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Cancers, Volume 13, Issue 18 (September-2 2021) – 236 articles

Cover Story (view full-size image): The mechanisms leading to anti-PD-L1/PD-1 resistance in cancer remain elusive. Exosomes (extracellular nanovesicles secreted by almost all cells, including tumor cells) are key actors in this resistance. Exosomes released by tumor cells (TEXs) express different immune checkpoints and disseminate immune-suppressive properties. Their impact is mediated by a wide range of actions, exerting an overall effect on immunity by inactivating immune cells even before they get to the tumor. Much remains to be discovered to understand the molecular mechanisms through which TEXs modulate resistance to immunotherapies. Blocking TEXs bearing immune checkpoints might be a way to counteract PD-L1/PD-1 blockade resistance. Therefore, TEXs have potential clinical interest as new targets for immunotherapy and as biomarkers in liquid biopsies. View this paper
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Article
The Survival Benefit of Chemoradiotherapy following Induction Chemotherapy with Gemcitabine Plus Nab-Paclitaxel for Unresectable Locally Advanced Pancreatic Cancer
Cancers 2021, 13(18), 4733; https://doi.org/10.3390/cancers13184733 - 21 Sep 2021
Cited by 5 | Viewed by 1754
Abstract
An optimal therapeutic strategy for unresectable locally advanced pancreatic cancer (UR-LAPC) has not been established. This study investigated the therapeutic efficacy of chemoradiotherapy (CRT) following induction chemotherapy with gemcitabine plus nab-paclitaxel (GnP) (CRT group) compared with systemic chemotherapy alone (CTx group) in patients [...] Read more.
An optimal therapeutic strategy for unresectable locally advanced pancreatic cancer (UR-LAPC) has not been established. This study investigated the therapeutic efficacy of chemoradiotherapy (CRT) following induction chemotherapy with gemcitabine plus nab-paclitaxel (GnP) (CRT group) compared with systemic chemotherapy alone (CTx group) in patients with UR-LAPC. This was a retrospective study of 63 consecutive patients with UR-LAPC treated at our department in a Japanese cancer referral center between February 2015 and July 2018. We excluded patients who underwent other regimens and those enrolled in another prospective study. The CRT group (n = 25) exhibited significantly better progression-free survival (PFS) and overall survival (OS) than the CTx group (n = 20, PFS 17.9 vs. 7.6 months, p = 0.044; OS 29.2 vs. 17.4 months, p < 0.001). In the multivariate analyses, CRT following induction chemotherapy was identified as an independent prognostic factor for OS. Seven (15.6%) patients underwent conversion surgery, all of whom were in the CRT group. The R0 resection rate was 85.7% (6/7). In summary, patients with UR-LAPC experienced favorable treatment outcomes after receiving GnP as the first-line chemotherapy, especially when receiving additional CRT. Thus, this treatment strategy represents a promising treatment option for selected patients with UR-LAPC. Full article
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Review
Senescence in HBV-, HCV- and NAFLD- Mediated Hepatocellular Carcinoma and Senotherapeutics: Current Evidence and Future Perspective
Cancers 2021, 13(18), 4732; https://doi.org/10.3390/cancers13184732 - 21 Sep 2021
Cited by 4 | Viewed by 2086
Abstract
Cell senescence constitutes a physiological process that serves as protection from malignant transformation of cells. However, recent scientific discoveries also identify cell senescence as pivotal in hepatocellular cancer (HCC) biology. The review herein aimed to accumulate evidence on senescence as a mediator of [...] Read more.
Cell senescence constitutes a physiological process that serves as protection from malignant transformation of cells. However, recent scientific discoveries also identify cell senescence as pivotal in hepatocellular cancer (HCC) biology. The review herein aimed to accumulate evidence on senescence as a mediator of HCC occurrence in hepatitis B (HBV), C (HCV) virus infections, and non-alcoholic fatty liver disease (NAFLD). In HBV infection, the carcinogenic HBV X protein frequently mutates during chronic infection, and subsequently exhibits different effects on senescence. In HCV infection, senescent non-functional T-cells do not effectively clear pre-malignant hepatocytes. Furthermore, the HCV Core protein inhibits the occurrence of normal stress-induced hepatocyte senescence, allowing damaged cells to maintain their proliferative potential. In NAFLD-mediated HCC, current data point towards the gut microbiome and hepatic stellate cell senescence. Additionally, senescence contributes in the development of resistance in targeted therapies, such as sorafenib. Finally, the promising role of senotherapeutics in HCC was also explored. Overall, although we may still be at a primitive stage in fully unraveling the role of senescence in cancer, it seems that understanding and harnessing senescence may have the potential to revolutionize the way we treat hepatocellular cancer. Full article
(This article belongs to the Special Issue Senescent Cells and Cancer Therapy)
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Article
Regorafenib in Recurrent Glioblastoma Patients: A Large and Monocentric Real-Life Study
Cancers 2021, 13(18), 4731; https://doi.org/10.3390/cancers13184731 - 21 Sep 2021
Cited by 14 | Viewed by 2559
Abstract
Despite multimodal treatment with surgery and radiochemotherapy, the prognosis of glioblastoma remains poor, and practically all glioblastomas relapse. To date, no standard treatment exists for recurrent glioblastoma patients and traditional therapies have showed limited efficacy. Regorafenib is an oral multi-targeted tyrosine kinase inhibitor [...] Read more.
Despite multimodal treatment with surgery and radiochemotherapy, the prognosis of glioblastoma remains poor, and practically all glioblastomas relapse. To date, no standard treatment exists for recurrent glioblastoma patients and traditional therapies have showed limited efficacy. Regorafenib is an oral multi-targeted tyrosine kinase inhibitor showing encouraging benefits in recurrent GBM patients enrolled in the REGOMA trial. We performed a large study to investigate clinical outcomes and the safety of regorafenib in a real-life population of recurrent glioblastoma patients. Patients receiving regorafenib outside clinical trials at the Veneto Institute of Oncology were retrospectively reviewed. The major inclusion criteria were: histologically confirmed diagnosis of glioblastoma, prior first line therapy according to “Stupp protocol”, Eastern Cooperative Oncology Group (ECOG) performance status score ≤1. According to the original schedule, patients received regorafenib 160 mg once daily for the first 3 weeks of each 4-week cycle. The primary endpoints of the study were overall survival and safety. A total of 54 consecutive patients were enrolled. The median age was 56, MGMT methylated status was found in 28 out of 53 available patients (52.8%), IDH mutation in 5 (9.3%) and 22 patients were receiving steroids at baseline. The median overall survival was 10.2 months (95% CI, 6.4–13.9), the OS-12 was 43%. Age, MGMT methylation status and steroid use at baseline were not statistically significant on a multivariate analysis for OS. Patients reporting a disease control as best response to regorafenib demonstrated a significant longer survival (24.8 months vs. 6.2 months for patients with progressive disease, p = 0.0001). Grade 3 drug-related adverse events occurred in 10 patients (18%); 1 patient (2%) reported a grade 4 adverse event (rash maculo-papular). No death was considered to be drug-related. This study reported the first large “real-life” experience of regorafenib in recurrent glioblastoma. Overall, our results are close to the ones reported in the previous phase 2 study, despite the fact that we had a longer survival. We showed the encouraging activity and tolerability of this treatment in recurrent glioblastoma patients when used as a second-line treatment. Full article
(This article belongs to the Special Issue Recurrent Glioblastoma)
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Article
HPV Status as Prognostic Biomarker in Head and Neck Cancer—Which Method Fits the Best for Outcome Prediction?
Cancers 2021, 13(18), 4730; https://doi.org/10.3390/cancers13184730 - 21 Sep 2021
Cited by 7 | Viewed by 1647
Abstract
The incidence of human papillomavirus (HPV)-related head and neck cancer (HNSCC) is rising globally, presenting challenges for optimized clinical management. To date, it remains unclear which biomarker best reflects HPV-driven carcinogenesis, a process that is associated with better therapeutic response and outcome compared [...] Read more.
The incidence of human papillomavirus (HPV)-related head and neck cancer (HNSCC) is rising globally, presenting challenges for optimized clinical management. To date, it remains unclear which biomarker best reflects HPV-driven carcinogenesis, a process that is associated with better therapeutic response and outcome compared to tobacco/alcohol-induced cancers. Six potential HPV surrogate biomarkers were analyzed using FFPE tissue samples from 153 HNSCC patients (n = 78 oropharyngeal cancer (OPSCC), n = 35 laryngeal cancer, n = 23 hypopharyngeal cancer, n = 17 oral cavity cancer): p16, CyclinD1, pRb, dual immunohistochemical staining of p16 and Ki67, HPV-DNA-PCR, and HPV-DNA-in situ hybridization (ISH). Biomarkers were analyzed for correlation with one another, tumor subsite, and patient survival. P16-IHC alone showed the best performance for discriminating between good (high expression) vs poor outcome (low expression; p = 0.0030) in OPSCC patients. Additionally, HPV-DNA-ISH (p = 0.0039), HPV-DNA-PCR (p = 0.0113), and p16-Ki67 dual stain (p = 0.0047) were significantly associated with prognosis in uni- and multivariable analysis for oropharyngeal cancer. In the non-OPSCC group, however, none of the aforementioned surrogate markers was prognostic. Taken together, P16-IHC as a single biomarker displays the best diagnostic accuracy for prognosis stratification in OPSCC patients with a direct detection of HPV-DNA by PCR or ISH as well as p16-Ki67 dual stain as potential alternatives. Full article
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Article
Characteristics of a Novel ATP2B3 K416_F418delinsN Mutation in a Classical Aldosterone-Producing Adenoma
Cancers 2021, 13(18), 4729; https://doi.org/10.3390/cancers13184729 - 21 Sep 2021
Cited by 1 | Viewed by 1378
Abstract
In patients with primary aldosteronism (PA), the prevalence of ATP2B3 mutation is rare. The aim of this study is to report a novel ATP2B3 mutation in a PA patient. Based on our tissue bank of aldosterone-producing adenomas (APA), we identified a novel somatic [...] Read more.
In patients with primary aldosteronism (PA), the prevalence of ATP2B3 mutation is rare. The aim of this study is to report a novel ATP2B3 mutation in a PA patient. Based on our tissue bank of aldosterone-producing adenomas (APA), we identified a novel somatic ATP2B3 K416_F418delinsN mutation. The affected individual was a 53 year-old man with a 4 year history of hypertension. Computed tomography (CT) showed bilateral adrenal masses of 1.6 (left) and 0.5 cm (right) in size. An adrenal venous sampling (AVS) showed a lateralization index (LI) of 2.2 and a contralateral suppression index (CLS) of 0.12; indicating left functional predominance. After a left unilateral adrenalectomy, he achieved partial biochemical and hypertension–remission. This classical adenoma harbored a novel ATP2B3 K416_F418delinsN somatic mutation, which is a deletion from nucleotides 1248 to 1253. The translated amino acid sequence from 416 to 418, reading as lysine-phenylalanine-phenylalanine, was deleted; however, an asparagine was inserted due to merging of residual nucleotide sequences. The CYP11B2 immunohistochemistry staining demonstrated strong immunoreactivity in this classical adenoma. The ATP2B3 K416_F418delinsN mutation is a functional mutation in APA, since HAC15 cells, a human adrenal cell line, transfected with the mutant gene showed increased CYP11B2 expression and aldosterone production. Full article
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Article
Chronic Obstructive Pulmonary Disease and Its Acute Exacerbation before Colon Adenocarcinoma Treatment Are Associated with Higher Mortality: A Propensity Score-Matched, Nationwide, Population-Based Cohort Study
Cancers 2021, 13(18), 4728; https://doi.org/10.3390/cancers13184728 - 21 Sep 2021
Cited by 1 | Viewed by 1261
Abstract
Purpose: To investigate whether chronic obstructive pulmonary disease (COPD) and COPD severity (acute exacerbation of COPD (AECOPD)) affect the survival outcomes of patients with colon adenocarcinoma receiving standard treatments. Methods: From the Taiwan Cancer Registry Database, we recruited patients with clinical stage I–III [...] Read more.
Purpose: To investigate whether chronic obstructive pulmonary disease (COPD) and COPD severity (acute exacerbation of COPD (AECOPD)) affect the survival outcomes of patients with colon adenocarcinoma receiving standard treatments. Methods: From the Taiwan Cancer Registry Database, we recruited patients with clinical stage I–III colon adenocarcinoma who had received surgery. The Cox proportional hazards model was used to analyze all-cause mortality. We categorized the patients into COPD and non-COPD (Group 1 and 2) groups through propensity score matching. Results: In total, 1512 patients were eligible for further comparative analysis between non-COPD (1008 patients) and COPD (504 patients) cohorts. In the multivariate Cox regression analysis, the adjusted hazard ratio (aHR; 95% confidence interval (CI)) for all-cause mortality for Group 1 compared with Group 2 was 1.17 (1.03, 1.29). In patients with colon adenocarcinoma undergoing curative resection, the aHRs (95% CIs) for all-cause mortality in patients with hospitalization frequencies of ≥1 and ≥2 times for AECOPD within 1 year before adenocarcinoma diagnosis were 1.08 (1.03, 1.51) and 1.55 (1.15, 2.09), respectively, compared with those without AECOPD. Conclusion: In patients with colon adenocarcinoma undergoing curative resection, COPD was associated with worse survival outcomes. Being hospitalized at least once for AECOPD within 1 year before colon adenocarcinoma diagnosis was an independent risk factor for poor overall survival in these patients, and a higher number of hospitalizations for AECOPD within 1 year before diagnosis was associated with poorer survival. Our study highlights the importance of COPD management, particularly the identification of frequent exacerbators and the prevention of AECOPD before standard colon adenocarcinoma treatments are applied. Full article
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Article
Liver Transplantation for HCC in HIV-Infected Patients: Long-Term Single-Center Experience
Cancers 2021, 13(18), 4727; https://doi.org/10.3390/cancers13184727 - 21 Sep 2021
Cited by 4 | Viewed by 1182
Abstract
Background: HIV-infected patients now have long life expectation since the introduction of the highly active antiretroviral therapy (HAART). Liver diseases, especially cirrhosis and hepatocellular carcinoma (HCC), currently represent a leading cause of death in this setting of patients. Aim: To address the results [...] Read more.
Background: HIV-infected patients now have long life expectation since the introduction of the highly active antiretroviral therapy (HAART). Liver diseases, especially cirrhosis and hepatocellular carcinoma (HCC), currently represent a leading cause of death in this setting of patients. Aim: To address the results of liver transplantation (LT) for HCC in HIV-infected patients. Methods: All patients with and without HIV infection who underwent LT for HCC (n = 420) between 2001 and 2021 in our center were analyzed with the intent of comparing graft and patient survival. Cox regression analysis was used to determine prognostic survival factors and logistic regression to determine the predictor factors of post-LT recurrence. Results: Among 1010 LT, 32 were HIV-infected recipients. With an average follow-up of 62 ± 51 months, 5-year overall survival in LT recipients with and without HIV-infection was 71.6% and 69.9%, respectively (p = ns), whereas 5-year graft survival in HIV-infected and HIV-non infected was 68.3% and 68.2%, respectively (p = ns). The independent predictive factor of survival in the study group was: HCV infection (HR 1.83, p = 0.024). There were no significant differences in the pathological characteristics of HCC between the two groups. The logistic regression analysis of the study population demonstrated that microvascular invasion (HR 5.18, p< 0.001), HCC diameter (HR 1.16, p = 0.028), and number of HCC nodules (HR 1.26, p = 0.003) were predictors of recurrence post-LT. Conclusion: Our study shows that HIV patients undergoing LT for HCC have comparable results in terms of post-LT survival. Excellent results can be achieved for HIV-infected patients with HCC, as long as a strategy of close surveillance and precise treatment of the tumor is adopted while on the waiting list. Full article
(This article belongs to the Special Issue HCC and Virus: From Carcinogenesis to New Therapeutic Approaches)
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Systematic Review
Meta-Analysis of Isolated Hepatic Perfusion and Percutaneous Hepatic Perfusion as a Treatment for Uveal Melanoma Liver Metastases
Cancers 2021, 13(18), 4726; https://doi.org/10.3390/cancers13184726 - 21 Sep 2021
Cited by 5 | Viewed by 1500
Abstract
Background: Uveal melanoma is the most commonly occurring primary intraocular malignancy in adults, and patients have a high risk of developing metastatic disease, mostly in the liver. Isolated hepatic perfusion (IHP) with melphalan is a liver-directed therapy for patients with liver metastases. Percutaneous [...] Read more.
Background: Uveal melanoma is the most commonly occurring primary intraocular malignancy in adults, and patients have a high risk of developing metastatic disease, mostly in the liver. Isolated hepatic perfusion (IHP) with melphalan is a liver-directed therapy for patients with liver metastases. Percutaneous hepatic perfusion (PHP), a minimally invasive technique, is available as well. PHP benefits from the fact that the procedure can be repeated and therefore possibly offers better survival. We conducted a systematic review and meta-analysis comparing both techniques. Methods: A systematic literature search was performed using the electronic databases of Scopus, MEDLINE, Web of Science, PubMed and Cochrane CENTRAL. A total of nine articles reporting on eight studies were included in the analysis. Individual survival data were extracted from each study. Results: The median overall survival (OS) was 17.1 months for IHP and 17.3 months for PHP. The median progression-free survival (PFS) was 7.2 months for IHP and 9.6 months for PHP. The median hepatic progression-free survival was 10 months for IHP and 9.5 months for PHP. The complication rate and 30-day mortality rate were 39.1% and 5.5% for IHP and 23.8% and 1.8% for PHP. Conclusion: There was no difference in OS or PFS between IHP and PHP for patients with uveal melanoma liver metastases, but patients have significantly less of a risk for complications and mortality following PHP. Full article
(This article belongs to the Special Issue Advances in the Treatment of Metastatic Uveal Melanoma)
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Article
Prognostic Role of Preoperative Sarcopenia Evaluation of Cervical Muscles with Long-Term Outcomes of Patients with Oral Squamous Cell Carcinoma
Cancers 2021, 13(18), 4725; https://doi.org/10.3390/cancers13184725 - 21 Sep 2021
Cited by 5 | Viewed by 1396
Abstract
Accumulating evidence has shown that sarcopenia in patients with oral squamous cell carcinoma (OSCC) is at a risk of poor prognosis. There is no universal consensus on how to assess sarcopenia in patients with OSCC in daily practice. It is important to validate [...] Read more.
Accumulating evidence has shown that sarcopenia in patients with oral squamous cell carcinoma (OSCC) is at a risk of poor prognosis. There is no universal consensus on how to assess sarcopenia in patients with OSCC in daily practice. It is important to validate the usefulness of sarcopenia assessment from cervical muscles, which are frequently used in routine clinical practice in patients with OSCC. In this study, we investigated whether preoperative lumbar (L3) skeletal muscle mass and adiposity in OSCC patients were associated with cervical (C3) skeletal muscle mass and adiposity from CT measurements. We also investigated whether skeletal muscle mass and adiposity in the C3 muscles were associated with survival rates in patients with OSCC. We demonstrated that both the quality and quantity of muscle between the C3 and L3 levels were positively correlated with each other. We also demonstrated that the survival rates in patients with low sternocleidomastoid muscle mass index, high processus spinosus muscle-intramuscular adipose tissue content, and the combination of both were significantly lower than those in the controls. These results suggest that the assessment of sarcopenia from multiple neck muscles by preoperative CT measurements may be useful in predicting the prognosis of patients with OSCC. Full article
(This article belongs to the Special Issue Approaches to Improve the Prognosis of Head-and-Neck Cancer)
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Review
Neoadjuvant Treatment Strategies in Resectable Pancreatic Cancer
Cancers 2021, 13(18), 4724; https://doi.org/10.3390/cancers13184724 - 21 Sep 2021
Cited by 10 | Viewed by 1491
Abstract
Complete surgical resection is the cornerstone of curative therapy for resectable pancreatic adenocarcinoma. Upfront surgery is the gold standard, but it is rarely curative. Neoadjuvant treatment is a logical option, as it may overcome some of the limitations of adjuvant therapy and has [...] Read more.
Complete surgical resection is the cornerstone of curative therapy for resectable pancreatic adenocarcinoma. Upfront surgery is the gold standard, but it is rarely curative. Neoadjuvant treatment is a logical option, as it may overcome some of the limitations of adjuvant therapy and has already shown some encouraging results. The main concern regarding neoadjuvant therapy is the risk of disease progression during chemotherapy, meaning the opportunity to undergo the intended curative surgery is missed. We reviewed all recent literature in the following areas: major surveys, retrospective studies, meta-analyses, and randomized trials. We then selected the ongoing trials that we believe are of interest in this field and report here the results of a comprehensive review of the literature. Meta-analyses and randomized trials suggest that neoadjuvant treatment has a positive effect. However, no study to date can be considered practice changing. We considered design, endpoints, inclusion criteria and results of available randomized trials. Neoadjuvant treatment appears to be at least a feasible strategy for patients with resectable pancreatic cancer. Full article
(This article belongs to the Special Issue Combination and Innovative Therapies for Pancreatic Cancer)
Article
Prostate Health Index and Multiparametric MRI: Partners in Crime Fighting Overdiagnosis and Overtreatment in Prostate Cancer
Cancers 2021, 13(18), 4723; https://doi.org/10.3390/cancers13184723 - 21 Sep 2021
Cited by 20 | Viewed by 2184
Abstract
Widespread use of PSA as the standard tool for prostate cancer (PCa) diagnosis led to a high rate of overdiagnosis and overtreatment. In this study, we evaluated the performance of the prostate health index (PHI) and multiparametric magnetic resonance imaging (mpMRI) for the [...] Read more.
Widespread use of PSA as the standard tool for prostate cancer (PCa) diagnosis led to a high rate of overdiagnosis and overtreatment. In this study, we evaluated the performance of the prostate health index (PHI) and multiparametric magnetic resonance imaging (mpMRI) for the prediction of positive biopsy and of high-grade PCa at radical prostatectomy (RP). To this end, we prospectively enrolled 196 biopsy-naïve patients who underwent mpMRI. A subgroup of 116 subjects with biopsy-proven PCa underwent surgery. We found that PHI significantly outperformed both PI-RADS score (difference in AUC: 0.14; p < 0.001) and PHI density (difference in AUC: 0.08; p = 0.002) in the ability to predict positive biopsy with a cut-off value of 42.7 as the best threshold. Conversely, comparing the performance in the identification of clinically significant prostate cancer (csPCa) at RP, we found that PHI ≥ 61.68 and PI-RADS score ≥ 4 were able to identify csPCa (Gleason score ≥ 7 (3 + 4)) both alone and added to a base model including age, PSA, fPSA-to-tPSA ratio and prostate volume. In conclusion, PHI had a better ability than PI-RADS score to predict positive biopsy, whereas it had a comparable performance in the identification of pathological csPCa. Full article
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Review
Adoptive NK Cell Therapy: A Promising Treatment Prospect for Metastatic Melanoma
Cancers 2021, 13(18), 4722; https://doi.org/10.3390/cancers13184722 - 21 Sep 2021
Cited by 9 | Viewed by 2925
Abstract
Adoptive cell therapy (ACT) represents a promising alternative approach for patients with treatment-resistant metastatic melanoma. Lately, tumor infiltrating lymphocyte (TIL) therapy and chimeric antigen receptor (CAR)-T cell therapy have shown improved clinical outcome, compared to conventional chemotherapy or immunotherapy. Nevertheless, they are limited [...] Read more.
Adoptive cell therapy (ACT) represents a promising alternative approach for patients with treatment-resistant metastatic melanoma. Lately, tumor infiltrating lymphocyte (TIL) therapy and chimeric antigen receptor (CAR)-T cell therapy have shown improved clinical outcome, compared to conventional chemotherapy or immunotherapy. Nevertheless, they are limited by immune escape of the tumor, cytokine release syndrome, and manufacturing challenges of autologous therapies. Conversely, the clinical use of Natural Killer (NK) cells has demonstrated a favorable clinical safety profile with minimal toxicities, providing an encouraging treatment alternative. Unlike T cells, NK cells are activated, amongst other mechanisms, by the downregulation of HLA class I molecules, thereby overcoming the hurdle of tumor immune escape. However, impairment of NK cell function has been observed in melanoma patients, resulting in deteriorated natural defense. To overcome this limitation, “activated” autologous or allogeneic NK cells have been infused into melanoma patients in early clinical trials, showing encouraging clinical benefit. Furthermore, as several NK cell-based therapeutics are being developed for different cancers, an emerging variety of approaches to increase migration and infiltration of adoptively transferred NK cells towards solid tumors is under preclinical investigation. These developments point to adoptive NK cell therapy as a highly promising treatment for metastatic melanoma in the future. Full article
(This article belongs to the Section Cancer Therapy)
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Review
The Role of Extracellular HSP70 in the Function of Tumor-Associated Immune Cells
Cancers 2021, 13(18), 4721; https://doi.org/10.3390/cancers13184721 - 21 Sep 2021
Cited by 10 | Viewed by 2395
Abstract
Extracellular vesicles released by tumor cells (T-EVs) are known to contain danger-associated molecular patterns (DAMPs), which are released in response to cellular stress to alert the immune system to the dangerous cell. Part of this defense mechanism is the heat shock protein 70 [...] Read more.
Extracellular vesicles released by tumor cells (T-EVs) are known to contain danger-associated molecular patterns (DAMPs), which are released in response to cellular stress to alert the immune system to the dangerous cell. Part of this defense mechanism is the heat shock protein 70 (HSP70), and HSP70-positive T-EVs are known to trigger anti-tumor immune responses. Moreover, extracellular HSP70 acts as an immunogen that contributes to the cross-presentation of major histocompatibility complex (MHC) class I molecules. However, the release of DAMPs, including HSP70, may also induce chronic inflammation or suppress immune cell activity, promoting tumor growth. Here, we summarize the current knowledge on soluble, membrane-bound, and EV-associated HSP70 regarding their functions in regulating tumor-associated immune cells in the tumor microenvironment. The molecular mechanisms involved in the translocation of HSP70 to the plasma membrane of tumor cells and its release via exosomes or soluble proteins are summarized. Furthermore, perspectives for immunotherapies aimed to target HSP70 and its receptors for cancer treatment are discussed and presented. Full article
(This article belongs to the Special Issue Exosomes in Cancers Therapy)
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Review
The Role of Cancer-Associated Fibroblasts in Cancer Invasion and Metastasis
Cancers 2021, 13(18), 4720; https://doi.org/10.3390/cancers13184720 - 21 Sep 2021
Cited by 30 | Viewed by 2869
Abstract
Cancer-associated fibroblasts (CAFs) play a key role in cancer progression by contributing to extracellular matrix (ECM) deposition and remodeling, extensive crosstalk with cancer cells, epithelial-to-mesenchymal transition (EMT), invasion, metastasis, and therapy resistance. As metastasis is a main reason for cancer-related deaths, it is [...] Read more.
Cancer-associated fibroblasts (CAFs) play a key role in cancer progression by contributing to extracellular matrix (ECM) deposition and remodeling, extensive crosstalk with cancer cells, epithelial-to-mesenchymal transition (EMT), invasion, metastasis, and therapy resistance. As metastasis is a main reason for cancer-related deaths, it is crucial to understand the role of CAFs in this process. Colorectal cancer (CRC) is a heterogeneous disease and lethality is especially common in a subtype of CRC with high stromal infiltration. A key component of stroma is cancer-associated fibroblasts (CAFs). To provide new perspectives for research on CAFs and CAF-targeted therapeutics, especially in CRC, we discuss the mechanisms, crosstalk, and functions involved in CAF-mediated cancer invasion, metastasis, and protection. This summary can serve as a framework for future studies elucidating these roles of CAFs. Full article
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Review
How Immunotherapy Has Changed the Continuum of Care in Hepatocellular Carcinoma
Cancers 2021, 13(18), 4719; https://doi.org/10.3390/cancers13184719 - 21 Sep 2021
Cited by 5 | Viewed by 2124
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of death worldwide. The use of local treatment, such as surgical resection, liver transplant, and local ablation, has improved the survival of patients with HCC detected at an early stage. Until recently, the treatment [...] Read more.
Hepatocellular carcinoma (HCC) is one of the leading causes of death worldwide. The use of local treatment, such as surgical resection, liver transplant, and local ablation, has improved the survival of patients with HCC detected at an early stage. Until recently, the treatment of patients with metastatic disease was limited to the use of the multikinase inhibitor (MKI) sorafenib with a marginal effect on survival outcome. New target approaches, such as the oral MKI lenvatinib in first-line treatment and regorafenib, ramucirumab, and cabozantinib in later lines of therapy, have demonstrated efficacy in patients with preserved liver function (Child–Pugh class A) and good performance status. On the other hand, the implementation of immune checkpoint inhibitors directed against PD-1 (nivolumab and pembrolizumab), PD-L1 (atezolizumab), and anti-CTLA4 (ipilimumab) in the management of advanced HCC has strongly changed the continuum of care of HCC. Future research should include the evaluation of molecular biomarkers that can help patient selection and provide new insight on potential combined approaches. In this review, we provide an overview of the clinical evidence of the use of immune checkpoint inhibitors in HCC, and discuss how immunotherapy has been implemented into the continuum of HCC care. Full article
(This article belongs to the Collection Novel Therapies for Hepatocellular Carcinoma)
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Article
Reproducibility of mRNA-Based Testing of ESR1, PGR, ERBB2, and MKI67 Expression in Invasive Breast Cancer—A Europe-Wide External Quality Assessment
Cancers 2021, 13(18), 4718; https://doi.org/10.3390/cancers13184718 - 21 Sep 2021
Cited by 2 | Viewed by 1825
Abstract
Estrogen receptor (ER), progesterone receptor (PgR), Ki-67, and HER2 immunohistochemistry (IHC) together with HER2 in situ hybridization (ISH) are utilized to classify invasive breast cancer (IBC) into predictive molecular subtypes. As IHC evaluation may be hampered by analytical errors, gene expression assays could [...] Read more.
Estrogen receptor (ER), progesterone receptor (PgR), Ki-67, and HER2 immunohistochemistry (IHC) together with HER2 in situ hybridization (ISH) are utilized to classify invasive breast cancer (IBC) into predictive molecular subtypes. As IHC evaluation may be hampered by analytical errors, gene expression assays could offer a reliable alternative. In this first Europe-wide external quality assessment (EQA) study, we investigated performance of mRNA-based Xpert® Breast Cancer STRAT4 (CE-IVD) in five European laboratories. The cohort comprised ten pre-therapy IBC core biopsies diagnosed in the coordinating center (CC). STRAT4 binary (positive or negative) mRNA results of each marker (ESR1, PGR, ERBB2, MKI67) were compared with the gold standard IHC/ISH performed by the CC. Sensitivity, specificity, and accuracy of ESR1 and ERBB2 mRNA were 100% for all samples. In contrast, PGR expression was falsely negative for one case by two sites and MKI67 falsely negative for two cases (respectively by four and one sites). These cases had STRAT4 expression values close to assay cut-offs and immunohistochemically presented heterogeneous low positive PgR and heterogeneous Ki-67. Our EQA shows that STRAT4 mRNA assay may be a reproducible method to evaluate ER, PgR, HER2, and Ki-67 status. However, cases with expression values close to assay cut-offs should be carefully reviewed. Full article
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Article
Tumour-Derived Cell Lines and Their Potential for Therapy Prediction in Patients with Metastatic Colorectal Cancer
Cancers 2021, 13(18), 4717; https://doi.org/10.3390/cancers13184717 - 21 Sep 2021
Cited by 3 | Viewed by 1180
Abstract
The prognosis of metastatic colorectal cancer (CRC) remains poor. Patients and physicians are in need of individual therapies and precise response predictions. We investigated the predictive capacity of primary tumour material for treatment response of metastases. Mutational landscapes of primary tumours and corresponding [...] Read more.
The prognosis of metastatic colorectal cancer (CRC) remains poor. Patients and physicians are in need of individual therapies and precise response predictions. We investigated the predictive capacity of primary tumour material for treatment response of metastases. Mutational landscapes of primary tumours and corresponding metastases of 10 CRC patients were compared. Cell line characteristics and chemosensitivity were investigated pairwise for primary and metastatic tumours of four patients. PDX models of one patient were treated in vivo for proof of concept. Driver mutations did not differ between primaries and metastases, while the latter accumulated additional mutations. In vitro chemosensitivity testing revealed no differences for responses to 5-FU and oxaliplatin between primary and metastatic cell lines. However, irinotecan response differed significantly: the majority of metastases-derived cell lines was less sensitive to irinotecan than their matching primary counterpart. Therapy recommendations based on these findings were compared to clinical treatment response and mostly in line with the predicted outcome. Therefore, primary tumour cell models seem to be a good tool for drug response testing and conclusion drawing for later metastases. With further data from tumour-derived cell models, such predictions could improve clinical treatment decisions, both recommending likely effective therapeutic options while excluding ineffective treatments. Full article
(This article belongs to the Special Issue Patient-Derived Cancer Models)
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Review
Determinants of Homologous Recombination Deficiency in Pancreatic Cancer
Cancers 2021, 13(18), 4716; https://doi.org/10.3390/cancers13184716 - 21 Sep 2021
Cited by 5 | Viewed by 1722
Abstract
Pancreatic cancer is a treatment-resistant malignancy associated with high mortality. However, defective homologous recombination (HR), a DNA repair mechanism required for high-fidelity repair of double-strand DNA breaks, is a therapeutic vulnerability. Consistent with this, a subset of patients with pancreatic cancer show unique [...] Read more.
Pancreatic cancer is a treatment-resistant malignancy associated with high mortality. However, defective homologous recombination (HR), a DNA repair mechanism required for high-fidelity repair of double-strand DNA breaks, is a therapeutic vulnerability. Consistent with this, a subset of patients with pancreatic cancer show unique tumor responsiveness to HR-dependent DNA damage triggered by certain treatments (platinum chemotherapy and PARP inhibitors). While pathogenic mutations in HR genes are a major driver of this sensitivity, another layer of diverse tumor intrinsic and extrinsic factors regulate the HR deficiency (HRD) phenotype. Defining the mechanisms that drive HRD may guide the development of novel strategies and therapeutics to induce treatment sensitivity in non-HRD tumors. Here, we discuss the complexity underlying HRD in pancreatic cancer and highlight implications for identifying and treating this distinct subset of patients. Full article
(This article belongs to the Special Issue Prognostic and Predictive Markers in Pancreatic Cancer)
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Article
RAD50 Loss of Function Variants in the Zinc Hook Domain Associated with Higher Risk of Familial Esophageal Squamous Cell Carcinoma
Cancers 2021, 13(18), 4715; https://doi.org/10.3390/cancers13184715 - 21 Sep 2021
Viewed by 1520
Abstract
Unbiased whole-exome sequencing approaches in familial esophageal squamous cell carcinoma (ESCC) initially prioritized RAD50 as a candidate cancer predisposition gene. The combined study with 3289 Henan individuals from Northern China identified two pathogenic RAD50 protein truncation variants, p.Q672X and a recurrent p.K722fs variant [...] Read more.
Unbiased whole-exome sequencing approaches in familial esophageal squamous cell carcinoma (ESCC) initially prioritized RAD50 as a candidate cancer predisposition gene. The combined study with 3289 Henan individuals from Northern China identified two pathogenic RAD50 protein truncation variants, p.Q672X and a recurrent p.K722fs variant at the zinc hook domain significantly conferring increased familial ESCC risk. Effects of ~10-fold higher familial ESCC risk were observed, when compared to East Asians from the gnomAD database. Functional characterization suggested that the RAD50Q672X mutation contributes a dominant-negative effect in DNA repair of double-stranded breaks. Overexpression of the RAD50Q672X and RAD50L1264F missense mutation also sensitized cell death upon replication stress stimuli induced by formaldehyde treatment and the CHK1 inhibitor, AZD7762. Our study suggested the novel insight of the potential for synthetic lethal therapeutic options for RAD50Q672X and the East-Asian-specific RAD50L1264F variants and CHK1 inhibitors. Our study also suggested the association of RAD50 LOF variants in the zinc hook domain with a higher risk of familial ESCC in Chinese. Full article
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Article
Spectrum of Germline Pathogenic Variants in BRCA1/2 Genes in the Apulian Southern Italy Population: Geographic Distribution and Evidence for Targeted Genetic Testing
Cancers 2021, 13(18), 4714; https://doi.org/10.3390/cancers13184714 - 21 Sep 2021
Cited by 1 | Viewed by 1693
Abstract
BRCA1/2-associated hereditary breast and ovarian cancer is the most common form of hereditary breast and ovarian cancer and occurs in all ethnicities and racial populations. Different BRCA1/BRCA2 pathogenic variants (PVs) have been reported with a wide variety among populations. In this study, we [...] Read more.
BRCA1/2-associated hereditary breast and ovarian cancer is the most common form of hereditary breast and ovarian cancer and occurs in all ethnicities and racial populations. Different BRCA1/BRCA2 pathogenic variants (PVs) have been reported with a wide variety among populations. In this study, we retrospectively analyzed prevalence and geographic distribution of pathogenic germline BRCA1/2 variants in families from Apulia in southern Italy and evaluated the genotype–phenotype correlations. Data were collected from Oncogenetic Services present in Apulian hospitals and a shared database was built containing Apulian native probands (n = 2026) that had undergone genetic testing from 2004 to 2019. PVs were detected in 499 of 2026 (24.6%) probands and 68.5% of them (342 of 499) were in the BRCA1 gene. We found 65 different PVs in BRCA1 and 46 in BRCA2. There were 10 most recurrent PVs and their geographical distribution appears to be significantly specific for each province. We have assumed that these PVs are related to the historical and geopolitical changes that occurred in Apulia over time and/or to a “founder effect”. Broader knowledge of BRCA1/2 prevalence and recurring PVs in specific geographic areas could help establish more flexible genetic testing strategies that may enhance our ability to detect high-risk subjects. Full article
(This article belongs to the Special Issue Changing Landscape of Hereditary Breast and Ovarian Cancer)
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Article
Comparison of the Clinical Features and Outcomes of Gallbladder Neuroendocrine Carcinoma with Those of Adenocarcinoma: A Propensity Score-Matched Analysis
Cancers 2021, 13(18), 4713; https://doi.org/10.3390/cancers13184713 - 21 Sep 2021
Cited by 1 | Viewed by 1432
Abstract
Neuroendocrine neoplasms (NENs) of the gallbladder (GB) are extremely rare. We aimed to compare the clinical features, disease progression, management, and prognosis of patients with GB-NENs with those of patients with GB-adenocarcinomas (ADCs). A total of 21 patients with GB-NENs and 206 patients [...] Read more.
Neuroendocrine neoplasms (NENs) of the gallbladder (GB) are extremely rare. We aimed to compare the clinical features, disease progression, management, and prognosis of patients with GB-NENs with those of patients with GB-adenocarcinomas (ADCs). A total of 21 patients with GB-NENs and 206 patients with GB-ADCs, treated at three tertiary medical centers between January 2010 and December 2020, were enrolled. Of the 21 patients with GB-NENs, 20 were diagnosed with poorly differentiated small-cell neuroendocrine carcinomas (NECs), and 1 patient had large-cell NEC. All patients presented with advanced stages of cancer with extensive local extension and/or distant metastasis and non-specific symptoms. Tumor-node-metastasis stage IIIB and IV (A/B) tumors were found in 6 and 15 (1/14) patients, respectively. Nine patients with GB-NEC who underwent surgical resection had a significantly better progression-free survival (PFS) than those who did not undergo surgery. After a propensity score matching with a 1:1 ratio using the American Joint Committee on Cancer stage, age, sex, and operation status, 19 pairs of patients were included. Compared with stage-matched patients with GB-ADC, patients with GB-NEC had similar overall survival and PFS. However, as GB-NEC is rarely diagnosed early, further studies investigating methods for the early diagnosis and improvement in the survival of patients with GB-NEC are needed. Full article
(This article belongs to the Special Issue Neuroendocrine Carcinoma of the Gallbladder)
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Review
Tumor-Associated Macrophages in Bladder Cancer: Biological Role, Impact on Therapeutic Response and Perspectives for Immunotherapy
Cancers 2021, 13(18), 4712; https://doi.org/10.3390/cancers13184712 - 21 Sep 2021
Cited by 10 | Viewed by 2499
Abstract
Tumor-associated macrophages (TAMs) are one of the most abundant infiltrating immune cells of solid tumors. Despite their possible dual role, i.e., pro- or anti-tumoral, there is considerable evidence showing that the accumulation of TAMs promotes tumor progression rather than slowing it. Several strategies [...] Read more.
Tumor-associated macrophages (TAMs) are one of the most abundant infiltrating immune cells of solid tumors. Despite their possible dual role, i.e., pro- or anti-tumoral, there is considerable evidence showing that the accumulation of TAMs promotes tumor progression rather than slowing it. Several strategies are being developed and clinically tested to target these cells. Bladder cancer (BCa) is one of the most common cancers, and despite heavy treatments, including immune checkpoint inhibitors (ICIs), the overall patient survival for advanced BCa is still poor. TAMs are present in bladder tumors and play a significant role in BCa development. However, few investigations have analyzed the effect of targeting TAMs in BCa. In this review, we focus on the importance of TAMs in a cancerous bladder, their association with patient outcome and treatment efficiency as well as on how current BCa treatments impact these cells. We also report different strategies used in other cancer types to develop new immunotherapeutic strategies with the aim of improving BCa management through TAMs targeting. Full article
(This article belongs to the Special Issue Targeted Therapy for Bladder Cancer)
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Article
Whole-Brain Radiotherapy vs. Localized Radiotherapy after Resection of Brain Metastases in the Era of Targeted Therapy: A Retrospective Study
Cancers 2021, 13(18), 4711; https://doi.org/10.3390/cancers13184711 - 20 Sep 2021
Cited by 1 | Viewed by 1189
Abstract
Whether targeted therapy (TT) and radiotherapy impact survival after resection of brain metastases (BM) is unknown. The purpose of this study was to analyze the factors affecting overall survival (OS), local control (LC), distant control (DC), and leptomeningeal metastases (LMM) in patients who [...] Read more.
Whether targeted therapy (TT) and radiotherapy impact survival after resection of brain metastases (BM) is unknown. The purpose of this study was to analyze the factors affecting overall survival (OS), local control (LC), distant control (DC), and leptomeningeal metastases (LMM) in patients who had undergone resection of BM. We retrospectively analyzed 124 consecutive patients who had undergone resection of BM between 2004 and 2020. Patient information about age, sex, Karnofsky Performance Scale (KPS), origin of cancer, synchronicity, tumor size, status of primary cancer, use of TT, extent of resection, and postoperative radiotherapy was collected. Radiation therapy was categorized into whole-brain radiotherapy (WBRT), localized radiotherapy (local brain radiotherapy or stereotactic radiosurgery (LBRT/SRS)), and no radiation. We identified factors that affect OS, LC, DC, and LMM. In multivariable analysis, significant factors for OS were higher KPS score (≥90) (HR 0.53, p = 0.011), use of TT (HR 0.43, p = 0.001), controlled primary disease (HR 0.63, p = 0.047), and single BM (HR 0.55, p = 0.016). Significant factors for LC were gross total resection (HR 0.29, p = 0.014) and origin of cancer (p = 0.041). Both WBRT and LBRT/SRS showed superior LC than no radiation (HR 0.32, p = 0.034 and HR 0.38, p = 0.018, respectively). Significant factors for DC were use of TT (HR 0.54, p = 0.022) and single BM (HR 0.47, p = 0.004). Reduced incidence of LMM was associated with use of TT (HR 0.42, p = 0.038), synchronicity (HR 0.25, p = 0.028), and controlled primary cancer (HR 0.44, p = 0.047). TT was associated with prolonged OS, improved DC, and reduced LMM in resected BM patients. WBRT and LBRT/SRS showed similar benefits on LC. Considering the extended survival of cancer patients and the long-term effect of WBRT on cognitive function, LBRT/SRS appears to be a good option after resection of BM. Full article
(This article belongs to the Section Cancer Therapy)
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Article
Virtual Monoenergetic Images of Dual-Energy CT—Impact on Repeatability, Reproducibility, and Classification in Radiomics
Cancers 2021, 13(18), 4710; https://doi.org/10.3390/cancers13184710 - 20 Sep 2021
Cited by 4 | Viewed by 1706
Abstract
The purpose of this study was to (i) evaluate the test–retest repeatability and reproducibility of radiomic features in virtual monoenergetic images (VMI) from dual-energy CT (DECT) depending on VMI energy (40, 50, 75, 120, 190 keV), radiation dose (5 and 15 mGy), and [...] Read more.
The purpose of this study was to (i) evaluate the test–retest repeatability and reproducibility of radiomic features in virtual monoenergetic images (VMI) from dual-energy CT (DECT) depending on VMI energy (40, 50, 75, 120, 190 keV), radiation dose (5 and 15 mGy), and DECT approach (dual-source and split-filter DECT) in a phantom (ex vivo), and (ii) to assess the impact of VMI energy and feature repeatability on machine-learning-based classification in vivo in 72 patients with 72 hypodense liver lesions. Feature repeatability and reproducibility were determined by concordance–correlation–coefficient (CCC) and dynamic range (DR) ≥0.9. Test–retest repeatability was high within the same VMI energies and scan conditions (percentage of repeatable features ranging from 74% for SFDE mode at 40 keV and 15 mGy to 86% for DSDE at 190 keV and 15 mGy), while reproducibility varied substantially across different VMI energies and DECTs (percentage of reproducible features ranging from 32.8% for SFDE at 5 mGy comparing 40 with 190 keV to 99.2% for DSDE at 15 mGy comparing 40 with 50 keV). No major differences were observed between the two radiation doses (<10%) in all pair-wise comparisons. In vivo, machine learning classification using penalized regression and random forests resulted in the best discrimination of hemangiomas and metastases at low-energy VMI (40 keV), and for cysts at high-energy VMI (120 keV). Feature selection based on feature repeatability did not improve classification performance. Our results demonstrate the high repeatability of radiomics features when keeping scan and reconstruction conditions constant. Reproducibility diminished when using different VMI energies or DECT approaches. The choice of optimal VMI energy improved lesion classification in vivo and should hence be adapted to the specific task. Full article
(This article belongs to the Collection Advances in Diagnostic and Interventional Radiology in Oncology)
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Article
Feasibility and Short-Term Outcomes of Three-Dimensional Hand-Sewn Esophago-Jejunal Anastomosis in Completely Laparoscopic Total Gastrectomy for Cancer
Cancers 2021, 13(18), 4709; https://doi.org/10.3390/cancers13184709 - 20 Sep 2021
Cited by 1 | Viewed by 1305
Abstract
Laparoscopic total gastrectomy is on the rise. One of the most technically demanding steps of the approach is the construction of esophago-jejunal anastomosis. Several laparoscopic anastomotic techniques have been described, like linear stapler side-to-side or circular stapler end-to-side anastomosis; limited data exist regarding [...] Read more.
Laparoscopic total gastrectomy is on the rise. One of the most technically demanding steps of the approach is the construction of esophago-jejunal anastomosis. Several laparoscopic anastomotic techniques have been described, like linear stapler side-to-side or circular stapler end-to-side anastomosis; limited data exist regarding hand-sewn esophago-jejunal anastomosis. The study took place between January 2018 and June 2021. Patients enrolled in this study were adults with proximal gastric or esophago-gastric junction Siewert type III tumors that underwent 3D-assisted laparoscopic total gastrectomy. A hand-sewn esophago-jejunal anastomosis was performed in all cases laparoscopically. Forty consecutive cases were performed during the study period. Median anastomotic suturing time was 55 min, with intra-operative methylene blue leak test being negative in all cases. Median operating time was 240 min, and there were no conversions to open. The anastomotic leak rate and postoperative stricture rate were zero. The 30- and 90-day mortality rates were zero. Laparoscopic manual esophago-jejunal anastomosis utilizing a 3D platform in total gastrectomy for cancer can be performed with excellent outcomes regarding anastomotic leak and stricture rate. This anastomotic approach, although technically challenging, is safe and reproducible, with prominent results that can be disseminated in the surgical community. Full article
(This article belongs to the Special Issue Treatment of Gastric Cancer)
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Article
Effect of Vitamin D Supplements on Relapse of Digestive Tract Cancer with Tumor Stromal Immune Response: A Secondary Analysis of the AMATERASU Randomized Clinical Trial
Cancers 2021, 13(18), 4708; https://doi.org/10.3390/cancers13184708 - 20 Sep 2021
Viewed by 1343
Abstract
The aim was to examine whether vitamin D supplementation (2000 IU/day) reduces the risk of relapse in a subgroup of patients with digestive tract cancer, showing a sufficient immune response in tumor stroma by conducting secondary subgroup analyses of the AMATERASU randomized, double-blind, [...] Read more.
The aim was to examine whether vitamin D supplementation (2000 IU/day) reduces the risk of relapse in a subgroup of patients with digestive tract cancer, showing a sufficient immune response in tumor stroma by conducting secondary subgroup analyses of the AMATERASU randomized, double-blind, placebo-controlled trial (UMIN000001977). A total of 372 patients were divided into two subgroups stratified by the median density of immune cells infiltrating in tumor stroma into higher and lower halves. In the higher-half subgroup of CD56+ cells, the relapse ratio was significantly lower in the vitamin D group (7.4%) than in the placebo group (20.5%) (subdistribution hazard ratio (SHR), 0.35; 95% confidence interval (CI), 0.15–0.82), but it was equivalent (25.2% vs. 22.7%) in the lower-half subgroup of CD56+ cells (SHR, 1.21; 95% CI, 0.68–2.19) with a significant interaction (Pinteraction = 0.02). Although there were no significant differences, the risk of relapse was lower in the vitamin D group than in the placebo group in the higher half of CD45RO+ memory T cells (8.9% vs. 19.2%), and of CD8+ cytotoxic T cells (11.3% vs. 22.5%). In patients with digestive tract cancer, vitamin D supplementation was hypothesized to reduce the risk of relapse in the subgroup of patients who already have an adequate infiltration of immune cells in their tumor stroma. Full article
(This article belongs to the Special Issue Targeting the Innate Immune Cells in Cancers)
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Article
The Value of SSTR2 Receptor-Targeted PET/CT in Proton Irradiation of Grade I Meningioma
Cancers 2021, 13(18), 4707; https://doi.org/10.3390/cancers13184707 - 20 Sep 2021
Cited by 3 | Viewed by 1241
Abstract
Grade I meningioma is the most common intracranial tumor in adults. The standard imaging for its radiation treatment planning is MRI, and [68Ga]1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-conjugated PET/CT can further improve delineation. We investigated the impact of PET/CT on interobserver variability in identifying [...] Read more.
Grade I meningioma is the most common intracranial tumor in adults. The standard imaging for its radiation treatment planning is MRI, and [68Ga]1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-conjugated PET/CT can further improve delineation. We investigated the impact of PET/CT on interobserver variability in identifying the tumor in 30 anonymized patients. Four radiation oncologists independently contoured residual tumor volume, first using only MRI and subsequently with the addition of PET/CT. Conformity indices (CIs) were calculated between common volumes, observer pairs and compared to the volumes previously used. Overall, 29/30 tumors (96.6%) showed [68Ga]Ga-DOTA avidity. With help of PET/CT, the participants identified six cases with new lesions not recognized in MRI, including two where new findings would critically alter the target volume used for radiation. The PET/CT-aided series demonstrated superior conformity, as compared to MRI-only between observer pairs (median CI = 0.58 vs. 0.49; p = 0.002), common volumes (CI = 0.34; vs. 0.29; p = 0.002) and matched better the reference volumes actually used for patient treatment (CI = 0.55 vs. 0.39; p = 0.008). Cis in the PET/CT-aided series were lower for meningiomas outside of the skull base (0.2 vs. 0.44; p = 0.03). We conclude that SSTR2 receptor-targeted PET/CT is a valuable tool for planning particle therapy of incompletely resected meningioma. It serves both as a workup procedure and an aid for delineation process that reduces the likelihood of marginal misses. Full article
(This article belongs to the Special Issue Neuroradiology in Cancer)
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Article
Carfilzomib, Lenalidomide, and Dexamethasone Followed by Salvage Autologous Stem Cell Transplant with or without Maintenance for Relapsed or Refractory Multiple Myeloma
Cancers 2021, 13(18), 4706; https://doi.org/10.3390/cancers13184706 - 20 Sep 2021
Cited by 2 | Viewed by 1474
Abstract
Salvage high-dose chemotherapy and autologous stem cell transplantation (HDCT/ASCT) is a treatment option for relapsed and/or refractory multiple myeloma (RRMM). No data are available on salvage HDCT/ASCT following re-induction treatment with state-of-the-art triplet regimens. We retrospectively report on 44 patients receiving salvage HDCT/ASCT [...] Read more.
Salvage high-dose chemotherapy and autologous stem cell transplantation (HDCT/ASCT) is a treatment option for relapsed and/or refractory multiple myeloma (RRMM). No data are available on salvage HDCT/ASCT following re-induction treatment with state-of-the-art triplet regimens. We retrospectively report on 44 patients receiving salvage HDCT/ASCT following re-induction with carfilzomib/lenalidomide/dexamethasone (KRd). All patients received frontline HDCT/ASCT with median time to progression (TTP1) of 2.9 (1.2–13.5) years, enabling paired comparison of frontline and salvage HDCT/ASCT. After re-induction and before salvage transplant, 25/44 patients (57%) attained ≥ very good partial response (VGPR), which increased to 34/44 (77%) at best response after salvage HDCT/ASCT. Median progression-free survival (PFS) was 23.3 months from salvage HDCT/ASCT. Patients with ≥ VGPR at the time of salvage HDCT/ASCT and those receiving maintenance treatment post salvage HDCT/ASCT had significantly superior PFS (hazard ratio (HR) 0.19, p = 0.001 and HR 0.20, p = 0.009). In patients achieving at least an equal depth of response before salvage HDCT/ASCT as before frontline HDCT/ASCT, PFS after salvage HDCT/ASCT was comparable to the frontline situation (p = 0.3). This is the first report of state-of-the-art triplet re-induction and salvage HDCT/ASCT for RRMM after frontline transplantation. Deep remissions achieved with KRd translate into prolonged PFS following salvage HDCT/ASCT and are enhanced by maintenance treatment. Full article
(This article belongs to the Special Issue Autologous and Allogeneic Stem Cell Transplant in Cancer Therapy)
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Review
Current Landscape of Non-Small Cell Lung Cancer: Epidemiology, Histological Classification, Targeted Therapies, and Immunotherapy
Cancers 2021, 13(18), 4705; https://doi.org/10.3390/cancers13184705 - 20 Sep 2021
Cited by 32 | Viewed by 5956
Abstract
Non-small cell lung cancer (NSCLC) is a subtype of the most frequently diagnosed cancer in the world. Its epidemiology depends not only on tobacco exposition but also air quality. While the global trends in NSCLC incidence have started to decline, we can observe [...] Read more.
Non-small cell lung cancer (NSCLC) is a subtype of the most frequently diagnosed cancer in the world. Its epidemiology depends not only on tobacco exposition but also air quality. While the global trends in NSCLC incidence have started to decline, we can observe region-dependent differences related to the education and the economic level of the patients. Due to an increasing understanding of NSCLC biology, new diagnostic and therapeutic strategies have been developed, such as the reorganization of histopathological classification or tumor genotyping. Precision medicine is focused on the recognition of a genetic mutation in lung cancer cells called “driver mutation” to provide a variety of specific inhibitors of improperly functioning proteins. A rapidly growing group of approved drugs for targeted therapy in NSCLC currently allows the following mutated proteins to be treated: EGFR family (ERBB-1, ERBB-2), ALK, ROS1, MET, RET, NTRK, and RAF. Nevertheless, one of the most frequent NSCLC molecular sub-types remains without successful treatment: the K-Ras protein. In this review, we discuss the current NSCLC landscape treatment focusing on targeted therapy and immunotherapy, including first- and second-line monotherapies, immune checkpoint inhibitors with chemotherapy treatment, and approved predictive biomarkers. Full article
(This article belongs to the Special Issue Advances in Lung Cancer Therapy)
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Review
Chimeric Antigen Receptor T cell Therapy and the Immunosuppressive Tumor Microenvironment in Pediatric Sarcoma
Cancers 2021, 13(18), 4704; https://doi.org/10.3390/cancers13184704 - 20 Sep 2021
Cited by 4 | Viewed by 2483
Abstract
Sarcomas are a diverse group of bone and soft tissue tumors that account for over 10% of childhood cancers. Outcomes are particularly poor for children with refractory, relapsed, or metastatic disease. Chimeric antigen receptor T (CAR T) cells are an exciting form of [...] Read more.
Sarcomas are a diverse group of bone and soft tissue tumors that account for over 10% of childhood cancers. Outcomes are particularly poor for children with refractory, relapsed, or metastatic disease. Chimeric antigen receptor T (CAR T) cells are an exciting form of adoptive cell therapy that potentially offers new hope for these children. In early trials, promising outcomes have been achieved in some pediatric patients with sarcoma. However, many children do not derive benefit despite significant expression of the targeted tumor antigen. The success of CAR T cell therapy in sarcomas and other solid tumors is limited by the immunosuppressive tumor microenvironment (TME). In this review, we provide an update of the CAR T cell therapies that are currently being tested in pediatric sarcoma clinical trials, including those targeting tumors that express HER2, NY-ESO, GD2, EGFR, GPC3, B7-H3, and MAGE-A4. We also outline promising new CAR T cells that are in pre-clinical development. Finally, we discuss strategies that are being used to overcome tumor-mediated immunosuppression in solid tumors; these strategies have the potential to improve clinical outcomes of CAR T cell therapy for children with sarcoma. Full article
(This article belongs to the Special Issue Targeted Therapies for Pediatric Solid Tumors)
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