Cancers, Volume 16, Issue 1 (January-1 2024) – 236 articles

The blood–brain barrier (BBB) poses a significant challenge to drug delivery for brain tumors, with most chemotherapeutics having limited permeability into non-malignant brain tissue and only restricted access to primary and metastatic brain cancers. Consequently, due to the drug’s inability to effectively penetrate the BBB, outcomes following brain chemotherapy continue to be suboptimal. Several methods to open the BBB and obtain higher drug concentrations in tumors have been proposed, with the selection of the optimal method depending on the size of the targeted tumor volume, the chosen therapeutic agent, and individual patient characteristics. Herein, we aim to comprehensively describe osmotic disruption with intra-arterial drug administration, intrathecal/intraventricular administration, laser interstitial thermal therapy, convection-enhanced delivery, and ultrasound methods, including high-intensity focused and low-intensity ultrasound as well as tumor-treating fields. We explain the scientific concept behind each method, preclinical/clinical research, advantages and disadvantages, indications, and potential avenues for improvement. Given that each method has its limitations, it is unlikely that the future of BBB disruption will rely on a single method but rather on a synergistic effect of a combined approach. Disruption of the BBB with osmotic infusion or high-intensity focused ultrasound, followed by the intra-arterial delivery of drugs, is a promising approach. Real-time monitoring of drug delivery will be necessary for optimal results. Full article

We investigated transarterial radioembolization (TARE) as a palliative measure and bridging-to-transplant therapy in hepatocellular carcinoma (HCC) patients. A total of 167 patients (50 bridging, 117 palliative) with 245 TARE procedures were assessed. Fourteen patients underwent subsequent liver transplantation (LT). Patients undergoing LT exhibited significantly prolonged progression-free survival (PFS) compared to those with bridging-without-transplant (p = 0.033). No significant differences were observed between patients with bridging-without-transplant and palliative cases (p = 0.116). Median overall survival (OS) post-TARE was 16.6 months, with estimated OS rates at 6/12 months of 82.0%/60.5%, respectively. Patients who underwent LT demonstrated statistically significantly longer OS compared to those with bridging-without-transplant (p = 0.001). No marked outcome distinctions were found between bridging-without-transplant and palliative groups. The findings underscored the superiority of LT over alternative treatments. TARE served as an important component in non-LT scenarios, allowing for subsequent therapeutic options. The study reflected the highly variable and complex situations of patients with HCC, emphasizing the need for further investigations to define an optimal multimodal approach. Full article

Metastasis-associated lung adenocarcinoma transcript-1 (MALAT-1) is a long intergenic non-coding RNA (lncRNA) located on chr11q13. It is overexpressed in several cancers and controls gene expression through chromatin modification, transcriptional regulation, and post-transcriptional regulation. Importantly, MALAT-1 stimulates cell proliferation, migration, and metastasis and serves a vital role in driving the epithelial-to-mesenchymal transition (EMT), subsequently acquiring cancer stem cell-like properties and developing drug resistance. MALAT-1 modulates EMT by interacting with various intracellular signaling pathways, notably the phosphoinositide 3-kinase (PI3K)/Akt and Wnt/β-catenin pathways. It also behaves like a sponge for microRNAs, preventing their interaction with target genes and promoting EMT. In addition, we have used bioinformatics online tools to highlight the disparities in the expression of MALAT-1 between normal and cancer samples using data from The Cancer Genome Atlas (TCGA). Furthermore, the intricate interplay of MALAT-1 with several essential targets of cancer progression and metastasis renders it a good candidate for therapeutic interventions. Several innovative approaches have been exploited to target MALAT-1, such as short hairpin RNAs (shRNAs), antisense oligonucleotides (ASOs), and natural products. This review emphasizes the interplay between MALAT-1 and EMT in modulating cancer metastasis, stemness, and chemoresistance in different cancers. Full article

We analyzed whether preoperative ¹⁸F-FDG PET/CT adds to conventional primary staging in patients with presumed non-metastatic colonic cancer (CC). The prognostic role of ¹⁸F-FDG uptake in the primary tumor was evaluated after a mean follow-up of 15 years. Patients with a new diagnosis of presumed localized CC were prospectively enrolled and underwent presurgical ¹⁸F-FDG PET/CT. For each colon lesion, SUVmax, SUVpeak, TLG, and MTV were assessed and tested as prognostic factors. Forty-eight patients were included. Post-surgery pathology identified a total of 103 colon lesions, including 58 invasive adenocarcinomas, 4 in situ adenocarcinomas, 3 adenomas with high-grade dysplasia, and 38 adenomas with low-grade dysplasia. Per lesion sensitivity, specificity, positive (PPVs) and negative predictive values (NPVs) for colonic primary tumor detection were 78%, 97%, 98%, and 73% for conventional workup, and 94%, 87%, 92%, and 89% for ¹⁸F-FDG PET/CT. Only sensitivity was significantly different between ¹⁸F-FDG PET/CT and conventional workup. PET detected an additional ten pathological colonic lesions in seven patients. SUVmax, SUVpeak, and TLG showed significant differences between invasive adenocarcinomas, in situ adenocarcinomas, and high-grade dysplasia compared to low-grade dysplasia. There was a statistically significant difference between pT1-pT2 and pT3-pT4 adenocarcinomas. On patient-based analysis, sensitivity, specificity, PPV, and NPV for nodal staging were 22%, 84%, 44%, and 65% for CECT, and 33%, 90%, 67%, and 70% for ¹⁸F-FDG PET/CT, without a statistically significant difference. PET/CT also identified unknown metastatic spread and one synchronous lung cancer in four patients. Overall, ¹⁸F-FDG PETCT had an additional diagnostic value in 11 out of 48 patients (23%). ¹⁸F-FDG uptake of the primary tumor did not predict nodal or distant metastases. The difference in disease-free survival categorized by median SUVmax, SUVpeak, TLG, and MTV was not significant. Finally, preoperative ¹⁸F-FDG PET/CT is valuable in detecting potential colon lesions not visualized by conventional workups, especially in cases of incomplete colonoscopy. It effectively highlights distant metastases but exhibits limitations for N staging. Mainly due to the relatively small sample size, the quantitative analysis of ¹⁸F-FDG uptake in the primary tumor did not reveal any association with recurrence or disease-free survival, adding no significant prognostic information. Full article

Pediatric high-grade gliomas (HGG) of the cerebellum are rare, and only a few cases have been documented in detail in the literature. A major differential diagnosis for poorly differentiated tumors in the cerebellum in children is medulloblastoma. In this study, we described the histological and molecular features of a series of five pediatric high-grade gliomas of the cerebellum. They actually showed histological and immunohistochemical features that overlapped with those of medulloblastomas and achieved high scores in NanoString-based medulloblastoma diagnostic assay. Methylation profiling demonstrated these tumors were heterogeneous epigenetically, clustering to GBM_MID, DMG_K27, and GBM_RTKIII methylation classes. MYCN amplification was present in one case, and PDGFRA amplification in another two cases. Interestingly, target sequencing showed that all tumors carried TP53 mutations. Our results highlight that pediatric high-grade gliomas of the cerebellum can mimic medulloblastomas at histological and transcriptomic levels. Our report adds to the rare number of cases in the literature of cerebellar HGGs in children. We recommend the use of both methylation array and TP53 screening in the differential diagnoses of poorly differentiated embryonal-like tumors of the cerebellum. Full article

The internal organ at risk volume (IRV) concept might improve toxicity profiles in stereotactic body radiation therapy (SBRT) for non-small cell lung cancer (NSCLC). We studied (1) clinical aspects in central vs. peripheral tumors, (2) the IRV concept in central tumors, (3) organ motion, and (4) associated normal tissue complication probabilities (NTCPs). We analyzed patients who received SBRT for NSCLC (clinical aspects, n = 78; motion management, n = 35). We found lower biologically effective doses, larger planning target volume sizes, higher lung doses, and worse locoregional control for central vs. peripheral tumors. Organ motion was greater in males and tall patients (bronchial tree), whereas volume changes were lower in patients with a high body mass index (BMI) (esophagus). Applying the IRV concept (retrospectively, without new optimization), we found an absolute increase of >10% in NTCPs for the bronchial tree in three patients. This study emphasizes the need to optimize methods to balance dose escalation with toxicities in central tumors. There is evidence that organ motion/volume changes could be more pronounced in males and tall patients, and less pronounced in patients with higher BMI. Since recent studies have made efforts to further subclassify central tumors to refine treatment, the IRV concept should be considered for optimal risk assessment. Full article

Among patients with advanced NSCLC, there is a group of patients with synchronous oligometastatic disease (sOMD), defined as a limited number of metastases detected at the time of diagnosis. As cachexia and sarcopenia are linked to poor survival, incorporating this information could assist clinicians in determining whether a radical treatment should be administered. In a retrospective multicenter study, including all patients with adequately staged (FDG-PET, brain imaging) sOMD according to the EORTC definition, we aimed to assess the relationship between cachexia and/or sarcopenia and survival. Of the 439 patients that were identified between 2015 and 2021, 234 met the criteria for inclusion and were included. The median age of the cohort was 67, 52.6% were male, and the median number of metastasis was 1. Forty-six (19.7%) patients had cachexia, thirty-four (14.5%) had sarcopenia and twenty-one (9.0%) had both. With a median follow-up of 49.7 months, median PFS and OS were 8.6 and 17.3 months, respectively. Moreover, a trend toward longer PFS was found in patients without cachexia and sarcopenia compared to those with cachexia and/or sarcopenia. In multivariate analysis, cachexia and sarcopenia were not associated with an inferior survival, irrespective of receiving radical treatment. High CRP was associated with inferior survival and could be a prognostic factor, helping the decision of clinicians in selecting patients who may benefit from the addition of LRT. However, despite the homogeneous definition of oligometastatic disease and the adequate staging, our subgroups were small. Therefore, further studies are needed to better understand our hypothesis and generating findings. Full article

The nerve injury-induced protein 1 (NINJ1) and NINJ2 constitute a family of homophilic adhesion molecules and are involved in nerve regeneration. Previously, we showed that NINJ1 and p53 are mutually regulated and the NINJ1-p53 loop plays a critical role in p53-dependent tumor suppression. However, the biology of NINJ2 has not been well-explored. By using multiple in vitro cell lines and genetically engineered mouse embryo fibroblasts (MEFs), we showed that NINJ2 is induced by DNA damage in a p53-dependent manner. Moreover, we found that the loss of NINJ2 promotes p53 expression via mRNA translation and leads to growth suppression in wild-type p53-expressing MCF7 and Molt4 cells and premature senescence in MEFs in a wild-type p53-dependent manner. Interestingly, NINJ2 also regulates mutant p53 expression, and the loss of NINJ2 promotes cell growth and migration in mutant p53-expressing MIA-PaCa2 cells. Together, these data indicate that the mutual regulation between NINJ2 and p53 represents a negative feedback loop, and the NINJ2-p53 loop has opposing functions in wild-type p53-dependent growth suppression and mutant p53-dependent growth promotion. Full article

The objective of this study was to investigate IL13Ra2 expression in brainstem glioma (BSG) and its correlation with key markers, functions, and prognostic implications, evaluating its therapeutic potential. A total of 80 tumor samples from BSG patients were analyzed. Multiplex immunofluorescence was used to examine six markers—IL13Ra2, H3.3K27M, CD133, Ki67, HLA-1, and CD4—establishing relationships between IL13Ra2 and these markers. Survival analysis, employing Kaplan–Meier and Cox proportional hazard regression models, encompassed 66 patients with complete follow-up. RNA-Seq data from a previously published study involving 98 patients were analyzed using the DESeq2 library to determine differential gene expression between groups. Gene Ontology (GO) enrichment and single-sample gene set enrichment analysis (ssGSEA) via the clusterProfiler library were used to delineate the gene functions of differentially expressed genes (DEGs). Nearly all the BSG patients displayed varying IL13Ra2 expression, with 45.0% (36/80) exhibiting over a 20% increase. Elevated IL13Ra2 levels were notably observed in pontine gliomas, diffuse intrinsic pontine gliomas (DIPGs), H3F3A-mutant gliomas, and WHO IV gliomas. IL13Ra2 expression was strongly correlated with H3.3K27M mutant protein, Ki67, and CD133. Patients with IL13Ra2 expression >20% showed shorter overall survival compared to those with ≤20% IL13Ra2 expression. The Cox proportional hazard regression model identified H3F3A mutations, rather than IL13Ra2 expression, as an independent prognostic factor. Analysis of RNA-Seq data from our prior cohort confirmed IL13Ra2’s correlation with H3.3, CD133, and Ki67 levels. Widespread IL13Ra2 expression in BSG, particularly elevated in the H3F3A mutant group, was strongly correlated with H3F3A mutations, increased proliferation, and heightened tumor stemness. IL13Ra2 represents a promising therapeutic target for BSGs, potentially benefiting patients with H3K27M mutations, DIPGs, WHO Grade IV, and pontine location-specific BSGs, particularly those with H3K27M mutations. Full article

Mucosal melanoma (MM) is an uncommon melanoma subtype affecting mucosal surfaces of the head and neck, anorectal region, and vulvovaginal area. We aimed to present our experience at a tertiary-level hospital regarding MM diagnosis, management, monitoring of progression, mutations, and outcome predictors. We performed a registry-based cohort study including MM cases diagnosed from 2012 to 2022 and retrospectively characterized somatic mutations on BRAF, NRAS and c-KIT. We employed Kaplan–Meier curves, log-rank tests, and Cox regression analysis to explore prognostic factors and survival outcomes in a cohort of 35 patients, mainly women (63%) with a median age of 70 years. Predominantly, MM occurred in the vulvovaginal region (48.6%). At diagnosis, 28.6% had lymph node involvement, and 31.4% also had distant metastasis. Mutations in BRAF and c-KIT were identified in 3/35 (9%) and 2/6 patients (33%), respectively. Surgery was performed in 71.4% of patients, and most received systemic treatment (65.7%). Lower disease stage, thinner Breslow depth, and surgical resection were associated with improved overall survival. Notably, age, sex, radiotherapy, and BRAF mutant status did not affect survival. Standard management typically involves immunotherapy. Cases with BRAF or c-KIT mutations may be considered for targeted therapies. Unfortunately, MM prognosis remains unfavorable, with a less than 50% survival rate at 2 years. Full article

The incidence of human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) is rising in the West, but little is known in Asia. This study elucidated changes in the incidence and HPV-positive portion of OPSCC in Hong Kong. Data from population-based cancer registry were used to analyze the incidence of OPSCC in association with other head and neck cancers. Archived tumor tissues were tested for HPV. From 1986 to 2020, there was a marked decrease in the incidence of nasopharyngeal and laryngeal cancers, but a persistent increase in OPSCC from 36 cases in 1986 to 116 cases in 2020. The average positive rate for high-risk HPV was 36.1% (112/310) among OPSCC diagnosed in 2010–2020. The HPV-positive rate in recent years was significantly higher than earlier cases (tonsil SCC: 64.7% (55/85) in 2016–2020 vs. 40.4% (19/47) in 2010–2015, p = 0.007). Patients with HPV-positive tonsil cancers were significantly younger than those negative (mean [SD]: 58.9 [9.9] vs. 64.3 [13.3] years, p = 0.006), but no significant difference was observed between genders. A persistent increase in the incidence of oropharyngeal cancer over the last few decades was observed in Hong Kong, which can be explained by the remarkable increase in HPV-positive tonsil cancers. Full article

Cholangiocarcinoma (CCA), the second most common primary liver tumor, is associated with a dismal outcome, and useful prognostic markers are not currently available in clinical practice. SerpinB3, a serine protease inhibitor, was recently found to play a relevant role in malignant transformation in different cancers. The aim of the present study was to determine the expression of SerpinB3/4 in tissue and serum samples of patients with CCA in relation to clinical outcomes. SerpinB3/4 was assessed in the tissue microarrays (TMAs) of 123 surgically resected CCAs. ELISA assays were carried out in 188 patients with CCA to detect the free and IgM-linked forms of SerpinB3/4. Overall survival was analyzed in relation to SerpinB3/4 expression, and Cox models were used to identify the variables associated with survival. High levels of SerpinB3/4 (TMA score 2+/3+) were detected in 15 tumors (12.2%), characterized by a more advanced TNM stage (III/IV: 64.3% vs. 31.3%; p = 0.031) and lower overall patient survival, independently of CCA subclass (intrahepatic CCA: median 1.1 (0.8—Not Estimable, NE) vs. 2.4 (1.8–3.4) years; p = 0.0007; extrahepatic CCA: median 0.8 (0.2—NE) vs. 2.2 (1.5–5.4) years; p = 0.011). Vascular invasion (p = 0.027) and SerpinB3/4 scores (p = 0.0016) were independently associated with mortality in multivariate analysis. Patients who had detectable free or IgM-linked SerpinB3/4 in their serum showed poorer survival (1 vs. 2.4 years, p = 0.015, for free SerpinB3/4, and 1 vs. 2.6 years, p = 0.0026, for SerpinB3/4–IgM). In conclusion, high levels of SerpinB3/4 in tissue and serum in CCA are associated with poor outcomes after surgery, regardless of tumor subclass. Full article

The secreted protein transforming growth factor-beta (TGFβ) plays essential roles, ranging from cell growth regulation and cell differentiation in both normal and cancer cells. In melanoma, TGFβ acts as a potent tumor suppressor in melanoma by blocking cell cycle progression and inducing apoptosis. In the present study, we found TGFβ to regulate cancer stemness in melanoma through the Smad signaling pathway. We discovered that TGFβ/Smad signaling inhibits melanosphere formation in multiple melanoma cell lines and reduces expression of the CD133+ cancer stem cell subpopulation in a Smad3-dependent manner. Using preclinical models of melanoma, we further showed that preventing Smad3/4 signaling, by means of CRISPR knockouts, promoted both tumorigenesis and lung metastasis in vivo. Collectively, our results define new functions for the TGFβ/Smad signaling axis in melanoma stem-cell maintenance and open avenues for new therapeutic approaches to this disease. Full article

The benefit of aspirin on cancer survival is debated. Data from randomized clinical trials and cohort studies are discordant, although a meta-analysis shows a clear survival advantage when aspirin is added to the standard of care. However, the mechanism by which aspirin improves cancer survival is not clear. A PubMed search was carried out to identify articles reporting genes and pathways that are associated with aspirin and cancer survival. Gene ontology and pathway enrichment analysis was carried out using web-based tools. Gene–gene and protein–protein interactions were evaluated. Crosstalk between pathways was identified and plotted. Forty-one genes were identified and classified into primary genes (PTGS2 and PTGES2), genes regulating cellular proliferation, interleukin and cytokine genes, and DNA repair genes. The network analysis showed a rich gene–gene and protein–protein interaction between these genes and proteins. Pathway enrichment showed the interleukin and cellular transduction pathways as the main pathways involved in aspirin-related survival, in addition to DNA repair, autophagy, extracellular matrix, and apoptosis pathways. Crosstalk of PTGS2 with EGFR, JAK/AKT, TP53, interleukin/TNFα/NFκB, GSK3B/BRCA/PARP, CXCR/MUC1, and WNT/CTNNB pathways was identified. The results of the present study demonstrate that aspirin improves cancer survival by the interplay of 41 genes through a complex mechanism. PTGS2 is the primary target of aspirin and impacts cancer survival through six primary pathways: the interleukin pathway, extracellular matrix pathway, signal transduction pathway, apoptosis pathway, autophagy pathway, and DNA repair pathway. Full article

Background: Vulvar dermatofibrosarcoma protuberans is an extremely rare disease. Its rarity can hamper the quality of treatment; deeper knowledge is necessary to plan appropriate management. The purpose of this review is to analyse the data reported in the literature to obtain evidence regarding appropriate disease management. Methods: We made a systematic search of the literature, including the terms “dermatofibrosarcoma protuberans”, “vulva”, and “vulvar”, alone or in combination. We selected articles published in English from two electronic databases, PubMed and MEDLINE, and we analysed their reference lists to include other potentially relevant studies. Results: We selected 39 articles, with a total of 68 cases reported; they were retrospective case reports and case series. Dermatofibrosarcoma protuberans of the vulva tends towards local recurrence; an early and timely pathological diagnosis, together with an appropriate surgical approach, are of utmost importance to ensure free margins and maximise the curative potential. Conclusions: Even if this is an indolent disease and it generally shows a good prognosis, appropriate management may help in reducing the rate of local recurrences that may hamper patients’ quality of life. Management by a multidisciplinary team is highly recommended. Full article

Background: This study aims to present the feasibility of developing a synchrotron-based proton ultra-high dose rate (UHDR) pencil beam scanning (PBS) system. Methods: The RF extraction power in the synchrotron system was increased to generate 142.4 MeV pulsed proton beams for UHDR irradiation at ~100 nA beam current. The charge per spill was measured using a Faraday cup. The spill length and microscopic time structure of each spill was measured with a 2D strip transmission ion chamber. The measured UHDR beam fluence was used to derive the spot dwell time for pencil beam scanning. Absolute dose distributions at various depths and spot spacings were measured using Gafchromic films in a solid-water phantom. Results: For proton UHDR beams at 142.4 MeV, the maximum charge per spill is 4.96 ± 0.10 nC with a maximum spill length of 50 ms. This translates to an average beam current of approximately 100 nA during each spill. Using a 2 × 2 spot delivery pattern, the delivered dose per spill at 5 cm and 13.5 cm depth is 36.3 Gy (726.3 Gy/s) and 56.2 Gy (1124.0 Gy/s), respectively. Conclusions: The synchrotron-based proton therapy system has the capability to deliver pulsed proton UHDR PBS beams. The maximum deliverable dose and field size per pulse are limited by the spill length and extraction charge. Full article

Background: Polymorphous adenocarcinoma (PAC) is the second-most common malignant tumour of the minor salivary glands. Although PAC predominantly affects the palate, it can also involve the buccal mucosa. This systematic review aims to investigate the literature data about PAC. Furthermore, we report two cases of patients affected by PAC in an infrequently considered anatomical site. Methods: According to PRISMA guidelines, a systematic review search was conducted on PubMed, Scopus, and Web of Science. Observational studies conducted on patients with a histological diagnosis of PAC were selected and analysed. Furthermore, two cases of patients with PAC affecting the buccal mucosa were reported. Results: Twenty-nine studies were included, and 143 patients affected by PAC were analysed (62 males, 75 females, and 6 undefined, with a mean age of 57.4 ± 14.5 years). The palate was the most affected site (99/143, 69.2%), followed by the buccal mucosa (12/143, 8.4%). Moreover, we report two cases of patients with PAC affecting the buccal mucosa (one male and one female, with a mean age of 70.5 ± 2.5 years). Conclusions: The present study underscores the importance of considering the buccal mucosa as a possible location of minor salivary gland tumours; although it is a less-considered affliction, it is not uncommon. Full article

Diffuse intrinsic pontine glioma (DIPG) was first described by Harvey Cushing, the father of modern neurosurgery, a century ago. Since then, the classification of this tumor changed significantly, as it is now part of the broader family of diffuse midline gliomas (DMGs), a heterogeneous group of tumors of midline structures encompassing the entire rostro-caudal space, from the thalamus to the spinal cord. DMGs are characterized by various epigenetic events that lead to chromatin remodeling similarities, as two decades of studies made possible by increased tissue availability showed. This new understanding of tumor (epi)biology is now driving novel clinical trials that rely on targeted agents, with finally real hopes for a change in an otherwise unforgiving prognosis. This biological discovery is being paralleled with equally exciting work in therapeutic drug delivery. Invasive and noninvasive platforms have been central to early phase clinical trials with a promising safety track record and anecdotal benefits in outcome. Full article

Due to the impact of nodal metastasis on colon cancer prognosis, adequate regional lymph node resection and accurate pathological evaluation are required. The ratio of metastatic to examined nodes may bring an additional prognostic value to the actual staging system. This study analyzes the identification of factors influencing a high lymph node yield and its impact on survival. The lymph node ratio was determined in patients with fewer than 12 or at least 12 evaluated nodes. The study included patients after radical colon cancer resection in UICC stages II and III. For the lymph node ratio (LNR) analysis, node-positive patients were divided into four categories: i.e., LNR 1 (<0.05), LNR 2 (≥0.05; <0.2), LNR 3 (≥0.2; <0.4), and LNR 4 (≥0.4), and classified into two groups: i.e., those with <12 and ≥12 evaluated nodes. The study was conducted on 7012 patients who met the set criteria and were included in the data analysis. The mean number of examined lymph nodes was 22.08 (SD 10.64, median 20). Among the study subjects, 94.5% had 12 or more nodes evaluated. These patients were more likely to be younger, women, with a lower ASA classification, pT3 and pN2 categories. Also, they had no risk factors and frequently had a right-sided tumor. In the multivariate analysis, a younger age, ASA classification of II and III, high pT and pN categories, absence of risk factors, and right-sided location remained independent predictors for a lymph node yield ≥12. The univariate survival analysis of the entire cohort demonstrated a better five-year overall survival (OS) in patients with at least 12 lymph nodes examined (68% vs. 63%, p = 0.027). The LNR groups showed a significant association with OS, reaching from 75.5% for LNR 1 to 33.1% for LNR 4 (p < 0.001) in the ≥12 cohort, and from 74.8% for LNR2 to 49.3% for LNR4 (p = 0.007) in the <12 cohort. This influence remained significant and independent in multivariate analyses. The hazard ratios ranged from 1.016 to 2.698 for patients with less than 12 nodes, and from 1.248 to 3.615 for those with at least 12 nodes. The LNR allowed for a more precise estimation of the OS compared with the pN classification system. The metastatic lymph node ratio is an independent predictor for survival and should be included in current staging and therapeutic decision-making processes. Full article

This study pioneers the application of artificial intelligence (AI) and hyperspectral imaging (HSI) in the diagnosis of skin cancer lesions, particularly focusing on Mycosis fungoides (MF) and its differentiation from psoriasis (PsO) and atopic dermatitis (AD). By utilizing a comprehensive dataset of 1659 skin images, including cases of MF, PsO, AD, and normal skin, a novel multi-frame AI algorithm was used for computer-aided diagnosis. The automatic segmentation and classification of skin lesions were further explored using advanced techniques, such as U-Net Attention models and XGBoost algorithms, transforming images from the color space to the spectral domain. The potential of AI and HSI in dermatological diagnostics was underscored, offering a noninvasive, efficient, and accurate alternative to traditional methods. The findings are particularly crucial for early-stage invasive lesion detection in MF, showcasing the model’s robust performance in segmenting and classifying lesions and its superior predictive accuracy validated through k-fold cross-validation. The model attained its optimal performance with a k-fold cross-validation value of 7, achieving a sensitivity of 90.72%, a specificity of 96.76%, an F1-score of 90.08%, and an ROC-AUC of 0.9351. This study marks a substantial advancement in dermatological diagnostics, thereby contributing significantly to the early and precise identification of skin malignancies and inflammatory conditions. Full article

The conjugate N-adducts of thio-1,3,4-diazole and 2-thiazoline with levoglucosenone were synthesized via a stereoselective, base-catalyzed conjugate N-Michael addition to levoglucosenone at C-4. Structural assignments were established using 1H and 13C NMR analysis, and X-ray single-crystal analysis for one of the compounds. The biological properties of the novel compounds were tested on a cell model. Cytotoxicity was analyzed via colorimetric assay. Two distinct types of cell death, apoptosis and necrosis, were analyzed by determining the phosphatidylserine levels from the outer leaflet of the plasma membrane, caspase activation, and lactate dehydrogenase release. We also evaluated DNA damage using an alkaline comet assay. The level of oxidative stress was measured with a modified comet assay and an H2DCFDA probe. The thio-1,3,4-diazole adduct (FCP23) and the 2-thiazoline adduct (FCP26) exhibit similar cytotoxicity values for cancer cells (ovarian (A2780), breast (MCF-7), cervix (HeLa), colon (LoVo), and brain (MO59J and MO59K)), but their mechanism of action is drastically different. While FCP23 induces oxidative stress, DNA damage, and necrosis, FCP26 induces apoptosis through caspase activation. Full article

We described the diagnostic performance of [¹⁸F]F-FDG-PET in malignant melanoma by conducting a comprehensive systematic review and meta-analysis of the existing literature. The study was designed following PRISMA-DTA. Original articles with adequate crude data for meta-analytic calculations that evaluated [¹⁸F]F-FDG-PET and compared it with a valid reference standard were considered eligible. The pooled measurements were calculated based on the data level (patient/lesion-based). Regarding sub-groups, diagnostic performances were calculated for local, regional and distant involvement. The bivariate model was employed to calculate sensitivity and specificity. The initial search resulted in 6678 studies. Finally, 100 entered the meta-analysis, containing 82 patient-based (10,403 patients) and 32 lesion-based (6188 lesions) datasets. At patient level, overall, [¹⁸F]F-FDG-PET had pooled sensitivity and specificity of 81% (95%CI: 73–87%) and 92% (95%CI: 90–94%), respectively. To detect regional lymph node metastasis, the pooled sensitivity and specificity were 56% (95%CI: 40–72%) and 97% (95%CI: 94–99%), respectively. To detect distant metastasis, they were 88% (95%CI: 81–93%) and 94% (95%CI: 91–96%), respectively. At lesion level, [¹⁸F]F-FDG-PET had a pooled sensitivity and specificity of 70% (95%CI: 57–80%) and 94% (95%CI: 88–97%), respectively. Thus, [¹⁸F]F-FDG-PET is a valuable diagnostic modality for melanoma assessment. It was accurate in various clinical scenarios. However, despite its high specificity, it showed low sensitivity in detecting regional lymph node metastasis and could not replace lymph node biopsy. Full article

Background: The purpose of this study is to compare turbo spin echo diffusion-weighted images in radial trajectory (BLADE DWI) with multi-shot echoplanar imaging (RESOLVE DWI) for imaging the metastatic lesion in the pelvic bone to find a correlation between ADC values and standardized uptake values (SUVs) of FDG uptake in PET/CT. The study also seeks to compare the values of metastatic lesions with those of benign bone lesions, specifically red marrow hyperplasia. Methods: The retrospective IRB-approved study included patients with bone metastasis and red marrow hyperplasia in the pelvic bone who underwent 3.0 T MRI with BLADE/RESOLVE DWI sequences and F-18 FDG PET/CT within one month. BVC (best value comparator) was used in determining the nature of bone lesions. Apparent diffusion coefficient (ADC) and standardized uptake value (SUV) were measured by a radiologist and a nuclear medicine physician. MRI image quality was graded with a Likert scale regarding the visualization of the sacroiliac joint, sacral neural foramen, hamstring tendon at ischial tuberosity, and tumor border. Signal-to-noise ratio (SNR) and imaging time were compared between the two DWIs. Mean, peak, and maximum SUVs between metastatic and benign red marrow lesions were compared. SUVs and ADC values were compared. AUROC analyses and cut-off values were obtained for each parameter. Mann–Whitney U, Spearman’s rho, and Kolmogorov–Smirnov tests were applied using SPSS. Results: The final study group included 58 bone lesions (19 patients (male: female = 6:13, age 52.5 ± 9.6, forty-four (75.9%) bone metastasis, fourteen (24.1%) benign red marrow hyperplasia). ADCs from BLADE and RESOLVE were significantly higher in bone metastasis than red marrow hyperplasia. BLADE showed higher ADC values, higher anatomical scores, and higher SNR than RESOLVE DWI (p < 0.05). Imaging times were longer for BLADE than RESOLVE (6 min 3 s vs. 3 min 47 s, p < 0.05). There was a poor correlation between ADC values and SUVs (correlation coefficient from 0.04 to 0.31). The AUROC values of BLADE and RESOLVE MRI ranged from 0.892~0.995. Those of PET ranged from 0.877~0.895. The cut-off ADC values between the bone metastasis and red marrow hyperplasia were 355.0, 686.5, 531.0 for BLADE min, max, and average, respectively, and 112.5, 737.0, 273.0 for RESOLVE min, max, and average, respectively. The cut-off SUV values were 1.84, 5.01, and 3.81 for mean, peak, and max values, respectively (p < 0.05). Conclusions: Compared with RESOLVE DWI, BLADE DWI showed improved image quality of pelvic bone MRI in the aspect of anatomical depiction and SNR, higher ADC values, albeit longer imaging time. BLADE and RESOLVE could differentiate bone metastasis and red marrow hyperplasia with quantifiable cut-off values. Further study is necessary to evaluate the discrepancy between the quantifiers between PET and MRI. Full article

Our objective was to identify variations in gene expression that could help elucidate the pathways for the development of prostate cancer (PCa) in men with Benign Prostatic Hyperplasia (BPH). We included 98 men with BPH, a positive prostate MRI (Prostate Imaging Reporting and Data System; PIRADS ≥ 4), and a negative biopsy from November 2014 to January 2018. RNA sequencing (RNA-Seq) was performed on tissue cores from the MRI lesion and a geographically distant region (two regions per patient). All patients were followed for at least three years to identify who went on to develop PCa. We compared the gene expressions of those who did not develop PCa (“BPH-only”) vs. those who did (“BPH/PCa”). Then, we identified the subset of men with BPH who had the highest American Urological Association (AUA) symptom scores (“symptomatic BPH”) and compared their gene expression to the BPH/PCa group. At a median follow-up of 47.5 months, 15 men had developed PCa while 83 did not. We compared gene expressions of 14 men with symptomatic BPH (AUAss ≥ 18) vs. 15 with BPH/PCa. We found two clusters of genes, suggesting the two groups had distinctive molecular features. Differential analysis revealed genes that were upregulated in BPH-only and downregulated in BPH/PCa, and vice versa. Symptomatic BPH men had upregulation of T-cell activation markers (TCR, CD3, ZAP70, IL-2 and IFN-γ and chemokine receptors, CXCL9/10) expression. In contrast, men with BPH/PCa had upregulation of NKX3-1 and HOXB13 transcription factors associated with luminal epithelial progenitors but depleted of immune cells, suggesting a cell-autonomous role in immune evasion. Symptomatic BPH with immune-enriched landscapes may support anti-tumor immunity. RNA sequencing of benign prostate biopsy tissue showing upregulation of NKX3-1 and HOXB13 with the absence of T-cells might help in identifying men at higher risk of future PCa development, which may be useful in determining ongoing PCa screening. Full article

Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer-related deaths in the world. Patients with early-stage HCC are treated with liver-directed therapies to bridge or downstage for liver transplantation (LT). In this study, the impact of HCC care delay on HCC progression among early-stage patients was investigated. Early-stage HCC patients undergoing their first cycle of liver-directed therapy (LDT) for bridge/downstaging to LT between 04/2016 and 04/2022 were retrospectively analyzed. Baseline variables were analyzed for risk of disease progression and time to progression (TTP). HCC care delay was determined by the number of rescheduled appointments related to HCC care. The study cohort consisted of 316 patients who received first-cycle LDT. The HCC care no-show rate was associated with TTP (p = 0.004), while the overall no-show rate was not (p = 0.242). The HCC care no-show rate and HCC care delay were further expanded as no-show rates and rescheduled appointments for imaging, laboratory, and office visits, respectively. More than 60% of patients experienced HCC care delay for imaging and laboratory appointments compared to just 8% for office visits. Multivariate analysis revealed that HCC-specific no-show rates and HCC care delay for imaging (p < 0.001) were both independently associated with TTP, highlighting the importance of minimizing delays in early-stage HCC imaging surveillance to reduce disease progression risk. Full article

Purpose: The FNA-CT is useful for the diagnosis of MTC. The aim of this study was to evaluate the performance of FNA-CT in TNs coexisting with CCH. Methods: This study retrospectively reviewed the records of 11 patients with TNs submitted to thyroidectomy on the basis of elevated basal and/or stimulated serum CT values, which at histology were not confirmed to be MTC. The results obtained in this group were compared with those of a previously reported group of histologically proven MTC patients submitted to an identical presurgical evaluation. All patients, negative for known mutations in the RET proto-oncogene, were preoperatively submitted to neck ultrasound, FNA-cytology, and FNA-CT. Results: Approximately 6 of 11 patients showed increased (>36 ng/mL, as established in previous studies not involving patients with CCH) FNA-CT. All these patients showed diffuse CCH at histology in the thyroid lobe submitted to FNA; 5 of them were benign at histology, while only one was malignant (papillary thyroid carcinoma, PTC). The remaining 5 of 11 patients had low FNA-CT (<36 ng/mL), and all of them showed only focal CCH in the lobe submitted to FNA; three of them were malignant (2 PTC, 1 follicular carcinoma), while two were benign. Conclusions: Employing the currently proposed cut-off values, false-positive FNA-CT results may be observed in benign/malignant TNs with coexisting diffuse CCH. FNA-CT must therefore be cautiously used in the diagnostic approach for patients with TNs and a slightly increased basal or stimulated serum CT concentration in order to avoid unnecessary surgery. Full article

Background/Aim: Triple negative breast cancer belongs to the most aggressive breast cancer forms. Histone deacetylases (HDACs) constitute a class of enzymes that exhibit a significant role in breast cancer genesis and progression. In this study, we aimed at assessing the clinical importance of HDAC-2 in triple negative breast cancer. Materials and Methods: A total of 138 breast cancer specimens were examined on an immunohistochemical basis. A statistical analysis was performed in order to examine the association between HDAC-2 and the survival and clinicopathological features of the patients. Results: Increased HDAC-2 expression was observed in every fourth case of triple negative breast cancer with positive HDAC-2 staining, whereas only 12 out of 98 non-triple negative breast cancer samples showed high HDAC-2 expression. HDAC-2 overexpression correlated with prolonged overall survival (OS) and disease-free survival (DFS) in triple negative breast cancer. Conclusions: High HDAC-2 levels in triple negative breast cancer seem to positively influence patient survival, disease stage and recurrence. Full article

Device-assisted enteroscopy (DAE) is capable of evaluating the entire gastrointestinal tract, identifying multiple lesions. Nevertheless, DAE’s diagnostic yield is suboptimal. Convolutional neural networks (CNN) are multi-layer architecture artificial intelligence models suitable for image analysis, but there is a lack of studies about their application in DAE. Our group aimed to develop a multidevice CNN for panendoscopic detection of clinically relevant lesions during DAE. In total, 338 exams performed in two specialized centers were retrospectively evaluated, with 152 single-balloon enteroscopies (Fujifilm®, Porto, Portugal), 172 double-balloon enteroscopies (Olympus^®, Porto, Portugal) and 14 motorized spiral enteroscopies (Olympus^®, Porto, Portugal); then, 40,655 images were divided in a training dataset (90% of the images, n = 36,599) and testing dataset (10% of the images, n = 4066) used to evaluate the model. The CNN’s output was compared to an expert consensus classification. The model was evaluated by its sensitivity, specificity, positive (PPV) and negative predictive values (NPV), accuracy and area under the precision recall curve (AUC-PR). The CNN had an 88.9% sensitivity, 98.9% specificity, 95.8% PPV, 97.1% NPV, 96.8% accuracy and an AUC-PR of 0.97. Our group developed the first multidevice CNN for panendoscopic detection of clinically relevant lesions during DAE. The development of accurate deep learning models is of utmost importance for increasing the diagnostic yield of DAE-based panendoscopy. Full article

The evaluation of surveillance imaging of OSCC patients is a difficult task physicians have to face daily. Multiple patients experience a recurrence of this disease, which underlines the importance of regular patient monitoring programs. Our study analysed the value of surveillance imaging, such as computed tomography (CT) and nuclear magnetic resonance imaging (NMRI), as a patient monitoring programme and its effectiveness in achieving improvement in early recurrence detection. The study comprised 125 patients, out of which 56 (n = 56) showed radiological and 69 (n = 69) showed clinical and radiological conspicuous patterns in domestic follow-ups, respectively. The use of CT and NMRI showed a significant dependence on the histological result (p = 0.03). However, the different groups showed no significant dependence on the histological result (p = 0.96). The distribution of the histological biopsies, which were taken due to radiological changes, were prone to wrong positive diagnoses (false positives) in 71 percent. To conclude, imaging modalities should be chosen for each patient individually to reduce false positives, improve the early detection of recurrence, and increase the cure rate. Full article