Cancers, Volume 14, Issue 16 (August-2 2022) – 221 articles

Cancer guidelines are ideally based on high levels of evidence (LOE). We aim to evaluate the LOE supporting recommendations in United States (US) guidelines on pancreatic adenocarcinoma (PDAC) treatment and its evolution over time. We searched for current guidelines from the American Society of Clinical Oncology (ASCO) and National Comprehensive Cancer Network (NCCN) and their prior publicly available versions on societies’ websites and/or MEDLINE. We recorded the LOE and class of recommendation (opinion of the writing panel) for each recommendation. We defined high LOE as: a “high” quality of evidence from the GRADE methodology (ASCO) and “Category 1” (NCCN). Our main outcome was the proportion of PDAC recommendations supported by high LOE. Proportions of high LOE recommendations were 5% (2/40) and 8% (12/153) in current ASCO and NCCN guidelines, respectively. Less than 10% of class I recommendations were based on high LOE. For NCCN guidelines, the proportion of high LOE recommendations did not improve over time and only three recommendations increased their LOE. We identified a small percentage of high LOE recommendations for PDAC treatment in US guidelines. However, guidelines authors can only deal with the available evidence. The current framework of evidence should be challenged with consideration of observational evidence. Full article

The objective of our paper was to answer the following question: how do patients with HPV-related oropharyngeal squamous cell carcinoma OPSCC (Population) enrolled in clinical trials (Intervention), compared with national database reports of HPV-associated OPSCC patients (Comparison), present demographically (Outcome)? We conducted a systematic review and meta-analysis of studies pertaining to clinical trials of HPV-associated OPSCC and participant demographics in the United States. PubMed, Scopus, CINAHL, and the Cochrane Library were searched from inception to 2 February 2022. Studies of overlapping participant cohorts and/or studies conducted outside of the United States were excluded. Primary outcomes were patient age, sex, and race. Secondary outcomes were smoking history, alcohol history, history of prior cancer, and tumor origin site. Meta-analysis of single means (mean, N for each study, and standard deviation) for age, pack years, and smoking years was performed. Pooled prevalence rates of gender, race, alcohol history, tobacco history, and tumor origin site were expressed as a percentage, with 95% confidence intervals. Meta-analysis found patients to be predominately non-smoking white males, with tumors originating from the tonsil. Our findings reflected the demographics reported by the National Cancer Database (NCDB) for HPV-associated OPSCC. This indicates that HPV-associated OPSCC patients are appropriately represented in clinical trial demographics. Full article

Background: Natural killer (NK) cells play a key role in immune surveillance and response to tumors, their function regulated by NK cell receptors and their ligands. The DNAM-1 activating receptor recognizes the CD155 molecule expressed in several tumor cells, such as hepatocellular carcinoma (HCC). This study aims to investigate the role of the DNAM-1/CD155 axis in mediating the NK cell response in patients with HCC. Methods: Soluble CD155 was measured by ELISA. CD155 expression was sought in HCC cells by immunohistochemistry, qPCR, and flow cytometry. DNAM-1 modulation in NK cells was evaluated in transwell experiments and by a siRNA-mediated knockdown. NK cell functions were examined by direct DNAM-1 triggering. Results: sCD155 was increased in sera from HCC patients and correlated with the parameters of an advanced disease. The expression of CD155 in HCC showed a positive trend toward better overall survival. DNAM-1 downmodulation was induced by CD155-expressing HCC cells, in agreement with lower DNAM-1 expressions in tumor-infiltrating NK (NK-TIL) cells. DNAM-1-mediated cytotoxicity was defective both in circulating NK cells and in NK-TIL of HCC patients. Conclusions: We provide evidence of alterations in the DNAM-1/CD155 axis in HCC, suggesting a possible mechanism of tumor resistance to innate immune surveillance. Full article

With 400,000 diagnosed and 180,000 deaths in 2020, renal cell carcinoma (RCC) accounts for 2.4% of all cancer diagnoses worldwide. The highest disease burden developed countries, primarily in Europe and North America. Incidence is projected to increase in the future as more countries shift to Western lifestyles. Risk factors for RCC include fixed factors such as gender, age, and hereditary diseases, as well as intervening factors such as smoking, obesity, hypertension, diabetes, diet and alcohol, and occupational exposure. Intervening factors in primary prevention, understanding of congenital risk factors and the establishment of early diagnostic tools are important for RCC. This review will discuss RCC epidemiology, risk factors, and biomarkers involved in reducing incidence and improving survival. Full article

Background and Objectives: Cannabinoids are currently used in cancer patients primarily for their pain-relieving and antiemetic properties. The aim of our review was to synthesize all available data of studies evaluating the therapeutic efficacy of cannabis in combination with oncological treatments in cancer patients and to explore ongoing studies with different goals and medical areas registered in the field of oncology worldwide. Materials and Methods: This study was performed in accordance with the PRISMA guidelines. A search using MEDLINE/PubMed database was performed between 1 January 2006 and 1 March 2022. Search terms included the following: cannabidiol, cannabis, CBD, dronabinol, endocannabinoids, medical marijuana, nabiximols, nabilone, THC, and cancer. All studies that examined the efficacy of cannabis administered during oncological treatments, regardless of cancer localization, subtype, and sample size, were considered eligible. Results: In three studies, cannabis was administered to patients with glioblastoma, and in two other studies, cannabis was used in combination with immunotherapy in various cancer subgroups. The results of the clinical trials in cancer patients are not sufficient to draw conclusions at this time. Interestingly, several other studies addressing the systemic effects of cannabinoids in cancer patients are currently listed in the U.S. National Library of Medicine’s registry on the ClinicalTrials.gov website. However, only one of the registered studies examined the efficacy of cannabinoids as a potential option for systemic cancer treatment. Conclusions: Although cannabis is touted to the public as a cancer cure, clinical trials need to clarify which combinations of chemotherapeutic agents with cannabinoids are useful for cancer patients. Full article

Background: OV is the most lethal gynecological malignancy. M6A and lncRNAs have a great impact on OV development and patient immunotherapy response. In this paper, we decided to establish a reliable signature of mRLs. Method: The lncRNAs associated with m6A in OV were analyzed and obtained by co-expression analysis of the TCGA-OV database. Univariate, LASSO and multivariate Cox regression analyses were employed to establish the model of mRLs. K-M analysis, PCA, GSEA and nomogram based on the TCGA-OV and GEO database were conducted to prove the predictive value and independence of the model. The underlying relationship between the model and TME and cancer stemness properties were further investigated through immune feature comparison, consensus clustering analysis and pan-cancer analysis. Results: A prognostic signature comprising four mRLs, WAC-AS1, LINC00997, DNM3OS and FOXN3-AS1, was constructed and verified for OV according to the TCGA and GEO database. The expressions of the four mRLs were confirmed by qRT-PCR in clinical samples. Applying this signature, one can identify patients more effectively. The samples were divided into two clusters, and the clusters had different overall survival rates, clinical features and tumor microenvironments. Finally, pan-cancer analysis further demonstrated that the four mRLs were significantly related to immune infiltration, TME and cancer stemness properties in various cancer types. Conclusions: This study provided an accurate prognostic signature for patients with OV and elucidated the potential mechanism of the mRLs in immune modulation and treatment response, giving new insights into identifying new therapeutic targets. Full article

Tumor necrosis factor (TNF) receptor associated factor-2 (TRAF2) has been originally identified as a protein interacting with TNF receptor 2 (TNFR2) but also binds to several other receptors of the TNF receptor superfamily (TNFRSF). TRAF2, often in concert with other members of the TRAF protein family, is involved in the activation of the classical NFκB pathway and the stimulation of various mitogen-activated protein (MAP) kinase cascades by TNFRSF receptors (TNFRs), but is also required to inhibit the alternative NFκB pathway. TRAF2 has also been implicated in endoplasmic reticulum (ER) stress signaling, the regulation of autophagy, and the control of cell death programs. TRAF2 fulfills its functions by acting as a scaffold, bringing together the E3 ligase cellular inhibitor of apoptosis-1 (cIAP1) and cIAP2 with their substrates and various regulatory proteins, e.g., deubiquitinases. Furthermore, TRAF2 can act as an E3 ligase by help of its N-terminal really interesting new gene (RING) domain. The finding that TRAF2 (but also several other members of the TRAF family) interacts with the latent membrane protein 1 (LMP1) oncogene of the Epstein–Barr virus (EBV) indicated early on that TRAF2 could play a role in the oncogenesis of B-cell malignancies and EBV-associated non-keratinizing nasopharyngeal carcinoma (NPC). TRAF2 can also act as an oncogene in solid tumors, e.g., in colon cancer by promoting Wnt/β-catenin signaling. Moreover, tumor cell-expressed TRAF2 has been identified as a major factor-limiting cancer cell killing by cytotoxic T-cells after immune checkpoint blockade. However, TRAF2 can also be context-dependent as a tumor suppressor, presumably by virtue of its inhibitory effect on the alternative NFκB pathway. For example, inactivating mutations of TRAF2 have been associated with tumor development, e.g., in multiple myeloma and mantle cell lymphoma. In this review, we summarize the various TRAF2-related signaling pathways and their relevance for the oncogenic and tumor suppressive activities of TRAF2. Particularly, we discuss currently emerging concepts to target TRAF2 for therapeutic purposes. Full article

The advent of trastuzumab has significantly improved the prognosis of HER2-positive (HER2+) breast cancer patients; nevertheless, drug resistance limits its clinical benefit. Anti-HER2 active immunotherapy represents an attractive alternative strategy, but effective immunization needs to overcome the patient’s immune tolerance against the self-HER2. Phage display technology, taking advantage of phage intrinsic immunogenicity, permits one to generate effective cancer vaccines able to break immune tolerance to self-antigens. In this study, we demonstrate that both preventive and therapeutic vaccination with M13 bacteriophages, displaying the extracellular (EC) and transmembrane (TM) domains of human HER2 or its Δ16HER2 splice variant on their surface (ECTM and Δ16ECTM phages), delayed mammary tumor onset and reduced tumor growth rate and multiplicity in ∆16HER2 transgenic mice, which are tolerant to human ∆16HER2. This antitumor protection correlated with anti-HER2 antibody production. The molecular mechanisms underlying the anticancer effect of vaccine-elicited anti-HER2 antibodies were analyzed in vitro against BT-474 human breast cancer cells, sensitive or resistant to trastuzumab. Immunoglobulins (IgG) purified from immune sera reduced cell viability mainly by impairing ERK phosphorylation and reactivating retinoblastoma protein function in both trastuzumab-sensitive and -resistant BT-474 cells. In conclusion, we demonstrated that phage-based HER2 vaccines impair mammary cancer onset and progression, opening new perspectives for HER2+ breast cancer treatment. Full article

Purpose: Preoperative concurrent chemoradiotherapy (CCRT) is the standard treatment for locally advanced rectal cancer patients. However, the poor therapeutic efficacy of CCRT was found in rectal cancer patients with hyperglycemia. This study investigated how hyperglycemia affects radiochemotherapy resistance in rectal cancer. Methods and Materials: We analyzed the correlation between prognosis indexes with hypoxia-inducible factor-1 alpha (HIF-1α) in rectal cancer patients with preoperative CCRT. In vitro, we investigated the effect of different concentrated glucose of environments on the radiation tolerance of rectal cancers. Further, we analyzed the combined HIF-1α inhibitor with radiation therapy in hyperglycemic rectal cancers. Results: The prognosis indexes of euglycemic or hyperglycemic rectal cancer patients after receiving CCRT treatment were investigated. The hyperglycemic rectal cancer patients (n = 13, glycosylated hemoglobin, HbA1c > 6.5%) had poorer prognosis indexes. In addition, a positive correlation was observed between HIF-1α expression and HbA1c levels (p = 0.046). Therefore, it is very important to clarify the relationship between HIF-1α and poor response in patients with hyperglycemia receiving pre-operative CCRT. Under a high glucose environment, rectal cancer cells express higher levels of glucose transport 1 (GLUT1), O-GlcNAc transferase (OGT), and HIF-1α, suggesting that the high glucose environment might stimulate HIF-1α expression through the GLUT1-OGT-HIF-1α pathway promoting tolerance to Fluorouracil (5-FU) and radiation. In the hyperglycemic rectal cancer animal model, rectal cancer cells confirmed that radiation exposure reduces apoptosis by overexpressing HIF-1α. Combining HIF-1α inhibitors was able to reverse radioresistance in a high glucose environment. Lower HIF-1α levels increased DNA damage in tumors leading to apoptosis. Conclusions: The findings here show that hyperglycemia induces the expression of GLUT1, OGT, and HIF-1α to cause CCRT tolerance in rectal cancer and suggest that combining HIF-1α inhibitors could reverse radioresistance in a high glucose environment. HIF-1α inhibitors may be useful for development as CCRT sensitizers in patients with hyperglycemic rectal cancer. Full article

Brain tumor characterization (BTC) is the process of knowing the underlying cause of brain tumors and their characteristics through various approaches such as tumor segmentation, classification, detection, and risk analysis. The substantial brain tumor characterization includes the identification of the molecular signature of various useful genomes whose alteration causes the brain tumor. The radiomics approach uses the radiological image for disease characterization by extracting quantitative radiomics features in the artificial intelligence (AI) environment. However, when considering a higher level of disease characteristics such as genetic information and mutation status, the combined study of “radiomics and genomics” has been considered under the umbrella of “radiogenomics”. Furthermore, AI in a radiogenomics’ environment offers benefits/advantages such as the finalized outcome of personalized treatment and individualized medicine. The proposed study summarizes the brain tumor’s characterization in the prospect of an emerging field of research, i.e., radiomics and radiogenomics in an AI environment, with the help of statistical observation and risk-of-bias (RoB) analysis. The PRISMA search approach was used to find 121 relevant studies for the proposed review using IEEE, Google Scholar, PubMed, MDPI, and Scopus. Our findings indicate that both radiomics and radiogenomics have been successfully applied aggressively to several oncology applications with numerous advantages. Furthermore, under the AI paradigm, both the conventional and deep radiomics features have made an impact on the favorable outcomes of the radiogenomics approach of BTC. Furthermore, risk-of-bias (RoB) analysis offers a better understanding of the architectures with stronger benefits of AI by providing the bias involved in them. Full article

Hepatocellular carcinoma (HCC) is the most frequent primary hepatic malignancy and a leading cause of cancer-related death globally. HCC is associated with an indolent clinical presentation, resulting in frequent advanced stage diagnoses where surgical resection or transplant therapies are not an option and medical therapies are largely ineffective at improving survival. As such, there is a critical need to identify and enhance primary prevention strategies to mitigate HCC-related morbidity and mortality. Obesity is an independent risk factor for the onset and progression of HCC. Furthermore, obesity is a leading cause of nonalcoholic steatohepatitis (NASH), the fasting growing etiological factor of HCC. Herein, we review evolving clinical and mechanistic associations between obesity and hepatocarcinogenesis with an emphasis on the therapeutic efficacy of prevailing lifestyle/behavioral, medical, and surgical treatment strategies for weight reduction and NASH reversal. Full article

Synthetic lethality strategies are likely to be integrated in effective and specific cancer treatments. These strategies combine different specific targets, either in similar or cooperating pathways. Chromatin remodeling underlies, directly or indirectly, all processes of tumor biology. In this context, the combined targeting of proteins associated with different aspects of chromatin remodeling can be exploited to find new alternative targets or to improve treatment for specific individual tumors or patients. There are two major types of proteins, epigenetic modifiers of histones and nuclear or chromatin kinases, all of which are druggable targets. Among epigenetic enzymes, there are four major families: histones acetylases, deacetylases, methylases and demethylases. All these enzymes are druggable. Among chromatin kinases are those associated with DNA damage responses, such as Aurora A/B, Haspin, ATM, ATR, DNA-PK and VRK1—a nucleosomal histone kinase. All these proteins converge on the dynamic regulation chromatin organization, and its functions condition the tumor cell viability. Therefore, the combined targeting of these epigenetic enzymes, in synthetic lethality strategies, can sensitize tumor cells to toxic DNA-damage-based treatments, reducing their toxicity and the selective pressure for tumor resistance and increasing their immunogenicity, which will lead to an improvement in disease-free survival and quality of life. Full article

Background: Accurate removal of basal cell carcinoma (BCC) is challenging due to the subtle contrast between cancerous and normal skin. A method aiding with preoperative delineation of BCC margins would be valuable. The aim of this study was to implement and clinically validate a novel handheld optical polarization imaging (OPI) device for rapid, noninvasive, in vivo assessment of skin cancer margins. Methods: The handheld imager was designed, built, and tested. For clinical validation, 10 subjects with biopsy-confirmed BCC were imaged. Presumable cancer margins were marked by the study surgeon. The optical images were spectrally encoded to mitigate the impact of endogenous skin chromophores. The results of OPI and of the surgeon’s preoperative visual assessment were compared to clinical intraoperative histopathology. Results: As compared to the previous prototype, the handheld imager incorporates automated image processing and has 10-times shorter acquisition times. It is twice as light and provides twice as large a field of view. Clinical validation demonstrated that margin assessments using OPI were more accurate than visual assessment by the surgeon. The images were in good correlation with histology in 9 out of 10 cases. Conclusions: Handheld OPI could improve the outcomes of skin cancer treatments without impairing clinical workflows. Full article

Cavernous sinus meningiomas (CSMs) remain a surgical challenge due to the intimate involvement of their contained nerves and blood vessels. Stereotactic radiosurgery (SRS) is a safe and effective minimally invasive alternative for the treatment of small- to medium-sized CSMs. Objective: To assess the medium- to long-term outcomes of SRS for CSMs with respect to tumour growth, prevention of further neurological deterioration and improvement of existing neurological deficits. This multicentric study included data from 15 European institutions. We performed a retrospective observational analysis of 1222 consecutive patients harbouring 1272 benign CSMs. All were treated with Gamma Knife stereotactic radiosurgery (SRS). Clinical and imaging data were retrieved from each centre and entered into a common database. All tumours with imaging follow-up of less than 24 months were excluded. Detailed results from 945 meningiomas (86%) were then analysed. Clinical neurological outcomes were available for 1042 patients (85%). Median imaging follow-up was 67 months (mean 73.4, range 24–233). Median tumour volume was 6.2 cc (+/−7), and the median marginal dose was 14 Gy (+/−3). The post-treatment tumour volume decreased in 549 (58.1%), remained stable in 336 (35.6%) and increased in only 60 lesions (6.3%), yielding a local tumour control rate of 93.7%. Only 27 (2.8%) of the 60 enlarging tumours required further treatment. Five- and ten-year actuarial progression-free survival (PFS) rates were 96.7% and 90.1%, respectively. Tumour control rates were higher for women than men (p = 0.0031), and also for solitary sporadic meningiomas (p = 0.0201). There was no statistically significant difference in outcome for imaging-defined meningiomas when compared with histologically proven WHO Grade-I meningiomas (p = 0.1212). Median clinical follow up was 61 months (mean 64, range 6–233). Permanent morbidity occurred in 5.9% of cases at last follow-up. Stereotactic radiosurgery is a safe and effective method for treating benign CSM in the medium term to long term. Full article

Sexual dysfunction is common in patients with advanced cancer, although it is frequently belittled, and thus consistently underdiagnosed and untreated. Opioid analgesics remain fundamental and are widely used in cancer pain treatment. However, they affect sexual functions primarily due to their action on the hypothalamus–pituitary–gonadal axis. Other mechanisms such as the impact on the central and peripheral nervous systems are also possible. The opioid-induced sexual dysfunction includes erectile dysfunction, lack of desire and arousal, orgasmic disorder, and lowered overall sexual satisfaction. Around half of the individuals taking opioids chronically may be affected by sexual dysfunction. The relative risk of sexual dysfunction in patients on chronic opioid therapy and opioid addicts increased two-fold in a large meta-analysis. Opioids differ in their potential to induce sexual dysfunctions. Partial agonists and short-acting opioids may likely cause sexual dysfunction to a lesser extent. Few pharmaceutical therapies proved effective: testosterone replacement therapy, PDE5 inhibitors, bupropion, trazodone, opioid antagonists, and plant-derived medicines such as Rosa damascena and ginseng. Non-pharmacological options, such as psychosexual or physical therapies, should also be considered. However, the evidence is scarce and projected primarily from non-cancer populations, including opioid addicts. Further research is necessary to explore the problem of sexuality in cancer patients and the role of opioids in inducing sexual dysfunction. Full article

Early-stage esophageal cancer is often primarily managed surgically, with the addition of radiotherapy for locally advanced disease. However, current photon-based radiotherapy regimens and surgery results in a high incidence of treatment-related cardiac and pulmonary complications due to the involvement of proximal organs at risk. In addition, the anatomic location of the esophagus raises challenges for radiotherapy due to the anatomical changes associated with diaphragmatic motion, weight loss, tumor changes, and set-up variability. These challenges propelled the interest in proton beam therapy (PBT), which theoretically offers a reduction in the radiation exposure to healthy neighboring tissues with improvements in the therapeutic ratio. Several dosimetric studies support the potential advantages of PBT for esophageal cancer treatment however, translation of these results to improved clinical outcomes remains unclear with limited clinical data, especially in large populations. Studies on the effect on quality of life are likewise lacking. Here, we review the existing and emerging role of PBT for esophageal cancer, including treatment planning, early clinical comparisons of PBT with photon-based techniques, recently concluded and ongoing clinical trials, challenges and toxicities, effects on quality of life, and global inequities in the treatment of esophageal cancer. Full article

Invasion of the mandibular bone is frequent in oral squamous cell carcinoma (OSCC), which often results in extensive ablative and reconstructive procedures for the patient. The purpose of this single-center, retrospective study was to identify and evaluate potential biomarkers and risk factors for bone invasion in OSCC. Initially, in silico gene expression analysis was performed for different HNSCC tumor T-stages to find factors associated with invasive (T4a) tumor growth. Afterwards, the protein expression of bone-metabolizing MMP-27, TNFRSF11B (Osteoprotegerin, OPG), and TNFSF11 (RANKL) was investigated via Tissue Microarrays (TMAs) for their impact on mandibular bone invasion. TMAs were assembled from the bone–tumor interface of primary OSCCs of the floor of the mouth and gingiva from 119 patients. Sixty-four carcinomas with patho-histological jaw invasion (pT4a) were compared to 55 carcinomas growing along the mandible without invasion (pT2, pT3). Tissue samples were additionally evaluated for patterns of invasion using the WPOI grading system. Statistical analysis of in silico data revealed decreased MMP-27 mRNA expression to be strongly associated with the pT4a-stage in OSCC, indicating invasive tumor growth with infiltration of adjacent anatomical structures. Our own clinico-pathological data on OSCCs presented a significant decrease of MMP-27 in tumors invading the nearby mandible (pT4a), compared to pT2 and pT3 tumors without bone invasion. Loss of MMP27 evolved as the strongest predictor of mandibular bone invasion in binary logistic regression analysis. To our knowledge, this is the first study investigating the role of MMP-27 expression in OSCC and demonstrating the importance of the loss of MMP-27 in mandibular bone invasion. Full article

Background: We evaluated the value of pre-treatment positron-emission tomography–computed tomography (PET-CT)-based radiomic features in predicting the locoregional progression-free survival (LR-PFS) of patients with inoperable or unresectable oesophageal cancer. Material and Methods: Forty-six patients were included and 230 radiomic parameters were extracted. After a principal component analysis (PCA), we identified the more robust radiomic parameters, and we used them to develop a heatmap. Finally, we correlated these radiomic features with LR-PFS. Results: The median follow-up time was 17 months. The two-year LR-PFS and PFS rates were 35.9% (95% CI: 18.9–53.3) and 21.6% (95%CI: 10.0–36.2), respectively. After the correlation analysis, we identified 55 radiomic parameters that were included in the heatmap. According to the results of the hierarchical clustering, we identified two groups of patients presenting statistically different median LR-PFSs (22.8 months vs. 9.9 months; HR = 2.64; 95% CI 0.97–7.15; p = 0.0573). We also identified two radiomic features (“F_rlm_rl_entr_per” and “F_rlm_2_5D_rl_entr”) significantly associated with LR-PFS. Patients expressing a “F_rlm_2_5D_rl_entr” of <3.3 had a better median LR- PFS (29.4 months vs. 8.2 months; p = 0.0343). Patients presenting a “F_rlm_rl_entr_per” of <4.7 had a better median LR-PFS (50.4 months vs. 9.9 months; p = 0.0132). Conclusion: We identified two radiomic signatures associated with a lower risk of locoregional relapse after CRT. Full article

Near-infrared photoimmunotherapy (NIR-PIT) is a newly developed cancer therapy that targets cancer cells using a monoclonal antibody-photon absorber conjugate (APC) that is bound to the target cell surface. Subsequent application of low levels of NIR light results in immediate cancer cell death. The anti-tumor effect of NIR-PIT in immunocompromised mice depends on immediate cancer cell death; therefore, the efficacy increases in a light-dose-dependent manner. However, NIR-PIT also induces a strong anti-tumor immune activation in immunocompetent mice that begins soon after therapy. Thus, it may be possible to reduce the light dose, which might otherwise cause local edema while maintaining therapeutic efficacy. In this study, we determined the optimal dose of NIR light in NIR-PIT based on a comparison of the therapeutic and adverse effects. Either one of two monoclonal antibodies (mAbs) against human epidermal growth factor receptor (hEGFR), Cetuximab or Panitumumab, were conjugated with a photo-absorbing chemical, IRDye700DX (IR700), and then injected in hEGFR-expressing mEERL (mEERL-hEGFR) tumor-bearing C57BL/6 immunocompetent mice or A431-GFP-luc tumor-bearing athymic immunocompromised mice. NIR light was varied between 0 to 100 J/cm² one day after administration of APC. In an immunocompromised mouse model, tumor growth was inhibited in a light-dose-dependent manner, yet extensive local edema and weight loss were observed at 100 J/cm². On the other hand, in an immunocompetent mouse model using the mEERL-hEGFR cell line, maximal tumor response was achieved at 50 J/cm², with a commensurate decrease in local edema. In this study, we show that a relatively low dose of NIR light is sufficient in an immunocompetent mouse model and avoids side effects seen with higher light doses required in immunocompetent mice. Thus, light dosing can be optimized in NIR-PIT based on the expected immune response. Full article

Background: Artificial intelligence (AI) has contributed substantially in recent years to the resolution of different biomedical problems, including cancer. However, AI tools with significant and widespread impact in oncology remain scarce. The goal of this study is to present an AI-based solution tool for cancer patients data analysis that assists clinicians in identifying the clinical factors associated with poor prognosis, relapse and survival, and to develop a prognostic model that stratifies patients by risk. Materials and Methods: We used clinical data from 5275 patients diagnosed with non-small cell lung cancer, breast cancer, and non-Hodgkin lymphoma at Hospital Universitario Puerta de Hierro-Majadahonda. Accessible clinical parameters measured with a wearable device and quality of life questionnaires data were also collected. Results: Using an AI-tool, data from 5275 cancer patients were analyzed, integrating clinical data, questionnaires data, and data collected from wearable devices. Descriptive analyses were performed in order to explore the patients’ characteristics, survival probabilities were calculated, and a prognostic model identified low and high-risk profile patients. Conclusion: Overall, the reconstruction of the population’s risk profile for the cancer-specific predictive model was achieved and proved useful in clinical practice using artificial intelligence. It has potential application in clinical settings to improve risk stratification, early detection, and surveillance management of cancer patients. Full article

Background: In spite of the frequency and clinical impact of BRCA1/2 alterations in high-grade epithelial ovarian cancer (HGEOC), real-world information based on robust data warehouse has been scarce to date. Methods: Consecutive patients with BRCA-mutated HGEOC treated between 2011 and 2016 within French comprehensive cancer centers from the Unicancer network were extracted from the ESME database. The main objective of the study was the assessment of clinicopathological and treatments parameters. Results: Out of the 8021 patients included in the ESME database, 266 patients matching the selection criteria were included. BRCA1 mutation was found in 191 (71.8%) patients, while 75 (28.2%) had a BRCA2 mutation only; 95.5% of patients received a cytoreductive surgery. All patients received a taxane/platinum-based chemotherapy (median = six cycles). Complete and partial response were obtained in 53.3% and 20.4% of the cases, respectively. Maintenance therapy was administered in 55.3% of the cases, bevacizumab being the most common agent. After a median follow up of 51.7 months, a median progression-free survival of 28.6 months (95% confidence interval (CI) [26.5; 32.7]) and an estimated 5-year median overall survival of 69.2% (95% CI [61.6; 70.3]) were reported. Notably, BRCA1- and BRCA2-mutated cases exhibited a trend towards different median progression-free survivals, with 28.0 (95% CI [24.4; 32.3]) and 33.3 months (95% CI [26.7; 46.1]), respectively (p-value = 0.053). Furthermore, five-year OS for BRCA1-mutated patients was 64.5% (95% CI [59.7; 69.2]), while it was 82.5% (95% CI [76.6; 88.5]) for BRCA2-mutated ones (p-value = 0.029). Conclusions: This study reports the largest French multicenter cohort of BRCA-mutated HGEOCs based on robust data from the ESME, exhibiting relevant real-world data regarding this specific population. Full article

Due to its overexpression on the surface of prostate cancer cells, prostate-specific membrane antigen (PSMA) is a relatively novel effective target for molecular imaging and radioligand therapy (RLT) in prostate cancer. Recent studies reported that PSMA is expressed in the neovasculature of various types of cancer and regulates tumour cell invasion as well as tumour angiogenesis. Several authors explored the role of diagnostic and therapeutic PSMA radioligands in various malignancies. In this narrative review, we describe the current status of the literature on PSMA radioligands’ application in solid tumours other than prostate cancer to explore their potential role as diagnostic or therapeutic agents, with particular regard to the relevance of PSMA radioligand uptake as neoangiogenetic biomarker. Hence, a comprehensive review of the literature was performed to find relevant articles on the applications of PSMA radioligands in non-prostate solid tumours. Data on the general, methodological and clinical aspects of all included studies were collected. Forty full-text papers were selected for final review, 8 of which explored PSMA radioligand PET/CT performances in gliomas, 3 in salivary gland malignancies, 6 in thyroid cancer, 2 in breast cancer, 16 in renal cell carcinoma and 5 in hepatocellular carcinoma. In the included studies, PSMA radioligand PET showed promising performance in patients with non-prostate solid tumours. Further studies are needed to better define its potential role in oncological patients management, especially in those undergoing antineoangiogenic therapies, and to assess the efficacy of PSMA-RLT in this clinical context. Full article

Background: Cholangiocarcinoma (CCA) is a rare malignant disease of the biliary tract with an increasing incidence and a high mortality worldwide. Systematic data on epidemiological trends, treatment strategies, and in-hospital mortality of CCA in Germany are largely missing. However, the evaluation and careful interpretation of these data could help to further improve the treatment strategies and outcome of CCA patients in the future. Methods: Standardized hospital discharge data from the German Federal Statistical Office were used to evaluate epidemiological and clinical trends as well as the in-hospital mortality of CCA in Germany between 2010 and 2019. Results: A total of 154,515 hospitalized CCA cases were included into the analyses. The number of cases significantly increased over time (p < 0.001), with intrahepatic CCA (62.5%) being the most prevalent tumor localization. Overall, in-hospital mortality was 11.4% and remained unchanged over time. In-hospital mortality was significantly associated with patients’ age and tumor localization. The presence of clinical complications such as (sub)acute liver failure, acute respiratory distress syndrome (ARDS), or acute renal failure significantly increased in-hospital mortality up to 77.6%. In-hospital mortality was significantly lower among patients treated at high annual case volume centers. Finally, treatment strategies for CCA significantly changed over time and showed decisive differences with respect to the hospitals’ annual case volume. Conclusions: Our data provide a systematic overview on hospitalized CCA patients in Germany. We identified relevant clinical and epidemiological risk factors associated with an increased in-hospital mortality that could help to further improve framework conditions for the management of CCA patients in the future. Full article

Ovarian cancer (OC) is the deadliest gynecological malignancy in developed countries and is the seventh-highest cause of death in women diagnosed with cancer worldwide. Currently, several therapies are in use against OC, including debulking surgery, chemotherapy, as well as targeted therapies. Even though the current standard-of-care therapies improve survival, a vast majority of OC patients relapse. Additionally, immunotherapies have only resulted in meager patient outcomes, potentially owing to the intricate immunosuppressive nexus within the tumor microenvironment. In this scenario, dendritic cell (DC) vaccination could serve as a potential addition to the therapeutic options available against OC. In this review, we provide an overview of current therapies in OC, focusing on immunotherapies. Next, we highlight the potential of using DC vaccines in OC by underscoring the different DC subsets and their functions in OC. Finally, we provide an overview of the advances and pitfalls of current DC vaccine strategies in OC while providing future perspectives that could improve patient outcomes. Full article

Hepatocellular carcinoma (HCC) is one of the most lethal malignancies, having a significantly poor prognosis and no sufficiently efficient treatments. Immunotherapy, especially immune checkpoint inhibitors (ICIs), has provided new therapeutic approaches for HCC patients. Nevertheless, most patients with HCC do not benefit from immunotherapy. Exosomes are biologically active lipid bilayer nano-sized vesicles ranging in size from 30 to 150 nm and can be secreted by almost any cell. In the HCC tumor microenvironment (TME), numerous cells are involved in tumor progression, and exosomes—derived from tumor cells and immune cells—exhibit unique composition profiles and act as intercellular communicators by transporting various substances. Showing the dual characteristics of tumor promotion and suppression, exosomes exert multiple functions in shaping tumor immune responses in the crosstalk between tumor cells and surrounding immune cells, mediating immunotherapy resistance by affecting the PD-1/PD-L1 axis or the anti-tumor function of immune cells in the TME. Targeting exosomes or the application of exosomes as therapies is involved in many aspects of HCC immunotherapies (e.g., ICIs, tumor vaccines, and adoptive cell therapy) and may substantially enhance their efficacy. In this review, we discuss the impact of exosomes on the HCC TME and comprehensively summarize the role of exosomes in immunotherapy resistance and therapeutic application. We also discuss the potential of exosomes as biomarkers for predicting the efficacy of immunotherapy to help clinicians in identifying HCC patients who are amenable to immunotherapies. Full article

Prostate cancer (PCa) is one of the most common cancers in men. Usually, most PCas at initial diagnosis are localized and hormone-dependent, and grow slowly. Patients with localized PCas have a nearly 100% 5-year survival rate; however, the 5-year survival rate of metastatic or progressive PCa is still dismal. N6-methyladenosine (m⁶A) is the most common post-transcriptional mRNA modification and is dynamically regulated by m⁶A regulators. A few studies have shown that the abnormal expression of m⁶A regulators is significantly associated with cancer progression and immune cell infiltration, but the roles of these regulators in PCa remain unclear. Here, we examined the expression profiles and methylation levels of 21 m⁶A regulators across the Cancer Genome Atlas (TCGA), 495 PCas by consensus clustering, and correlated the expression of m⁶A regulators with PCa progression and immune cell infiltration. Consensus clustering was applied for subtyping Pca samples into clusters based on the expression profiles of m⁶A regulators. Each subtype’s signature genes were obtained by a pairwise differential expression analysis. Featured pathways of m⁶A subtypes were predicted by Gene Ontology. The m⁶A score was developed to predict m⁶A activation. The association of the m⁶A score with patients’ survival, metastasis and immune cell infiltration was also investigated. We identified three distinct clusters in PCa based on the expression profiles of 21 m⁶A regulators by consensus clustering. The differential expression and pathway analyses on the three clusters uncovered the m⁶A regulators involved in metabolic processes and immune responses in PCa. Moreover, we developed an m⁶A score to evaluate the m⁶A regulator activation for PCa. The m⁶A score is significantly associated with Gleason scores and metastasis in PCa. The predictive capacity of the m⁶A score on PCa metastasis was also validated in another independent cohort with an area under the curve of 89.5%. Hence, our study revealed the critical role of m⁶A regulators in PCa progression and the m⁶A score is a promising predictive biomarker for PCa metastasis. Full article

Six-Transmembrane Epithelial Antigen of the Prostate 1–4 (STEAP1–4) compose a family of metalloproteinases involved in iron and copper homeostasis and other cellular processes. Thus far, five homologs are known: STEAP1, STEAP1B, STEAP2, STEAP3, and STEAP4. In prostate cancer, STEAP1, STEAP2, and STEAP4 are overexpressed, while STEAP3 expression is downregulated. Although the metalloreductase activities of STEAP1–4 are well documented, their other biological functions are not. Furthermore, the properties and expression levels of STEAP heterotrimers, homotrimers, heterodimers, and homodimers are not well understood. Nevertheless, studies over the last few decades have provided sufficient impetus to investigate STEAP1–4 as potential biomarkers and therapeutic targets for prostate cancer. In particular, STEAP1 is the target of many emerging immunotherapies. Herein, we give an overview of the structure, physiology, and pathophysiology of STEAP1–4 to provide context for past and current efforts to translate STEAP1–4 into the clinic. Full article

Prostate cancer is a serious public health concern in the United States. The primary obstacle to effective long-term management for prostate cancer patients is the eventual development of treatment resistance. Due to the uniquely chaotic nature of the neoplastic genome, it is difficult to determine the evolution of tumor composition over the course of treatment. Hence, a drug is often applied continuously past the point of effectiveness, thereby losing any potential treatment combination with that drug permanently to resistance. If a clinician is aware of the timing of resistance to a particular drug, then they may have a crucial opportunity to adjust the treatment to retain the drug’s usefulness in a potential treatment combination or strategy. In this study, we investigate new methods of predicting treatment failure due to treatment resistance using a novel mechanistic model built on an evolutionary interpretation of Droop cell quota theory. We analyze our proposed methods using patient PSA and androgen data from a clinical trial of intermittent treatment with androgen deprivation therapy. Our results produce two indicators of treatment failure. The first indicator, proposed from the evolutionary nature of the cancer population, is calculated using our mathematical model with a predictive accuracy of 87.3% (sensitivity: 96.1%, specificity: 65%). The second indicator, conjectured from the implication of the first indicator, is calculated directly from serum androgen and PSA data with a predictive accuracy of 88.7% (sensitivity: 90.2%, specificity: 85%). Our results demonstrate the potential and feasibility of using an evolutionary tumor dynamics model in combination with the appropriate data to aid in the adaptive management of prostate cancer. Full article