bluuebunny/crossref_metadata_2025 huggingface dataset:
Can the Addition of Maintenance Electroconvulsive Therapy to Pharmacotherapy Improve Relapse Prevention in Severe Major Depressive Disorder? A Randomized Controlled Trial
Authors: Martínez-Amorós Erika , Cardoner Narcís , Gálvez Verònica , de Arriba-Arnau Aida , Soria Virginia , Palao Diego J. , Menchón José M. , Urretavizcaya Mikel
Published: October 2021

Few systematic evaluations have been performed of the efficacy of electroconvulsive therapy (ECT) as a relapse prevention strategy in major depressive disorder (MDD). This is a single-blind, multicenter, randomized controlled trial to compare the efficacy and tolerability of pharmacotherapy plus maintenance ECT (M-Pharm/ECT) versus pharmacotherapy alone (M-Pharm) in the prevention of MDD relapse. Subjects with MDD who had remitted with bilateral acute ECT (n = 37) were randomly assigned to receive M-Pharm/ECT (n = 19, 14 treatments) or M-Pharm (n = 18) for nine months. The subjects were followed up for 15 months. The main outcome was relapse of depression, defined as a score of 18 or more on the Hamilton Depression Rating Scale. At nine months, 35% of the subjects treated with M-Pharm/ECT relapsed as compared with 61% of the patients treated with M-Pharm. No statistically significant differences between groups were indicated by either Kaplan–Meier or Cox proportional hazards regression analyses. The subjects without psychotic features were at higher risk of relapse. There were no statistically significant differences in the MMSE scores of the two groups at the end of the study. Further studies are needed to better define the indications for M-ECT in order to improve its efficacy as a relapse prevention strategy.
Recent Advances in Molecular Diagnostics and Targeted Therapy of Myeloproliferative Neoplasms
Authors: Stivala Simona , Meyer Sara C.
Published: October 2021

Somatic mutations in JAK2, calreticulin, and MPL genes drive myeloproliferative neoplasms (MPN), and recent technological advances have revealed a heterogeneous genomic landscape with additional mutations in MPN. These mainly affect genes involved in epigenetic regulation and splicing and are of diagnostic and prognostic value, predicting the risk of progression and informing decisions on therapeutic management. Thus, genetic testing has become an integral part of the current state-of-the-art laboratory work-up for MPN patients and has been implemented in current guidelines for disease classification, tools for prognostic risk assessment, and recommendations for therapy. The finding that JAK2, CALR, and MPL driver mutations activate JAK2 signaling has provided a rational basis for the development of targeted JAK2 inhibitor therapies and has fueled their translation into clinical practice. However, the disease-modifying potential of JAK2 inhibitors remains limited and is further impeded by loss of therapeutic responses in a substantial proportion of patients over time. Therefore, the investigation of additional molecular vulnerabilities involved in MPN pathogenesis is imperative to advance the development of new therapeutic options. Combination of novel compounds with JAK2 inhibitors are of specific interest to enhance therapeutic efficacy of molecularly targeted treatment approaches. Here, we summarize the current insights into the genetic basis of MPN, its use as a diagnostic and prognostic tool in clinical settings, and the most recent advances in targeted therapies for MPN.
Advances in the Treatment of Relapsed and Refractory Multiple Myeloma in Patients with Renal Insufficiency: Novel Agents, Immunotherapies and Beyond
Authors: Bozic Boris , Rutner Jens , Zheng Chang , Ruckser Reinhard , Selimi Flonza , Racz Krysztina , Köcher Martin , Tatzreiter Georg , Sebesta Christian
Published: October 2021

Background: Renal insufficiency is one of the most frequent complications in multiple myeloma. The incidence of renal insufficiency in patients with multiple myeloma ranges from 20% to 50%. Renal impairment in patients with multiple myeloma results primarily from the toxic effects of monoclonal light chains on the kidneys. Dehydration, hypercalcemia, hyperuricemia, the application of nephrotoxic NSARs, antibiotics, contrast agents, etc., all play a major role in the deterioration of renal function in patients with multiple myeloma. The diagnosis and treatment of these patients use an interdisciplinary approach in consultation with hematologist–oncologists, radiologists, nephrologists and intensive care specialists. Using new drugs in the treatment of patients with refractory/relapsed multiple myeloma and renal insufficiency markedly improves progression-free survival and overall survival in these patients. Conclusions: New drugs have helped to widen the treatment options available for patients with renal impairment and refractory/relapsed multiple myeloma, since dose adjustments are unnecessary with carfilzomib as well as with panobinostat, elotuzumab, pomalidomide or daratumumab in patients with renal impairment. Several new substances for the treatment of refractory/relapsed multiple myeloma have been approved in the meantime, including belantamab mafodotin, selinexor, melflufen, venetoclax, CAR T-cell therapy and checkpoint inhibitors. Ongoing studies are investigating their administration in patients with renal impairment.
Microenvironmental Reactive Oxygen Species in Colorectal Cancer: Involved Processes and Therapeutic Opportunities
Authors: Sorolla Maria Alba , Hidalgo Ivan , Sorolla Anabel , Montal Robert , Pallisé Ona , Salud Antonieta , Parisi Eva
Published: October 2021

Colorectal cancer (CRC) is the fourth most common cause of cancer deaths worldwide. Although screening programs have reduced mortality rates, there is a need for research focused on finding the main factors that lead primary CRC to progress and metastasize. During tumor progression, malignant cells modify their habitat, corrupting or transforming cells of different origins and creating the tumor microenvironment (TME). Cells forming the TME like macrophages, neutrophils, and fibroblasts generate reactive oxygen species (ROS) that modify the cancer niche. The effects of ROS in cancer are very diverse: they promote cellular proliferation, epithelial-to-mesenchymal transition (EMT), evasion of cell death programs, migration, and angiogenesis. Due to the multifaceted role of ROS in cancer cell survival and function, ROS-modulating agents such as antioxidants or pro-oxidants could have therapeutic potential in cancer prevention and/or as a complement to systemic treatments. In this review, we will examine the main ROS producer cells and their effects on cancer progression and metastasis. Furthermore, we will enumerate the latest clinical trials where pro-oxidants and antioxidants have therapeutic uses in CRC.
Enhancing Therapeutic Efficacy of Double Negative T Cells against Acute Myeloid Leukemia Using Idelalisib
Authors: Kang Hyeonjeong , Lee Jong Bok , Khatri Ismat , Na Yoosu , D’Souza Cheryl , Arruda Andrea , Minden Mark D. , Zhang Li
Published: October 2021

The double negative T cell (DNT) is a unique subset of T cells with potent anti-leukemic potential. Previously, DNT therapy has been shown to effectively target AML cells in patient-derived xenograft (PDX) models. Further, a recently completed phase I/IIa clinical study demonstrated the safety, feasibility, and potential efficacy in AML patients that relapsed after allogeneic hematopoietic stem cell transplantation. However, the persistence and durability of DNT-mediated anti-leukemic response is less well understood. In this study, we characterized the in vivo persistence of DNTs in PDX models. Further, we improved the efficacy and durability of DNT-mediated activity with phosphoinositide 3-kinase delta (PI3Kδ) inhibition. Mechanistically, DNTs treated with the PI3Kδ inhibitor, Idelalisib (Ide), exhibited early memory phenotype with superior viability and proliferative capacity but less cell exhaustion. Collectively, the findings from this study support the use of Ide-treated DNTs to improve its therapeutic outcome.
Associations between Nutritional and Immune Status and Clinicopathologic Factors in Patients with Pancreatic Cancer: A Comprehensive Analysis
Authors: Jabłońska Beata , Pawlicki Krzysztof , Mrowiec Sławomir
Published: October 2021

The aim of this study was to assess and analyze the nutritional status (NS) and immune status of pancreatic cancer (PC) patients. The retrospective analysis included 80 PC patients undergoing curative pancreatic resection in the Department of Digestive Tract Surgery of the Medical University (Katowice, Poland). Patients were divided by the tumor location (proximal vs. distal), age (≤65 years vs. >65 years), Nutritional Risk Score 2002 (NRS 2002) (<3 vs. ≥3), prognostic nutritional index (PNI) (<45 vs. ≥45), and the presence of postoperative complications (no-complication vs. complication) as well as the use of neoadjuvant chemotherapy (no neoadjuvant chemotherapy vs. neoadjuvant chemotherapy) into two subgroups, which were compared. Significantly higher weight loss was related to the proximal tumor location (p = 0.0104). Significantly lower serum total protein (p = 0.0447), albumin (p = 0.0468), hemoglobin (p = 0.0265) levels, and PNI (p = 0.03) were reported in older patients. The higher nutritional risk according to NRS 2002 was significantly associated with higher age (p = 0.0187), higher weight loss (p < 0.01), lower body mass index (BMI) (p = 0.0293), lower total lymphocyte count (p = 0.0292), longer duration of hospitalization (p = 0.020), neoadjuvant chemotherapy (p < 0.01), and preoperative biliary drainage (p = 0.0492). The lower PNI was significantly associated with higher weight loss (p = 0.0407), lower serum total protein and albumin concentration, lymphocyte count (p < 0.01) and higher neutrophil/lymphocyte (NLR), monocyte/lymphocyte (MLR), platelet/lymphocyte (PLR) ratios, and duration of hospitalization (p < 0.01). In the multiple logistic regression analysis, BMI ≥ 30 kg/m2 (OR: 8.62; 95% CI: 1.24–60.04; p = 0.029521) and NRS 2002 ≥ 3 (OR: 2.87; 95% CI: 0.88–9.33; p = 0.048818) predicted postoperative complications. In the multiple linear regression analysis, the higher NRS 2002 score was linked with the longer duration of hospitalization (b = 7.67948; p = 0.043816), and longer duration of postoperative hospitalization was associated with a higher complication rate (b = 0.273183; p = 0.003100). Nutritional impairment correlates with a systemic inflammatory response in PC patients. Obesity (BMI ≥ 30 kg/m2) and malnutrition (NRS 2002 ≥ 3) predict postoperative complications, which are associate with a longer hospital stay. Assessment of nutritional and immune status using basic diagnostic tools and PNI and immune ratio (NLR, MLR, PLR) calculation should be the standard management of PC patients before surgery to improve the postoperative outcome.
Modern Rotational Radiation Techniques with Volumetric Modulated Arc Therapy or Helical Tomotherapy for Optimal Sparing of the Lung and Heart in Left-Breast Cancer Radiotherapy Plus Regional Nodal Irradiation: A Comparative Dosimetric Analysis
Authors: Hou Pei-Yu , Hsieh Chen-Hsi , Wu Le-Jung , Hsu Chen-Xiong , Kuo Deng-Yu , Lu Yueh-Feng , Tien Hui-Ju , Hsiao Hsiu-Wen , Shueng Pei-Wei , Hsu Shih-Ming
Published: October 2021

Background: For advanced breast cancer with lymph node involvement, adjuvant radiotherapy (RT) with regional nodal irradiation (RNI) has been indicated to reduce cancer recurrence and mortality. However, an extensive RT volume is associated with normal organ exposure, which increases the toxicity and affects patient outcomes. Modern arc RT techniques can improve normal organ sparing compared with conventional techniques. The aim of this study was to explore the optimal technique for left-breast RT with RNI. Methods: We retrospectively reviewed patients receiving RT with RNI for left-breast cancer. We used modern arc RT techniques with either volumetric-modulated arc therapy (VMAT) or helical tomotherapy (HT) with a novel block technique, and compared differences in dosimetry parameters between the two groups. Subgroup analysis of RNI with or without internal mammary node (IMN) volume was also performed. Results: A total of 108 eligible patients were enrolled between 2017 and 2020, of whom 70 received VMAT and 38 received HT. The median RT dose was 55 Gy. No significant differences were found regarding the surgery, RT dose, number of fractions, target volume, and RNI volume between the VMAT and HT groups. VMAT reduced the heart mean dose more than HT (3.82 vs. 5.13 Gy, p < 0.001), as well as the cardiac parameters of V5–V20, whole-lung mean dose, lung parameters of V5–V20, and contralateral-breast and esophagus mean dose. In the subgroup analysis of RNI with IMNs, the advantage of VMAT persisted in protecting the heart, lung, contralateral breast, and esophagus. HT was beneficial for lowering the thyroid mean dose. For RNI without IMN, VMAT improved the low-dose exposure of the heart and lung, but HT was similar to VMAT in terms of heart, whole-lung, and contralateral-breast mean dose. Conclusions: For patients with left-breast cancer receiving adjuvant RT with RNI, VMAT reduced the exposure dose to the heart, lung, contralateral breast, and esophagus compared with HT. VMAT was superior to HT in terms of normal organ sparing in the patients who underwent RNI with IMN irradiation. Considering the reduction in normal organ exposure and potential toxicity, VMAT is the optimal technique for patients receiving RNI when deep inspiration breath-hold is not available.
Inflammatory and Non-Inflammatory Mechanisms Controlling Cirrhosis Development
Authors: Sánchez Paula Sánchez , Rigual María del Mar , Djouder Nabil
Published: October 2021

Because the liver is considered to be one of the most important metabolic organs in the body, it is continuously exposed to damaging environmental agents. Upon damage, several complex cellular and molecular mechanisms in charge of liver recovery and regeneration are activated to prevent the failure of the organ. When liver injury becomes chronic, the regenerative response goes awry and impairs the liver function, consequently leading to cirrhosis, a liver disorder that can cause patient death. Cirrhosis has a disrupted liver architecture and zonation, along with the presence of fibrosis and parenchymal nodules, known as regenerative nodules (RNs). Inflammatory cues contribute to the cirrhotic process in response to chronic damaging agents. Cirrhosis can progress to HCC, the most common and one of the most lethal liver cancers with unmet medical needs. Considering the essential role of inflammatory pathways in the development of cirrhosis, further understanding of the relationship between immune cells and the activation of RNs and fibrosis would guide the design of innovative therapeutic strategies to ameliorate the survival of cirrhotic and HCC patients. In this review, we will summarize the inflammatory mechanisms implicated in the development of cirrhosis.
Copy Neutral LOH Affecting the Entire Chromosome 6 Is a Frequent Mechanism of HLA Class I Alterations in Cancer
Authors: Garrido Maria Antonia , Perea Francisco , Vilchez Jose Ramon , Rodríguez Teresa , Anderson Per , Garrido Federico , Ruiz-Cabello Francisco , Aptsiauri Natalia
Published: October 2021

Total or partial loss of HLA class I antigens reduce the recognition of specific tumor peptides by cytotoxic T lymphocytes favoring cancer immune escape during natural tumor evolution. These alterations can be caused by genomic defects, such as loss of heterozygosity at chromosomes 6 and 15 (LOH-6 and LOH-15), where HLA class I genes are located. There is growing evidence indicating that LOH in HLA contributes to the immune selection of HLA loss variants and influences the resistance to immunotherapy. Nevertheless, the incidence and the mechanism of this chromosomal aberration involving HLA genes has not been systematically assessed in different types of tumors and often remains underestimated. Here, we used SNP arrays to investigate the incidence and patterns of LOH-6 and LOH-15 in a number of human cancer cell lines and tissues of different histological types. We observed that LOH in HLA is a common event in cancer samples with a prevalence of a copy neutral type of LOH (CN-LOH) that affects entire chromosome 6 or 15 and involves chromosomal duplications. LOH-6 was observed more often and was associated with homozygous HLA genotype and partial HLA loss of expression. We also discuss the immunologic and clinical implications of LOH in HLA on tumor clonal expansion and association with the cancer recurrence after treatment.
CX-5461 Treatment Leads to Cytosolic DNA-Mediated STING Activation in Ovarian Cancer
Authors: Cornelison Robert , Biswas Kuntal , Llaneza Danielle C. , Harris Alexandra R. , Sosale Nisha G. , Lazzara Matthew J. , Landen Charles N.
Published: October 2021

Epithelial ovarian cancer (EOC) is the deadliest of the gynecologic malignancies, with an overall survival rate of <30%. Recent research has suggested that targeting RNA polymerase I (POL I) with small-molecule inhibitors may be a viable therapeutic approach to combating EOC, even when chemoresistance is present. CX-5461 is one of the most promising POL I inhibitors currently being investigated, and previous reports have shown that CX-5461 treatment induces DNA damage response (DDR) through ATM/ATR kinase. Investigation into downstream effects of CX-5461 led us to uncovering a previously unreported phenotype. Treatment with CX-5461 induces a rapid accumulation of cytosolic DNA. This accumulation leads to transcriptional upregulation of ‘STimulator of Interferon Genes’ (STING) in the same time frame, phosphorylation of IRF3, and activation of type I interferon response both in vitro and in vivo. This activation is mediated and dependent on cyclic GMP–AMP synthase (cGAS). Here, we show THAT CX-5461 leads to an accumulation of cytosolic dsDNA and thereby activates the cGAS–STING–TBK1–IRF3 innate immune pathway, which induces type I IFN. CX-5461 treatment-mediated immune activation may be a powerful mechanism of action to exploit, leading to novel drug combinations with a chance of increasing immunotherapy efficacy, possibly with some cancer specificity limiting deleterious toxicities.
Daratumumab May Attenuate Cardiac Dysfunction Related to Carfilzomib in Patients with Relapsed/Refractory Multiple Myeloma: A Prospective Study
Authors: Terpos Evangelos , Stamatelopoulos Kimon , Makris Nikolaos , Georgiopoulos Georgios , Ntanasis-Stathopoulos Ioannis , Gavriatopoulou Maria , Laina Ageliki , Eleutherakis-Papaiakovou Evangelos , Fotiou Despina , Kanellias Nikolaos , Malandrakis Panagiotis , Delialis Dimitris , Andreadou Ioanna , Kastritis Efstathios , Dimopoulos Meletios A.
Published: October 2021

Carfilzomib has improved survival in patients with relapsed/refractory multiple myeloma (RRMM), but it may exert cardiovascular adverse events (CVAEs). The aim of this study was to assess whether treatment with daratumumab may ameliorate carfilzomib-related toxicity. We prospectively evaluated 25 patients with RRMM who received either daratumumab in combination with carfilzomib and dexamethasone (DaraKd) (n = 14) or Kd (n = 11). Cardiac ultrasound was performed before treatment initiation and C6D16 or at the time of treatment interruption. Patients were followed for a median of 10 months for CVAEs. The mean (± SD) age was 67.8 ± 7.6 years and 60% were men. The two treatment groups did not significantly differ in baseline demographic characteristics (p > 0.1 for all). In the DaraKd group, we did not observe any significant change in markers of ventricular systolic function. However, these markers deteriorated in the Kd group; left ventricular (LV) ejection fraction, LV global longitudinal strain, tricuspid annular plane systolic excursion and RV free wall longitudinal strain significantly decreased from baseline to second visit (p < 0.05). A significant group interaction (p < 0.05) was observed for the abovementioned changes. CVAEs occurred more frequently in the Kd than the DaraKd group (45% vs. 28.6%). DaraKd was associated with preserved post-treatment cardiac systolic function and lower CVAE rate compared with Kd. The clinical significance and the underlying mechanisms merit further investigation.
Transcriptomics and Metabolomics Integration Reveals Redox-Dependent Metabolic Rewiring in Breast Cancer Cells
Authors: Bonanomi Marcella , Salmistraro Noemi , Fiscon Giulia , Conte Federica , Paci Paola , Bravatà Valentina , Forte Giusi Irma , Volpari Tatiana , Scorza Manuela , Mastroianni Fabrizia , D’Errico Stefano , Avolio Elenio , Piccialli Gennaro , Colangelo Anna Maria , Vanoni Marco , Gaglio Daniela , Alberghina Lilia
Published: October 2021

Rewiring glucose metabolism toward aerobic glycolysis provides cancer cells with a rapid generation of pyruvate, ATP, and NADH, while pyruvate oxidation to lactate guarantees refueling of oxidized NAD+ to sustain glycolysis. CtPB2, an NADH-dependent transcriptional co-regulator, has been proposed to work as an NADH sensor, linking metabolism to epigenetic transcriptional reprogramming. By integrating metabolomics and transcriptomics in a triple-negative human breast cancer cell line, we show that genetic and pharmacological down-regulation of CtBP2 strongly reduces cell proliferation by modulating the redox balance, nucleotide synthesis, ROS generation, and scavenging. Our data highlight the critical role of NADH in controlling the oncogene-dependent crosstalk between metabolism and the epigenetically mediated transcriptional program that sustains energetic and anabolic demands in cancer cells.
Progress on Ras/MAPK Signaling Research and Targeting in Blood and Solid Cancers
Authors: Dillon Martha , Lopez Antonio , Lin Edward , Sales Dominic , Perets Ron , Jain Pooja
Published: October 2021

The mitogen-activated protein kinase (MAPK) pathway, consisting of the Ras-Raf-MEK-ERK signaling cascade, regulates genes that control cellular development, differentiation, proliferation, and apoptosis. Within the cascade, multiple isoforms of Ras and Raf each display differences in functionality, efficiency, and, critically, oncogenic potential. According to the NCI, over 30% of all human cancers are driven by Ras genes. This dysfunctional signaling is implicated in a wide variety of leukemias and solid tumors, both with and without viral etiology. Due to the strong evidence of Ras-Raf involvement in tumorigenesis, many have attempted to target the cascade to treat these malignancies. Decades of unsuccessful experimentation had deemed Ras undruggable, but recently, the approval of Sotorasib as the first ever KRas inhibitor represents a monumental breakthrough. This advancement is not without novel challenges. As a G12C mutant-specific drug, it also represents the issue of drug target specificity within Ras pathway; not only do many drugs only affect single mutational profiles, with few pan-inhibitor exceptions, tumor genetic heterogeneity may give rise to drug-resistant profiles. Furthermore, significant challenges in targeting downstream Raf, especially the BRaf isoform, lie in the paradoxical activation of wild-type BRaf by BRaf mutant inhibitors. This literature review will delineate the mechanisms of Ras signaling in the MAPK pathway and its possible oncogenic mutations, illustrate how specific mutations affect the pathogenesis of specific cancers, and compare available and in-development treatments targeting the Ras pathway.
Connexin Hemichannel Activation by S-Nitrosoglutathione Synergizes Strongly with Photodynamic Therapy Potentiating Anti-Tumor Bystander Killing
Authors: Nardin Chiara , Peres Chiara , Putti Sabrina , Orsini Tiziana , Colussi Claudia , Mazzarda Flavia , Raspa Marcello , Scavizzi Ferdinando , Salvatore Anna Maria , Chiani Francesco , Tettey-Matey Abraham , Kuang Yuanyuan , Yang Guang , Retamal Mauricio A. , Mammano Fabio
Published: October 2021

In this study, we used B16-F10 cells grown in the dorsal skinfold chamber (DSC) preparation that allowed us to gain optical access to the processes triggered by photodynamic therapy (PDT). Partial irradiation of a photosensitized melanoma triggered cell death in non-irradiated tumor cells. Multiphoton intravital microscopy with genetically encoded fluorescence indicators revealed that bystander cell death was mediated by paracrine signaling due to adenosine triphosphate (ATP) release from connexin (Cx) hemichannels (HCs). Intercellular calcium (Ca2+) waves propagated from irradiated to bystander cells promoting intracellular Ca2+ transfer from the endoplasmic reticulum (ER) to mitochondria and rapid activation of apoptotic pathways. Combination treatment with S-nitrosoglutathione (GSNO), an endogenous nitric oxide (NO) donor that biases HCs towards the open state, greatly potentiated anti-tumor bystander killing via enhanced Ca2+ signaling, leading to a significant reduction of post-irradiation tumor mass. Our results demonstrate that HCs can be exploited to dramatically increase cytotoxic bystander effects and reveal a previously unappreciated role for HCs in tumor eradication promoted by PDT.
Possible Mechanisms of Subsequent Neoplasia Development in Childhood Cancer Survivors: A Review
Authors: Kruseova Jarmila , Vicha Ales , Feriancikova Barbara , Eckschlager Tomas
Published: October 2021

Advances in medicine have improved outcomes in children diagnosed with cancer, with overall 5-year survival rates for these children now exceeding 80%. Two-thirds of childhood cancer survivors have at least one late effect of cancer therapy, with one-third having serious or even life-threatening effects. One of the most serious late effects is a development of subsequent malignant neoplasms (histologically different cancers, which appear after the treatment for primary cancer), which occur in about 3–10% of survivors and are associated with high mortality. In cancers with a very good prognosis, subsequent malignant neoplasms significantly affect long-term survival. Therefore, there is an effort to reduce particularly hazardous treatments. This review discusses the importance of individual factors (gender, genetic factors, cytostatic drugs, radiotherapy) in the development of subsequent malignant neoplasms and the possibilities of their prediction and prevention in the future.
Immunotherapies in Genitourinary Oncology: Where Are We Now? Where Are We Going?
Authors: Jang Albert , Adler David M. , Rauterkus Grant P. , Bilen Mehmet A. , Barata Pedro C.
Published: October 2021

For decades, limited options existed to treat metastatic genitourinary cancers, including treatment options that could be classified as immunotherapy. Historically, immunotherapy centered on systemic cytokines for the treatment of metastatic kidney cancer, which had several adverse effects, as well as the Bacillus Calmette–Guérin vaccine for non-metastatic bladder cancer. Within the past decade, advances in immunotherapy have led to several approvals from the United States Food and Drug Administration, particularly in the field of immune checkpoint inhibition. Immune checkpoint inhibitors (ICIs) are now being used extensively to treat multiple solid tumors, including kidney and bladder cancers, and they are also being tested in many other cancers. Despite encouraging data from phase 2/3 clinical trials, less is known about biomarkers that may predict better response to ICIs. The effect of ICIs in genitourinary cancers is heterogeneous, with some tumor types having little clinical data available, or ICIs having limited activity in other tumors. In this review, we briefly discuss approved immunotherapy agents prior to the time of ICIs. Then, given the emergence of this class of agents, we summarize the several important ICIs and the clinical trials that led to their approval. Finally, we mention ongoing and future clinical trials.
The Effect of a Histone Deacetylase Inhibitor (AR-42) and Zoledronic Acid on Adult T-Cell Leukemia/Lymphoma Osteolytic Bone Tumors
Authors: Elshafae Said M. , Kohart Nicole A. , Breitbach Justin T. , Hildreth Blake E. , Rosol Thomas J.
Published: October 2021

Adult T-cell leukemia/lymphoma (ATL) is an intractable disease affecting nearly 4% of Human T-cell Leukemia Virus Type 1 (HTLV-1) carriers. Acute ATL has a unique interaction with bone characterized by aggressive bone invasion, osteolytic metastasis, and hypercalcemia. We hypothesized that dual tumor and bone-targeted therapies would decrease tumor burden in bone, the incidence of metastasis, and ATL-associated osteolysis. Our goal was to evaluate dual targeting of both ATL bone tumors and the bone microenvironment using an anti-tumor HDACi (AR-42) and an osteoclast inhibitor (zoledronic acid, Zol), alone and in combination. Our results showed that AR-42, Zol, and AR-42/Zol significantly decreased the viability of multiple ATL cancer cell lines in vitro. Zol and AR-42/Zol decreased tumor growth in vivo. Zol ± AR-42 significantly decreased ATL-associated bone resorption and promoted new bone formation. AR-42-treated ATL cells had increased mRNA levels of PTHrP, ENPP2 (autotaxin) and MIP-1α, and TAX viral gene expression. AR-42 alone had no significant effect on tumor growth or osteolysis in mice. These findings indicate that Zol adjuvant therapy has the potential to reduce growth of ATL in bone and its associated osteolysis.
In Vivo PET Imaging of Monocytes Labeled with [89Zr]Zr-PLGA-NH2 Nanoparticles in Tumor and Staphylococcus aureus Infection Models
Authors: Krekorian Massis , Cortenbach Kimberley R. G. , Boswinkel Milou , Kip Annemarie , Franssen Gerben M. , Veltien Andor , Scheenen Tom W. J. , Raavé René , van Riessen Nicolaas Koen , Srinivas Mangala , de Vries Ingrid Jolanda M. , Figdor Carl G. , Aarntzen Erik H. J. G. , Heskamp Sandra
Published: October 2021

The exponential growth of research on cell-based therapy is in major need of reliable and sensitive tracking of a small number of therapeutic cells to improve our understanding of the in vivo cell-targeting properties. 111In-labeled poly(lactic-co-glycolic acid) with a primary amine endcap nanoparticles ([111In]In-PLGA-NH2 NPs) were previously used for cell labeling and in vivo tracking, using SPECT/CT imaging. However, to detect a low number of cells, a higher sensitivity of PET is preferred. Therefore, we developed 89Zr-labeled NPs for ex vivo cell labeling and in vivo cell tracking, using PET/MRI. We intrinsically and efficiently labeled PLGA-NH2 NPs with [89Zr]ZrCl4. In vitro, [89Zr]Zr-PLGA-NH2 NPs retained the radionuclide over a period of 2 weeks in PBS and human serum. THP-1 (human monocyte cell line) cells could be labeled with the NPs and retained the radionuclide over a period of 2 days, with no negative effect on cell viability (specific activity 279 ± 10 kBq/106 cells). PET/MRI imaging could detect low numbers of [89Zr]Zr-THP-1 cells (10,000 and 100,000 cells) injected subcutaneously in Matrigel. Last, in vivo tracking of the [89Zr]Zr-THP-1 cells upon intravenous injection showed specific accumulation in local intramuscular Staphylococcus aureus infection and infiltration into MDA-MB-231 tumors. In conclusion, we showed that [89Zr]Zr-PLGA-NH2 NPs can be used for immune-cell labeling and subsequent in vivo tracking of a small number of cells in different disease models.
Phospho-Ser784-VCP Drives Resistance of Pancreatic Ductal Adenocarcinoma to Genotoxic Chemotherapies and Predicts the Chemo-Sensitizing Effect of VCP Inhibitor
Authors: Wang Faliang , Vij Kiran , Li Lin , Dodhiawala Paarth , Lim Kian-Huat , Shao Jieya
Published: October 2021

Pancreatic ductal adenocarcinoma (PDAC) patients have a dismal prognosis due in large part to chemotherapy resistance. However, a small subset containing defects in the DNA damage response (DDR) pathways are chemotherapy-sensitive. Identifying intrinsic and therapeutically inducible DDR defects can improve precision and efficacy of chemotherapies for PDAC. DNA repair requires dynamic reorganization of chromatin-associated proteins, which is orchestrated by the AAA+ ATPase VCP. We recently discovered that the DDR function of VCP is selectively activated by Ser784 phosphorylation. In this paper, we show that pSer784-VCP but not total VCP levels in primary PDAC tumors negatively correlate with patient survival. In PDAC cell lines, different pSer784-VCP levels are induced by genotoxic chemotherapy agents and positively correlate with genome stability and cell survival. Causal effects of pSer784-VCP on DNA repair and cell survival were confirmed using VCP knockdown and functional rescue. Importantly, DNA damage-induced pSer784-VCP rather than total VCP levels in PDAC cell lines predict their chemotherapy response and chemo-sensitizing ability of selective VCP inhibitor NMS-873. Therefore, pSer784-VCP drives genotoxic chemotherapy resistance of PDAC, and can potentially be used as a predictive biomarker as well as a sensitizing target to enhance the chemotherapy response of PDAC.
Hospital Variation in Cancer Treatments and Survival OutComes of Advanced Melanoma Patients: Nationwide Quality Assurance in The Netherlands
Authors: van Breeschoten Jesper , van den Eertwegh Alfonsus J. M. , de Wreede Liesbeth C. , Hilarius Doranne L. , van Zwet Erik W. , Haanen John B. , Blank Christian U. , Aarts Maureen J. B. , van den Berkmortel Franchette W. P. J. , de Groot Jan Willem B. , Hospers Geke A. P. , Kapiteijn Ellen , Piersma Djura , van Rijn Rozemarijn S. , Stevense-den Boer Marion A. M. , van der Veldt Astrid A. M. , Vreugdenhil Gerard , Boers-Sonderen Marye J. , Suijkerbuijk Karijn P. M. , Wouters Michel W. J. M.
Published: October 2021

Background: To assure a high quality of care for patients treated in Dutch melanoma centers, hospital variation in treatment patterns and outcomes is evaluated in the Dutch Melanoma Treatment Registry. The aim of this study was to assess center variation in treatments and 2-year survival probabilities of patients diagnosed between 2013 and 2017 in the Netherlands. Methods: We selected patients diagnosed between 2013 and 2017 with unresectable IIIC or stage IV melanoma, registered in the Dutch Melanoma Treatment Registry. Centers’ performance on 2-year survival was evaluated using Empirical Bayes estimates calculated in a random effects model. Treatment patterns of the centers with the lowest and highest estimates for 2-year survival were compared. Results: For patients diagnosed between 2014 and 2015, significant center variation in 2-year survival probabilities was observed even after correcting for case-mix and treatment with new systemic therapies. The different use of new systemic therapies partially explained the observed variation. From 2016 onwards, no significant difference in 2-year survival was observed between centers. Conclusion: Our data suggest that between 2014 and 2015, after correcting for patient case-mix, significant variation in 2-year survival probabilities between Dutch melanoma centers existed. The use of new systemic therapies could partially explain this variation. In 2013 and between 2016 and 2017, no significant variation between centers existed.
A Novel Pro-Inflammatory Mechanosensing Pathway Orchestrated by the Disintegrin Metalloproteinase ADAM15 in Synovial Fibroblasts
Authors: Janczi Tomasz , Meier Florian , Fehrl Yuliya , Kinne Raimund W. , Böhm Beate , Burkhardt Harald
Published: October 2021

Mechanotransduction is elicited in cells upon the perception of physical forces transmitted via the extracellular matrix in their surroundings and results in signaling events that impact cellular functions. This physiological process is a prerequisite for maintaining the integrity of diarthrodial joints, while excessive loading is a factor promoting the inflammatory mechanisms of joint destruction. Here, we describe a mechanotransduction pathway in synovial fibroblasts (SF) derived from the synovial membrane of inflamed joints. The functionality of this pathway is completely lost in the absence of the disintegrin metalloproteinase ADAM15 strongly upregulated in SF. The mechanosignaling events involve the Ca2+-dependent activation of c-Jun-N-terminal kinases, the subsequent downregulation of long noncoding RNA HOTAIR, and upregulation of the metabolic energy sensor sirtuin-1. This afferent loop of the pathway is facilitated by ADAM15 via promoting the cell membrane density of the constitutively cycling mechanosensitive transient receptor potential vanilloid 4 calcium channels. In addition, ADAM15 reinforces the Src-mediated activation of pannexin-1 channels required for the enhanced release of ATP, a mediator of purinergic inflammation, which is increasingly produced upon sirtuin-1 induction.
Cisplatin Reduces the Frequencies of Radiotherapy-Induced Micronuclei in Peripheral Blood Lymphocytes of Patients with Gynaecological Cancer: Possible Implications for the Risk of Second Malignant Neoplasms
Authors: Węgierek-Ciuk Aneta , Lankoff Anna , Lisowska Halina , Kędzierawski Piotr , Akuwudike Pamela , Lundholm Lovisa , Wojcik Andrzej
Published: October 2021

Gynaecologic cancers are common among women and treatment includes surgery, radiotherapy or chemotherapy, where the last two methods induce DNA damage in non-targeted cells like peripheral blood lymphocytes (PBL). Damaged normal cells can transform leading to second malignant neoplasms (SMN) but the level of risk and impact of risk modifiers is not well defined. We investigated how radiotherapy alone or in combination with chemotherapy induce DNA damage in PBL of cervix and endometrial cancer patients during therapy. Blood samples were collected from nine endometrial cancer patients (treatment with radiotherapy + chemotherapy—RC) and nine cervical cancer patients (treatment with radiotherapy alone—R) before radiotherapy, 3 weeks after onset of radiotherapy and at the end of radiotherapy. Half of each blood sample was irradiated ex vivo with 2 Gy of gamma radiation in order to check how therapy influenced the sensitivity of PBL to radiation. Analysed endpoints were micronucleus (MN) frequencies, apoptosis frequencies and cell proliferation index. The results were characterised by strong individual variation, especially the MN frequencies and proliferation index. On average, despite higher total dose and larger fields, therapy alone induced the same level of MN in PBL of RC patients as compared to R. This result was accompanied by a higher level of apoptosis and stronger inhibition of cell proliferation in RC patients. The ex vivo dose induced fewer MN, more apoptosis and more strongly inhibited proliferation of PBL of RC as compared to R patients. These results are interpreted as evidence for a sensitizing effect of chemotherapy on radiation cytotoxicity. The possible implications for the risk of second malignant neoplasms are discussed.
The Long Terminal Repeats of ERV6 Are Activated in Pre-Implantation Embryos of Cynomolgus Monkey
Authors: Duan Kui , Si Chen-Yang , Zhao Shu-Mei , Ai Zong-Yong , Niu Bao-Hua , Yin Yu , Xiang Li-Feng , Ding Hao , Zheng Yun
Published: October 2021

Precise gene regulation is critical during embryo development. Long terminal repeat elements (LTRs) of endogenous retroviruses (ERVs) are dynamically expressed in blastocysts of mammalian embryos. However, the expression pattern of LTRs in monkey blastocyst is still unknown. By single-cell RNA-sequencing (seq) data of cynomolgus monkeys, we found that LTRs of several ERV families, including MacERV6, MacERV3, MacERV2, MacERVK1, and MacERVK2, were highly expressed in pre-implantation embryo cells including epiblast (EPI), trophectoderm (TrB), and primitive endoderm (PrE), but were depleted in post-implantation. We knocked down MacERV6-LTR1a in cynomolgus monkeys with a short hairpin RNA (shRNA) strategy to examine the potential function of MacERV6-LTR1a in the early development of monkey embryos. The silence of MacERV6-LTR1a mainly postpones the differentiation of TrB, EPI, and PrE cells in embryos at day 7 compared to control. Moreover, we confirmed MacERV6-LTR1a could recruit Estrogen Related Receptor Beta (ESRRB), which plays an important role in the maintenance of self-renewal and pluripotency of embryonic and trophoblast stem cells through different signaling pathways including FGF and Wnt signaling pathways. In summary, these results suggest that MacERV6-LTR1a is involved in gene regulation of the pre-implantation embryo of the cynomolgus monkeys.
Peripartum Investigation of Red Blood Cell Properties in Women Diagnosed with Early-Onset Preeclampsia
Authors: Csiszar Beata , Galos Gergely , Funke Simone , Kevey Dora Kinga , Meggyes Matyas , Szereday Laszlo , Kenyeres Peter , Toth Kalman , Sandor Barbara
Published: October 2021

We investigated peripartum maternal red blood cell (RBC) properties in early-onset preeclampsia (PE). Repeated blood samples were taken prospectively for hemorheological measurements at PE diagnosis (n = 13) or during 26–34 weeks of gestation in healthy pregnancies (n = 24), then at delivery, and 72 h postpartum. RBC aggregation was characterized by M index (infrared light transmission between the aggregated RBCs in stasis) and aggregation index (AI—laser backscattering from the RBC aggregates). We observed significantly elevated RBC aggregation (M index = 9.8 vs. 8.5; AI = 72.9% vs. 67.5%; p < 0.001) and reduced RBC deformability in PE (p < 0.05). A positive linear relationship was observed between AI and gestational age at birth in PE by regression analysis (R2 = 0.554; p = 0.006). ROC analysis of AI showed an AUC of 0.84 (0.68–0.99) (p = 0.001) for PE and indicated a cutoff of 69.4% (sensitivity = 83.3%; specificity = 62.5%), while M values showed an AUC of 0.75 (0.58–0.92) (p = 0.019) and indicated a cutoff of 8.39 (sensitivity = 90.9% and specificity = 50%). The predicted probabilities from the combination of AI and M variables showed increased AUC = 0.90 (0.79–1.00) (p < 0.001). Our results established impaired microcirculation in early-onset PE manifesting as deteriorated maternal RBC properties. The longer the pathologic pregnancy persists, the more pronounced the maternal erythrocyte aggregation. AI and M index could help in the prognostication of early-onset PE, but further investigations are warranted to confirm the prognostic role before the onset of symptoms.
Effect of Perioperative Lipid Status on Clinical Outcomes after Cardiac Surgery
Authors: Mihalj Maks , Heinisch Paul Philipp , Huber Markus , Schefold Joerg C. , Hartmann Alexander , Walter Michael , Steinhagen-Thiessen Elisabeth , Schmidli Juerg , Stüber Frank , Räber Lorenz , Luedi Markus M.
Published: October 2021

Patients undergoing cardiac surgery are at increased cardiovascular risk, which includes altered lipid status. However, data on the effect of cardiac surgery and cardiopulmonary bypass (CPB) on plasma levels of key lipids are scarce. We investigated potential effects of CPB on plasma lipid levels and associations with early postoperative clinical outcomes. This is a prospective bio-bank study of patients undergoing elective cardiac surgery at our center January to December 2019. The follow-up period was 1 year after surgery. Blood sampling was performed before induction of general anesthesia, upon weaning from cardiopulmonary bypass (CPB), and on the first day after surgery. Clinical end points included the incidence of postoperative stroke, myocardial infarction, and death of any cause at 30 days after surgery as well as 1-year all-cause mortality. A total of 192 cardiac surgery patients (75% male, median age 67.0 years (interquartile range 60.0–73.0), median BMI 26.1 kg/m2 (23.7–30.4)) were included. A significant intraoperative decrease in plasma levels compared with preoperative levels (all p < 0.0001) was observed for total cholesterol (TC) (Cliff’s delta d: 0.75 (0.68–0.82; 95% CI)), LDL-Cholesterol (LDL-C) (d: 0.66 (0.57–0.73)) and HDL-Cholesterol (HDL-C) (d: 0.72 (0.64–0.79)). At 24h after surgery, the plasma levels of LDL-C (d: 0.73 (0.650.79)) and TC (d: 0.77 (0.69–0.82)) continued to decrease compared to preoperative levels, while the plasma levels of HDL-C (d: 0.46 (0.36–0.55)) and TG (d: 0.40 (0.29–0.50)) rebounded, but all remained below the preoperative levels (p < 0.001). Mortality at 30 days was 1.0% (N = 2/192), and 1-year mortality was 3.8% (N = 7/186). Postoperative myocardial infarction occurred in 3.1% of patients (N = 6/192) and postoperative stroke in 5.8% (N = 11/190). Adjusting for age, sex, BMI, and statin therapy, we noted a protective effect of postoperative occurrence of stroke for pre-to-post-operative changes in TC (adjusted odds ratio (OR) 0.29 (0.07–0.90), p = 0.047), in LDL-C (aOR 0.19 (0.03–0.88), p = 0.045), and in HDL-C (aOR 0.01 (0.00–0.78), p = 0.039). No associations were observed between lipid levels and 1-year mortality. In conclusion, cardiac surgery induces a significant sudden drop in levels of key plasma lipids. This effect was pronounced during the operation, and levels remained significantly lowered at 24 h after surgery. The intraoperative drops in LDL-C, TC, and HDL-C were associated with a protective effect against occurrence of postoperative stroke in adjusted models. We demonstrate that the changes in key plasma lipid levels during surgery are strongly correlated, which makes attributing the impact of each lipid to the clinical end points, such as postoperative stroke, a challenging task. Large-scale analyses should investigate additional clinical outcome measures.
Transition of Adolescents with Inflammatory Bowel Disease—Are the Pediatric Teams up to the Task?
Authors: Hald Mette , Carlsen Katrine , Wewer Vibeke
Published: October 2021

Our aim was to describe the challenges of the transition process of adolescents with inflammatory bowel disease (IBD), as seen from a pediatric-care perspective, to clarify the key obstacles and propose how to move forward. Semi-structured individual interviews of pediatric gastroenterologists and nurses were analyzed and interpreted according to the principles of social science. It is a challenge for the pediatric team to continuously match, support, and gently guide the ever-changing adolescent patient. All adolescent patients should be offered guidance regardless of their starting point, and specific individual needs should be taken into consideration. Adolescents burdened by psychosocial challenges require extra support. Early and continued interdisciplinary effort is essential. Collaboration with the parents must be continuously adapted to prepare them for their new roles and responsibilities. The shift from the pediatric family-focused approach to the individualistic approach of the Adult Gastroenterology Department signifies a fundamental change. Equipping adolescents with disease-management skills remains a comprehensive task. The following crucial questions remain: Who is capable of performing the transition? Who can dedicate the necessary resources for performing the transition? A transition center led by both pediatricians and adult gastroenterologists in an interdisciplinary setting that includes transition-trained persons may be the solution.
Pediatric Palliative Care Pharmacy Pearls—A Focus on Pain and Sedation
Authors: Placencia Jennifer , Madden Kevin
Published: October 2021

Determining the optimal dosing regimen for pediatric patients is a challenge due to the lack of dosing guidelines and studies. In addition, many developmental pharmacology changes that occur throughout childhood that have profound impacts on the absorption, distribution, metabolism, and elimination of medications are commonly used in palliative care. Adding to that complexity, certain medications have different effects in the pediatric patient compared to the adult patient. Being aware of the pharmacokinetic changes, impact on neurodevelopment and unique medication factors that are present in pediatric patients helps clinicians treat the pediatric palliative care patient in the best and safest way possible.