Cancers

28 pages, 2331 KiB

Open AccessReview

Ewing Sarcoma Meets Epigenetics, Immunology and Nanomedicine: Moving Forward into Novel Therapeutic Strategies

by Sara Sánchez-Molina, Elisabet Figuerola-Bou, Víctor Sánchez-Margalet, Luis de la Cruz-Merino, Jaume Mora, Enrique de Álava Casado, Daniel José García-Domínguez and Lourdes Hontecillas-Prieto

Cancers 2022, 14(21), 5473; https://doi.org/10.3390/cancers14215473 - 7 Nov 2022

Cited by 5 | Viewed by 4846

Abstract

Ewing Sarcoma (EWS) is an aggressive bone and soft tissue tumor that mainly affects children, adolescents, and young adults. The standard therapy, including chemotherapy, surgery, and radiotherapy, has substantially improved the survival of EWS patients with localized disease. Unfortunately, this multimodal treatment remains [...] Read more.

Ewing Sarcoma (EWS) is an aggressive bone and soft tissue tumor that mainly affects children, adolescents, and young adults. The standard therapy, including chemotherapy, surgery, and radiotherapy, has substantially improved the survival of EWS patients with localized disease. Unfortunately, this multimodal treatment remains elusive in clinics for those patients with recurrent or metastatic disease who have an unfavorable prognosis. Consistently, there is an urgent need to find new strategies for patients that fail to respond to standard therapies. In this regard, in the last decade, treatments targeting epigenetic dependencies in tumor cells and the immune system have emerged into the clinical scenario. Additionally, recent advances in nanomedicine provide novel delivery drug systems, which may address challenges such as side effects and toxicity. Therefore, therapeutic strategies stemming from epigenetics, immunology, and nanomedicine yield promising alternatives for treating these patients. In this review, we highlight the most relevant EWS preclinical and clinical studies in epigenetics, immunotherapy, and nanotherapy conducted in the last five years. Full article

(This article belongs to the Special Issue Ewing Sarcoma: Basic Biology, Clinical Challenges and Future Perspectives)

► Show Figures

Figure 1

22 pages, 735 KiB

Open AccessReview

Histone Deacetylase Functions in Gastric Cancer: Therapeutic Target?

by Amandine Badie, Christian Gaiddon and Georg Mellitzer

Cancers 2022, 14(21), 5472; https://doi.org/10.3390/cancers14215472 - 7 Nov 2022

Cited by 10 | Viewed by 2439

Abstract

Gastric cancer (GC) is one of the most aggressive cancers. Therapeutic treatments are based on surgery combined with chemotherapy using a combination of platinum-based agents. However, at metastatic stages of the disease, survival is extremely low due to late diagnosis and resistance mechanisms [...] Read more.

Gastric cancer (GC) is one of the most aggressive cancers. Therapeutic treatments are based on surgery combined with chemotherapy using a combination of platinum-based agents. However, at metastatic stages of the disease, survival is extremely low due to late diagnosis and resistance mechanisms to chemotherapies. The development of new classifications has not yet identified new prognostic markers for clinical use. The studies of epigenetic processes highlighted the implication of histone acetylation status, regulated by histone acetyltransferases (HATs) and by histone deacetylases (HDACs), in cancer development. In this way, inhibitors of HDACs (HDACis) have been developed and some of them have already been clinically approved to treat T-cell lymphoma and multiple myeloma. In this review, we summarize the regulations and functions of eighteen HDACs in GC, describing their known targets, involved cellular processes, associated clinicopathological features, and impact on survival of patients. Additionally, we resume the in vitro, pre-clinical, and clinical trials of four HDACis approved by Food and Drug Administration (FDA) in cancers in the context of GC. Full article

► Show Figures

Graphical abstract

13 pages, 775 KiB

Open AccessReview

Aptamers, a New Therapeutic Opportunity for the Treatment of Multiple Myeloma

by Ane Amundarain, Fernando Pastor, Felipe Prósper and Xabier Agirre

Cancers 2022, 14(21), 5471; https://doi.org/10.3390/cancers14215471 - 7 Nov 2022

Cited by 2 | Viewed by 2631

Abstract

Multiple Myeloma (MM) remains an incurable disease due to high relapse rates and fast development of drug resistances. The introduction of monoclonal antibodies (mAb) has caused a paradigm shift in MM treatment, paving the way for targeted approaches with increased efficacy and reduced [...] Read more.

Multiple Myeloma (MM) remains an incurable disease due to high relapse rates and fast development of drug resistances. The introduction of monoclonal antibodies (mAb) has caused a paradigm shift in MM treatment, paving the way for targeted approaches with increased efficacy and reduced toxicities. Nevertheless, antibody-based therapies face several difficulties such as high immunogenicity, high production costs and limited conjugation capacity, which we believe could be overcome by the introduction of nucleic acid aptamers. Similar to antibodies, aptamers can bind to their targets with great affinity and specificity. However, their chemical nature reduces their immunogenicity and production costs, while it enables their conjugation to a wide variety of cargoes for their use as delivery agents. In this review, we summarize several aptamers that have been tested against MM specific targets with promising results, establishing the rationale for the further development of aptamer-based strategies against MM. In this direction, we believe that the study of novel plasma cell surface markers, the development of intracellular aptamers and further research on aptamers as building blocks for complex nanomedicines will lead to the generation of next-generation targeted approaches that will undoubtedly contribute to improve the management and life quality of MM patients. Full article

(This article belongs to the Special Issue Aptamers and Cancer)

► Show Figures

Figure 1

Figure 1
Overview of purified protein-based SELEX. The initial RNA/ssDNA aptamer pool is generated from a commercial ssDNA oligonucleotide library consisting of a central random core sequence flanked by fixed 5′ and 3′ primer binding regions to allow library amplification. To obtain RNA/ssDNA aptamers for the first selection cycle, the library is amplified by PCR and subjected to in vitro transcription or strand separation, respectively. A purified protein-based SELEX approach has four key steps: (1) the aptamer library is initially incubated with the purified target protein and (2) bound sequences are isolated from the unbound ones via different partitioning strategies. The bound sequences are then (3) recovered and (4) re-amplified to obtain the new aptamer library for the next selection cycle. For RNA aptamers, recovered RNA aptamers must be retrotranscribed for subsequent PCR amplification, and the amplification product is then converted into RNA again via in vitro transcription. For ssDNA, recovered aptamers are directly amplified by PCR and ssDNA aptamers are obtained by strand separation. After n selection cycles, the aptamer pool is sequenced to identify the enriched aptamer sequences. Image made in ©BioRender. Full article ">Figure 2
Current aptamers for precision medicine in MM. (1) Aptamer against AXII, (2) BCMA targeted aptamer, (3) aptamer against C-MET, (4) conjugated CD38-doxorubicin aptamer and (5) NOX-A12 RNA aptamer for CXCL12. All the aptamers except the NOX-A12 spiegelmer are directed towards receptors expressed in the MM plasma cell membrane. Receptor–ligand interactions are depicted with black arrows, while the mechanism of action of aptamers is depicted with red arrows for antagonist aptamers, and blue arrows for cargo delivery aptamers. BM: bone marrow; Doxo: doxorubicin; OBL: osteoblast; sAXII: soluble annexin A2. Image made in ©BioRender. Full article ">

12 pages, 947 KiB

Open AccessSystematic Review

The Effects of Patient-Reported Outcome Screening on the Survival of People with Cancer: A Systematic Review and Meta-Analysis

by Caterina Caminiti, Giuseppe Maglietta, Francesca Diodati, Matteo Puntoni, Barbara Marcomini, Silvia Lazzarelli, Carmine Pinto and Francesco Perrone

Cancers 2022, 14(21), 5470; https://doi.org/10.3390/cancers14215470 - 7 Nov 2022

Cited by 22 | Viewed by 2327

Abstract

This study examined the effects of the routine assessment of patient-reported outcomes (PROs) on the overall survival of adult patients with cancer. We included clinical trials and observational studies with a control group that compared PRO monitoring interventions in cancer clinical practice to [...] Read more.

This study examined the effects of the routine assessment of patient-reported outcomes (PROs) on the overall survival of adult patients with cancer. We included clinical trials and observational studies with a control group that compared PRO monitoring interventions in cancer clinical practice to usual care. The Cochrane risk-of-bias tools were used. In total, six studies were included in the systematic review: two randomized trials, one population-based retrospectively matched cohort study, two pre–post with historical control studies and one non-randomized controlled trial. Half were multicenter, two were conducted in Europe, three were conducted in the USA and was conducted in Canada. Two studies considered any type of cancer, two were restricted to lung cancer and two were restricted to advanced forms of cancer. PRO screening was electronic in four of the six studies. The meta-analysis included all six studies (intervention = 130.094; control = 129.903). The pooled mortality outcome at 1 year was RR = 0.77 (95%CI 0.76–0.78) as determined by the common effect model and RR = 0.82 (95%CI 0.60–1.12; p = 0.16) as determined by the random-effects model. Heterogeneity was statistically significant (I² = 73%; p < 0.01). The overall risk of bias was rated as moderate in five studies and serious in one study. This meta-analysis seemed to indicate the survival benefits of PRO screening. As routine PRO monitoring is often challenging, more robust evidence regarding the effects of PROs on mortality would support systematic applications. Full article

(This article belongs to the Special Issue Quality of Life and Side Effects Management in Cancer Treatment)

► Show Figures

Figure 1

9 pages, 1057 KiB

Open AccessArticle

Reinduction of Hedgehog Inhibitors after Checkpoint Inhibition in Advanced Basal Cell Carcinoma: A Series of 12 Patients

by Viola K. DeTemple, Jessica C. Hassel, Michael M. Sachse, Imke Grimmelmann, Ulrike Leiter, Christoffer Gebhardt, Julia Eckardt, Claudia Pföhler, Yenny Angela, Hanna Hübbe and Ralf Gutzmer

Cancers 2022, 14(21), 5469; https://doi.org/10.3390/cancers14215469 - 7 Nov 2022

Cited by 3 | Viewed by 1997

Abstract

For patients with advanced basal cell carcinoma (aBCC) first-line treatment with hedgehog inhibitors (HHIs) and second-line treatment with PD1 inhibitors (PD1i) is available, offering combination and sequencing options. Here, we focus on the efficacy and safety of HHI reinduction after PD1i failure. Retrospective [...] Read more.

For patients with advanced basal cell carcinoma (aBCC) first-line treatment with hedgehog inhibitors (HHIs) and second-line treatment with PD1 inhibitors (PD1i) is available, offering combination and sequencing options. Here, we focus on the efficacy and safety of HHI reinduction after PD1i failure. Retrospective data analysis was performed with 12 patients with aBCC (locally advanced (n = 8)/metastatic (n = 4)). These patients (male:female 6:6, median age 68 years) initially received HHIs, leading to complete/partial response (66%) or stable disease (33%). Median treatment duration was 20.8 (2–64.5) months until discontinuation due to progression (n = 8), adverse events (n = 3), or patient request (n = 1). Subsequent PD1 inhibition (pembrolizumab 42%, cemiplimab 58%) yielded a partial response (8%), stable disease (33%), or progression (59%). Median treatment duration was 4.1 (0.8–16.3) months until discontinuation due to progression (n = 9), adverse events (n = 1), patient request (n = 1), or missing drug approval (n = 1). HHI reinduction resulted in complete/partial response (33%), stable disease (50%), or progression (17%). Median treatment duration was 3.6 (1–29) months. Response duration in the four responding patients was 2–29+ months. Thus, a subgroup of patients with aBCC responded to reinduction of HHI following PD1i failure. Therefore, this sequential treatment represents a feasible treatment option. Full article

(This article belongs to the Special Issue Skin Cancer: Epidemiology, Prevention and Quality of Life)

► Show Figures

Graphical abstract

26 pages, 2070 KiB

Open AccessReview

Wnt/β-Catenin Signaling as a Driver of Stemness and Metabolic Reprogramming in Hepatocellular Carcinoma

by Rainbow Wing Hei Leung and Terence Kin Wah Lee

Cancers 2022, 14(21), 5468; https://doi.org/10.3390/cancers14215468 - 7 Nov 2022

Cited by 21 | Viewed by 5019

Abstract

Hepatocellular carcinoma (HCC) is a major cause of cancer death worldwide due to its high rates of tumor recurrence and metastasis. Aberrant Wnt/β-catenin signaling has been shown to play a significant role in HCC development, progression and clinical impact on tumor behavior. Accumulating [...] Read more.

Hepatocellular carcinoma (HCC) is a major cause of cancer death worldwide due to its high rates of tumor recurrence and metastasis. Aberrant Wnt/β-catenin signaling has been shown to play a significant role in HCC development, progression and clinical impact on tumor behavior. Accumulating evidence has revealed the critical involvement of Wnt/β-catenin signaling in driving cancer stemness and metabolic reprogramming, which are regarded as emerging cancer hallmarks. In this review, we summarize the regulatory mechanism of Wnt/β-catenin signaling and its role in HCC. Furthermore, we provide an update on the regulatory roles of Wnt/β-catenin signaling in metabolic reprogramming, cancer stemness and drug resistance in HCC. We also provide an update on preclinical and clinical studies targeting Wnt/β-catenin signaling alone or in combination with current therapies for effective cancer therapy. This review provides insights into the current opportunities and challenges of targeting this signaling pathway in HCC. Full article

(This article belongs to the Special Issue Wnt Pathway Targets in Cancer)

► Show Figures

Figure 1

18 pages, 804 KiB

Open AccessReview

Post-Neoadjuvant Treatment Strategies for Patients with Early Breast Cancer

by Elisa Agostinetto, Flavia Jacobs, Véronique Debien, Alex De Caluwé, Catalin-Florin Pop, Xavier Catteau, Philippe Aftimos, Evandro de Azambuja and Laurence Buisseret

Cancers 2022, 14(21), 5467; https://doi.org/10.3390/cancers14215467 - 7 Nov 2022

Cited by 8 | Viewed by 6074

Abstract

Pre-surgical treatments in patients with early breast cancer allows a direct estimation of treatment efficacy, by comparing the tumor and the treatment. Patients who achieve a pathological complete response at surgery have a better prognosis, with lower risk of disease recurrence and death. [...] Read more.

Pre-surgical treatments in patients with early breast cancer allows a direct estimation of treatment efficacy, by comparing the tumor and the treatment. Patients who achieve a pathological complete response at surgery have a better prognosis, with lower risk of disease recurrence and death. Hence, clinical research efforts have been focusing on high-risk patients with residual disease at surgery, who may be “salvaged” through additional treatments administered in the post-neoadjuvant setting. In the present review, we aim to illustrate the development and advantages of the post-neoadjuvant setting, and to discuss the available strategies for patients with early breast cancer, either approved or under investigation. This review was written after literature search on main scientific databases (e.g., PubMed) and conference proceedings from major oncology conferences up to 1 August 2022. T-DM1 and capecitabine are currently approved as post-neoadjuvant treatments for patients with HER2-positive and triple-negative breast cancer, respectively, with residual disease at surgery. More recently, other treatment strategies have been approved for patients with high-risk early breast cancer, including the immune checkpoint inhibitor pembrolizumab, the PARP inhibitor olaparib and the CDK 4/6 inhibitor abemaciclib. Novel agents and treatment combinations are currently under investigation as promising post-neoadjuvant treatment strategies. Full article

(This article belongs to the Special Issue Post-neoadjuvant Strategies in Breast Cancer)

► Show Figures

Figure 1

Figure 1
Simplified representation of post-neoadjuvant treatment strategy for breast cancer patients. Patients eligible for preoperative treatment receive neoadjuvant chemotherapy. If at the time of surgery the tumor is no longer detectable in the specimen (i.e., a pathological complete response (pCR) is achieved), these patients could be potentially candidate to de-escalation treatment strategies, as pCR is associated with lower risk of disease recurrence. The potential de-escalation strategy can apply to surgery, radiotherapy, or systemic adjuvant therapy. Of note, the management of a patient with a pCR is multifactorial, and requires multidisciplinary discussion. Indeed, caution should be paid to avoid the removal of too many treatment components. In case of invasive residual disease, patients may be considered for additional post-neoadjuvant treatments, for instance with chemotherapy (i.e., capecitabine in triple-negative breast cancer) or antibody drug conjugates (i.e., T-DM1 in HER2-positive breast cancer). The evaluation of residual disease can be done using various biomarkers for risk assessment (e.g., Ki67, TILs, RCB, gene expression, and genetic alterations). Residual disease can be classified according to the Residual Cancer Burden index, that combines pathologic measurements of primary tumor (size and cellularity) and nodal metastases (number and size), and classifies the specimen in one of four classes (RCB 0, i.e., pCR, RCB I, RCB II, RCB III). A higher RCB index (i.e., RCB III) indicates a larger amount of residual disease, and it is associated with a higher risk of recurrence.Abbreviations: CDKi 4/6: cyclin-dependent kinase inhibitor; ctDNA: circulating tumor DNA; HER2, human epidermal growth factor receptor 2; HR+, hormone receptor-positive breast cancer; LVI: lymphovascular invasion; NAC: neoadjuvant chemotherapy; NGS: next-generation sequencing; PARPi: poly ADP-ribose polymerase inhibitor; pCR: pathologic complete response; RCB: residual cancer burden; RD: residual disease; TDM1: trastuzumab-emtansine; TILS: tumors-infiltrating lymphocytes. Full article ">Figure 2
Proportion of pathological complete response (pCR) after neoadjuvant therapy according to breast cancer subtypes. HR-positive/HER2-negative (HR+/HER2−) is the most prevalent subtype in breast cancer, occurring in approximately 70% of patients, followed by HER2−positive (HER2+) and TNBC subtypes (approximately 20% and 10%, respectively). Subtype-specific pCR rate are 8.3% in HR+/HER2−, 18.7% in HER2+/HR+, 38.9% in HER2+/HR− and 31.1% in TNBC (original figure based on literature data, i.e., Houssami et al., Meta-analysis of the association of breast cancer subtype and pathologic complete response to neoadjuvant chemotherapy, Eur J Cancer 2012. doi: 10.1016/j.ejca.2012.05.023) [<a href="#B9-cancers-14-05467" class="html-bibr">9</a>]. Abbreviations: HR: hormonal receptors; TNBC: triple-negative breast cancer; pCR: pathological complete response. Full article ">

16 pages, 1185 KiB

Open AccessSystematic Review

Speech and Language Errors during Awake Brain Surgery and Postoperative Language Outcome in Glioma Patients: A Systematic Review

by Ellen Collée, Arnaud Vincent, Clemens Dirven and Djaina Satoer

Cancers 2022, 14(21), 5466; https://doi.org/10.3390/cancers14215466 - 7 Nov 2022

Cited by 9 | Viewed by 3093

Abstract

Awake craniotomy with direct electrical stimulation (DES) is the standard treatment for patients with gliomas in eloquent areas. Even though language is monitored carefully during surgery, many patients suffer from postoperative aphasia, with negative effects on their quality of life. Some perioperative factors [...] Read more.

Awake craniotomy with direct electrical stimulation (DES) is the standard treatment for patients with gliomas in eloquent areas. Even though language is monitored carefully during surgery, many patients suffer from postoperative aphasia, with negative effects on their quality of life. Some perioperative factors are reported to influence postoperative language outcome. However, the influence of different intraoperative speech and language errors on language outcome is not clear. Therefore, we investigate this relation. A systematic search was performed in which 81 studies were included, reporting speech and language errors during awake craniotomy with DES and postoperative language outcomes in adult glioma patients up until 6 July 2020. The frequencies of intraoperative errors and language status were calculated. Binary logistic regressions were performed. Preoperative language deficits were a significant predictor for postoperative acute (OR = 3.42, p < 0.001) and short-term (OR = 1.95, p = 0.007) language deficits. Intraoperative anomia (OR = 2.09, p = 0.015) and intraoperative production errors (e.g., dysarthria or stuttering; OR = 2.06, p = 0.016) were significant predictors for postoperative acute language deficits. Postoperatively, the language deficits that occurred most often were production deficits and spontaneous speech deficits. To conclude, during surgery, intraoperative anomia and production errors should carry particular weight during decision-making concerning the optimal onco-functional balance for a given patient, and spontaneous speech should be monitored. Further prognostic research could facilitate intraoperative decision-making, leading to fewer or less severe postoperative language deficits and improvement of quality of life. Full article

(This article belongs to the Special Issue Advances of Brain Mapping in Cancer Research)

► Show Figures

Figure 1

18 pages, 1941 KiB

Open AccessArticle

The Glasgow Prognostic Score Predicts Survival Outcomes in Neuroendocrine Neoplasms of the Gastro–Entero–Pancreatic (GEP-NEN) System

by Niklas Gebauer, Maria Ziehm, Judith Gebauer, Armin Riecke, Sebastian Meyhöfer, Birte Kulemann, Nikolas von Bubnoff, Konrad Steinestel, Arthur Bauer and Hanno M. Witte

Cancers 2022, 14(21), 5465; https://doi.org/10.3390/cancers14215465 - 7 Nov 2022

Cited by 1 | Viewed by 1854

Abstract

Background: Across a variety of solid tumors, prognostic implications of nutritional and inflammation-based risk scores have been identified as a complementary resource of risk stratification. Methods: In this retrospective study, we performed a comparative analysis of several established risk scores and ratios, such [...] Read more.

Background: Across a variety of solid tumors, prognostic implications of nutritional and inflammation-based risk scores have been identified as a complementary resource of risk stratification. Methods: In this retrospective study, we performed a comparative analysis of several established risk scores and ratios, such as the Glasgow Prognostic Score (GPS), in neuroendocrine neoplasms of the gastro–entero–pancreatic (GEP-NEN) system with respect to their prognostic capabilities. Clinicopathological and treatment-related data for 102 GEP-NEN patients administered to the participating institutions between 2011 and 2021 were collected. Scores/ratios significantly associated with overall or progression-free survival (OS, PFS) upon univariate analysis were subsequently included in a Cox-proportional hazard model for the multivariate analysis. Results: The median age was 62 years (range 18–95 years) and the median follow-up period spanned 51 months. Pancreatic or intestinal localization at the initial diagnosis were present in 41 (40.2%) and 44 (43.1%) cases, respectively. In 17 patients (16.7%), the primary manifestation could not be ascertained (NNUP; neuroendocrine neoplasms of unknown primary). Histological grading (HG) revealed 24/102 (23.5%) NET/NEC (poorly differentiated; high grade G3) and 78/102 (76.5%) NET (highly or moderately differentiated; low–high grade G1–G2). In total, 53/102 (51.9%) patients presented with metastatic disease (UICC IV), 11/102 (10.7%) patients presented with multifocal disease, and 56/102 (54.9%) patients underwent a primary surgical or endoscopic approach, whereas 28 (27.5%) patients received systemic cytoreductive treatment. The univariate analysis revealed the GPS and PI (prognostic index), as well as UICC-stage IV, HG, and the Charlson comorbidity index (CCI) to predict both the PFS and OS in GEP-NEN patients. However, the calculation of the survival did not separate GPS subgroups at lower risk (GPS 0 versus GPS 1). Upon the subsequent multivariate analysis, GPS was the only independent predictor of both OS (p < 0.0001; HR = 3.459, 95% CI = 1.263–6.322) and PFS (p < 0.003; HR = 2.119, 95% CI = 0.944–4.265). Conclusion: In line with previous results for other entities, the present study revealed the GPS at baseline to be the only independent predictor of survival across all stages of GEP-NEN, and thus supports its clinical utility for risk stratification in this group of patients. Full article

(This article belongs to the Section Cancer Causes, Screening and Diagnosis)

► Show Figures

Figure 1

19 pages, 3728 KiB

Open AccessSystematic Review

Anastomotic Leak in Ovarian Cancer Cytoreduction Surgery: A Systematic Review and Meta-Analysis

by Massimiliano Fornasiero, Georgios Geropoulos, Konstantinos S. Kechagias, Kyriakos Psarras, Konstantinos Katsikas Triantafyllidis, Panagiotis Giannos, Georgios Koimtzis, Nikoletta A. Petrou, James Lucocq, Christos Kontovounisios and Dimitrios Giannis

Cancers 2022, 14(21), 5464; https://doi.org/10.3390/cancers14215464 - 7 Nov 2022

Cited by 2 | Viewed by 2640

Abstract

Introduction: Anastomotic leaks (AL) following ovarian cytoreduction surgery could be detrimental, leading to significant delays in commencing adjuvant chemotherapy, prolonged hospital stays and increased morbidity. The aim of this study was to investigate risk factors associated with anastomotic leaks after ovarian cytoreduction surgery. [...] Read more.

Introduction: Anastomotic leaks (AL) following ovarian cytoreduction surgery could be detrimental, leading to significant delays in commencing adjuvant chemotherapy, prolonged hospital stays and increased morbidity. The aim of this study was to investigate risk factors associated with anastomotic leaks after ovarian cytoreduction surgery. Material and methods: The MEDLINE (via PubMed), Cochrane Library, EMBASE and Scopus bibliographical databases were searched. Original clinical studies investigating risk factors for AL in ovarian cytoreduction surgery were included. Results: Eighteen studies with non-overlapping populations reporting on patients undergoing cytoreduction surgery for ovarian cancer (n = 4622, including 344 cases complicated by AL) were included in our analysis. Patients undergoing ovarian cytoreduction surgery complicated by AL had a significantly higher rate of 30-day mortality but no difference in 60-day mortality. Multiple bowel resections were associated with an increased risk of postoperative AL, while no association was observed with body mass index (BMI), American Society of Anesthesiologists (ASA) score, age, smoking, operative approach (primary versus interval cytoreductive, stapled versus hand-sewn anastomoses and formation of diverting stoma), neoadjuvant chemotherapy and use of hyperthermic intraperitoneal chemotherapy (HIPEC). Discussion: Multiple bowel resections were the only clinical risk factor associated with increased risk for AL after bowel surgery in the ovarian cancer population. The increased 30-day mortality rate in patients undergoing ovarian cytoreduction complicated by AL highlights the need to minimize the number of bowel resections in this population. Further studies are required to clarify any association between neoadjuvant chemotherapy and decreased AL rates. Full article

(This article belongs to the Special Issue Systematic Reviews and Meta-Analyses of Genitourinary Cancers)

► Show Figures

Figure 1

14 pages, 1640 KiB

Open AccessArticle

Enhanced Recovery after Uterine Corpus Cancer Surgery: A 10 Year Retrospective Cohort Study of Robotic Surgery in an NHS Cancer Centre

by Christina Uwins, Radwa Hablase, Hasanthi Assalaarachchi, Anil Tailor, Alexandra Stewart, Jayanta Chatterjee, Patricia Ellis, Simon S. Skene, Agnieszka Michael and Simon Butler-Manuel

Cancers 2022, 14(21), 5463; https://doi.org/10.3390/cancers14215463 - 7 Nov 2022

Cited by 4 | Viewed by 2690

Abstract

Royal Surrey NHS Foundation Trust introduced robotic surgery for uterine corpus cancer in 2010 to support increased access to minimally invasive surgery, a central element of an enhanced recovery after surgery (ERAS) pathway. More than 1750 gynaecological oncology robotic procedures have now been [...] Read more.

Royal Surrey NHS Foundation Trust introduced robotic surgery for uterine corpus cancer in 2010 to support increased access to minimally invasive surgery, a central element of an enhanced recovery after surgery (ERAS) pathway. More than 1750 gynaecological oncology robotic procedures have now been performed at Royal Surrey NHS Foundation Trust. A retrospective cohort study was performed of patients undergoing surgery for uterine corpus cancer between the 1 January 2010 and the 31 December 2019 to evaluate its success. Data was extracted from the dedicated gynaecological oncology database and a detailed notes review performed. During this time; 952 patients received primary surgery for uterine corpus cancer; robotic: n = 734; open: n = 164; other minimally invasive surgery: n = 54. The introduction of the Da Vinci^TM robot to Royal Surrey NHS Foundation Trust was associated with an increase in the minimally invasive surgery rate. Prior to the introduction of robotic surgery in 2008 the minimally invasive surgery (MIS) rate was 33% for women with uterine corpus cancer undergoing full surgical staging. In 2019, 10 years after the start of the robotic surgery program 91.3% of women with uterine corpus cancer received robotic surgery. Overall the MIS rate increased from 33% in 2008 to 92.9% in 2019. Robotic surgery is associated with a low 30-day mortality (0.1%), low return to theatre (0.5%), a low use of blood transfusion and intensive care (1.8% & 7.2% respectively), low conversion to open surgery (0.5%) and a reduction in median length of stay from 6 days (in 2008) to 1 day, regardless of age/BMI. Robotic survival is consistent with published data. Introduction of the robotic program for the treatment of uterine cancer increased productivity and was associated with a highly predicable patient pathway of care, for high-risk patients, with reduced demands on health services. Future health care commissioning should further expand access to robotic surgery nationally for women with uterine corpus cancer. Full article

(This article belongs to the Special Issue Gynaecological Cancer and Surgery: Current Practice, Novel Technologies and Future Developments)

► Show Figures

Graphical abstract

13 pages, 281 KiB

Open AccessArticle

Impact of Lymph Node Dissection on Postoperative Complications of Total Thyroidectomy in Patients with Thyroid Carcinoma

by Gregory Baud, Arnaud Jannin, Camille Marciniak, Benjamin Chevalier, Christine Do Cao, Emmanuelle Leteurtre, Amandine Beron, Georges Lion, Samuel Boury, Sebastien Aubert, Brigitte Bouchindhomme, Marie-Christine Vantyghem, Robert Caiazzo and François Pattou

Cancers 2022, 14(21), 5462; https://doi.org/10.3390/cancers14215462 - 7 Nov 2022

Cited by 17 | Viewed by 2447

Abstract

Background: Lymph node dissection (LND) in primary treatment of differentiated thyroid carcinoma is controversial. The aim of our retrospective study was to analyse the risk factors of post-thyroidectomy complications and to assess the morbidity of lymph node dissection, especially in the central neck [...] Read more.

Background: Lymph node dissection (LND) in primary treatment of differentiated thyroid carcinoma is controversial. The aim of our retrospective study was to analyse the risk factors of post-thyroidectomy complications and to assess the morbidity of lymph node dissection, especially in the central neck compartment, since prophylactic central lymph node dissection has not been proven to bring an overall survival benefit. Methods: We performed a retrospective analysis of postoperative complications from 1547 consecutive patients with differentiated thyroid carcinoma in an academic department of endocrine surgery over a period of 10 years. Results: A total of 535 patients underwent lymph node dissection, whereas the other 1012 did not. The rate of postoperative hypoparathyroidism was higher in patients with LND (17.6% vs. 11.4%, p = 0.001). No significant difference in the rate of permanent hypoparathyroidism (2.4% vs. 1.3%, p = 0.096) was observed between these two groups. A multivariate analysis was performed. Female gender, ipsilateral and bilateral central LND (CLND), parathyroid autotransplantation, and the presence of the parathyroid gland on the resected thyroid were associated with transient hypoparathyroidism. Bilateral CLND and the presence of the parathyroid gland on specimen were associated with permanent hypoparathyroidism. The rate of transient recurrent laryngeal nerve (RLN) injury (15.3% vs. 5.4%, p < 0.001) and permanent RLN injury (6.5% vs. 0.9%, p < 0.001) were higher in the LND group. In multivariate analysis, ipsilateral and bilateral lateral LND (LLND) were the main predictive factors of transient and permanent RLN injury. Bilateral RLN injury (2.6% vs. 0.4%, p < 0.001), chyle leakage (2.4% vs. 0%, p < 0.001), other nerve injuries (2.2% vs. 0%, p < 0.001), and abscess (2.4% vs. 0.5%, p = 0.001) were higher in the patients with LND. Conclusions: The surgical technique and the extent of lymph node dissection during surgery for thyroid carcinoma increase postoperative morbidity. A wider knowledge of lymph-node-dissection-related complications associated with thyroid surgery could help surgeons to carefully evaluate the surgical and medical therapeutic options. Full article

(This article belongs to the Special Issue Management and Treatment of Endocrine Tumors)

14 pages, 1759 KiB

Open AccessArticle

A Risk Model for Patients with PSA-Only Recurrence (Biochemical Recurrence) Based on PSA and PSMA PET/CT: An Individual Patient Data Meta-Analysis

by Rie von Eyben, Daniel S. Kapp, Manuela Andrea Hoffmann, Cigdem Soydal, Christian Uprimny, Irene Virgolini, Murat Tuncel, Mathieu Gauthé and Finn E. von Eyben

Cancers 2022, 14(21), 5461; https://doi.org/10.3390/cancers14215461 - 7 Nov 2022

Cited by 4 | Viewed by 2258 | Correction

Abstract

An individual patient meta-analysis followed 1216 patients with PSA-only recurrence (biochemical recurrence, BCR) restaged with [⁶⁸Ga]Ga-PSMA-11 PET/CT before the salvage treatment for median 3.5 years and analyzed the overall survival (OS). A new risk model included a good risk group with [...] Read more.

An individual patient meta-analysis followed 1216 patients with PSA-only recurrence (biochemical recurrence, BCR) restaged with [⁶⁸Ga]Ga-PSMA-11 PET/CT before the salvage treatment for median 3.5 years and analyzed the overall survival (OS). A new risk model included a good risk group with a prescan PSA < 0.5 ng/mL (26%), an intermediate risk group with a prescan PSA > 0.5 ng/mL and a PSMA PET/CT with 1 to 5 positive sites (65%), and a poor risk group with a prescan PSA > 0.5 ng/mL and a PSA PET/CT with > 5 positive sites (9%) (p < 0.0001, log rank test). The poor risk group had a five-year OS > 60%. Adding a BCR risk score by the European Association of Urology did not significantly improve the prediction of OS (p = 0.64). In conclusion, the restaging PSMA PET/CT markedly predicted the 5-year OS. The new risk model for patients with PSA-only relapse requires a restaging PSMA PET/CT for patients with a prescan PSA > 0.5 ng/mL and has a potential use in new trials aiming to improve the outcome for patients with PSA-only recurrence who have polysites prostate cancer detected on PSMA PET/CT. Full article

(This article belongs to the Special Issue Prostate-Specific Membrane Antigen (PSMA))

► Show Figures

Figure 1

Figure 1
The PRISMA chart diagram shows how the meta-analysis selected and included the cohorts. Full article ">Figure 2
The five cohorts had grossly similar relation between the prescan PSA and the number of positive sites on the restaging PSMA PET/CT. The cohorts are named by the cities for the study centers. Full article ">Figure 3
The Forest plot of the patients with PSA-only relapse in the five cohorts. (A) a third of the patients had a negative restaging PSMA PET/CT, (B) more than half of the patients had one to five positive sites, (C) a tenth of the patients had more than five positive sites. Full article ">Figure 3 Cont.
The Forest plot of the patients with PSA-only relapse in the five cohorts. (A) a third of the patients had a negative restaging PSMA PET/CT, (B) more than half of the patients had one to five positive sites, (C) a tenth of the patients had more than five positive sites. Full article ">Figure 4
A new risk model shows a significant difference in overall survival between the good-, intermediate-, and poor risk groups (p < 0.0001). The figure compares the overall survival for two patient groups by the number of positive findings on restaging PSMA PET/CT: 1–5 sites vs. > 5 sites. Full article ">Figure 5
The EAU BCR risk classification significantly separates the patients with PSA relapse into two groups with different overall survival (p < 0.0001). Full article ">Figure 6
Design for a phase III trial of patients with PSA-only recurrence and high risk according to the new risk model. The trial compares an aggressive multimodality salvage treatment with salvage treatment with established treatments. Abbreviations: ARI second generation androgen receptor inhibitor, MDT metastasis directed therapy, OS overall survival, PFS progression-free survival, SaRT Salvage radiation therapy. Full article ">

22 pages, 1413 KiB

Open AccessFeature PaperReview

The Monocyte, a Maestro in the Tumor Microenvironment (TME) of Breast Cancer

by Hoda T. Amer, Ulrike Stein and Hend M. El Tayebi

Cancers 2022, 14(21), 5460; https://doi.org/10.3390/cancers14215460 - 7 Nov 2022

Cited by 21 | Viewed by 4707

Abstract

Breast cancer (BC) is well-known for being a leading cause of death worldwide. It is classified molecularly into luminal A, luminal B HER2−, luminal B HER2+, HER2+, and triple-negative breast cancer (TNBC). These subtypes differ in their prognosis; thus, understanding the tumor microenvironment [...] Read more.

Breast cancer (BC) is well-known for being a leading cause of death worldwide. It is classified molecularly into luminal A, luminal B HER2−, luminal B HER2+, HER2+, and triple-negative breast cancer (TNBC). These subtypes differ in their prognosis; thus, understanding the tumor microenvironment (TME) makes new treatment strategies possible. The TME contains populations that exhibit anti-tumorigenic actions such as tumor-associated eosinophils. Moreover, it contains pro-tumorigenic populations such as tumor-associated neutrophils (TANs), or monocyte-derived populations. The monocyte-derived populations are tumor-associated macrophages (TAMs) and MDSCs. Thus, a monocyte can be considered a maestro within the TME. Moreover, the expansion of monocytes in the TME depends on many factors such as the BC stage, the presence of macrophage colony-stimulating factor (M-CSF), and the presence of some chemoattractants. After expansion, monocytes can differentiate into pro-inflammatory populations such as M1 macrophages or anti-inflammatory populations such as M2 macrophages according to the nature of cytokines present in the TME. Differentiation to TAMs depends on various factors such as the BC subtype, the presence of anti-inflammatory cytokines, and epigenetic factors. Furthermore, TAMs and MDSCs not only have a role in tumor progression but also are key players in metastasis. Thus, understanding the monocytes further can introduce new target therapies. Full article

(This article belongs to the Special Issue Tumor Microenvironment and Molecular Aberrations Convey Immune Evasion)

► Show Figures

Figure 1

13 pages, 1123 KiB

Open AccessArticle

Preoperative Serum Markers and Risk Classification in Intrahepatic Cholangiocarcinoma: A Multicenter Retrospective Study

by Masaki Kaibori, Kengo Yoshii, Hisashi Kosaka, Masato Ota, Koji Komeda, Masaki Ueno, Daisuke Hokutou, Hiroya Iida, Kosuke Matsui and Mitsugu Sekimoto

Cancers 2022, 14(21), 5459; https://doi.org/10.3390/cancers14215459 - 7 Nov 2022

Cited by 4 | Viewed by 2163

Abstract

Accurate risk stratification selects patients who are expected to benefit most from surgery. This retrospective study enrolled 225 Japanese patients with intrahepatic cholangiocellular carcinoma (ICC) who underwent hepatectomy between January 2009 and December 2020 and identified preoperative blood test biomarkers to formulate a [...] Read more.

Accurate risk stratification selects patients who are expected to benefit most from surgery. This retrospective study enrolled 225 Japanese patients with intrahepatic cholangiocellular carcinoma (ICC) who underwent hepatectomy between January 2009 and December 2020 and identified preoperative blood test biomarkers to formulate a classification system that predicted prognosis. The optimal cut-off values of blood test parameters were determined by ROC curve analysis, with Cox univariate and multivariate analyses identifying prognostic factors. Risk classifications were established using classification and regression tree (CART) analysis. CART analysis revealed decision trees for recurrence-free survival (RFS) and overall survival (OS) and created three risk classifications based on machine learning of preoperative serum markers. Five-year rates differed significantly (p < 0.001) between groups: 60.4% (low-risk), 22.8% (moderate-risk), and 4.1% (high-risk) for RFS and 69.2% (low-risk), 32.3% (moderate-risk), and 9.2% (high-risk) for OS. No difference in OS was observed between patients in the low-risk group with or without postoperative adjuvant chemotherapy, although OS improved in the moderate group and was prolonged significantly in the high-risk group receiving chemotherapy. Stratification of patients with ICC who underwent hepatectomy into three risk groups for RFS and OS identified preoperative prognostic factors that predicted prognosis and were easy to understand and apply clinically. Full article

(This article belongs to the Collection Treatment of Hepatocellular Carcinoma and Cholangiocarcinoma)

► Show Figures

Figure 1

18 pages, 4588 KiB

Open AccessReview

Intravascular NK/T-Cell Lymphoma: What We Know about This Diagnostically Challenging, Aggressive Disease

by Magda Zanelli, Paola Parente, Francesca Sanguedolce, Maurizio Zizzo, Andrea Palicelli, Alessandra Bisagni, Illuminato Carosi, Domenico Trombetta, Luca Mastracci, Linda Ricci, Saverio Pancetti, Giovanni Martino, Giuseppe Broggi, Rosario Caltabiano, Alberto Cavazza and Stefano Ascani

Cancers 2022, 14(21), 5458; https://doi.org/10.3390/cancers14215458 - 6 Nov 2022

Cited by 10 | Viewed by 2320

Abstract

Intravascular lymphoma is a form of lymphoid malignancy characterized by neoplastic cells growing almost exclusively within the lumina of small- to medium-sized blood vessels. Most cases are of B-cell origin with rare cases of natural killer or T-cell lineage. Extranodal sites are affected, [...] Read more.

Intravascular lymphoma is a form of lymphoid malignancy characterized by neoplastic cells growing almost exclusively within the lumina of small- to medium-sized blood vessels. Most cases are of B-cell origin with rare cases of natural killer or T-cell lineage. Extranodal sites are affected, mainly the skin and central nervous system, although any organ may be involved. Intravascular NK/T-cell lymphoma deserves special attention because of its clinicopathologic features and the need for adequate immunophenotyping combined with clonality test for a proper diagnosis. Moreover, intravascular NK/T-cell lymphoma is strongly linked to Epstein–Barr virus (EBV), which is considered to play a role in tumorigenesis and to be responsible for the aggressive behavior of the disease. In this paper, we review the current knowledge on this rare lymphoma and, in particular, the most recent advances about its molecular landscape. The main distinguishing features with other EBV-related entities, such as extranodal NK/T-cell lymphoma, EBV-positive primary nodal T/NK-cell lymphoma, and aggressive NK-cell leukemia, are discussed to help pathologists obtain the correct diagnosis and consequently develop an adequate and prompt therapy response. Full article

(This article belongs to the Special Issue Advances in NK/T-cell Lymphoma, Epidemiology, Biology and Therapy)

► Show Figures

Figure 1

Figure 1
High-power view showing kidney parenchyma with large, atypical cells growing within vascular spaces (see within red circle; hematoxylin and eosin, 200× magnification, previously unpublished, original image from S.A.). Full article ">Figure 2
High-power view showing central nervous system parenchyma with atypical cells within a vascular space (hematoxylin and eosin, 400× magnification, previously unpublished, original image from S.A.). Full article ">Figure 3
Medium-power view showing bone marrow with CD3-positive atypical cells within sinusoidal spaces (CD3 immunostaining, 100× magnification, previously unpublished, original image from S.A.). Full article ">Figure 4
High-power view showing lung parenchyma with perforin-positive atypical cells within vascular spaces (perforin immunostaining, 200× magnification, previously unpublished, original image from S.A.). Full article ">Figure 5
High-power view showing lung parenchyma with EBER-positive atypical cells within vascular spaces (in situ hybridization for EBV-encoded RNA, 400× magnification, previously unpublished, original image from S.A.). Full article ">Figure 6
High-power view showing a diffuse and polymorphic proliferation of atypical, medium- to large-sized lymphoid cells (hematoxylin and eosin, 200× magnification, previously unpublished, original image from S.A.). Full article ">Figure 7
High-power view showing a diffuse proliferation of CD56-positive atypical cells (CD56 immunostaining, 200× magnification, previously unpublished, original image from S.A.). Full article ">Figure 8
High-power view showing CD30-positive atypical cells (CD30 immunostaining, 400× magnification, previously unpublished, original image from S.A.). Full article ">Figure 9
Medium-power view showing a diffuse proliferation of EBER-positive cells (in situ hybridization for EBV-encoded RNA, 100× magnification, previously unpublished, original image from S.A.). Full article ">

18 pages, 1880 KiB

Open AccessEditor’s ChoiceArticle

An Effective Method for Lung Cancer Diagnosis from CT Scan Using Deep Learning-Based Support Vector Network

by Imran Shafi, Sadia Din, Asim Khan, Isabel De La Torre Díez, Ramón del Jesús Palí Casanova, Kilian Tutusaus Pifarre and Imran Ashraf

Cancers 2022, 14(21), 5457; https://doi.org/10.3390/cancers14215457 - 6 Nov 2022

Cited by 57 | Viewed by 11922

Abstract

The diagnosis of early-stage lung cancer is challenging due to its asymptomatic nature, especially given the repeated radiation exposure and high cost of computed tomography(CT). Examining the lung CT images to detect pulmonary nodules, especially the cell lung cancer lesions, is also tedious [...] Read more.

The diagnosis of early-stage lung cancer is challenging due to its asymptomatic nature, especially given the repeated radiation exposure and high cost of computed tomography(CT). Examining the lung CT images to detect pulmonary nodules, especially the cell lung cancer lesions, is also tedious and prone to errors even by a specialist. This study proposes a cancer diagnostic model based on a deep learning-enabled support vector machine (SVM). The proposed computer-aided design (CAD) model identifies the physiological and pathological changes in the soft tissues of the cross-section in lung cancer lesions. The model is first trained to recognize lung cancer by measuring and comparing the selected profile values in CT images obtained from patients and control patients at their diagnosis. Then, the model is tested and validated using the CT scans of both patients and control patients that are not shown in the training phase. The study investigates 888 annotated CT scans from the publicly available LIDC/IDRI database. The proposed deep learning-assisted SVM-based model yields 94% accuracy for pulmonary nodule detection representing early-stage lung cancer. It is found superior to other existing methods including complex deep learning, simple machine learning, and the hybrid techniques used on lung CT images for nodule detection. Experimental results demonstrate that the proposed approach can greatly assist radiologists in detecting early lung cancer and facilitating the timely management of patients. Full article

► Show Figures

Figure 1

22 pages, 1365 KiB

Open AccessReview

Targeted Therapy and Immunotherapy for Heterogeneous Breast Cancer

by Xiaolu Sun, Kuai Liu, Shuli Lu, Weina He and Zixiu Du

Cancers 2022, 14(21), 5456; https://doi.org/10.3390/cancers14215456 - 6 Nov 2022

Cited by 16 | Viewed by 3935

Abstract

Breast cancer (BC) is the most common malignancy in women worldwide, and it is a molecularly diverse disease. Heterogeneity can be observed in a wide range of cell types with varying morphologies and behaviors. Molecular classifications are broadly used in clinical diagnosis, including [...] Read more.

Breast cancer (BC) is the most common malignancy in women worldwide, and it is a molecularly diverse disease. Heterogeneity can be observed in a wide range of cell types with varying morphologies and behaviors. Molecular classifications are broadly used in clinical diagnosis, including estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor (VEGFR), and breast cancer gene (BRCA) mutations, as indicators of tumor heterogeneity. Treatment strategies differ according to the molecular subtype. Besides the traditional treatments, such as hormone (endocrine) therapy, radiotherapy, and chemotherapy, innovative approaches have accelerated BC treatments, which contain targeted therapies and immunotherapy. Among them, monoclonal antibodies, small-molecule inhibitors and antibody–drug conjugates, and targeted delivery systems are promising armamentarium for breast cancer, while checkpoint inhibitors, CAR T cell therapy, cancer vaccines, and tumor-microenvironment-targeted therapy provide a more comprehensive understanding of breast cancer and could assist in developing new therapeutic strategies. Full article

(This article belongs to the Special Issue Nanobiomaterials for Cancer Early Detection and Therapy)

► Show Figures

Figure 1

10 pages, 19804 KiB

Open AccessArticle

Recurrence of Oral Leukoplakia after CO₂ Laser Resection: A Prospective Longitudinal Study

by Adela Rodriguez-Lujan, Pia López-Jornet and Eduardo Pons-Fuster López

Cancers 2022, 14(21), 5455; https://doi.org/10.3390/cancers14215455 - 6 Nov 2022

Cited by 4 | Viewed by 4965

Abstract

Aim: The aim of this study is to assess the efficacy of CO₂ laser treatment in oral leukoplakia and to analyse the recurrence rate of oral leukoplakia lesions at 18-month follow-up. Materials and methods: A prospective clinical study regarding CO₂ laser [...] Read more.

Aim: The aim of this study is to assess the efficacy of CO₂ laser treatment in oral leukoplakia and to analyse the recurrence rate of oral leukoplakia lesions at 18-month follow-up. Materials and methods: A prospective clinical study regarding CO₂ laser treatment for oral leukoplakia was conducted, in which 39 patients with a total of 53 oral leukoplakias were included. Follow-up was performed at 18 months post-surgery and the following variables were studied: sex, age, associated risk factors, clinical classification, size, location and presence of epithelial dysplasia, recurrence, and rate of malignant transformation after resection. Results: In the analysis of the final results 18 months after baseline, a treatment success rate of 43.75% was observed. Oral leukoplakia recurred in 54.17% of cases, and 2.08% of leukoplakias progressed to cancer. Among all the studied variables (age, tobacco use, size, location, clinical type or histology), no significant differences were found with regard to recurrence. Conclusion: The use of CO₂ laser therapy to treat leukoplakia lesions is sufficient to remove such lesions. However, parameters that can assess recurrence need to be sought. Full article

► Show Figures

Figure 1

15 pages, 7120 KiB

Open AccessArticle

Discovery of Mitochondrial Complex I Inhibitors as Anticancer and Radiosensitizer Drugs Based on Compensatory Stimulation of Lactate Release

by Junjie Lan, Octavia Cadassou, Cyril Corbet, Olivier Riant and Olivier Feron

Cancers 2022, 14(21), 5454; https://doi.org/10.3390/cancers14215454 - 6 Nov 2022

Cited by 7 | Viewed by 2313

Abstract

Cancer cells may stimulate glycolytic flux when O₂ becomes insufficient. Increase in L-lactate release therefore appears as an escape mechanism to drugs targeting mitochondrial respiration but also represents a response that may be exploited to screen for compounds blocking either mitochondrial carriers [...] Read more.

Cancer cells may stimulate glycolytic flux when O₂ becomes insufficient. Increase in L-lactate release therefore appears as an escape mechanism to drugs targeting mitochondrial respiration but also represents a response that may be exploited to screen for compounds blocking either mitochondrial carriers of oxidizable substrates or the electron transport chain. Here, we developed a screening procedure based on the capacity of cancer cells to release L-lactate to gain insights on the development of mitochondrial complex I inhibitors. For this purpose, we synthesized derivatives of carboxyamidotriazole, a compound previously described as a potential OXPHOS inhibitor. Two series of derivatives were generated by cycloaddition between benzylazide and either cyanoacetamides or alkynes. A primary assay measuring L-lactate release as a compensatory mechanism upon OXPHOS inhibition led us to identify 15 hits among 28 derivatives. A secondary assay measuring O₂ consumption in permeabilized cancer cells confirmed that 12 compounds among the hits exhibited reversible complex I inhibitory activity. Anticancer effects of a short list of 5 compounds identified to induce more L-lactate release than reference compound were then evaluated on cancer cells and tumor-mimicking 3D spheroids. Human and mouse cancer cell monolayers exhibiting high level of respiration in basal conditions were up to 3-fold more sensitive than less oxidative cancer cells. 3D tumor spheroids further revealed potency differences between selected compounds in terms of cytotoxicity but also radiosensitizing activity resulting from local reoxygenation. In conclusion, this study documents the feasibility to efficiently screen in 96-well plate format for mitochondrial complex I inhibitors based on the capacity of drug candidates to induce L-lactate release. Full article

(This article belongs to the Special Issue The Role of Lactate Isomers in Cancer)

► Show Figures

Figure 1

Figure 1
Main synthetic paths to generate carboxyamidotriazole derivatives. The key fragments benzyl azide, N-substituted-2-cyanoacetamides and alkynes were prepared by conventional synthetic methods. The 5-amino-4-carboxyamido-1,2,3-triazole derivatives were assembled by a 1,3-dipolar cycloaddition between 2-cyanoacetamide or N-substituted 2-cyanoacetamides with the corresponding benzyl azides, using sodium ethoxide as a base, as previously reported [<a href="#B31-cancers-14-05454" class="html-bibr">31</a>,<a href="#B32-cancers-14-05454" class="html-bibr">32</a>]. Another series of N-substituted 1,2,3-triazoles, lacking the amino group on the 5-position of the heterocycle, were also prepared by Huisgen-Click cycloaddition reaction between a suitable benzyl azide and an alkyne, using the standard copper acetate/sodium ascorbate system as a catalyst [<a href="#B33-cancers-14-05454" class="html-bibr">33</a>]. Full article ">Figure 2
Screening procedure to identify anticancer activity of bona fide mitochondrial complex I inhibitors. The 3-step procedure includes the evaluation of (1) the stimulation of glycolysis upon OXPHOS inhibition (based on the increase in extracellular L-lactate release), (2) complex I inhibition (based on the measurement of real-time oxygen consumption rate (OCR) in permeabilized cancer cells exposed to a NADH-generating system and (3) the capacity to impact the growth of 3D tumor spheroids recapitulating tumor metabolic heterogeneity (through the determination of growth inhibitory effects, re-oxygenation and radio-sensitization). Full article ">Figure 3
Compound-induced L-lactate release (Assay #1). Culture medium was collected after 24 h exposure to the indicated compounds (10 µM) and the amount of extracellular L-lactate release was determined in a semi-automated manner; dose-dependent effects of complex I inhibitor IACS are shown on the right (shaded bars). Bar graph depicts the extent of L-lactate secretion above the basal release as determined in the absence of any compound (n = 3, ** p < 0.01 for increased L-lactate release vs. reference compound aa). Full article ">Figure 4
Mitochondrial complex I activity inhibition (Assay #2). (A–D). Graphs depict changes in O2 consumption rate (OCR) measured with the Seahorse technology on permeabilized CT26 cancer cells upon successive addition of pyruvate/malate, the indicated inhibitor and succinate. OXPHOS I inhibitor IACS was used as a control in the experiments testing reference compound aa (A), and compound aa (10µM) was used as reference for testing au, ah and at derivatives (B–D) (n = 6 per compound). (E,F). Growth inhibitory effects of cultured CT26 (E) and 4T1 (B) cancer cells exposed to 100 nM IACS or 1 µM aa, ag, aj and au compounds for 72 h; data represent the reduced extent (expressed as %) of cell viability (determined with Presto Blue) when compared with vehicle conditions (n = 3). Full article ">Figure 5
Inhibition of 3D tumor spheroid growth (Assay #3). Graphs depict (A) the direct growth inhibitory effects of the indicated compounds and (B) their capacity to exert radiosensitizing effects as determined using 3D tumor CT26 spheroids (n = 6 per condition). ** p < 0.01 for spheroid sizes at day 10 significantly smaller than spheroids treated with aa (A) or aa + irradiation (B) and §§ p < 0.01 for spheroid sizes at day 10 significantly smaller than corresponding spheroids at day 3 (B). Drug exposure without (A) or with irradiation (B) was associated with a significant reduction in spheroid sizes vs. untreated spheroids (not shown). Full article ">Figure 6
Radiosensitizing effects of selected complex I inhibitors. (A) Extent of surviving cancer cells post-exposure to radiotherapy and the indicated compounds (n = 3, * p < 0.05, ** p < 0.01 vs. vehicle condition). (B) Representative pictures of pimonidazole immunostaining revealing a reduction in the hypoxic fraction of 3D tumor CT26 spheroids induced by the indicated compound; this experiment was repeated twice with similar results. Full article ">

19 pages, 3903 KiB

Open AccessArticle

CAXII Is a Surrogate Marker for Luminal Breast Tumors Regulated by ER and GATA3

by Lucas Porras, Faustine Gorse, Ndeye Khady Thiombane, Louis Gaboury and Sylvie Mader

Cancers 2022, 14(21), 5453; https://doi.org/10.3390/cancers14215453 - 6 Nov 2022

Cited by 1 | Viewed by 2412

Abstract

Estrogen receptor alpha (ERα) expression in ~2/3 breast tumors selects patients for hormonal therapies. Tumors negative for ERα but positive for the progesterone receptor (PR, encoded by PGR) have also been candidates for ER-targeting therapies, as PR expression may reflect undetected ER [...] Read more.

Estrogen receptor alpha (ERα) expression in ~2/3 breast tumors selects patients for hormonal therapies. Tumors negative for ERα but positive for the progesterone receptor (PR, encoded by PGR) have also been candidates for ER-targeting therapies, as PR expression may reflect undetected ER activity. Conversely, PR⁻ status in ER⁺ tumors predicts a worse therapeutic response. Our analysis of breast tumor transcriptome datasets, however, revealed that in tumors with lower PGR expression, the clinical PR status does not correlate accurately with the expression of ESR1 or of ER target genes, including PGR itself. We identified carbonic anhydrase 12 (CA12) as an estrogen target gene better correlated with ESR1 than PGR, reflecting CA12 regulation by both ERα and the luminal factor and upstream ESR1 regulator GATA3. Immunostaining supported strong positive correlations at the protein level with ERα and GATA3 in a cohort of 118 tumors. Most ER⁺PR⁻ tumors expressed CAXII at levels similar to those of ER⁺PR⁺ tumors, consistent with observations in tumor transcriptome datasets and with active estrogenic signaling in some ER⁺PR⁻ breast cancer cell lines. The few ER⁻PR⁺ tumors did not express CAXII or the other luminal markers FOXA1 and GATA3. Overall, CAXII is a luminal marker that can help interpret ER status in single ER/PR positive tumors. Full article

(This article belongs to the Section Cancer Biomarkers)

► Show Figures

Graphical abstract

Graphical abstract
Full article ">Figure 1
PR status imperfectly reflects ESR1 expression, ER status and activity. Pair-wise scatterplots for the expression of ESR1 vs PGR (A,B,E), TFF1 (C), GREB1 (D) and CA12 (F) generated using MiSTIC [<a href="#B55-cancers-14-05453" class="html-bibr">55</a>]. Boxes identify 90% of ESR1low tumors, and the portion of ESR1high tumors identified using the same threshold of positivity for different ER target genes. Percentages of total tumors are shown. Enrichment of ESR1highPGRlow tumors (highlighted in green) in the CIT luminal B tumor subtype is shown in the inset of panel (E). Full article ">Figure 2
CA12 mRNA levels are highly correlated with those of ESR1, FOXA1 and GATA3 in breast tumors. (A) Minimum spanning tree representing a cluster of genes expressed preferentially in luminal and molecular apocrine breast tumors, identified by gene correlation analysis from a TCGA breast cancer transcriptomic dataset comprising 754 tumors using MiSTIC software [<a href="#B55-cancers-14-05453" class="html-bibr">55</a>]. Genes encoding transcription factors (ESR1, FOXA1, GATA3, SPDEF, XBP1 and AR) are highlighted in orange, whereas CA12 is indicated in red. (B) Pair-wise correlation scatterplots for CA12 and ESR1 (top), GATA3 (middle) or FOXA1 (bottom) expression levels in the same cohort, with CIT tumor subtypes highlighted by different colors. Luminal A tumors appear in dark blue, luminal B in green, luminal C in light blue, molecular apocrine in magenta and basal-like in red. Normal-like or non-classified tumors are shown in black. Pearson correlation coefficients are indicated at the bottom of each pair-wise correlation scatterplot. Full article ">Figure 3
ESR1high cell lines express high levels of CA12, but variable levels of PGR. Pair-wise scatterplots for the expression of ESR1 vs those of CA12 (A) or PGR (B). Values are Log2(Rpkm+1). RNA levels and cell line subtyping are from [<a href="#B61-cancers-14-05453" class="html-bibr">61</a>]. Selected cell lines are labeled. Full article ">Figure 4
ERα and GATA3 positively regulate CA12 expression in luminal breast cancer cell lines. (A) Schematic CA12 gene organization with exons (grey boxes) and putative enhancers (red boxes). Predicted binding motifs for ERα and GATA3 are highlighted in bold in sequences for enhancers 1 and 2. (B) MCF-7, T-47D and ZR-75-1 cell lines were cultured in hormone-depleted medium for five days and then treated with E2 (25 nM). CA12 mRNA levels were measured by RT-qPCR at 4, 8 and 16 h. RPLP0 and YWHAZ were used as housekeeping genes for normalization. Values are presented as ratios over the expression in vehicle-treated samples for each time point. Asterisks indicate statistically significant regulations (Average of n = 3; *, p ≤ 0.05; **, p ≤ 0.01; ****, p ≤ 0.0001; Student’s unpaired t-test). (C) CAXII protein levels from MCF-7, T-47D and ZR-75-1 cells were analyzed at 0, 4, 8, 16 and 24 h after treatment with E2 by Western blotting (n = 3, a representative blot is shown). β-actin or Lamin B1 housekeeping proteins were used as loading controls. (D) MCF-7 cells were cultured in hormone-depleted medium for three days and then treated with E2 (25 nM) for 1 h before fixation and collection. Binding of ERα, FOXA1 and GATA3 to CA12 enhancers was examined by ChIP-qPCR. Relative immunoprecipitation levels (ratios to IgG in vehicle-treated cells) are shown. The assay was performed twice with similar results. Asterisks indicate statistically significant binding compared to IgG in vehicle-treated cells for each enhancer from one experiment performed in triplicates (*, p ≤ 0.05; one-way ANOVA test, Dunnett’s multiple comparisons test). (E) MCF-7 cells were cultured in hormone-depleted medium for three days and transfected with a SMARTpool of siRNAs targeting CA12 and two different siRNAs targeting ESR1, FOXA1 or GATA3. Cells were then collected two days after transfection. Protein levels of CAXII, ERα, FOXA1 and GATA3 were analyzed by Western blotting (n = 2). β-actin was used as a loading control. (F,G) T-47D and ZR-75-1 cells were cultured in hormone-depleted medium for three days and transfected with two different siRNAs targeting GATA3. Cells were then collected two days after transfection. Protein levels of CAXII and GATA3 were analyzed by Western blotting in T-47D (F) and ZR-75-1 (G) cells; CAXII levels were quantified for both cell lines using ImageJ (average of n = 3 for quantification, one representative blot shown; *, p ≤ 0.05; **, p ≤ 0.01; Student’s unpaired t-test). Lamin B1 was used as a loading control. Full article ">Figure 5
CAXII expression is increased in tumoral epithelial cells with loss of polarity. CAXII staining (in brown) of normal adjacent mammary tissue (A), columnar cell lesion (B), in situ breast ductal carcinoma (C) and invasive breast ductal carcinoma (D) at 20× and 40× magnification. The apical (A) and basal (B) poles of a luminal cell are labeled. Full article ">Figure 6
Protein expression levels of CAXII and of the luminal transcription factors ERα, FOXA1 and GATA3 are correlated in breast tumors. Correlations between CAXII and ERα (A), GATA3 (B) or FOXA1 (C) expression scores are shown for all tumors in the TMAs. Scores were computed by QuPath using membrane (CAXII) and nuclear signal intensities (ERα, GATA3, FOXA1). ER+PR+ tumors are highlighted in dark blue circles, ER+PR− tumors in light blue circles, ER−PR+ tumors in yellow diamonds, ER−HER2+ tumors in green squares and ER−HER2− tumors in red circles. Representative co-staining for CAXII (brown) and each of these luminal transcription factors (green) is also shown. Full article ">Figure 7
CAXII expression discriminates ER+ from ER− breast tumors. (A) Boxplot representing CAXII score distribution according to ER, PR and HER2 status (7 arrays, n = 118; ns, p > 0.05; ****, p ≤ 0.0001; Dunn’s multiple comparisons post-hoc test performed after Kruskall-Wallis test (p < 0.0001)). ER−PR+ tumors are highlighted in yellow in the ER−HER2− group. (B) Representative cores for the four observed phenotypes of CAXII and ER status after co-staining with CAXII (brown) and ERα (green). Scores were computed by QuPath using membrane (CAXII) and nuclear (ERα) signal intensities. Full article ">

16 pages, 1397 KiB

Open AccessArticle

Oncological Outcomes of Distal Ureterectomy for High-Risk Urothelial Carcinoma: A Multicenter Study by The French Bladder Cancer Committee

by Alexandra Masson-Lecomte, Victoire Vaillant, Mathieu Roumiguié, Stéphan Lévy, Benjamin Pradère, Michaël Peyromaure, Igor Duquesne, Alexandre De La Taille, Cédric Lebâcle, Adrien Panis, Olivier Traxer, Priscilla Leon, Maud Hulin, Evanguelos Xylinas, François Audenet, Thomas Seisen, Yohann Loriot, Yves Allory, Morgan Rouprêt and Yann Neuzillet

Cancers 2022, 14(21), 5452; https://doi.org/10.3390/cancers14215452 - 6 Nov 2022

Cited by 14 | Viewed by 2751

Abstract

Upper urinary tract urothelial carcinoma (UTUC) is an uncommon disease and its gold-standard treatment is radical nephroureterectomy (RNU). Distal ureterectomy (DU) might be an alternative for tumors of the distal ureter but its indications remain unclear. Here, we aimed to evaluate the oncological [...] Read more.

Upper urinary tract urothelial carcinoma (UTUC) is an uncommon disease and its gold-standard treatment is radical nephroureterectomy (RNU). Distal ureterectomy (DU) might be an alternative for tumors of the distal ureter but its indications remain unclear. Here, we aimed to evaluate the oncological outcomes of DU for UTUC of the pelvic ureter. We performed a multicenter retrospective analysis of patients with UTUC who underwent DU. The primary endpoint was 5-year cancer-specific survival (CSS), followed by overall survival (OS), intravesical recurrence-free (IVR) and homolateral urinary tract recurrence-free (HUR) survivals as secondary endpoints. Univariate and multivariate Cox regressions were performed to assess factors associated with outcomes. 155 patients were included, 91% of which were high-risk. 5-year CSS was 84.4%, OS was 71.9%, IVR-free survival was 43.6% and HUR-free survival was 74.4%. Multifocality, high grade and tumor size were the most significant predictors of survival endpoints. Of note, neither hydronephrosis nor pre-operative diagnostic ureteroscopy/JJ stent were associated with any of the endpoints. Perioperative morbidity was minimal. In conclusion, DU stands as a possible alternative to RNU for UTUC of the pelvic ureter. Close monitoring is mandatory due to the high risk of recurrence in the remaining urinary tract. Full article

(This article belongs to the Special Issue Advance and New Insights in Bladder Cancer)

► Show Figures

Figure 1

20 pages, 1034 KiB

Open AccessArticle

A Retrospective, Single-Institution Experience of Bullous Pemphigoid as an Adverse Effect of Immune Checkpoint Inhibitors

by Walid Shalata, Sarah Weissmann, Sapir Itzhaki Gabay, Kim Sheva, Omar Abu Saleh, Ashraf Abu Jama, Alexander Yakobson and Keren Rouvinov

Cancers 2022, 14(21), 5451; https://doi.org/10.3390/cancers14215451 - 5 Nov 2022

Cited by 17 | Viewed by 2965

Abstract

Immune checkpoint inhibitors are a class of cancer treatment drugs that stimulate the immune system’s ability to fight tumor cells. These drugs are monoclonal antibodies targeting im-mune-inhibiting proteins on cancer cells, such as CTLA-4 and PD-1/PD-L1. Immune checkpoint inhibitors cause many immune-related adverse [...] Read more.

Immune checkpoint inhibitors are a class of cancer treatment drugs that stimulate the immune system’s ability to fight tumor cells. These drugs are monoclonal antibodies targeting im-mune-inhibiting proteins on cancer cells, such as CTLA-4 and PD-1/PD-L1. Immune checkpoint inhibitors cause many immune-related adverse events. Cutaneous toxicities are of the most common adverse effects and occur with a range of severity. Bullous Pemphigoid is a rare adverse event with a high impact on quality of life that may occur after immune checkpoint inhibitor treatment. In this article, we investigate current research on immune checkpoint inhibitors, cutaneous adverse events, and common presentations and treatments, with a specific focus on Bullous Pemphigoid, its characteristics, onset timing, and treatment. Significant findings include a negative skew in the onset of presentation. Furthermore, we describe exclusive cases. Full article

(This article belongs to the Special Issue Immune Checkpoint Inhibitors in Cancer Therapy—How Can We Improve Clinical Benefits?)

► Show Figures

Figure 1

13 pages, 623 KiB

Open AccessReview

Long Non-Coding RNA and microRNA Interplay in Colorectal Cancer and Their Effect on the Tumor Microenvironment

by Marie Rajtmajerová, Andriy Trailin, Václav Liška, Kari Hemminki and Filip Ambrozkiewicz

Cancers 2022, 14(21), 5450; https://doi.org/10.3390/cancers14215450 - 5 Nov 2022

Cited by 9 | Viewed by 3093

Abstract

As the current staging and grading systems are not sufficient to stratify patients for therapy and predict the outcome of the disease, there is an urgent need to understand cancer in its complexity. The mutual relationship between tumour and immune or stromal cells [...] Read more.

As the current staging and grading systems are not sufficient to stratify patients for therapy and predict the outcome of the disease, there is an urgent need to understand cancer in its complexity. The mutual relationship between tumour and immune or stromal cells leads to rapid evolution and subsequent genetic and epigenetic changes. Immunoscore has been introduced as a diagnostic tool for colorectal cancer (CRC) only recently, emphasising the role of the specific tumor microenvironment in patient’s prognosis and overall outcome. Despite the fact that non-coding RNAs (ncRNAs), such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), cannot be translated into proteins, they significantly affect cell’s transcriptome and translatome. miRNA binding to mRNA efficiently blocks its translation and leads to mRNA destruction. On the other hand, miRNAs can be bound by lncRNAs or circular RNAs (circRNAs), which prevents them from interfering with translation. In this way, ncRNAs create a multi-step network that regulates the cell’s translatome. ncRNAs are also shed by the cell as exogenous RNAs and they are also found in exosomes, suggesting their role in intercellular communication. Hence, these mechanisms affect the tumor microenvironment as much as protein signal molecules. In this review, we provide an insight into the current knowledge of the microenvironment, lncRNAs’, and miRNAs’ interplay. Understanding mechanisms that underlie the evolution of a tissue as complex as a tumour is crucial for the future success in therapy. Full article

(This article belongs to the Special Issue Non-coding RNA in Gastrointestinal Tumours: New Opportunities for Diagnosis and Treatment)

► Show Figures

Figure 1

18 pages, 3411 KiB

Open AccessArticle

CRISPR/Cas9 Edited RAS & MEK Mutant Cells Acquire BRAF and MEK Inhibitor Resistance with MEK1 Q56P Restoring Sensitivity to MEK/BRAF Inhibitor Combo and KRAS G13D Gaining Sensitivity to Immunotherapy

by Elizabeth Turner, Luping Chen, John G. Foulke, Zhizhan Gu and Fang Tian

Cancers 2022, 14(21), 5449; https://doi.org/10.3390/cancers14215449 - 5 Nov 2022

Cited by 5 | Viewed by 3675

Abstract

BRAF V600E mutation drives uncontrolled cell growth in most melanomas. While BRAF V600E tumors are initially responsive to BRAF inhibitors, prolonged treatment results in inhibitor resistance and tumor regrowth. Clinical data have linked the NRAS Q61K, KRAS G13D and MEK1 Q56P mutations [...] Read more.

BRAF V600E mutation drives uncontrolled cell growth in most melanomas. While BRAF V600E tumors are initially responsive to BRAF inhibitors, prolonged treatment results in inhibitor resistance and tumor regrowth. Clinical data have linked the NRAS Q61K, KRAS G13D and MEK1 Q56P mutations to the BRAF inhibitor resistance. However, development of novel therapeutics is hindered by the lack of relevant isogeneic cell models. We employed CRISPR/Cas9 genome engineering to introduce NRAS Q61K, KRAS G13D and MEK1 Q56P mutations into the A375 melanoma cell line with endogenously high expression of BRAF V600E. The resulting isogenic cell lines are resistant to BRAF inhibitors. The A375 MEK1 Q56P isogenic cells are additionally resistant to MEK inhibitors as single agent, but interestingly, these cells become sensitive to MEK/BRAF inhibitor combo. Our results suggest that resistance in the NRAS and MEK isogenic lines is driven by constitutive MEK/ERK signaling, while the resistance in the KRAS isogenic line is driven by EGFR overexpression. Interestingly, the KRAS G13D isogenic line displays elevated PD-L1 expression suggesting the KRAS G13D mutation could be a potential indication for immunotherapy. Overall, these three novel isogenic cell models with endogenous level RAS and MEK1 point mutations provide direct bio-functional evidence demonstrating that acquiring a drug-resistant gene drives tumor cell survival and may simultaneously introduce new indications for combo therapy or immunotherapy in the clinic. Full article

(This article belongs to the Special Issue Targeting the (Un)Usual Suspects in Cancer)

► Show Figures

Figure 1

15 pages, 1168 KiB

Open AccessReview

Prostate Cancer Stem Cells: The Role of CD133

by Jianhui Yang, Omar Aljitawi and Peter Van Veldhuizen

Cancers 2022, 14(21), 5448; https://doi.org/10.3390/cancers14215448 - 5 Nov 2022

Cited by 17 | Viewed by 2859

Abstract

Prostate cancer stem cells (PCSCs), possessing self-renewal properties and resistance to anticancer treatment, are possibly the leading cause of distant metastasis and treatment failure in prostate cancer (PC). CD133 is one of the most well-known and valuable cell surface markers of cancer stem [...] Read more.

Prostate cancer stem cells (PCSCs), possessing self-renewal properties and resistance to anticancer treatment, are possibly the leading cause of distant metastasis and treatment failure in prostate cancer (PC). CD133 is one of the most well-known and valuable cell surface markers of cancer stem cells (CSCs) in many cancers, including PC. In this article, we focus on reviewing the role of CD133 in PCSC. Any other main stem cell biomarkers in PCSC reported from key publications, as well as about vital research progress of CD133 in CSCs of different cancers, will be selectively reviewed to help us inform the main topic. Full article

(This article belongs to the Special Issue Cancer Stem Cells (CSCs) in Drug Resistance and Their Therapeutic Implications in Cancer Treatment)

► Show Figures

Figure 1

23 pages, 2358 KiB

Open AccessArticle

Testicular Neoplasms: Primary Tumour Size Is Closely Interrelated with Histology, Clinical Staging, and Tumour Marker Expression Rates—A Comprehensive Statistical Analysis

by Klaus-Peter Dieckmann, Hendrik Isbarn, Francesca Grobelny, Cansu Dumlupinar, Julia Utschig, Christian Wülfing, Uwe Pichlmeier and Gazanfer Belge

Cancers 2022, 14(21), 5447; https://doi.org/10.3390/cancers14215447 - 5 Nov 2022

Cited by 12 | Viewed by 2359

Abstract

The role of primary tumour size (TS) in the clinical course of testicular tumours is incompletely understood. We retrospectively evaluated 641 consecutive patients with testicular neoplasms with regard to TS, histology, clinical stage (CS), serum tumour marker (STM) expression and patient age using [...] Read more.

The role of primary tumour size (TS) in the clinical course of testicular tumours is incompletely understood. We retrospectively evaluated 641 consecutive patients with testicular neoplasms with regard to TS, histology, clinical stage (CS), serum tumour marker (STM) expression and patient age using descriptive statistical methods. TS ≤ 10 mm was encountered in 13.6% of cases. Median TS of 10 mm, 30 mm, 35 mm, and 53 mm were found in benign tumours, seminomas, nonseminomas, and other malignant tumours, respectively. In cases with TS ≤ 10 mm, 50.6% had benign tumours. Upon receiver operating characteristics analysis, TS of > 16 mm revealed 81.5% sensitivity and 81.0% specificity for detecting malignancy. In subcentimeter germ cell tumours (GCTs), 97.7% of cases had CS1, and CS1 frequency dropped with increasing TS. Expression rates of all STMs significantly increased with TS. MicroRNA-371a-3p (M371) serum levels had higher expression rates than classical STMs, with a rate of 44.1% in subcentimeter GCTs. In all, TS is a biologically relevant factor owing to its significant associations with CS, STM expression rates and histology. Importantly, 50% of subcentimeter testicular neoplasms are of benign nature, and M371 outperforms the classical markers even in subcentimeter tumours. Full article

(This article belongs to the Section Cancer Biomarkers)

► Show Figures

Figure 1

Figure 1
Tumour sizes observed in the four histologic groups. Box and whisker plots showing the distribution of tumour sizes stratified by histologic subtypes of testicular neoplasms. The boxes display the first quartile, median and third quartile. The whiskers are defined as the largest or lowest observed value that falls within 1.5 times the interquartile range measured from Q3 or Q1, respectively. Area of box relates to sample size. □ outliers; + denotes arithmetic mean; SE seminoma; NS nonseminoma; BT benign tumours; OM other malignancies. Full article ">Figure 2
Typical subcentimeter testicular neoplasm. Surgical specimen of a 6 mm sized benign Leydig cell tumour excised by testis sparing surgery. Full article ">Figure 3
Proportions of histologic subgroups in testicular tumours sized >10 mm and ≤10 mm. Full article ">Figure 4
ROC analysis for predicting histology of a testicular neoplasm by its size. Full article ">Figure 5
Probability curve for prediction of malignant histology of a testicular neoplasm. The logistic regression curve indicates the probability of a given tumour size to predict malignancy. Shadowed area represents 95% confidence intervals. Neoplasms with a size of ≤8 mm involve a 50% probability of malignancy, while tumour sizes of ≥25 mm, ≥33 mm, and ≥39 mm involve probabilities of 95%, 99%, and 100%, respectively. Full article ">Figure 6
Tumour sizes in clinical stages in germ cell tumours. Box and whisker plots showing the distribution of tumour sizes stratified by clinical stages of testicular neoplasms. The boxes display the first quartile, median and third quartile. The whiskers are defined as the largest or lowest observed value that falls within 1.5 times the interquartile range measured from Q3 or Q1, respectively. Area of box denotes sample size. □ outliers; + denotes arithmetic mean; CS clinical stage. Full article ">Figure 7
Expression rates of M371 and AFP and/or bHCG in germ cell tumours in relation to size of primary tumour in seminoma (A) and in nonseminoma (B). Blue columns denote expression rates of AFP and/or bHCG in five categories of tumour size, red columns indicate expression rates of M371. Overall, the expression rates of all tumour markers were higher in nonseminoma than in seminoma. All markers showed a significant trend towards lower expression rates with decreasing tumour size. M371 had higher expression rates than the other markers even in the smallest tumour size category. Error bars represent 95% CIs. Full article ">

18 pages, 5727 KiB

Open AccessArticle

Water-Soluble Truncated Fatty Acid–Porphyrin Conjugates Provide Photo-Sensitizer Activity for Photodynamic Therapy in Malignant Mesothelioma

by Sam Bonsall, Simeon Hubbard, Uthaman Jithin, Joseph Anslow, Dylan Todd, Callum Rowding, Tom Filarowski, Greg Duly, Ryan Wilson, Jack Porter, Simon Turega and Sarah Haywood-Small

Cancers 2022, 14(21), 5446; https://doi.org/10.3390/cancers14215446 - 5 Nov 2022

Cited by 2 | Viewed by 2955

Abstract

Clinical trials evaluating intrapleural photodynamic therapy (PDT) are ongoing for mesothelioma. Several issues still hinder the development of PDT, such as those related to the inherent properties of photosensitizers. Herein, we report the synthesis, photophysical, and photobiological properties of three porphyrin-based photosensitizers conjugated [...] Read more.

Clinical trials evaluating intrapleural photodynamic therapy (PDT) are ongoing for mesothelioma. Several issues still hinder the development of PDT, such as those related to the inherent properties of photosensitizers. Herein, we report the synthesis, photophysical, and photobiological properties of three porphyrin-based photosensitizers conjugated to truncated fatty acids (C5SHU to C7SHU). Our photosensitizers exhibited excellent water solubility and high PDT efficiency in mesothelioma. As expected, absorption spectroscopy confirmed an increased aggregation as a consequence of extending the fatty acid chain length. In vitro PDT activity was studied using human mesothelioma cell lines (biphasic MSTO-211H cells and epithelioid NCI-H28 cells) alongside a non-malignant mesothelial cell line (MET-5A). The PDT effect of these photosensitizers was initially assessed using the colorimetric WST-8 cell viability assay and the mode of cell death was determined via flow cytometry of Annexin V-FITC/PI-stained cells. Photosensitizers appeared to selectively localize within the non-nuclear compartments of cells before exhibiting high phototoxicity. Both apoptosis and necrosis were induced at 24 and 48 h. As our pentanoic acid-derivatized porphyrin (C5SHU) induced the largest anti-tumor effect in this study, we put this forward as an anti-tumor drug candidate in PDT and photo-imaging diagnosis in mesothelioma. Full article

(This article belongs to the Special Issue Recent Research on Mesothelioma)

► Show Figures

Figure 1

14 pages, 820 KiB

Open AccessArticle

Reliable Flow-Cytometric Approach for Minimal Residual Disease Monitoring in Patients with B-Cell Precursor Acute Lymphoblastic Leukemia after CD19-Targeted Therapy

by Ekaterina Mikhailova, Olga Illarionova, Alexander Komkov, Elena Zerkalenkova, Ilgar Mamedov, Larisa Shelikhova, Yulia Olshanskaya, Natalia Miakova, Galina Novichkova, Alexander Karachunskiy, Michael Maschan and Alexander Popov

Cancers 2022, 14(21), 5445; https://doi.org/10.3390/cancers14215445 - 5 Nov 2022

Cited by 10 | Viewed by 2961

Abstract

We aimed to develop an antibody panel and data analysis algorithm for multicolor flow cytometry (MFC), which is a reliable method for minimal residual disease (MRD) detection in patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) treated with CD19-directed therapy. The development of [...] Read more.

We aimed to develop an antibody panel and data analysis algorithm for multicolor flow cytometry (MFC), which is a reliable method for minimal residual disease (MRD) detection in patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) treated with CD19-directed therapy. The development of the approach, which was adapted for the case of possible CD19 loss, was based on the additional B-lineage marker expression data obtained from a study of primary BCP-ALL patients, an analysis of the immunophenotypic changes that occur during blinatumomab or CAR-T therapy, and an analysis of very early CD19-negative normal BCPs. We have developed a single-tube 11-color panel for MFC-MRD detection. CD22- and iCD79a-based primary B-lineage gating (preferably consecutive) was recommended. Based on patterns of antigen expression changes and the relative expansion of normal CD19-negative BCPs, guidelines for MFC data analysis and interpretation were established. The suggested approach was tested in comparison with the molecular techniques: IG/TR gene rearrangement detection by next-generation sequencing (NGS) and RQ-PCR for fusion-gene transcripts (FGTs). Qualitative concordance rates of 82.8% and 89.8% were obtained for NGS-MRD and FGT-MRD results, respectively. We have developed a sensitive and reliable approach that allows MFC-MRD monitoring after CD19-directed treatment, even in the case of possible CD19 loss. Full article

(This article belongs to the Special Issue 2nd Edition: Minimal Residual Disease of Cancers)

► Show Figures

Figure 1

22 pages, 5079 KiB

Open AccessReview

Classic and New Markers in Diagnostics and Classification of Breast Cancer

by Roman Beňačka, Daniela Szabóová, Zuzana Guľašová, Zdenka Hertelyová and Jozef Radoňák

Cancers 2022, 14(21), 5444; https://doi.org/10.3390/cancers14215444 - 5 Nov 2022

Cited by 44 | Viewed by 9950

Abstract

Breast cancer remains the most frequently diagnosed form of female’s cancer, and in recent years it has become the most common cause of cancer death in women worldwide. Like many other tumours, breast cancer is a histologically and biologically heterogeneous disease. In recent [...] Read more.

Breast cancer remains the most frequently diagnosed form of female’s cancer, and in recent years it has become the most common cause of cancer death in women worldwide. Like many other tumours, breast cancer is a histologically and biologically heterogeneous disease. In recent years, considerable progress has been made in diagnosis, subtyping, and complex treatment of breast cancer with the aim of providing best suited tumour-specific personalized therapy. Traditional methods for breast cancer diagnosis include mammography, MRI, biopsy and histological analysis of tumour tissue in order to determine classical markers such as estrogen and progesterone receptors (ER, PR), cytokeratins (CK5/6, CK14, C19), proliferation index (Ki67) and human epidermal growth factor type 2 receptor (HER2). In recent years, these methods have been supplemented by modern molecular methodologies such as next-generation sequencing, microRNA, in situ hybridization, and RT-qPCR to identify novel molecular biomarkers. MicroRNAs (miR-10b, miR-125b, miR145, miR-21, miR-155, mir-30, let-7, miR-25-3p), altered DNA methylation and mutations of specific genes (p16, BRCA1, RASSF1A, APC, GSTP1), circular RNA (hsa_circ_0072309, hsa_circRNA_0001785), circulating DNA and tumour cells, altered levels of specific proteins (apolipoprotein C-I), lipids, gene polymorphisms or nanoparticle enhanced imaging, all these are promising diagnostic and prognostic tools to disclose any specific features from the multifaceted nature of breast cancer to prepare best suited individualized therapy. Full article

(This article belongs to the Special Issue Breast Cancer: Novel Histological and Molecular Markers for Diagnosis, Prognosis, Therapeutic Prediction, and Drug Resistance)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Cancers, Volume 14, Issue 21 (November-1 2022) – 301 articles

Further Information

Guidelines

MDPI Initiatives

Follow MDPI