Molecular Targeting of the Isocitrate Dehydrogenase Pathway and the Implications for Cancer Therapy.

The advent of comprehensive genomic profiling using next-generation sequencing (NGS) has unveiled an abundance of potentially actionable genetic aberrations that have shaped our understanding of the cancer biology landscape. Isocitrate dehydrogenase (IDH) is an enzyme present in the cytosol (IDH1) and mitochondria (IDH2 and IDH3). In the mitochondrion, it catalyzes the irreversible oxidative decarboxylation of isocitrate, yielding the production of α-ketoglutarate and nicotinamide adenine dinucleotide phosphate (NADPH) as well as carbon dioxide (CO2). In the cytosol, IDH catalyzes the decarboxylation of isocitrate to α-ketoglutarate as well as the reverse reductive carboxylation of α-ketoglutarate to isocitrate. These rate-limiting steps in the tricarboxylic acid cycle, as well as the cytoplasmic response to oxidative stress, play key roles in gene regulation, cell differentiation, and tissue homeostasis. Mutations in the genes encoding IDH1 and IDH2 and, less commonly, IDH3 have been found in a variety of cancers, most commonly glioma, acute myeloid leukemia (AML), chondrosarcoma, and intrahepatic cholangiocarcinoma. In this paper, we intend to elucidate the theorized pathophysiology behind IDH isomer mutation, its implication in cancer manifestation, and discuss some of the available clinical data regarding the use of novel IDH inhibitors and their role in therapy.

Efficacy of CD19 directed therapies in patients with relapsed or refractory large b-cell lymphoma relapsing after CD19 directed chimeric antigen receptor T-cell therapy.

Outcomes are poor for patients with relapsed and/or refractory (R/R) large B-cell lymphoma (LBCL) post chimeric antigen receptor T-cell (CAR-T) therapy. Two CD19-directed therapies, tafasitamab- cxix plus lenalidomide (tafa-len) and loncastuximab tesirine (loncaT) are approved in R/R LBCL. The efficacy of these CD19 directed therapies in patients who relapse after CD19 directed CAR-T (CD19-CART) therapy is not well understood. We conducted a multi-center study of patients with R/R LBCL that received either tafa-len or loncaT at any timepoint for R/R disease after CD19-CART therapy. Fifty-three patients were included in this study with the median follow up of 56 (9.1-199) weeks from CAR-T infusion. Median number of systemic therapies pre-CAR-T therapy was 3 (range: 1-6); axicabtagene ciloleucel was the most utilized CAR-T product (n = 32,60%). Median time from CAR-T therapy to tafa-len or loncaT was 7.3 (1.2-38.2) months with median number of lines of therapy between CAR-T therapy and these regimens of 1 (0-5). Combined overall response rate and complete response rates were 27% and 10%, respectively. Median duration of response was 13.3 (2.1-56.7) weeks. In this real-world study, the use of currently approved CD19-directed therapies to treat R/R LBCL after CD19-CAR-T therapy showed limited clinical activity and duration of responses.

Vanishing Bile Duct Syndrome in a Patient With Recurrent Hodgkin Lymphoma.

Vanishing bile duct syndrome (VBDS) is an acquired syndrome characterized by clinical and laboratory signs of cholestasis with pathologic findings of interlobular bile duct paucity in liver biopsy specimens. VBDS can result from a variety of conditions including infections, autoimmune diseases, adverse drug reactions, and neoplastic processes. Hodgkin lymphoma (HL) is a rare cause of VBDS. The mechanism by which HL leads to VBDS remains unknown. Development of VBDS in patients with HL portends an extremely poor prognosis due to the risk of progression to fulminant hepatic failure. Treatment of the underlying lymphoma has been demonstrated to offer increased probability of recovery from VBDS. The decision to treat and choice of treatment of the underlying lymphoma is often complicated by the hepatic dysfunction characteristic of VBDS. We present the case of a patient who presented with dyspnea and jaundice in the context of recurrent HL and VBDS. We additionally review the literature on HL complicated by VBDS with specific focus on treatment paradigms for management of these patients.

Efficacy and safety following two or more years of vagus nerve stimulation (VNS Therapy) in pediatric patients with drug-resistant epilepsy enrolled in a Russian VNS Registry.

INTRODUCTION: Following approval in 2009 of vagus nerve stimulation (VNS Therapy) for drug-resistant epilepsy (DRE) in the Russian Federation, this is the first multicenter study across Russia to evaluate the safety and efficacy of adjunctive VNS Therapy. METHODS: The retrospective, observational registry included 58 pediatric patients with DRE (5-17 years old at implantation) who had ≥2 years of VNS. To ensure a robust evaluation process, changes in seizure frequency were evaluated for all seizure types as well as "most disabling" seizures (defined as seizures accompanied by falls, physical trauma, and/or incontinence in the absence of preventative measures). RESULTS: With 2 years of VNS Therapy, 37 of 49 patients (76%) experiencing the most disabling epileptic seizures had a >50% decrease in frequency of such seizures, and 16 (33%) reported no longer experiencing the "most disabling" seizure type. In addition, based on the McHugh Outcome scale, VNS Therapy had a positive outcome on both frequency and severity of all epileptic seizure types, with a >50% decrease in frequency of all epileptic seizure types noted in 37 of 58 patients (64%), and 31% of patients had a Class I outcome, including 11 patients (19%) who achieved seizure freedom. VNS Therapy also had a positive effect on the frequency of status epilepticus: 13 patients (22%) had status epilepticus prior to implantation with a mean rate of 9.4 ± 17.7 events per year (range, 0-52), and after VNS Therapy, only one patient continued to experience status epilepticus (at 1 event per 4-6 months). VNS Therapy had an acceptable safety profile and no adverse events leading to VNS discontinuation were reported. CONCLUSIONS: The results demonstrate that VNS Therapy is being safely and effectively applied to pediatric patients in the Russian healthcare system.

TiNi-Based Material with Shape-Memory Effect for Surgical Treatment of Diseases of Small Intestine in Newborn and Young Children.

Alloys based on TiNi are widely used in various fields of technology and medicine. In the present work, we report on the preparation of TiNi-alloy-based wire with the shape-memory effect, which was used for compression clips for surgery. The composition and structure of the wire and its martensitic and physical-chemical properties were studied using SEM, TEM, optic microscopy, profilometry, mechanical tests, etc. The TiNi alloy was found to consist of B2 and B19' and secondary-phase particles of Ti2Ni, TiNi3 and Ti3Ni4. Its matrix was slightly enriched in Ni (50.3 at.% of Ni). A homogeneous grain structure was revealed (an average grain size of 19 ± 0.3 µm) with equal quantities of grain boundaries of special and general types. The surface oxide layer provides improved biocompatibility and promotes the adhesion of protein molecules. Overall, the obtained TiNi wire was concluded to exhibit martensitic, physical and mechanical properties suitable for its use as an implant material. The wire was then used for manufacturing compression clips with the shape-memory effect and applied in surgery. The medical experiment that involved 46 children demonstrated that the use of such clips in children with double-barreled enterostomies permitted improvement in the results of surgical treatment.

Mantle Cell Lymphoma: the Role of Risk-Adapted Therapy and Treatment of Relapsed Disease.

PURPOSE OF REVIEW: In this review, the current treatment strategies are recapped, evolving agents are discussed, and we provide guidance in treating R/R MCL. RECENT FINDINGS: There has been an advancement in treatment using targeted therapy, cellular therapies including chimeric antigen receptor (CAR) T cell therapy and hematopoietic stem cell transplantation (HSCT) and novel therapeutic agents including non-covalent BTKis, bispecific antibodies, and antibody-drug conjugates for treatment of refractory and relapsed mantle cell lymphoma. Mantle cell lymphoma (MCL) is a mature B-cell lymphoma that is associated with a poor prognosis. Current treatments include immunochemotherapy, chemotherapy and autologous stem cell transplantation (SCT) which place patients in remission but result in relapse. Chemoimmunotherapy uses chemotherapeutic agents paired with rituximab in patients who have chemo-sensitive disease with prolonged remission of at least > 2 years and/or have contraindications to chemotherapy that serve as bridges to more definitive treatment. Additional therapies including proteosome inhibitor-based therapies and immunomodulators, like bortezomib and lenalidomide, can be used as single agents or in combination with others. Bruton's tyrosine kinase (BTK) inhibitors including ibrutinib, acalaburtinib, and zanubrutinib have also been proven effective for the treatment of (R/R) disease. Another agent is Venetoclax, a robust drug that can be used in MCL after progression or intolerance to BTKi. Newer advances in the management of MCL have led to the utilization of cellular therapies including chimeric antigen receptor (CAR) T cell therapy and SCT that are options for healthy young (< 65 years old) who have progressed through several lines of therapies. With progression of disease, mutations are acquired that cause therapy resistance. Novel therapeutic agents such as non-covalent BTKis, bispecific antibodies, and antibody-drug conjugates are paving the way for advancements in treatment for R/R MCL. R/R MCL is a complex disease with many therapeutic options none of which has been proven superior in head-to-head comparison. In this review, the current treatment strategies are recapped, evolving agents are discussed, and we provide guidance in treating R/R MCL.

Early Clinical Effects of Novel Partial D3/D2 Agonist Cariprazine in Schizophrenia Patients With Predominantly Negative Symptoms (Open-Label, Non-controlled Study).

BACKGROUND: Because of limited efficacy of antipsychotics against negative symptoms in schizophrenia new drugs with wider spectrums of clinical efficacy are very desirable. The newer 3rd generation antipsychotic cariprazine presents the unique mode of action acting as partial agonist predominantly for dopamine D3- and in lesser extent D2-receptors. Cariprazine is found to be effective in the treatment of negative symptoms in schizophrenia comparing to second generation antipsychotic risperidone. OBJECTIVES: To evaluate initial effects of cariprazine in schizophrenia patients with predominantly negative symptoms. DESIGN AND PATIENTS: Open-label, non-controlled study included 60 adult schizophrenia patients (F20 on ICD-10, 49% males) with predominantly negative symptoms (Positive and Negative Syndrome Scale, S factor score for negative and positive symptoms, PANSS-FSNS ≥ 15 and PANSS-FSPS <19) treated with cariprazine (starting daily dose 1.5 mg followed by upward titration by 1.5 mg weekly up to 6 mg if needed) were assessed with PANSS, CAINS (The Clinical Assessment Interview for Negative Symptoms), CDSS (Calgary Depression Scale for Schizophrenia), and SAS (Simpson-Angus Scale for Extrapyramidal Symptoms) scales at baseline and on week 1, 2, and 4. RESULTS: Most patients (75%) improved during 28 days of cariprazine treatment. At the end of assessment (day 28) mean starting total scores for negative symptoms on PANSS-NS and CAINS scales significantly (p < 0.05) reduced by 4.3 and 4.9, respectively, with no significant changes in depression symptoms (CDSS). Cariprazine tolerability was very good, only four patients discontinued because of TEAEs (akathisia, insomnia). CONCLUSIONS: The results of this study suggest early effect of cariprazine on negative symptoms at least in some schizophrenia patients with predominantly negative symptoms starting from 1 to 2 weeks of treatment and could be useful for determination of early clinical predictors for efficacy. Considering limitations of open-label design with no control groups these data need to be confirmed.

A conceptual framework of the service delivery system design for hospitality firms in the (post-)viral world: The role of service robots.

This study aims to develop a conceptual framework of the service delivery system design for hospitality firms in the (post-)viral world. Several theoretical approaches such as resource-based view, value chain analysis, stakeholder theory, PESTEL analysis, positioning strategy, and service delivery system design were adopted. The paper identified three service delivery system designs (robotic, human-based, and mixed) and analyses their requirements, advantages, disadvantages, and potential target markets. According to the suggested model, hospitality firms need first to explore the expectations of tourists. Then comes the analysis phase (based on a holistic perspective, and consisting of RBV, Value chain, Stakeholder, and PESTEL analyses), which helps hospitality firms to identify how they should differentiate and position themselves in the market. Following, companies decide on what kind of service delivery system they should offer to their target customers, and position themselves in the market according to the chosen system.

Transformation of Chronic Myeloid Leukemia to Acute Biphenotypic Leukemia.

Chronic myeloid leukemia (CML) is a myeloproliferative disorder with clonal proliferation of all myeloid cell lines. The disease typically manifests in three phases: chronic course followed by an accelerated phase and finally a terminal blast crisis. A blast crisis is defined as the presence of > 20% blasts in the peripheral blood or bone marrow. The blasts could be characterized as either myeloid (60-80% of cases) resulting in acute myeloblastic leukemia or lymphoid (20-30% of cases) resulting in acute lymphoblastic leukemia. In rare instances, a blast crisis could present with biphenotypic expression for both myeloid and lymphoid blasts. In such cases, about 6-10% of the time, the course of the disease is more aggressive and renders a poorer prognosis especially if there is evidence of extramedullary involvement. We present a case of a 41-year-old woman with history of CML who presented with acute biphenotypic blast crisis with extramedullary involvement in the context of aggressive chemotherapy. Literature review reveals < 10 reported cases of CML with biphasic transformation and only three cases of CML with acute leukemia on presentation. Most cases described are in pediatric patients with varied presentations and none involving extramedullary sites. Mortality rates in such cases are near 100% despite aggressive chemotherapy.

Case Report: Two Cases of Cholangiocarcinoma in Patients with Opisthorchis felineus Infection in Western Siberia, Russian Federation.

Cholangiocarcinoma (CCA) is a cancer with high mortality owing to its aggressiveness and resistance to therapy. The liver flukes of the Opisthorchiidae family have been recognized as risk factors of CCA. Opisthorchis felineus infection occurs in Western Siberia, the biggest endemic area in the Russian Federation, and is associated with chronic inflammation of the bile ducts, which may be linked to severe hepatobiliary morbidity. We report two cases of confirmed CCA who had a chronic O. felineus infection. Both cases presented unspecific symptoms at the onset of the disease, a stage when severe pathological changes already had occurred. Both patients were living in endemic areas but did not receive any antihelminthic treatment. This report underlines the need for assessment of O. felineus infection as a causative factor of CCA. The results will provide further arguments for control of O. felineus in the Russian Federation.

Agomelatine in the treatment of depressive disorders in clinical practice: multicenter observational CHRONOS study.

BACKGROUND: CHRONOS was a large naturalistic study designed to evaluate the effectiveness and safety of agomelatine in the management of patients with major depression in routine clinical practice. METHODS: Patients (n=6,276) with a moderate or severe major depressive episode without psychotic symptoms were treated initially as outpatients (80.2%) or in psychiatric facilities (19.8%) in 54 regions of the Russian Federation. Patients received a flexible-dosing regimen of agomelatine 25 mg or 50 mg once daily for 8 weeks, with frequent study visits (weeks 1, 2, 3, 4, 6, and 8). RESULTS: Patients (mean age 44 years, 72.6% female) showed progressive improvement on the 17-item Hamilton Rating Scale for Depression (HAMD-17) total score from 22±6.9 at baseline to 4.7±4.7 at week 8 (P<0.0001). The proportion of responders (HAMD-17 decrease of ≥50%) was 90.1% and the proportion of remitters (HAMD-17 <7) was 79.1% at week 8. All individual HAMD-17 item scores improved rapidly, and the change relative to baseline was significant (P<0.0001) at week 1 and at each subsequent visit in all cases. There were corresponding rapid improvements in Clinical Global Impression Severity and Improvement scores. In the subgroup of patients with more severe illness (HAMD-17 ≥21 at baseline; n=3,478), the proportions of responders and remitters were 92.4% and 72.8%, respectively, at week 8. CONCLUSION: Agomelatine was effective and well tolerated in a large sample of depressed patients in an observational treatment setting, and showed a rapid onset of benefit across all HAMD-17 items.

The exchange-correlation potential in ab initio density functional theory.

From coupled-cluster theory and many-body perturbation theory we derive the local exchange-correlation potential of density functional theory in an orbital dependent form. We show the relationship between the coupled-cluster approach and density functional theory, and connections and comparisons with our previous second-order correlation potential [OEP-MBPT(2) (OEP-optimized effective potential)] [I. Grabowski, S. Hirata, S. Ivanov, and R. J. Bartlett, J. Chem. Phys. 116, 4415 (2002)]. Starting from a general theoretical framework based on the density condition in Kohn-Sham theory, we define a rigorous exchange-correlation functional, potential and orbitals. Specifying initially to second-order terms, we show that our ab initio correlation potential provides the correct shape compared to those from reference quantum Monte Carlo calculations, and we demonstrate the superiority of using Fock matrix elements or more general infinite-order semicanonical transformations. This enables us to introduce a method that is guaranteed to converge to the right answer in the correlation and basis set limit, just as does ab initio wave function theory. We also demonstrate that the energies obtained from this generalized second-order method [OEP-MBPT2-f] and [OEP-MBPT2-sc] are often of coupled-cluster accuracy and substantially better than ordinary Hartree-Fock based second-order MBPT=MP2.

Neoadjuvant chemotherapy and local radiotherapy for high-grade osteosarcoma of the extremities.

OBJECTIVE: To determine the effectiveness of radiation therapy for local control of nonmetastatic osteosarcoma of the extremities after induction chemotherapy. PATIENTS AND METHODS: Of 187 patients with nonmetastatic osteosarcoma of the extremities treated with induction chemotherapy since 1986, 31 refused surgery and underwent standard, fractionated external beam radiotherapy for local control. The median radiation dose to the limb was 60 Gy (range 40-68 Gy). Records were reviewed through April 2002, and outcomes including radiologic and biochemical response, local control, limb function, and survival were analyzed. The end points were local progression-free survival, metastases-free survival, and overall survival. RESULTS: Overall survival, local progression-free survival, and metastases-free survival at 5 years were a mean +/- SD of 61%+/-11%, 56%+/-12%, and 62%+/-10%, respectively. The outcome correlated significantly with patients' imaging and biochemical response. In patients who had a pronounced response, overall survival and metastases-free survival at 5 years were 90%+/-9% and 91%+/-9%, respectively, but it was only 35%+/-15% and 42%+/-13% in the nonresponders (P=.005 and P=.005, respectively). Local control was also related to response after induction chemotherapy. None of the 11 patients with both a good imaging and a good biochemical response had local relapse; median follow-up was 67 months. The estimated local progression-free survival among nonresponders was 31%+/-16% at 3 years and 0% at 5 years. Of 22 patients surviving without local disease progression, 19 (86%) had excellent limb function (Enneking score between 90% and 100%) at the time of most recent evaluation. CONCLUSION: When used after effective induction chemotherapy for osteosarcoma of the extremities, radiation therapy can be a reliable modality to control local disease and preserve limb function.