Cancers, Volume 16, Issue 6 (March-2 2024) – 165 articles

microRNAs (miRs) function in cancer progression as post-transcriptional regulators. We previously reported that endogenous circular RNAs (circRNAs) function as efficient miR sponges and could act as novel gene regulators in oral squamous cell carcinoma (OSCC). In this study, we carried out cellular and luciferase reporter assays to examine competitive inhibition of miR-1269a, which is upregulated expression in several cancers, by circRNA-1269a, a synthetic circRNA that contains miR-1269a binding sequences. We also used data-independent acquisition (DIA) proteomics and in silico analyses to determine how circRNA-1269a treatment affects molecules downstream of miR-1269a. First, we confirmed the circularization of the linear miR-1269a binding site sequence using RT-PCR with divergent/convergent primers and direct sequencing of the head-to-tail circRNA junction point. In luciferase reporter and cellular functional assays, circRNA-1269a significantly reduced miR-1269a function, leading to a significant decrease in cell proliferation and migration. DIA proteomics and gene set enrichment analysis of OSCC cells treated with circRNA-1269a indicated high differential expression for 284 proteins that were mainly enriched in apoptosis pathways. In particular, phospholipase C gamma 2 (PLCG2), which is related to OSCC clinical stage and overall survival, was affected by the circRNA-1269a/miR-1269a axis. Taken together, synthetic circRNA-1269a inhibits tumor progression via miR-1269a and its downstream targets, indicating that artificial circRNAs could represent an effective OSCC therapeutic. Full article

Objective: The present study aimed to assess long-term follow-up outcomes in women with in situ/microinvasive adenocarcinoma (AC) of the uterine cervix treated conservatively. Methods: Retrospective multi-institutional study including women with early glandular lesions and 5-year follow-up undergoing fertility-sparing treatment. Independent variables associated with recurrence were evaluated. Logistic regression analysis and Kaplan–Meier survival analysis with Logrank test were performed. Results: Of 269 women diagnosed with in situ/microinvasive AC, 127 participants underwent conservative treatment. During follow-up, recurrences were found in nine women (7.1%). The only factor associated with recurrence during follow-up was positive high-risk Human Papillomavirus (hr-HPV) testing (odds ratio 6.21, confidence interval 1.47–26.08, p = 0.012). HPV positivity in follow-up showed a recurrence rate of 21.7% against 3.8% in patients who were HPV-negative (p = 0.002, Logrank test). Among women with negative high-risk HPV tests in follow-up, recurrences occurred in 20.0% of non-usual-type histology vs. 2.1% of usual-type cases (p = 0.005). Conclusion: HPV testing in follow-up is of pivotal importance in women with early glandular lesions undergoing conservative treatment, given its recurrence predictive value. However, women who are high-risk HPV-negative in follow-up with non-usual-type histopathology may represent a sub-population at increased risk of recurrences. Further studies should confirm these findings. Full article

Naltrexone (NTX) is a non-selective antagonist of opioid receptors, primarily used in the therapy of opioid and alcohol dependence. Low-dose naltrexone (LDN) exhibits antagonistic action against the opioid growth factor receptor (OGFr), whose signaling is associated with the survival, proliferation, and invasion of cancer cells. The mechanism of action of LDN depends on the dose and duration of the OGFr blockade, leading to a compensatory increase in the synthesis of the opioid growth factor (OGF), which has an inhibitory effect on carcinogenesis. Numerous studies on in vitro and in vivo models provide evidence of LDN’s positive impact on inhibiting the OGF–OGFr axis in cancers. LDN’s unique mechanism of action on cancer cells, lack of direct cytotoxic effect, and immunomodulating action form the basis for its use as an adjuvant in chemotherapy and immunotherapy of cancerous lesions. Full article

The management of patients undergoing HSCT requires a multipurpose central venous catheter. Peripheral catheters (PCs), such as peripherally inserted central catheters (PICCs) and MidLine catheters (MLCs), appear to be adequate vascular catheters to be used for stem cell infusion, although their utilization in this indication is not yet common. We analyzed the infectious complications such as blood stream infection (BSI), febrile neutropenia (FN) and central line-associated bloodstream infection (CLBSI) in patients undergoing stem cell infusion through PC and conventionally inserted central catchers (CICCs), and evaluated their impacts on transplantation outcomes. Our results reveal no statistically significant differences between different types of catheter in terms of FN, BSI and CLABSI. Moreover, transplantation outcomes were comparable between the groups. Interestingly, according to our data, there were no differences in terms of abovementioned infectious complications between individuals who received antibiotic prophylaxis and those who did not. Our study has shown that infection complications are independent of the intravenous device and antibiotic prophylaxis. Considering that PCs are not associated with life-threatening complications, they should be considered more frequently in the stem cell transplantation setting. Full article

Pancreatic cancer is on track to become the second leading cause of cancer-related deaths by 2030, yet there is a lack of accurate diagnostic tests for early detection. Intraductal papillary mucinous neoplasms (IPMNs) are precursors to pancreatic cancer and are increasingly being detected. Despite the development and refinement of multiple guidelines, diagnosing high-grade dysplasia or cancer in IPMNs using clinical, radiologic, endosonographic, and cyst fluid features still falls short in terms of accuracy, leading to both under- and overtreatment. EUS-guided needle-based confocal laser endomicroscopy (nCLE) is a novel technology that allows real-time optical biopsies of pancreatic cystic lesions. Emerging data has demonstrated that EUS-nCLE can diagnose and risk stratify IPMNs more accurately than conventional diagnostic tools. Implementing EUS-nCLE in clinical practice can potentially improve early diagnosis of pancreatic cancer, reduce unnecessary surgeries of IPMNs with low-grade dysplasia, and advance the field of digital pathomics. In this review, we summarize the current evidence that supports using EUS-nCLE as a diagnostic imaging biomarker for diagnosing IPMNs and for risk stratifying their degree of neoplasia. Moreover, we will present emerging data on the role of adding artificial intelligence (AI) algorithms to nCLE and integrating novel fluid biomarkers into nCLE. Full article

During the last decade, we have witnessed several milestones in the treatment of various resistant cancers including immunotherapeutic strategies that have proven to be superior to conventional treatment options, such as chemotherapy and radiation. This approach utilizes the host’s immune response, which is triggered by cancer cells expressing tumor-associated antigens or neoantigens. The responsive immune cytotoxic CD8⁺ T cells specifically target and kill tumor cells, leading to tumor regression and prolongation of survival in some cancers; however, some cancers may exhibit resistance due to the inactivation of anti-tumor CD8⁺ T cells. One mechanism by which the anti-tumor CD8⁺ T cells become dysfunctional is through the activation of the inhibitory receptor programmed death-1 (PD-1) by the corresponding tumor cells (or other cells in the tumor microenvironment (TME)) that express the programmed death ligand-1 (PD-L1). Hence, blocking the PD-1/PD-L1 interaction via specific monoclonal antibodies (mAbs) restores the CD8⁺ T cells’ functions, leading to tumor regression. Accordingly, the Food and Drug Administration (FDA) has approved several checkpoint antibodies which act as immune checkpoint inhibitors. Their clinical use in various resistant cancers, such as metastatic melanoma and non-small-cell lung cancer (NSCLC), has shown significant clinical responses. We have investigated an alternative approach to prevent the expression of PD-L1 on tumor cells, through targeting the oncogenic transcription factor Yin Yang 1 (YY1), a known factor overexpressed in many cancers. We report the regulation of PD-L1 by YY1 at the transcriptional, post-transcriptional, and post-translational levels, resulting in the restoration of CD8⁺ T cells’ anti-tumor functions. We have performed bioinformatic analyses to further explore the relationship between both YY1 and PD-L1 in cancer and to corroborate these findings. In addition to its regulation of PD-L1, YY1 has several other anti-cancer activities, such as the regulation of proliferation and cell viability, invasion, epithelial–mesenchymal transition (EMT), metastasis, and chemo-immuno-resistance. Thus, targeting YY1 will have a multitude of anti-tumor activities resulting in a significant obliteration of cancer oncogenic activities. Various strategies are proposed to selectively target YY1 in human cancers and present a promising novel therapeutic approach for treating unresponsive cancer phenotypes. These findings underscore the distinct regulatory roles of YY1 and PD-L1 (CD274) in cancer progression and therapeutic response. Full article

Background: Lung cancer is associated with a high incidence of mortality worldwide. Molecular mechanisms governing the disease have been explored by genomic studies; however, several aspects remain elusive. The integration of genomic profiling with in-depth proteomic profiling has introduced a new dimension to lung cancer research, termed proteogenomics. The aim of this review article was to investigate proteogenomic approaches in lung cancer, focusing on how elucidation of proteogenomic features can evoke tangible clinical outcomes. Methods: A strict methodological approach was adopted for study selection and key article features included molecular attributes, tumor biomarkers, and major hallmarks involved in oncogenesis. Results: As a consensus, in all studies it becomes evident that proteogenomics is anticipated to fill significant knowledge gaps and assist in the discovery of novel treatment options. Genomic profiling unravels patient driver mutations, and exploration of downstream effects uncovers great variability in transcript and protein correlation. Also, emphasis is placed on defining proteogenomic traits of tumors of major histological classes, generating a diverse portrait of predictive markers and druggable targets. Conclusions: An up-to-date synthesis of landmark lung cancer proteogenomic studies is herein provided, underpinning the importance of proteogenomics in the landscape of personalized medicine for combating lung cancer. Full article

This study aimed to present the treatment patterns and outcomes for adenoid cystic carcinoma (ACC) arising in the nasal cavity and paranasal sinus. Sixty-one sinonasal ACC patients were retrospectively reviewed: 31 (50.8%) underwent surgery followed by postoperative radiation therapy (S+PORT), and 30 (49.2%) received definitive radiation therapy (D(C)RT). T4 disease was significantly more frequent in the D(C)RT group (25.8% vs. 80.0%, p < 0.001), where all T4b disease patients underwent D(C)RT. The 5-year local failure-free survival (LFFS), distant metastasis-free survival (DMFS), progression-free survival (PFS), and overall survival were 61.8% versus 37.8% (p = 0.003), 64.8% versus 38.1% (p = 0.036), 52.6% versus 19.3% (p = 0.010), and 93.2% versus 73.4% (p = 0.001) in the S+PORT and D(C)RT groups, respectively. The absolute differences in 5-year rates of LFFS, DMFS, and PFS between the two groups were smaller in the T3–4 subgroup. The univariate analysis showed that T4b disease, neurologic symptoms, longest diameter of tumor, radiological evidence of nerve involvement, and undergoing D(C)RT were associated with worse clinical outcomes, but the significance disappeared in the multivariate analysis, except for in the case of radiological evidence of nerve involvement. In conclusion, most patients with extensive disease underwent upfront D(C)RT and generally exhibited inferior clinical outcomes when compared to those with less extensive disease and who underwent S+PORT. Full article

The spectral quality of magnetic resonance spectroscopic imaging (MRSI) can be affected by strong magnetic field inhomogeneities, posing a challenge for 3D-MRSI’s widespread clinical use with standard scanner-equipped 2nd-order shim coils. To overcome this, we designed an empirical unified shim–RF head coil (32-ch RF receive and 51-ch shim) for 3D-MRSI improvement. We compared its shimming performance and 3D-MRSI brain coverages against the standard scanner shim (2nd-order spherical harmonic (SH) shim coils) and integrated parallel reception, excitation, and shimming (iPRES) 32-ch AC/DC head coil. We also simulated a theoretical 3rd-, 4th-, and 5th-order SH shim as a benchmark to assess the UNIfied shim–RF coil (UNIC) improvements. In this preliminary study, the whole-brain coverage was simulated by using B₀ field maps of twenty-four healthy human subjects (n = 24). Our results demonstrated that UNIC substantially improves brain field homogeneity, reducing whole-brain frequency standard deviations by 27% compared to the standard 2nd-order scanner shim and 17% compared to the iPRES shim. Moreover, UNIC enhances whole-brain coverage of 3D-MRSI by up to 34% compared to the standard 2nd-order scanner shim and up to 13% compared to the iPRES shim. UNIC markedly increases coverage in the prefrontal cortex by 147% and 47% and in the medial temporal lobe and temporal pole by 29% and 13%, respectively, at voxel resolutions of 1.4 cc and 0.09 cc for 3D-MRSI. Furthermore, UNIC effectively reduces variations in shim quality and brain coverage among different subjects compared to scanner shim and iPRES shim. Anticipated advancements in higher-order shimming (beyond 6th order) are expected via optimized designs using dimensionality reduction methods. Full article

(1) Background: Health-related quality of life (HRQoL) gains importance as novel treatment options for individuals with esophagogastric tumors to improve long-term survival. Impaired HRQoL has been shown to be a predictor of overall survival. Sarcopenia is a known prognostic factor for postoperative complications. As the regular control of sarcopenia through CT scans might not always be possible and HRQoL and nutritional scores are easier to obtain, this study aimed to assess the relationship between nutritional scores, HRQoL and skeletal muscle mass in patients undergoing chemotherapy for cancers of the upper gastrointestinal tract. (2) Methods: Eighty patients presenting with tumors of the upper GI tract were included and asked to fill out the standardized HRQoL questionnaire, EORTC’s QLQ-C30. Nutritional status was assessed using the MNA, MUST and NRS 2002 scores. Sarcopenia was determined semi-automatically based on the skeletal muscle index at the L3 vertebrae level in staging CT scans. (3) Results: In chemo-naïve patients, HRQoL summary scores correlated significantly with nutritional scores and SMI. SMI and HRQoL prior to neoadjuvant therapy correlated significantly with SMI after treatment. (4) Conclusions: HRQoL is a helpful tool for assessing patients’ overall constitution. The correlation of HRQoL summary scores and SMI might allow for a rough assessment of skeletal muscle status through HRQoL assessment in chemo-naïve patients. Full article

(1) Background: Although the incidence of glioblastoma (GB) has a peak in patients aged 75–84 years, no standard treatment regimen for elderly patients has been established so far. The goal of this study was to analyze the outcome of GB patients ≥ 65 years to detect predictors with relevant impacts on overall survival (OS) and progression-free survival (PFS). (2) Methods: Medical records referred to our institution from 2006 to 2020 were analyzed. Adult GB patients with clinical data, postoperative MRI data, and ≥1 follow-up investigation after surgical resection were included. The complete cohort was divided into a younger (<65) and an elderly group (≥65 years). Multiple factors regarding OS and PFS were scanned using univariate and multivariable regression with p < 0.05. (3) Results: 1004 patients were included with 322 (61.0%) male individuals in the younger and 267 (56.1%) males in the older cohort. The most common tumor localization was frontal in both groups. Gross total resection (GTR) was the most common surgical procedure in both groups, followed by subtotal resection (STR) (145; 27.5%) in the younger group, and biopsy (156; 32.8%) in the elderly group. Multivariate analyses detected that in the younger cohort, MGMT promoter methylation and GTR were predictors for a longer OS, while MGMT methylation, GTR, and hypofractionated radiation were significantly associated with a longer OS in the elderly group. (4) Conclusions: Elderly patients benefit from surgical resection of GB when they show MGMT promoter methylation, undergo GTR, and receive hypofractionated radiation. Furthermore, MGMT methylation seems to be associated with a longer PFS in elderly patients. Further investigations are required to confirm these findings, especially within prospective radiation therapy studies and molecular examinations. Full article

This study investigated whether virtual monoenergetic images (VMIs) and iodine mapping based on dual-energy CT (DECT) provide advantages in the assessment of endometrial cancer. A dual-source DECT was performed for primary staging of histologically proven endometrioid adenocarcinoma in 21 women (66.8 ± 12.0 years). In addition to iodine maps, VMIs at 40, 50, 60, 70, and 80 keV were reconstructed from polyenergetic images (PEIs). Objective analysis comprised the measurement of tumor contrast, contrast-to-noise ratio, and normalized iodine concentration (NIC). In addition, three radiologists independently rated tumor conspicuity. The highest tumor contrast (106.6 ± 45.0 HU) and contrast-to-noise ratio (4.4 ± 2.0) was established for VMIs at 40 keV. Tumor contrast in all VMIs ≤ 60 keV was higher than in PEIs (p < 0.001). The NIC of malignant tissue measured in iodine maps was substantially lower compared with a healthy myometrium (0.3 ± 0.1 versus 0.6 ± 0.1 mg/mL; p < 0.001). Tumor conspicuity was highest in 40 keV datasets, whereas no difference was found among PEIs and VMIs at 60 and 70 keV (p ≥ 0.334). Interobserver agreement was good, indicated by an intraclass correlation coefficient of 0.824 (0.772–0.876; p < 0.001). In conclusion, computation of VMIs at 40 keV and color-coded iodine maps aids the assessment of endometroid adenocarcinoma in primary staging. Full article

Real-world data in clinical practice are needed to confirm the efficacy and safety that ibrutinib has demonstrated in clinical trials of patients with chronic lymphocytic leukemia (CLL). We described the real-world persistence rate, patterns of use, and clinical outcomes in 309 patients with CLL receiving single-agent ibrutinib in first line (1L, n = 118), 2L (n = 127) and ≥3L (n = 64) in the prospective, real-world, Italian EVIdeNCE study. After a median follow-up of 23.9 months, 29.8% of patients discontinued ibrutinib (1L: 24.6%, 2L: 29.9%, ≥3L: 39.1%), mainly owing to adverse events (AEs)/toxicity (14.2%). The most common AEs leading to discontinuation were infections (1L, ≥3L) and cardiac events (2L). The 2-year retention rate was 70.2% in the whole cohort (1L: 75.4%, 2L: 70.1%, ≥3L: 60.9%). The 2-year PFS and OS were, respectively, 85.4% and 91.7% in 1L, 80.0% and 86.2% in 2L, and 70.1% and 80.0% in ≥3L. Cardiovascular conditions did not impact patients’ clinical outcomes. The most common AEs were infections (30.7%), bleeding (12.9%), fatigue (10.0%), and neutropenia (9.7%), while grade 3–4 atrial fibrillation occurred in 3.9% of patients. No new safety signals were detected. These results strongly support ibrutinib as a valuable treatment option for CLL. Full article

Gastric and gastroesophageal junction adenocarcinomas (GA/GEJA) are associated with a poor prognosis, primarily due to late disease diagnosis. Human Epidermal Growth Factor Receptor 2 (HER2) overexpression and programmed death-ligand 1 (PD-L1) expression are important biomarkers for treatment selection in locally advanced unresectable and metastatic GA/GEJA, and there is increasing interest in their role in earlier stages of disease. In this study, we aimed to evaluate HER2 and PD-L1 expression in a curative-intent GA/GEJA cohort to describe their expression patterns and analyze the association between HER2 expression and clinicopathological features. HER2 expression was evaluated in surgical and endoscopic submucosal dissection tumor samples, and PD-L1 was evaluated in HER2-positive cases. The clinical cohort included 107 patients, with 8.4% testing positive for HER2 (seven of whom also exhibited a PD-L1 combined positive score of ≥1. HER2 status was not significantly associated with survival outcomes. A pathologist-guided, region-specific analysis revealed that PD-L1 expression rarely overlaps with HER2-positive tumor areas. While the therapeutic implications of these observations remain unknown, these findings suggest that combination strategies targeting HER2 and PD-L1 might be directed toward distinct tumor subclones. The herein disclosed region-specific biomarker expression patterns may have important therapeutic and prognostic impacts, warranting further evaluation. Full article

Immune checkpoint inhibition (ICI) improves outcomes in melanoma patients, but associated T-cell activation frequently leads to immune-related cutaneous adverse events (cutAEs). To dynamically identify T-cell subtypes and immune signatures associated with cutAEs, a pilot study was performed in stage III-IV melanoma patients using blood samples for flow cytometry and cytokine analysis. Blood samples were taken from patients before initiation of ICI (naive), at the onset of a cutAE, and after 6 months of ICI treatment. Overall, 30 patients were treated either with anti-PD1 monotherapy or with anti-PD-1/anti-CTLA-4 combination therapy. Flow cytometry analysis of PBMCs showed that ICI induced an overall shift from a Th2 towards a Th1 profile. Twelve patients (40%) developed cutAEs, which were associated with increased Th22 cells and Th17 cells, supported by a tendency to have elevated Th17/Th22-associated cytokines such as IL-17A, IL-22 and IL-23 levels in the plasma. Cytokine signatures specific for urticaria and T-cell-mediated cutAEs were identified in the plasma of patients by a bead-based assay. IL-10 was elevated in non-responders and, interestingly, during cutAEs. In conclusion, we identified distinct immune signatures based on the Th17/Th22 pathway in cutAEs, both in PBMCs and plasma. In addition, our finding of upregulated IL-10 during cutAEs supports the notion of treating these patients early and adequately to avoid implications for the overall outcome. Full article

Immune-related adverse events (irAEs) are the most common complication of immune checkpoint inhibitor (ICI) therapy. With the widespread use of ICIs in patients with solid tumors, up to 40% of the patients develop irAEs within five months of treatment, and 11% develop severe irAEs requiring interventions. A predictive test for irAEs would be a crucial tool for monitoring for complications during and after ICI therapy. We performed an extensive review of potential predictive biomarkers for irAEs in patients who received ICI therapy. Currently, only thyroid-stimulating hormone is utilized in common clinical practice. This is due to the unavailability of commercial tests and unclear predictive values from various studies. Given the lack of single strong predictive biomarkers, some novel approaches using composite scores using genomic, transcriptomics, cytokine levels, or clinical parameters appear appealing. Still, these have yet to be validated and incorporated into clinical practice. Further research conducted to validate the models before implementing them into real-world settings will be of the utmost importance for irAE prediction. Full article

(1) Background: Skin cancer is the most common cancer in transplant recipients. Timely and regular screening may reduce advanced disease. The study aimed to determine referral rates to screening, the incidence, and risk factors of skin cancer in a Danish liver transplant recipient cohort. (2) Methods: All first-time liver transplant recipients, >18 years old, attending outpatient care between January 2018 and December 2021 were included. The referral rates and incidence of skin cancer/preneoplastic lesions were calculated. Risk factors were assessed using Cox regression analyses. (3) Results: Of the 246 included recipients, 219 (89.0%) were referred to screening, and 102 skin cancer/preneoplastic lesions were diagnosed in 32 (15.6%) recipients. The IR of any skin cancer/preneoplastic lesion was 103.2 per 1000 person-years. BCC was the most frequent skin cancer followed by SCC, IR: 51.3 vs. 27.1 per 1000 person-years, respectively. No cases of MM were observed. The IR of actinic keratosis and Bowen’s Disease were 48.1 vs. 13.2 per 1000 person-years, respectively. Time since transplantation was independently associated with skin cancer/preneoplastic lesions, HR (95%CI) 2.81 (1.64–4.80). (4) Conclusions: The study determined the incidence and risk factors of skin cancer/preneoplastic lesions in liver transplant recipients enrolled in a screening program, while demonstrating a high screening referral rate. Full article

Pediatric pilocytic astrocytoma (PA) is the most common brain tumor in children. Complete resection provides a favorable prognosis, except for unresectable PA forms. There is an incomplete understanding of the molecular and cellular pathogenesis of PA. Potential biomarkers for PA patients, especially the non-BRAF-mutated ones are needed. Cerebrospinal fluid (CSF) is a valuable source of brain tumor biomarkers. Extracellular vesicles (EVs), circulating in CSF, express valuable disease targets. These can be isolated from CSF from waste extraventricular drainage (EVD). We analyzed the proteome of EVD CSF from PA, congenital hydrocephalus (CH, non-tumor control), or medulloblastoma (MB, unrelated tumoral control) patients. A total of 3072 proteins were identified, 47.1%, 65.6%, and 86.2% of which were expressed in the unprocessed total and in its large-EV (LEV), and small-EV (SEV) fractions. Bioinformatics identified 50 statistically significant proteins in the comparison between PA and HC, and PA and MB patients, in the same fractions. Kinase enrichment analysis predicted five enriched kinases involved in signaling. Among these, only Cyclin-dependent kinase 2 (CDK2) kinase was overexpressed in PA samples. PLS-DA highlighted the inactive carboxypeptidase-like protein X2 (CPXM2) and aquaporin-4 (AQP4) as statistically significant in all the comparisons, with CPXM2 being overexpressed (validated by ELISA and Western blot) and AQP4 downregulated in PA. These proteins were considered the most promising potential biomarkers for discriminating among pilocytic astrocytoma and unrelated tumoral (MB) or non-tumoral conditions in all the fractions examined, and are proposed to be prospectively validated in the plasma for translational medicine applications. Full article

Early gastric cancers (EGCs) are confined to the gastric mucosa and submucosa irrespective of lymph node metastases and constitute only a minor proportion of gastric cancer in Western countries. We aimed to characterize EGCs and assess the survival of EGC in Central Norway during 2001–2016. A retrospective population-based study on 1205 patients with gastric cancer was performed. At the time, surgical resection was the standard treatment, and 88 (7.3%) EGCs were identified. Histopathological specimens were re-examined, and the eCura score and survival were evaluated. The number of gastric cancers declined (p = 0.010), but the relative proportion of EGC was unchanged during the study period. EGCs were more often of the Lauren intestinal type (p < 0.001) compared with controls. A significant proportion (9.4%, n = 5) of the patients with a low-risk eCura had lymph node metastases, whereas further exclusion of tumors with histological ulceration or SM2 invasion identified an N0 cohort. The median survival for EGC patients was 117.1 months (95% CI 99.8–134.3) and the 5-year overall survival was 75%. Twelve deaths were cancer-related, either due to postoperative complications (5.7%, n = 5) or cancer recurrence (8%, n = 7). In conclusion, EGCs constituted a minor but constant proportion of gastric cancers. eCura alone was insufficient in predicting patients with pN0 disease. Full article

Purpose: The usual workup for patients newly diagnosed with advanced non-small cell lung cancer (NSCLC) occurs in the ambulatory setting. A subset of patients present with acute care needs and receive the diagnosis while hospitalized. Palliative therapies are typically initiated when patients are outpatients, even when diagnoses are made when they are inpatients. Lengthy admission, rehabilitation needs after discharge, and readmissions are possible barriers to timely and adequate outpatient follow-up. The outcomes for these patients diagnosed in the hospital are not well characterized. We hypothesized that patients have been ill-served by current treatment patterns, as reflected by low rates of cancer-directed treatment and poor survival. Patients and methods: We performed a retrospective study of new inpatient diagnoses of metastatic NSCLC at our institution between 1 January 2012 and 1 January 2022. The primary outcome was the proportion of patients ultimately receiving cancer-directed therapy. Other outcomes included time to treatment, use of targeted therapy, palliative care/hospice utilization, and overall survival (OS). Results: Seventy-three patients were included, with a median age of 57 years. Twenty-seven patients (37%) ultimately received systemic therapy with a median time from diagnosis to treatment of 37.5 days. Overall, 5.4% patients died while admitted, 6.8% were discharged to a hospice, 21.9% were discharged to a facility, and 61.6% were discharged home. Only 20 patients (27%) received palliative care consultation. The median OS for our entire population was 2.3 months, with estimated 6-month and 1-year OS rates of 32% and 22%, respectively. Conclusion: Patients with new inpatient diagnoses of metastatic NSCLC have extremely poor outcomes. Current management strategies resulted in few patients starting systemic therapy, yet most of the patients did not receive palliative care or hospice involvement. These findings demonstrate that there is a high unmet need to optimally support and palliate these patients. Full article

Based on the multifaceted molecular machinery that tightly controls iron cellular homeostasis, this review delves into its paradoxical, potentially dangerous role in biological systems, with a special focus on double-edged sword correlations with cancer. Indeed, though iron is a vital micronutrient and a required cofactor participating in several essential cell functions, its tendency to cause oxidative stress can be related both to cancer risk and to the activation of cancer cell death pathways. In this scenario, ferroptosis refers to an iron-dependent form of regulated cell death (RCD) powered by an overload of lethal peroxides sharing distinctive oxidized phospholipid profiles. As a unique cell death pathway, ferroptosis is both morphologically and mechanistically different from other types of programmed cell death involving executioner family proteins. The accumulation of cytotoxic lipid peroxides encompasses a cellular antagonism between ferroptosis execution and defense systems, with iron-dependent death occurring when ferroptosis-promoting activities significantly exceed the cellular antioxidant defenses. The most recent molecular breakthroughs in the execution of ferroptosis have aroused great consideration in tumor biology, as targeting ferroptosis can provide new tools for exploring therapeutic strategies for tumor suppression. Mutations and death/survival pathway alterations, as well as distinctive metabolic regulations of cancer cells, including the propensity to generate ROS, are seen as features that can render cancer cells unprotected to ferroptosis, thereby exposing vulnerabilities which deserve further attention to be regarded as targetable for cancers with limited therapeutic options. Full article

Background: In the present study, we used the data from 14 hospitals to systematically evaluate the in-hospital mortality of patients with colorectal cancer as well as its influencing factors in Germany. Methods: This multicenter cross-sectional study included hospitalized patients with a main diagnosis of colorectal cancers in the period between January 2019 and July 2023. The outcome of the study was the prevalence of in-hospital mortality. To access the associations between demographic and clinical variables and in-hospital mortality, univariable and multivariable logistic regression analyses were conducted. Results: A total of 4146 colorectal cancer patients (mean age: 70.9 years; 45.3% female) were included. The in-hospital mortality rate was 8.7%. In a multivariable regression, seven variables were significantly associated with an increased in-hospital mortality, including ages of 71–80 years (OR: 2.08; 95% CI: 1.01–4.29), an age group >80 years (OR: 2.44; 95% CI: 1.18–5.05) as compared to an age group ≤ 50 years, patient clinical-complexity level (PCCL) 3 (OR: 3.01 95% CI: 1.81–4.99) and PCCL 4 (OR: 3.76; 95% CI: 2.22–6.38) as compared to PCCL 0, the presence of distant metastases (OR: 4.95; 95% CI: 3.79–6.48), renal failure (OR: 2.38; 95% CI: 1.80–3.14), peritonitis (OR: 1.87; 95% CI: 1.23–2.85), acute posthemorrhagic anemia (OR: 1.55; 95% CI: 1.11–2.15), and respiratory failure (OR: 3.28; 95% CI: 2.44–4.41). Conclusions: Our findings underscore the critical role of renal failure, peritonitis, acute posthemorrhagic anemia, and respiratory failure in influencing the mortality outcomes of colorectal cancer patients during hospitalization. The awareness and management of these risk factors may guide clinicians in formulating targeted interventions to improve patient outcomes and enhance the quality of care for individuals with colorectal cancer. Full article

Background and Objective: Brain metastases are common in lung cancer and increasingly treated using targeted radiotherapy techniques such as stereotactic radiosurgery (SRS). Using MRI, post-SRS changes may be difficult to distinguish from progressive brain metastasis. Contrast clearance analysis (CCA) uses T1-weighted MRI images to assess the clearance of gadolinium and can be thus used to assess vascularity and active tumours. Design and Methods: We retrospectively assessed CCAs in 62 patients with non-small cell lung cancer (NSCLC) undergoing 104 CCA scans in a single centre. Results: The initial CCA suggested the aetiology of equivocal changes on standard MRI in 80.6% of patients. In all patients whose initial CCA showed post-SRS changes and who underwent serial CCAs, the initial diagnosis was upheld with the serial imaging. In only two cases of a presumed progressive tumour on the initial CCA, subsequent treatment for radionecrosis was instigated; a retrospective review and re-evaluation of the CCAs show that progression was reported where a thin rim of rapid contrast clearance was seen, and this finding has been subsequently recognised as a feature of post-treatment change on CCAs. The lack of concordance with CCA findings in those who underwent surgical resection was also found to be due to the over-reporting of the thin blue rim as disease in the early cases of CCA use and, in three cases, potentially related to timelines longer than 7 days prior to surgery, both factors being unknown during the early implementation phase of CCA at our centre but subsequently learned. Conclusions: Our single-centre experience shows CCA to be feasible and useful in patients with NSCLC in cases of diagnostic uncertainty in MRI. It has helped guide treatment in the majority of patients, with subsequent outcomes following the implementation of the treatment based on the results, suggesting correct classification. Recommendations from our experience of the implementation include the careful consideration of the thin rim of the rapid contrast clearance and the timing of the CCA prior to surgery for suspected brain metastasis progression. Full article

Purpose: This retrospective cohort study aims to compare the quality of life (QoL) in patients with nasopharyngeal cancer (NPC) treated with intensity-modulated proton therapy (IMPT) versus volumetric modulated arc therapy (VMAT) at different time points. Materials and Methods: We conducted a longitudinal assessment of QoL on 287 newly diagnosed NPC patients (IMPT: 41 and VMAT: 246). We collected outcomes of global QoL, functional QoL, C30 symptoms, and HN35 symptoms from EORTC QLQ-C30 and QLQ-HN35 questionnaires at pre-radiotherapy, during radiotherapy (around 40 Gy), 3 months post radiotherapy, and 12-months post radiotherapy (RT). The generalized estimating equation was utilized to interpret the group effect, originating from inherent group differences; time effect, attributed to RT effects over time; and interaction of the group and time effect. Results: IMPT demonstrated superior mean dose reductions in 12 of the 16 organs at risk compared to VMAT, including a significant (>50%) reduction in the oral cavity and larynx. Both groups exhibited improved scores of global QoL, functional QoL, and C30 symptoms at 12 months post RT compared to the pre-RT status. Regarding global QoL and C30 symptoms, there was no interaction effect of group over time. In contrast, significant interaction effects were observed on functional QoL (p = 0.040) and HN35 symptoms (p = 0.004) during RT, where IMPT created an average of 7.5 points higher functional QoL and 10.7 points lower HN35 symptoms than VMAT. Conclusions: Compared to VMAT, dose reduction attributed to IMPT could translate into better functional QoL and HN35 symptoms, but the effect is time dependent and exclusively observed during the RT phase. Full article

The constantly escalating population of cancer survivors worldwide has prompted a focused exploration of their unique needs and experiences within the context of healthcare medicine. This review initiates its analysis inspired by Dr. Lidia Schapira’s insightful keynote conference on the Survivorship 1.0 and Survivorship 2.0 Programs, shedding light on their implementation challenges and setting the stage for a comprehensive analysis of cancer survivorship initiatives. Within the transformed landscape of cancer care, patient-centric strategies embedded in cancer survivorship programs comprising vital elements such as connection, support, and education are presented. While placing cancer recurrence surveillance at the forefront, the review underlines concern regarding the potential oversight of the enduring impact on mental and physical health. Dr. Schapira’s insights further extend into the exploration of mental health challenges faced by survivors, promoting an examination of diverse strategies to address these concerns. Furthermore, the discussion continues toward promising areas of research, notably Precision Medicine’s role in de-escalating cancer therapies, and advocates for measures such as early cancer awareness and timely referrals to supportive services. Highlighting the significance of education, the role of online resources in enhancing the knowledge of healthcare practitioners and future generations in cancer care is then explored. The paper concludes by presenting some of the most prominent global current survivorship programs, identifying critical knowledge gaps in cancer care and projecting future developments aimed at delivering accurate and holistic care, improving the quality of life for survivors, and enhancing both mental and physical well-being. Drawing upon the insights from Dr. Schapira, this review lays the groundwork for a nuanced exploration of cancer survivorship and its multifaceted implications. Full article

Since their discovery in 2002, BRAF mutations have been identified as clear drivers of oncogenesis in several cancer types. Currently, their incidence rate is nearly 7% of all solid tumors with BRAF V600E constituting approximately 90% of these diagnoses. In melanoma, thyroid cancer, and histiocytic neoplasms, BRAF hotspot mutations are found at a rate of about 50%, while in lung and colorectal cancers they range from 3% to 10% of reported cases. Though present in other malignancies such as breast and ovarian cancers, they constitute a small portion of diagnoses (<1%). Given their frequency along with advancements in screening technologies, various methods are used for the detection of BRAF-mutant cancers. Among these are targeted next-generation sequencing (NGS) on tumor tissue or circulating tumor DNA (ctDNA) and immunohistochemistry (IHC)-based assays. With advancements in detection technologies, several approaches to the treatment of BRAF-mutant cancers have been taken. In this review, we retrace the milestones that led to the clinical development of targeted therapies currently available for these tumors. Full article

The prevalence of metabolic-associated fatty liver disease (MAFLD) is increasing globally due to factors such as urbanization, obesity, poor nutrition, sedentary lifestyles, healthcare accessibility, diagnostic advancements, and genetic influences. Research on MAFLD and HCC risk factors, pathogenesis, and biomarkers has been conducted through a narrative review of relevant studies, with a focus on PubMed and Web of Science databases and exclusion criteria based on article availability and language. Steatosis marks the early stage of MASH advancement, commonly associated with factors of metabolic syndrome such as obesity and type 2 diabetes. Various mechanisms, including heightened lipolysis, hepatic lipogenesis, and consumption of high-calorie diets, contribute to the accumulation of lipids in the liver. Insulin resistance is pivotal in the development of steatosis, as it leads to the release of free fatty acids from adipose tissue. Natural compounds hold promise in regulating lipid metabolism and inflammation to combat these conditions. Liver fibrosis serves as a significant predictor of MASH progression and HCC development, underscoring the need to target fibrosis in treatment approaches. Risk factors for MASH-associated HCC encompass advanced liver fibrosis, older age, male gender, metabolic syndrome, genetic predispositions, and dietary habits, emphasizing the requirement for efficient surveillance and diagnostic measures. Considering these factors, it is important for further studies to determine the biochemical impact of these risk factors in order to establish targeted therapies that can prevent the development of HCC or reduce progression of MASH, indirectly decreasing the risk of HCC. Full article

Circulating tumor cells (CTCs) are cells released from the primary and metastatic tumor and intravasate into the blood or lymphatic vessels, where they are transported to distant sites and act as seeds that initiate cancer metastases or the development of further lesions. Recent advances in CTC research have shown their relevance as prognostic markers for early and metastatic disease detection, predictive biomarkers for relapse, and response to medical intervention or therapy. The rapidly evolving landscape of CTC biology has opened new avenues for understanding cancer progression, metastasis, and treatment response. Additionally, translating these findings into clinical applications holds promise for improving cancer diagnostics, prognosis, and personalized therapeutic strategies. This review discusses the significance of CTCs in cancer research and their associated challenges. We explore recent developments in the detection and characterization of CTCs and their implications in cancer research and clinical practice. Full article