculated. Patients randomized to T-VEC (n = 295) who experienced a durable response (continuous partial or complete response for ≥6 months) were evaluated for progression prior to response (PPR), defined as the appearance of a new lesion or >25 % increase in total baseline tumor area. RESULTS: T-VEC resulted in a decrease in size by ≥50 % in 64 % of injected lesions (N = 2116), 34 % of uninjected non-visceral lesions (N = 981), and 15 % of visceral lesions (N = 177). Complete resolution of lesions occurred in 47 % of injected lesions, 22 % of uninjected non-visceral lesions, and 9 % of visceral lesions. Of 48 patients with durable responses, 23 (48 %) experienced PPR, including 14 who developed new lesions only. No difference in overall survival was observed, and median duration of response was not reached in patients with PPR versus those without PPR. CONCLUSIONS: Responses in uninjected lesions provide validation of T-VEC-induced systemic immunotherapeutic effects against melanoma. PPR did not negatively impact the clinical effectiveness of T-VEC