bluuebunny/crossref_metadata_2025 huggingface dataset:
Prehabilitation to Improve Outcomes of Patients with Gynaecological Cancer: A New Window of Opportunity?
Authors: Dhanis Joëlle , Keidan Nathaniel , Blake Dominic , Rundle Stuart , Strijker Dieuwke , van Ham Maaike , Pijnenborg Johanna M. A. , Smits Anke
Published: July 2022

The literature evaluating the effect of prehabilitation programmes on postoperative outcomes and quality of life of patients with gynaecological cancer undergoing surgery was reviewed. Databases including Pubmed, Medline, EMBASE (Ovid) and PsycINFO were systematically searched to identify studies evaluating the effect of prehabilitation programmes on patients with gynaecological cancer. Both unimodal and multimodal prehabilitation programmes were included encompassing physical exercise and nutritional and psychological support. Primary outcomes were surgical complications and quality of life. Secondary outcomes were anthropometric changes and adherence to the prehabilitation programme. Seven studies fulfilled the inclusion criteria, comprising 580 patients. Included studies were nonrandomised prospective studies (n = 4), retrospective studies (n = 2) and one case report. Unimodal programmes and multimodal programmes were included. In patients with ovarian cancer, multimodal prehabilitation resulted in significantly reduced hospital stay and time to chemotherapy. In patients with endometrial and cervical cancer, prehabilitation was associated with significant weight loss, but had no significant effects on surgical complications or mortality. No adverse events of the programmes were reported. Evidence on the effect of prehabilitation for patients with gynaecological cancer is limited. Future studies are needed to determine the effects on postoperative complications and quality of life.
Visceral Obesity in Non-Small Cell Lung Cancer
Authors: Nitsche Lindsay , Vedire Yeshwanth , Kannisto Eric , Wang Xiaolong , Seager Robert J. , Pabla Sarabjot , Patnaik Santosh K. , Yendamuri Sai
Published: July 2022

While obesity measured by body mass index (BMI) has been paradoxically associated with reduced risk and better outcome for lung cancer, recent studies suggest that the harm of obesity becomes apparent when measured as visceral adiposity. However, the prevalence of visceral obesity and its associations with demographic and tumor features are not established. We therefore conducted an observational study of visceral obesity in 994 non-small cell lung cancer (NSCLC) patients treated during 2008–2020 at our institution. Routine computerized tomography (CT) images of the patients, obtained within a year of tumor resection or biopsy, were used to measure cross-sectional abdominal fat areas. Important aspects of the measurement approach such as inter-observer variability and time stability were examined. Visceral obesity was semi-quantified as visceral fat index (VFI), the fraction of fat area that was visceral. VFI was found to be higher in males compared to females, and in former compared to current or never smokers. There was no association of VFI with tumor histology or stage. A gene expression-based measure of tumor immunogenicity was negatively associated with VFI but had no bearing with BMI. Visceral obesity is appraisable in routine CT and can be an important correlate in lung cancer studies.
TP53-Status-Dependent Oncogenic EZH2 Activity in Pancreatic Cancer
Authors: Versemann Lennart , Patil Shilpa , Steuber Benjamin , Zhang Zhe , Kopp Waltraut , Krawczyk Hannah Elisa , Kaulfuß Silke , Wollnik Bernd , Ströbel Philipp , Neesse Albrecht , Singh Shiv K. , Ellenrieder Volker , Hessmann Elisabeth
Published: July 2022

Pancreatic Ductal Adenocarcinoma (PDAC) represents a lethal malignancy with a consistently poor outcome. Besides mutations in PDAC driver genes, the aggressive tumor biology of the disease and its remarkable therapy resistance are predominantly installed by potentially reversible epigenetic dysregulation. However, epigenetic regulators act in a context-dependent manner with opposing implication on tumor progression, thus critically determining the therapeutic efficacy of epigenetic targeting. Herein, we aimed at exploring the molecular prerequisites and underlying mechanisms of oncogenic Enhancer of Zeste Homolog 2 (EZH2) activity in PDAC progression. Preclinical studies in EZH2 proficient and deficient transgenic and orthotopic in vivo PDAC models and transcriptome analysis identified the TP53 status as a pivotal context-defining molecular cue determining oncogenic EZH2 activity in PDAC. Importantly, the induction of pro-apoptotic gene signatures and processes as well as a favorable PDAC prognosis upon EZH2 depletion were restricted to p53 wildtype (wt) PDAC subtypes. Mechanistically, we illustrate that EZH2 blockade de-represses CDKN2A transcription for the subsequent posttranslational stabilization of p53wt expression and function. Together, our findings suggest an intact CDKN2A-p53wt axis as a prerequisite for the anti-tumorigenic consequences of EZH2 depletion and emphasize the significance of molecular stratification for the successful implementation of epigenetic targeting in PDAC.
Alternative Treatment Options to ALK Inhibitor Monotherapy for EML4-ALK-Driven Lung Cancer
Authors: Papageorgiou Savvas , Pashley Sarah L. , O’Regan Laura , Khan Sam , Bayliss Richard , Fry Andrew M.
Published: July 2022

EML4-ALK is an oncogenic fusion protein that accounts for approximately 5% of NSCLC cases. Targeted inhibitors of ALK are the standard of care treatment, often leading to a good initial response. Sadly, some patients do not respond well, and most will develop resistance over time, emphasizing the need for alternative treatments. This review discusses recent advances in our understanding of the mechanisms behind EML4-ALK-driven NSCLC progression and the opportunities they present for alternative treatment options to ALK inhibitor monotherapy. Targeting ALK-dependent signalling pathways can overcome resistance that has developed due to mutations in the ALK catalytic domain, as well as through activation of bypass mechanisms that utilise the same pathways. We also consider evidence for polytherapy approaches that combine targeted inhibition of these pathways with ALK inhibitors. Lastly, we review combination approaches that use targeted inhibitors of ALK together with chemotherapy, radiotherapy or immunotherapy. Throughout this article, we highlight the importance of alternative breakpoints in the EML4 gene that result in the generation of distinct EML4-ALK variants with different biological and pathological properties and consider monotherapy and polytherapy approaches that may be selective to particular variants.
Targeting Acute Myeloid Leukemia with Venetoclax; Biomarkers for Sensitivity and Rationale for Venetoclax-Based Combination Therapies
Authors: Griffioen Mila S. , de Leeuw David C. , Janssen Jeroen J. W. M. , Smit Linda
Published: July 2022

Venetoclax is a BCL-2 inhibitor that effectively improves clinical outcomes in newly diagnosed, relapsed and refractory acute myeloid leukemia (AML) patients, with complete response rates (with and without complete blood count recovery) ranging between 34–90% and 21–33%, respectively. Here, we aim to give an overview of the efficacy of venetoclax-based therapy for AML patients, as compared to standard chemotherapy, and on factors and mechanisms involved in venetoclax sensitivity and resistance in AML (stem) cells, with the aim to obtain a perspective of response biomarkers and combination therapies that could enhance the sensitivity of AML cells to venetoclax. The presence of molecular aberrancies can predict responses to venetoclax, with a higher response in NPM1-, IDH1/2-, TET2- and relapsed or refractory RUNX1-mutated AML. Decreased sensitivity to venetoclax was observed in patients harboring FLT3-ITD, TP53, K/NRAS or PTPN11 mutations. Moreover, resistance to venetoclax was observed in AML with a monocytic phenotype and patients pre-treated with hypomethylating agents. Resistance to venetoclax can arise due to mutations in BCL-2 or pro-apoptotic proteins, an increased dependency on MCL-1, and usage of additional/alternative sources for energy metabolism, such as glycolysis and fatty acid metabolism. Clinical studies are testing combination therapies that may circumvent resistance, including venetoclax combined with FLT3- and MCL-1 inhibitors, to enhance venetoclax-induced cell death. Other treatments that can potentially synergize with venetoclax, including MEK1/2 and mitochondrial complex inhibitors, need to be evaluated in a clinical setting.
Contraception and Hormone Replacement Therapy in Healthy Carriers of Germline BRCA1/2 Genes Pathogenic Variants: Results from an Italian Survey
Authors: Massarotti Claudia , Buonomo Barbara , Dellino Miriam , Campanella Maria , De Stefano Cristofaro , Ferrari Alberta , Anserini Paola , Lambertini Matteo , Peccatori Fedro A.
Published: July 2022

Several myths and misconceptions exist about hormones in women with familial predisposition to cancer, and there are few real-life data on their prescription and uptake. To better understand how they are prescribed and accepted in healthy carriers of a BRCA1/2 pathogenetic variant, an online survey was uploaded on Google Forms and shared through social media closed groups of patients’ associations, aBRCAcadabra and ACTO Campania. A total of 241 questionnaires were collected. Sexual quality of life was considered of the utmost importance by most of the respondents (mean score of 7 ± 2.8/10), but they felt the counseling they received by healthcare professionals on the topic was insufficient (4.9 ± 3.2/10). Only 57 women out of 233 (24.5%) had used hormonal contraception after being diagnosed as carriers of a BRCA pathogenetic variant, and 42 out of 148 (28.4%) underwent menopause hormonal therapy. The majority of women (53.6% for contraception and 61.5% for menopause) reported being dissatisfied with the counseling received, and 58.2% were not aware of the protective effect of hormonal contraception on the risk of ovarian cancer. An educational effort is desirable to guarantee healthy BRCA carriers reliable contraception and evidence-based menopause counseling.
Formulation of a Thermosensitive Imaging Hydrogel for Topical Application and Rapid Visualization of Tumor Margins in the Surgical Cavity
Authors: Walker Ethan , Linders Daan G. J. , Abenojar Eric , Wang Xinning , Hazelbag Hans Marten , Straver Marieke E. , Bijlstra Okker D. , March Taryn L. , Vahrmeijer Alexander L. , Exner Agata , Bogyo Matthew , Basilion James P. , Straight Brian
Published: July 2022

Background: Tumor-positive surgical margins during primary breast cancer (BCa) surgery are associated with a two-fold increase in the risk of local recurrence when compared with tumor-negative margins. Pathological microscopic evaluation of the samples only assesses about 1/10 of 1% of the entire volume of the removed BCa specimens, leading to margin under-sampling and potential local recurrence in patients with pathologically clean margins, i.e., false negative margins. In the case of tumor-positive margins, patients need to undergo re-excision and/or radiation therapy, resulting in increases in complications, morbidity, and healthcare costs. Development of a simple real-time imaging technique to identify residual BCa in the surgical cavity rapidly and precisely could significantly improve the quality of care. Methods: A small-molecule, fluorescently quenched protease-substrate probe, AKRO-QC-ICG, was tested as part of a thermosensitive imaging gel formulated for topical application and imaging of the BCa surgical cavity. Results: More than forty formulations of gel mixtures were investigated to enable easy fluid application and subsequent solidification once applied, preventing dripping and pooling in the surgical cavity. The final formulation was tested using human BCa orthotopic implants in nude and NSG patient-derived xenografts (PDX) mice. This formulation of Pluronic F-127/DMSO/AKRO-QC-ICG imaging gel was found to be a good solvent for the probe, with a desirable thermo-reversible solid–gel transition and mechanical strength for distribution of AKRO-QC-ICG on the surfaces of tissue. It demonstrated excellent ability to detect BCa tissue after 10 min exposure, with a high signal-to-noise ratio both in mouse xenografts and freshly excised human lumpectomy tissue. The in vivo efficacy of the AKRO-QC-ICG imaging gel to detect BCa revealed the levels of sensitivity/specificity = 0.92/1 in 12 nude mice, which was corroborated with the sensitivity/specificity = 0.94/1 in 10 PDX mice. Conclusions: Utilization of Pluronic F-127/DMSO/AKRO-QC-ICG imaging gel for topical application to detect BCa in the surgical cavity during surgery has the potential to reduce re-excisions, with consequent savings in healthcare costs and enhancement in patient quality of life.
Identification and Assessment of Risks in Biobanking: The Case of the Cancer Institute of Bari
Authors: De Palma Giuseppe , Bolondi Giulia , Tufaro Antonio , Pelagio Giuseppe , Brando Giuseppe , Vitale Daniela , Paradiso Angelo Virgilio
Published: July 2022

Although research biobanks are among the most promising tools to fight disease and improve public health, there are a range of risks biobanks may face that mainly need to be assessed in an attempt to be relieved. We conducted a strategic insurance review of an institutional cancer biobank with the aim of both identifying the insurable risks of our own Biobank and gathering useful evidence of primary exposure to insurable risks. In this practical scenario, risks have been outlined and categorized into inherent and residual risks, along with their possible impact on biobank maintenance. Results at the Biobank of the Cancer Institute of Bari showed evidence of potentially significant and intrinsic risk due to highly relevant threats, along with already implemented improvements that significantly reduce risks to a range of relative acceptability.
Preclinical Cold Atmospheric Plasma Cancer Treatment
Authors: Limanowski Ruby , Yan Dayun , Li Lin , Keidar Michael
Published: July 2022

CAP is an ionized gas generated under atmospheric pressure conditions. Due to its reactive chemical components and near-room temperature nature, CAP has promising applications in diverse branches of medicine, including microorganism sterilization, biofilm inactivation, wound healing, and cancer therapy. Currently, hundreds of in vitro demonstrations of CAP-based cancer treatments have been reported. However, preclinical studies, particularly in vivo studies, are pivotal to achieving a final clinical application. Here, we comprehensively introduced the research status of the preclinical usage of CAP in cancer treatment, by primarily focusing on the in vivo studies over the past decade. We summarized the primary research strategies in preclinical and clinical studies, including transdermal CAP treatment, post-surgical CAP treatment, CAP-activated solutions treatment, and sensitization treatment to drugs. Finally, the underlying mechanism was discussed based on the latest understanding.
MiRNA-Mediated Fibrosis in the Out-of-Target Heart following Partial-Body Irradiation
Authors: Tanno Barbara , Novelli Flavia , Leonardi Simona , Merla Caterina , Babini Gabriele , Giardullo Paola , Kadhim Munira , Traynor Damien , Medipally Dinesh , Meade Aidan , Lyng Fiona , Tapio Soile , Marchetti Luca , Saran Anna , Pazzaglia Simonetta , Mancuso Mariateresa
Published: July 2022

Recent reports have shown a link between radiation exposure and non-cancer diseases such as radiation-induced heart disease (RIHD). Radiation exposures are often inhomogeneous, and out-of-target effects have been studied in terms of cancer risk, but very few studies have been carried out for non-cancer diseases. Here, the role of miRNAs in the pathogenesis of RIHD was investigated. C57Bl/6J female mice were whole- (WBI) or partial-body-irradiated (PBI) with 2 Gy of X-rays or sham-irradiated (SI). In PBI exposure, the lower third of the mouse body was irradiated, while the upper two-thirds were shielded. From all groups, hearts were collected 15 days or 6 months post-irradiation. The MiRNome analysis at 15 days post-irradiation showed that miRNAs, belonging to the myomiR family, were highly differentially expressed in WBI and PBI mouse hearts compared with SI hearts. Raman spectral data collected 15 days and 6 months post-irradiation showed biochemical differences among SI, WBI and PBI mouse hearts. Fibrosis in WBI and PBI mouse hearts, indicated by the increased deposition of collagen and the overexpression of genes involved in myofibroblast activation, was found 6 months post-irradiation. Using an in vitro co-culture system, involving directly irradiated skeletal muscle and unirradiated ventricular cardiac human cells, we propose the role of miR-1/133a as mediators of the abscopal response, suggesting that miRNA-based strategies could be relevant for limiting tissue-dependent reactions in non-directly irradiated tissues.
Salvage versus Primary Liver Transplantation for Hepatocellular Carcinoma: A Twenty-Year Experience Meta-Analysis
Authors: Guerrini Gian Piero , Esposito Giuseppe , Olivieri Tiziana , Magistri Paolo , Ballarin Roberto , Di Sandro Stefano , Di Benedetto Fabrizio
Published: July 2022

(1) Background: Primary liver transplantation (PLT) for HCC represents the ideal treatment. However, since organ shortage increases the risk of drop-out from the waiting list for tumor progression, a new surgical strategy has been developed: Salvage Liver Transplantation (SLT) can be offered as an additional curative strategy for HCC recurrence after liver resection. The aim of this updated meta-analysis is to compare surgical and long-term outcomes of SLT versus PLT for HCC. (2) Materials and Methods: A systematic review and meta-analysis was conducted using the published papers comparing SLT and PLT up to January 2022. (3) Results: 25 studies describing 11,275 patients met the inclusion criteria. The meta-analysis revealed no statistical difference in intraoperative blood loss, overall vascular complications, retransplantation rate, and hospital stay in the SLT group compared with the PLT group. However, the SLT group showed a slightly significant lower 5-year OS rate and 5-year disease-free survival rate. (4) Conclusion: meta-analysis advocates the relative safety and feasibility of both Salvage LT and Primary LT strategies. Specifically, SLT seems to have comparable surgical outcomes but slightly poorer long-term survival than PLT.
Review on Treatment Planning Systems for Cervix Brachytherapy (Interventional Radiotherapy): Some Desirable and Convenient Practical Aspects to Be Implemented from Radiation Oncologist and Medical Physics Perspectives
Authors: Otal Antonio , Celada Francisco , Chimeno Jose , Vijande Javier , Pellejero Santiago , Perez-Calatayud Maria-Jose , Villafranca Elena , Fuentemilla Naiara , Blazquez Francisco , Rodriguez Silvia , Perez-Calatayud Jose
Published: July 2022

Intracavitary brachytherapy (BT, Interventional Radiotherapy, IRT), plays an essential role in the curative intent of locally advanced cervical cancer, for which the conventional approach involves external beam radiotherapy with concurrent chemotherapy followed by BT. This work aims to review the different methodologies used by commercially available treatment planning systems (TPSs) in exclusive magnetic resonance imaging-based (MRI) cervix BT with interstitial component treatments. Practical aspects and improvements to be implemented into the TPSs are discussed. This review is based on the clinical expertise of a group of radiation oncologists and medical physicists and on interactive demos provided by the software manufacturers. The TPS versions considered include all the new tools currently in development for future commercial releases. The specialists from the supplier companies were asked to propose solutions to some of the challenges often encountered in a clinical environment through a questionnaire. The results include not only such answers but also comments by the authors that, in their opinion, could help solve the challenges covered in these questions. This study summarizes the possibilities offered nowadays by commercial TPSs, highlighting the absence of some useful tools that would notably improve the planning of MR-based interstitial component cervix brachytherapy.
A New Multi-Color FISH Assay for Brush Biopsy-Based Detection of Chromosomal Aneuploidy in Oral (Pre)Cancer in Patients with Fanconi Anemia
Authors: Silva de Araujo Bruno Eduardo , Markgraf Mona , de Santana Almeida Araujo Isabela Karoline , Velleuer Eunike , Dietrich Ralf , Pomjanski Natalia , Schramm Martin
Published: July 2022

Background: Fanconi anemia (FA) is a rare inherited DNA instability disorder with a remarkably elevated risk of oral squamous cell carcinoma. These cancers can be detected with oral brush biopsy-based cytology even at early stages. This study aims to determine the diagnostic accuracy of a new multi-color fluorescent in situ hybridization (FISH) assay consisting of probes for CCND1, TERC, MYC and centromere of chromosome 6, as well as a 9p21 FISH assay consisting of probes for CDKN2A and centromere of chromosome 9 for the detection of oral (pre) malignant lesions in FA. Methods: (I) Cutoffs for the dichotomization of positive or negative multi-color FISH results are determined and (II) retrospectively validated by using archived oral brush biopsy specimens from individuals with Fanconi anemia. In addition, the specimens for cutoff determination were re-hybridized with the 9p21 FISH assay. Results: A cutoff of six or more chromosomal aneuploid cells for a positive FISH result was determined in the cutoff study on 160 biopsy specimens. The validating of this cutoff on 152 specimens showed at best a sensitivity of 87% and a specificity of 82.9%. Conclusion: Multi-color FISH is a sufficient tool to detect chromosomal aneuploidy in oral (pre) malignant lesions of individuals with Fanconi anemia. However, some false positive results may hamper the application as an adjuvant method to oral brush biopsy-based cytology in an oral cancer surveillance program.
Overall Survival Improvement in Patients with Epidermal Growth Factor Receptor-Mutated Non-Small Cell Lung Cancer and Bone Metastasis Treated with Denosumab
Authors: Ko How-Wen , Chiu Chi-Tsun , Wang Chih-Liang , Yang Tsung-Ying , Liu Chien-Ying , Yu Chih-Teng , Tseng Li-Chuan , Kuo Chih-Hsi Scott , Wang Chin-Chou , Yang Muh-Hwa , Yang Cheng-Ta
Published: July 2022

The impact of an initial skeletal-related event (SRE) and denosumab adjuvant treatment on the survival outcome of epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) patients with bone metastasis remains unclear. This retrospective study included 400 metastatic EGFR-mutated NSCLC patients. Among 190 bone metastasis patients, 61 had initial SREs and 73 received denosumab. We analyzed patient characteristics, SRE-free survival (SRE-FS), and overall survival (OS). In metastatic EGFR-mutated NSCLC, bone metastasis was associated with a poorer OS (21.7 vs. 33.0 months; p < 0.001). Bone metastasis patients with initial SREs at diagnosis had an even shorter OS, compared with those without initial SRE (15.4 vs. 23.6 months; p = 0.026). Denosumab reduced SRE incidence (hazard ratio (HR) 0.57 (95% confidence interval (CI) 0.34–0.94; p = 0.027) and was associated with improved OS (26.6 vs. 20.1 months; p = 0.015). A multivariate analysis demonstrated that denosumab treatment was correlated with a lower incidence of SRE (HR 0.61 (95% CI 0.37–0.98); p = 0.042) and better OS (HR 0.60 (95% CI 0.41–0.88); p = 0.008). In subgroup analyses, denosumab prolonged SRE-FS (HR 0.36 (95% CI 0.19–0.79); p = 0.009) in patients without initial SREs and was related to a better OS (25.3 vs. 12.9 months; p = 0.016) in patients with initial or pre-existing SREs. Osteonecrosis of the jaw was diagnosed in two patients (2.74%) receiving denosumab. Our study confirmed the association between initial SREs and a worse outcome and provided novel evidence of the survival benefit of denosumab for EGFR-mutated NSCLC patients with bone metastasis.
Metformin Treatment Induces Different Response in Pheochromocytoma/Paraganglioma Tumour Cells and in Primary Fibroblasts
Authors: Martinelli Serena , Amore Francesca , Mello Tommaso , Mannelli Massimo , Maggi Mario , Rapizzi Elena
Published: July 2022

Pheochromocytoma/paragangliomas (PPGLs) are neuroendocrine tumours, often non-metastatic, but without available effective treatment for their metastatic form. Recent studies have shown that metformin exhibits antiproliferative activity in many human cancers, including PPGLs. Nevertheless, no data are available on the role of metformin on PPGL cells (two-dimension, 2D) and spheroids (three-dimension, 3D) migration/invasion. In this study, we observed that metformin exerts an antiproliferative effect on 2D and 3D cultures of pheochromocytoma mouse tumour tissue (MTT), either silenced or not for the SDHB subunit. However, metformin did not affect MTT migration. On the other hand, metformin did not have a short-term effect on the proliferation of mouse primary fibroblasts, but significantly decreased their ability to migrate. Although the metabolic changes induced by metformin were similar between MTT and fibroblasts (i.e., an overall decrease of ATP production and an increase in intracellular lactate concentration) the activated signalling pathways were different. Indeed, after metformin administration, MTT showed a reduced phosphorylation of Akt and Erk1/2, while fibroblasts exhibited a downregulation of N-Cadherin and an upregulation of E-Cadherin. Herein, we demonstrated that metformin has different effects on cell growth and spread depending on the cell type nature, underlining the importance of the tumour microenvironment in dictating the drug response.
Genomic Landscape, Clinical Features and Outcomes of Non-Small Cell Lung Cancer Patients Harboring BRAF Alterations of Distinct Functional Classes
Authors: Di Federico Alessandro , De Giglio Andrea , Gelsomino Francesco , De Biase Dario , Giunchi Francesca , Palladini Arianna , Sperandi Francesca , Melotti Barbara , Ardizzoni Andrea
Published: July 2022

Background: In non-small cell lung cancer (NSCLC), BRAF class 1 alterations are effectively targeted by BRAF inhibitors. Conversely, targeted therapies have very low or absent activity in patients carrying class 2 and 3 alterations. The spectrum of BRAF alterations in NSCLC patients, and their accompanying clinical features, genomic landscape and treatment outcomes have been poorly reported. Patients and methods: We identified BRAF alterations of defined functional class across different tumors through a systematic review. Then, we selected NSCLC patients carrying BRAF alterations, according to the systematic review, in the cBioPortal (cBioPortal cohort) to collect and analyze clinical, biomolecular and survival data. Finally, we identified NSCLC patients carrying BRAF non-V600 mutations enrolled in POPLAR and OAK trials (POPLAR/OAK cohort), extracting clinical and survival data for survival analyses. Results: 100 different BRAF non-V600 alterations were identified through the systematic review. In the cBioPortal cohort (n = 139), patients harboring class 2 and 3 alterations were more frequently smokers and had higher tumor mutational burden compared to those carrying class 1 alterations. The spectrum of most frequently co-altered genes was significantly different between BRAF alterations classes, including SETD2, STK11, POM121L12, MUC16, KEAP1, TERT, TP53 and other genes. In the POPLAR/OAK cohort, patients carrying non-V600 BRAF alterations were characterized by poor prognosis compared to BRAF wild-type patients. Conclusions: Different classes of BRAF alterations confer distinctive clinical features, biomolecular signature and disease behavior to NSCLC patients. Non-V600 alterations are characterized by poor prognosis, but key gene co-alterations involved in cancer cell survival and immune pathways may suggest their potential sensitivity to tailored treatments.
Systemic Mastocytosis and Other Entities Involving Mast Cells: A Practical Review and Update
Authors: El Hussein Siba , Chifotides Helen T. , Khoury Joseph D. , Verstovsek Srdan , Thakral Beenu
Published: July 2022

Evidence in the recent literature suggests that the presentation spectrum of mast cell neoplasms is broad. In this article, we elaborate on recent data pertaining to minor diagnostic criteria of systemic mastocytosis (SM), including sensitive testing methods for detection of activating mutations in the KIT gene or its variants, and adjusted serum tryptase levels in cases with hereditary α-tryptasemia. We also summarize entities that require differential diagnosis, such as the recently reclassified SM subtype named bone marrow mastocytosis, mast cell leukemia (an SM subtype that can be acute or chronic); the rare morphological variant of all SM subtypes known as well-differentiated systemic mastocytosis; the extremely rare myelomastocytic leukemia and its differentiating features from mast cell leukemia; and mast cell activation syndrome. In addition, we provide a concise clinical update of the latest adjusted risk stratification model incorporating genomic data to define prognosis in SM and new treatments that were approved for advanced SM (midostaurin, avapritinib).
Dietary Patterns and Prostate Cancer: CAPLIFE Study
Authors: Lozano-Lorca Macarena , Rodríguez-González Margarita , Salcedo-Bellido Inmaculada , Vázquez-Alonso Fernando , Arrabal Miguel , Martín-Castaño Benita , Sánchez María-José , Jiménez-Moleón José-Juan , Olmedo-Requena Rocío
Published: July 2022

The etiology of prostate cancer (PCa) remains uncertain, and the role of diet is unclear. We aimed to evaluate the role of diet, through dietary patterns, on PCa, considering tumor aggressiveness and extension. The CAPLIFE study is a population-based case-control study including a total of 428 incident PCa cases and 393 controls aged 40–80 years. Dietary information was collected through a validated food frequency questionnaire. Three dietary patterns were identified through principal component analysis: “Mediterranean,” “Western,” and “Unhealthy,” which were categorized into tertiles according to the control group cutoff points. Tumor aggressiveness and extension was determined. Logistic regression models were used to assess the association between dietary patterns and PCa. High adherence to an unhealthy dietary pattern was associated with higher odds of PCa, ORT3vsT1 = 1.52 (95% CI 1.02–2.27), especially for cases with ISUP 1–2 and localized PCa tumors. This association was not observed with a Western or Mediterranean pattern. In conclusion, adherence to an unhealthy diet appears to be associated with higher odds of PCa, especially for cases with ISUP 1–2 and localized PCa tumors.
A Critical Overview of Predictors of Heart Sparing by Deep-Inspiration-Breath-Hold Irradiation in Left-Sided Breast Cancer Patients
Authors: Ferini Gianluca , Valenti Vito , Viola Anna , Umana Giuseppe Emmanuele , Martorana Emanuele
Published: July 2022

Radiotherapy represents an essential part of the therapeutic algorithm for breast cancer patients after conservative surgery. The treatment of left-sided tumors has been associated with a non-negligible risk of developing late-onset cardiovascular disease. The cardiac risk perception has especially increased over the last years due to the prolongation of patients’ survival owing to the advent of new drugs and an ever earlier cancer detection through screening programs. Improvements in radiation delivery techniques could reduce the treatment-related heart toxicity. The deep-inspiration-breath-hold (DIBH) irradiation is one of the most advanced treatment approaches, which requires specific technical equipment and uses inspiration to displace the heart from the tangential radiation fields. However, not all patients benefit from its use. Moreover, DIBH irradiation needs patient compliance and accurate training. Therefore, such a technique may be unjustifiably cumbersome and time-consuming as well as unnecessarily expensive from a mere healthcare cost point of view. Hence the need to early select only the true beneficiaries while tailoring more effective heart-sparing techniques for the others and streamlining the workflow, especially in high-volume radiation oncology departments. In this literature overview, we collected some possible predictors of cardiac dose sparing in DIBH irradiation for left breast treatment in an effort to provide an easy-to-consult summary of simple instruments to insiders for identifying patients actually benefitting from this technique. We critically reviewed the reliability and weaknesses of each retrieved finding, aiming to inspire new insights and discussions on this much-debated topic.
Identification of Ubiquitin-Related Gene-Pair Signatures for Predicting Tumor Microenvironment Infiltration and Drug Sensitivity of Lung Adenocarcinoma
Authors: Li Yumei , An Lanfen , Jia Zhe , Li Jingxia , Zhou E , Wu Feng , Yin Zhengrong , Geng Wei , Liao Tingting , Xiao Wenjing , Deng Jingjing , Chen Wenjuan , Li Minglei , Jin Yang
Published: July 2022

Lung adenocarcinoma (LUAD) is a common pathological type of lung cancer worldwide, and new biomarkers are urgently required to guide more effective individualized therapy for patients. Ubiquitin-related genes (UbRGs) partially participate in the initiation and progression of lung cancer. In this study, we used ubiquitin-related gene pairs (UbRGPs) in tumor tissues to access the function of UbRGs in overall survival, immunocyte infiltration, and tumor mutation burden (TMB) of patients with LUAD from The Cancer Genome Atlas (TCGA) database. In addition, we constructed a prognostic signature based on six UbRGPs and evaluated its performance in an internal (TCGA testing set) and an external validation set (GSE13213). The prognostic signature revealed that risk scores were negatively correlated with the overall survival, immunocyte infiltration, and expression of immune checkpoint inhibitor-related genes and positively correlated with the TMB. Patients in the high-risk group showed higher sensitivity to partially targeted and chemotherapeutic drugs than those in the low-risk group. This study contributes to the understanding of the characteristics of UbRGPs in LUAD and provides guidance for effective immuno-, chemo-, and targeted therapy.
Effectiveness of Outpatient Pulmonary Rehabilitation in Patients with Surgically Resected Lung Cancer: A Retrospective Real-World Analysis
Authors: Illini Oliver , Valipour Arschang , Gattinger Dietlinde , Petrovic Milos , Fabikan Hannah , Hochmair Maximilian Johannes , Zwick Ralf Harun
Published: July 2022

Patients with lung cancer frequently suffer from physical deconditioning, low exercise capacity, and reduced quality of life. There is little evidence on the effects of a structured outpatient pulmonary rehabilitation program (OPR) on exercise capacity and symptom load in these patients. We performed a retrospective, single-center analysis of surgically resected lung cancer patients, who underwent a multiprofessional 6-week OPR. The primary endpoint was a change in the six-minute walk test distance (6 MWT). Secondary endpoints included changes in maximal workload and constant work-rate test results during cycle-ergometry, upper and lower extremity strength, and inspiratory muscle strength. The COPD Assessment Test (CAT) was used to assess symptom burden. Fifty-seven patients were included. Of those, fifty-two (91.2%) completed the full 6 weeks of OPR. The mean age was 56.4 (SD 9.2) years, and 58% were female. At completion of OPR, there was a statistically significant mean of a 50 m (95% CI, 29.6–70.7; p < 0.001) increase in 6 MWT. Significant improvements were also seen in all other exercise and strength tests (p < 0.001), accompanied by a significant reduction in the CAT score (mean difference −3.1, p = 0.001). No adverse effects were reported. OPR for surgically resected lung cancer patients was safe and effective and showed high adherence in the current study.
DDR2 Expression in Cancer-Associated Fibroblasts Promotes Ovarian Cancer Tumor Invasion and Metastasis through Periostin-ITGB1
Authors: Akinjiyan Favour A. , Dave Ritu M. , Alpert Emily , Longmore Gregory D. , Fuh Katherine C.
Published: July 2022

Ovarian cancer has the highest mortality of all gynecologic malignancies. As such, there is a need to identify molecular mechanisms that underlie tumor metastasis in ovarian cancer. Increased expression of receptor tyrosine kinase, DDR2, has been associated with worse patient survival. Identifying downstream targets of DDR2 may allow specific modulation of ovarian cancer metastatic pathways. Additionally, stromal cells play a critical role in metastasis. The crosstalk between tumor and stromal cells can lead to tumor progression. We first identified that tumor cells co-cultured with DDR2-expressing fibroblasts had lower periostin expression when compared to tumor cells co-cultured with DDR2-depleted fibroblasts. We confirmed that DDR2 regulates POSTN expression in ovarian cancer-associated fibroblasts (CAFs). We found that mesothelial cell clearance and invasion by tumor cells were enhanced three-fold when DDR2 and POSTN-expressing CAFs were present compared to DDR2 and POSTN-depleted CAFs. Furthermore, DDR2-depleted and POSTN-overexpressing CAFs co-injected with ovarian tumor cells had increased tumor burden compared to mice injected with tumor cells and DDR2 and POSTN-depleted CAFs. Furthermore, we demonstrated that DDR2 regulates periostin expression through integrin B1 (ITGB1). Stromal DDR2 is highly correlated with stromal POSTN expression in ovarian cancer patient tumors. Thus, DDR2 expression in CAFs regulates the steps of ovarian cancer metastasis through periostin.
A Prospective Study of Stereotactic Body Radiotherapy (SBRT) with Concomitant Whole-Pelvic Radiotherapy (WPRT) for High-Risk Localized Prostate Cancer Patients Using 1.5 Tesla Magnetic Resonance Guidance: The Preliminary Clinical Outcome
Authors: Poon Darren M. C. , Yuan Jing , Yang Bin , Wong Oi-Lei , Chiu Sin-Ting , Chiu George , Cheung Kin-Yin , Yu Siu-Ki , Yung Raymond W. H.
Published: July 2022

Background: Conventionally fractionated whole-pelvic nodal radiotherapy (WPRT) improves clinical outcome compared to prostate-only RT in high-risk prostate cancer (HR-PC). MR-guided stereotactic body radiotherapy (MRgSBRT) with concomitant WPRT represents a novel radiotherapy (RT) paradigm for HR-PC, potentially improving online image guidance and clinical outcomes. This study aims to report the preliminary clinical experiences and treatment outcome of 1.5 Tesla adaptive MRgSBRT with concomitant WPRT in HR-PC patients. Materials and methods: Forty-two consecutive HR-PC patients (72.5 ± 6.8 years) were prospectively enrolled, treated by online adaptive MRgSBRT (8 Gy(prostate)/5 Gy(WPRT) × 5 fractions) combined with androgen deprivation therapy (ADT) and followed up (median: 251 days, range: 20–609 days). Clinical outcomes were measured by gastrointestinal (GI) and genitourinary (GU) toxicities according to the Common Terminology Criteria for Adverse Events (CTCAE) Scale v. 5.0, patient-reported quality of life (QoL) with EPIC (Expanded Prostate Cancer Index Composite) questionnaire, and prostate-specific antigen (PSA) responses. Results: All MRgSBRT fractions achieved planning objectives and dose specifications of the targets and organs at risk, and they were successfully delivered. The maximum cumulative acute GI/GU grade 1 and 2 toxicity rates were 19.0%/81.0% and 2.4%/7.1%, respectively. The subacute (>30 days) GI/GU grade 1 and 2 toxicity rates were 21.4%/64.3% and 2.4%/2.4%, respectively. No grade 3 toxicities were reported. QoL showed insignificant changes in urinary, bowel, sexual, and hormonal domain scores during the follow-up period. All patients had early post-MRgSBRT biochemical responses, while biochemical recurrence (PSA nadir + 2 ng/mL) occurred in one patient at month 18. Conclusions: To our knowledge, this is the first prospective study that showed the clinical outcomes of MRgSBRT with concomitant WPRT in HR-PC patients. The early results suggested favorable treatment-related toxicities and encouraging patient-reported QoLs, but long-term follow-up is needed to confirm our early results.
Clinical Applications of Immuno-PET in Lymphoma: A Systematic Review
Authors: Triumbari Elizabeth Katherine Anna , Morland David , Laudicella Riccardo , Bauckneht Matteo , Albano Domenico , Annunziata Salvatore
Published: July 2022

Objective: Immuno-positron emission tomography (iPET) combines the sensitivity of the PET imaging technique and the targeting specificity of radio-labelled monoclonal antibodies (mAb). Its first clinical applications in humans were described in the late 1990s, and several pathologies have benefitted from this molecular imaging modality since then. Our scope was to assess current clinical applications of immuno-PET in patients with lymphoma. Therefore, a systematic review of the published literature was performed. Methods: PubMed/Medline and Scopus databases were independently searched by two nuclear medicine physicians, to identify studies describing the clinical use of immuno-PET in patients with lymphoma. Methodological quality of the included articles was assessed by using the Quality Assessment of Diagnostic Accuracy Studies criteria. The studies were then analyzed concerning the molecular target of interest. Results: The initial search yielded 1407 articles. After elimination of duplicates, 1339 titles/abstracts were evaluated. Only two articles were found to comply with the inclusion criteria and two more were found during the cross-reference check. Among the four included articles, three described the use of 89Zr-labelled antibodies targeting CD20+ relapsed/refractory B-cell lymphomas and one concerned the use of 68Ga-labelled mAb targeting CXCR4 in patients with non-Hodgkin lymphomas. Conclusions: Very limited literature data are currently available on the clinical use of iPET in patients with lymphoma. This technique is encountering obstacles in its wider use, possibly because of the need of specific facilities, unfavorable dosimetry, and unclear correlation of immuno-tracer biodistribution with patients’ clinical and tumors’ molecular characteristics. However, iPET may represent a useful tool to non-invasively visualize the heterogenous individual immunological environment, thus potentially guiding treatment-planning in lymphoma patients, and hence deserves further exploitation.
Selective Synthesis of Levulinic Ester from Furfural Catalyzed by Hierarchical Zeolites
Authors: Vasconcelos Sancler C. , Pinhel Luiz F. C. , Madriaga Vinicius G. C. , Rossa Vinicius , Batinga Leyliane G. S. , Silva Domingos S. A. , dos Santos Rodrigo D. , Soares André V. H. , Urquieta-González Ernesto A. , Passos Fabio Barboza , Varma Rajender S. , Lima Thiago M.
Published: July 2022

Furfural is a platform molecule that can be catalytically converted using a cascade series of reactions into levulinic esters, essential compounds used as fuel additives. Bifunctional catalysts containing Lewis and Brønsted acid sites such as zeolites are commonly used for these conversions. However, microporous zeolites often present diffusional restriction due to the size similarity of furfural and other molecules to the zeolites’ micropores. Thus, incorporating mesopores in these materials through post-synthetic protocols is a promising pathway to circumventing these limitations. This study presents the creation of hierarchical beta and mordenite using Si or Al removal and their employment in the furfural conversion to isopropyl levulinate (PL). Mordenite zeolite did not produce satisfactory mesopores, while the beta was more efficient in generating them by both acid and alkaline treatments. Beta zeolite treated in an alkaline solution presented larger mesopores (14.9 and 34.0 nm), maintaining a total acidity value close to its parent zeolite and a higher Lewis/Brønsted ratio. The combination of these features led to an improved diffusion of bulkier products and the highest furfural conversion (94%) and PL selectivity (90%), suggesting that a post-modification of beta zeolites produced efficient catalysts for upgrading abundantly available furfural.
Engineering Noble Metal-like Bi onto Hierarchical SrWO4 for the Enhancement of Photocatalytic Activity
Authors: Tang Liang , Zhao Jian , Wang Xiao , Wang Jiajun , Zhang Peng
Published: July 2022

Solar-driven hydrogen production from water has attracted increasing attention due to sustainable H2 fuel generation with zero-emissions. However, the design of a photocatalyst without noble metals to enable efficient water splitting is still critical for practical applications. In this study, the hierarchical microspheres of SrWO4 assembled with well-defined metallic Bi nanoparticles were synthesized through mild hydrothermal aging. The resultant photocatalyst with optimum proportion exhibited the competitive performance of a high hydrogen-generation rate at 4.5 mmol·h−1·g−1, outperforming SrWO4 and Bi by factors of 2.0 and 2.4, respectively. Both the experimental characterization and active analysis revealed that the synergistic effect of noble metal-like behavior of Bi and their electron-sink capacity mainly contribute to boosting the overall photocatalytic efficiency. This work may provide advanced insights into the application of economical bismuth elements as co-catalysts, instead of noble metals, to improve photocatalytic efficiency in solar-fuel conversion and environmental remediation.
Optimization of Autohydrolysis of Olive Pomaces to Obtain Bioactive Oligosaccharides: The Effect of Cultivar and Fruit Ripening
Authors: Freitas Laura , Simões Rita , Miranda Isabel , Peres Fátima , Ferreira-Dias Suzana
Published: July 2022

The valorisation of agro-industrial residues presents a challenge in obtaining economically sustainable and environmentally friendly industrial processes. Olive pomace is a by-product generated in large quantities, from olive oil extraction. This residue mostly consists of lignocellulosic materials. The aim of this study was to evaluate the potential use of extracted olive pomaces (EOP) obtained from olives with different ripening indexes (RI) and from different cultivars (Cobrançosa; RI = 2.5; 3.3 and 4.7; and Galega Vulgar; RI = 1.8; 2.9 and 4.8), to produce bioactive oligosaccharides from hemicelluloses by autohydrolysis. The hydrothermal treatment conditions were optimized by Response Surface Methodology, following a central composite rotatable design (CCRD), as a function of temperature (T: 142–198 °C) and time (t: 48–132 min), corresponding to severity factor (SF) values from 3.2 to 4.9. For all pomace samples, soluble sugar production was described by concave surfaces as a function of temperature and time. Autohydrolysis with SF equal or higher than 4.0 produced higher sugar yields, with maximum values around 180 g glucose equivalent/kg EOP for SF of 4.7 (190 °C/120 min) or 4.9 (198 °C/90 min). These values were similar for both cultivars and were not dependent on the ripening stage of the olives. Maximum oligosaccharide (OS) yields of 98% were obtained by autohydrolysis with SF of 4.0. The increase in SF to 4.9 resulted in a decrease in OS yield to 86–92%, due to the release of monomeric sugars. The monosaccharides were mostly xylose (55.8–67.7% in Galega; 50.4–69.0% in Cobrançosa liquid phases), and glucose, galactose, arabinose and rhamnose, in smaller quantities. Therefore, the production of bioactive xylo-oligosaccharides (XOS) from olive pomaces mainly depends on the hydrothermal conditions used.