Search Results (31,586)

Esophageal cancer, primarily comprising the squamous cell carcinoma (ESCC) and adenocarcinoma (EAC) subtypes, is the sixth leading cause of cancer deaths globally. In addition to many well-established endogenous and exogenous risk factors, there is emerging evidence for the etiologic role of infectious agents in esophageal cancer, although these associations are incompletely understood. Here, we review the currently available literature on the relationship between infectious agents and esophageal cancer. By far, human papilloma virus (HPV), particularly HPV 16 and 18, have the strongest etiologic association with ESCC. Less robust is the association of high-risk HPV (hr-HPV) with EAC. Although H. pylori has been implicated in the development of EAC via increased acid reflux, decreased lower esophageal sphincter tone, and the resultant Barrett’s metaplasia–dysplasia–adenocarcinoma pathway, some hypothesize based on epidemiological trends that H. pylori may in fact be a protective factor. In rare cases, EBV can cause esophageal lymphoepithelial carcinoma. Several other agents including HSV, polyomaviruses, and Candida are associated with esophageal cancer to varying degrees. In summary, while several studies, including those conflicting with each other, implicate several infectious agents, the evidence is weak, at best. Clearly, further work is needed to help solidify clear etiologies that will help facilitate prevention and treatment. Full article

Hematologic malignancies, including leukemia, lymphoma, and multiple myeloma, continue to challenge clinicians with complex treatment regimens that often involve significant side effects and limited success, especially in advanced stages. Recent advancements in nuclear medicine have introduced theranostic strategies that merge diagnostic imaging with targeted therapeutic approaches, offering the potential for more precise and personalized treatment. A key area of progress lies in the development of alpha-emitting radiopharmaceuticals, such as ²²⁵Ac, ²¹¹At, or ²¹²Pb, which can deliver potent radiation directly to tumor cells, sparing healthy tissue and minimizing collateral damage. In parallel with these therapeutic advancements, molecular imaging using radiolabeled agents enables better disease monitoring, assessment of treatment efficacy, and personalized management of patients with hematologic malignancies. The integration of diagnostic imaging with radiotherapy allows for a more tailored approach, where treatment can be adjusted based on real-time information about tumor progression and response. This review examines the recent strides made in both the development of radiopharmaceuticals and their applications in molecular imaging, with a focus on the potential to improve precision, reduce toxicity, and optimize patient outcomes. The synergy between targeted therapy and molecular imaging represents a transformative shift in the management of hematologic malignancies. As these technologies evolve, they are poised to redefine treatment paradigms, offering new hope for patients and potentially improving survival rates with more effective and less toxic treatment options. Full article

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related mortality in the United States, with poor overall survival across all stages. Less than 20% of patients are eligible for curative surgical resection at diagnosis, and despite adjuvant chemotherapy, most will experience disease recurrence within two years. The incorporation of immune-based strategies in the adjuvant setting remains an area of intense investigation with unrealized promise. It offers the potential of providing durable disease control for micro-metastatic disease following curative intent surgery and enabling personalized treatments based on mutational neoantigen profiles derived from resected specimens. However, most of these attempts have failed to demonstrate significant clinical success, likely due to the immunosuppressive tumor microenvironment (TME) and individual genetic heterogeneity. Despite these challenges, immune-based strategies, such as therapeutic vaccines targeted towards neoantigens, have demonstrated promise via immune activation and induction of T-cell tumor infiltration. In this review, we will highlight the foundational lessons learned from previous clinical trials of adjuvant immunotherapy, discussing the knowledge gained from analyses of trials with disappointing results. In addition, we will discuss how these data have been incorporated to design new agents and study concepts that are proving to be exciting in more recent trials, such as shared antigen vaccines and combination therapy with immune-checkpoint inhibitors and chemotherapy. This review will evaluate novel approaches in ongoing and future clinical studies and provide insight into how these immune-based strategies might evolve to address the unique challenges for treatment of PDAC in the adjuvant setting. Full article

Background/Objectives: Identifying tumor budding (TB) in colorectal cancer (CRC) is vital for better prognostic assessment as it may signify the initial stage of metastasis. Despite its importance, TB detection remains challenging due to subjectivity in manual evaluations. Identifying TBs remains difficult, especially at high magnification levels, leading to inconsistencies in prognosis. To address these issues, we propose an automated system for TB classification using deep learning. Methods: We trained a deep learning model to identify TBs through weakly supervised learning by aggregating positive and negative bags from the tumor invasive front. We assessed various foundation models for feature extraction and compared their performance. Attention heatmaps generated by attention-based multi-instance learning (ABMIL) were analyzed to verify alignment with TBs, providing insights into the interpretability of the features. The dataset includes 29 WSIs for training and 70 whole slide images (WSIs) for the hold-out test set. Results: In six-fold cross-validation, Phikon-v2 achieved the highest average AUC (0.984 ± 0.003), precision (0.876 ± 0.004), and recall (0.947 ± 0.009). Phikon-v2 again achieved the highest AUC (0.979) and precision (0.980) on the external hold-out test set. Moreover, its recall rate (0.910) was still higher than that of UNI’s (0.879). UNI exhibited a balanced performance on the hold-out test set, with an AUC of 0.960 and a precision of 0.968. CtransPath showed strong precision on the external hold-out test set (0.947) but had a slightly lower recall (0.911). Conclusions: The proposed technique enhances the accuracy of TB assessment, offering potential applications for CRC and other cancer types. Full article

Neoplastic cells are characterized by metabolic reprogramming, known as the Warburg effect, in which glucose metabolism is predominantly directed toward aerobic glycolysis, with reduced mitochondrial oxidative phosphorylation and increased lactate production even in the presence of oxygen. This phenomenon provides cancer cells with a proliferative advantage, allowing them to rapidly produce energy (in the form of ATP) and generate metabolic intermediates necessary for the biosynthesis of macromolecules essential for cell growth. It is important to understand the role of ion channels in the tumor context since they participate in various physiological processes and in the regulation of the tumor microenvironment. These changes may contribute to the development and transformation of cancer cells, as well as affect the communication between cells and the surrounding microenvironment, including impaired or altered expression and functionality of ion channels. Therefore, the aim of this review is to elucidate the impact of the tumor microenvironment on the electrical properties of the cellular membranes in several cancers as a possible therapeutic target. Full article

Cholangiocarcinoma (CCA) is an aggressive malignancy with limited methods for early detection, necessitating the development of reliable biomarkers for diagnosis and management. However, conventional tumor markers, such as CA19-9 and CEA, exhibit insufficient diagnostic accuracy. Recent advancements in molecular genetics have identified several actionable mutations in CCA, enabling molecularly targeted therapies that improve survival in patients harboring these genetic alterations. Cancer panels, which facilitate multiplex genetic profiling, are critical for identifying these mutations. Studies indicate that several actionable mutations are detected in CCA cases, with patients receiving mutation-guided therapies achieving markedly better outcomes. Liquid biopsies, including cell-free DNA and circulating tumor DNA, offer real-time, non-invasive approaches to monitoring tumor dynamics, heterogeneity, and treatment responses. Furthermore, numerous studies have identified non-coding RNAs in serum and bile as promising biomarkers for the diagnosis and management of CCA. On the other hand, immunotherapy, particularly immune checkpoint inhibitors, has shown efficacy in subsets of CCA patients. However, the success of these therapies is often affected by the status of the tumor immune microenvironment (TME), underscoring the need for comprehensive TME analysis to predict responses to immune checkpoint inhibitors. Despite these advances, no single biomarker currently demonstrates sufficient sensitivity or specificity for clinical application. The integration of multi-omics approaches with cutting-edge technologies holds promise for enhancing diagnostic accuracy, optimizing treatment stratification, and advancing precision medicine in CCA. These developments highlight the transformative potential of biomarkers to improve early detection, prognostic assessment, and personalized therapeutic interventions for CCA. Full article

Background/Objectives: The management of non-lifting colorectal lesions (NLCLs), often resulting from previous unsuccessful treatments or biopsies, remains challenging due to submucosal fibrosis that prevents adequate lifting. Endoscopic submucosal dissection (ESD) is a viable option for achieving complete resection in such cases. However, when standard ESD is not feasible, conversion to hybrid ESD (H-ESD) has been proposed as a rescue strategy. This study aimed to assess ESD’s feasibility, effectiveness, and safety for NLCLs, including cases requiring conversion to H-ESD, when performed by experienced endoscopists in tertiary referral centers. Methods: In this multicenter retrospective study, data from patients with NLCLs treated by ESD/H-ESD between January 2009 and September 2022 were analyzed. The primary endpoint was the recurrence rate (RR). Secondary endpoints included the adverse event (AE) rate, technical success (TS) rate (en bloc resection regardless of technique), complete resection (CR), curative resection (cR) rates, and surgical intervention rate. Predictors of ESD technical success were identified. Results: In total, 178 patients with NLCLs were included (52 previously biopsied, 126 recurrent after previous resection). ESD was used in 111 (62.4%) and H-ESD in 67 (37.6%) cases. During a median follow-up of 373 days (IQR 540), the overall RR was 3.6%. The overall AE rate was 13.4%, and perforation was the most frequent (8.4%). All AEs were successfully managed endoscopically. The TS rate was 71.9%, significantly higher in previously biopsied lesions compared to recurrent ones (78.8% vs. 55.6%, p = 0.04). On multivariate analysis, rectal location (p < 0.001), F1 fibrosis (p = 0.026), and previously biopsied lesions (p = 0.006) predicted ESD TS without the need for conversion to H-ESD. Conclusions: ESD/H-ESD is feasible and safe for NLCLs when performed by experienced operators, with low RR amenable to endoscopic treatment. Previously biopsied lesions, rectal location, and low fibrosis predict ESD TS. Full article

Objectives: We aimed to study the efficacy of fractional CO₂ laser for genitourinary syndrome of menopause (GSM) symptoms in breast cancer (BC) survivors through a randomized, sham-controlled study, followed by an open-phase study assessing the impact of additional treatments. Methods: BC survivors with GSM were randomized to receive either three sessions of intravaginal CO₂ laser or sham treatment every 3–4 weeks. The laser’s energy was 45–60 mJ/pixel. Outcomes were compared one month following the last session. Participants initially receiving laser treatment were offered three more sessions, while those receiving sham had six laser sessions in an open-label study. Results: Thirty-four BC survivors were randomized to laser (n = 19) or sham (n = 15) treatments. Dyspareunia and intercourse dryness scores improved in both groups one month post-treatment, without a significant advantage of laser over sham. The laser treatment resulted in a reduction in daily dryness (−1.30 ± 0.55, p = 0.017), an increase in vaginal hydration (3.24 ± 1.13, p = 0.004), and an increase in Vaginal Health Index (VHI) (2.26 ± 0.50, p < 0.001). Most participants (18/19 and 9/15, respectively) opted to continue laser treatments after unblinding, resulting in 27 patients receiving six laser treatments. Increasing the number of laser treatments was associated with a constant improvement in Visual Analogue Score (VAS) scores for dyspareunia, intercourse dryness, daily dryness, burning, discomfort, itch, and average VAS, as well as pH, VHI, and hydration. Conclusions Three fractional CO₂ laser treatments for BC survivors reduced daily dryness but did not improve dyspareunia and sexual dryness when compared to sham in this randomized trial. Increasing the number of treatment sessions seemed to improve outcomes; however, it remained clinically insufficient, even after six treatments. Full article

Background: Intraoperative radiation therapy (IORT) is the delivery of a single large dose of radiation to a limited volume of tissue at the time of surgery. The aim of this study is to assess outcomes in patients who underwent IORT for gynecologic malignancies and to identify parameters that can predict a good outcome. Methods: This is a retrospective single-center cohort study including all women treated with surgery and IORT for a primary or recurrent gynecologic cancer between 2014 and 2022 at the Bern University Hospital, Switzerland. Results: A total of 30 patients with gynecologic malignancies were treated with surgery and IORT. Of these patients, 63.3% presented with cervical cancer, 23.3% with sarcoma, 10% with endometrial cancer, and 3.3% with carcinosarcoma of the ovary. Seventy percent (21/30) of women had an ECOG performance status of 0 at time of IORT. There was no difference in survival among women with incomplete surgical resection (R1/2 vs. R0) at time of IORT. Fifty percent of patients suffered postoperative complication of Clavien-Dindo grade >III, but there was no significant correlation of these complications to overall survival (p = 0.58). Three-year disease-free survival was 53.3%, and five-year overall survival was 53.3%. ECOG status was a significant parameter in DSS (p = 0.002) and OS (p = 0.02). Conclusion: Surgery with IORT is potentially a good treatment option in selected patients with recurrent or locally advanced cervical or endometrial cancer. An ECOG status of 0 is a significant parameter for good outcomes and should be taken into consideration for treatment decisions. Full article

Background/Objectives: Prostate-specific membrane antigen (PSMA) is a well-established target in prostate cancer therapy that has shown potential as a theranostic target across non-central nervous system (CNS) and CNS tumor types. We aimed to investigate the pan-tissue expression pattern of the PSMA-encoding gene FOLH1 to assess whether transcriptome profiling can inform tumor diagnostic and theranostic probes. Methods: We assessed FOLH1 expression from the Open Pediatric Cancer Project (OpenPedCan, n = 2132 specimens), the Cancer Genome Atlas (TCGA, n = 10,411 specimens), and the Genotype Tissue Expression Project (GTEx, n = 17,382 specimens) in relation to published reports of PSMA radionuclide uptake in various tumors. Results: When comparing FOLH1 expression across tumor versus normal tissues, we found that non-CNS tumors exhibiting elevated expression of at least two-fold (FDR < 0.05) were reported to have significant PSMA radionuclide uptake in contrast to tumors with less than a two-fold elevation or with lower expression of FOLH1 relative to normal tissues. Notably, CNS tumors universally exhibited lower expression of FOLH1 relative to normal brain tissue, but we observed considerable variation in the expression of blood–tumor barrier (BTB) components associated with reports of BTB integrity and uptake of PSMA radiotracers. Conclusions: Large-scale transcriptomics data may help guide the application of PSMA-based radionuclide therapies in non-CNS tumors, but care should be taken to account for BTB effects in CNS tumors when assessing the potential for radionuclide success. This study demonstrates that FOLH1 showed a lack of tumor-specific expression for both adult and pediatric CNS tumors when compared to normal brain tissue, suggesting that PSMA is not a desirable target in brain tumors. Full article

Background/Objectives: Parents of children with acute lymphoblastic leukaemia (ALL) experience emotional distress throughout their child’s treatment course. This study describes the psychological experience of Australian and New Zealand parents of children diagnosed with ALL. Methods: This prospective, longitudinal study assessed distress, anxiety, depression, anger and the need for help in parents of children with newly diagnosed ALL across eight sites between October 2018 and November 2022. Psychological symptoms were quantified using the Emotion Thermometer (ET) tool and Patient-Reported Outcome Measurement Information System (PROMIS) questionnaires. Participants were recruited within ninety days of chemotherapy commencement, with surveys distributed bimonthly thereafter. Results: One hundred and seventeen participants completed 327 survey responses spanning 0 to 62 months post-diagnosis. Parental distress peaked within the first 6 months and 40% of parents reported clinically significant symptoms across four or more domains as measured by our questionnaires. Anxiety was the most consistently elevated symptom, with over 50% of responses above the clinical cut-off. Depression and the need for help also peaked closer to diagnosis and declined over time. In contrast, anger remained stable, with 27% reporting clinically significant scores across all time points. Increased time since diagnosis was significantly associated with reductions in distress, anxiety and depression scores. Conclusions: Australian and New Zealand parents experience high levels of psychological distress within the first six months following their child’s diagnosis of ALL. A notable minority continue to report elevated distress levels over time, identifying a need for improved psychological support for family wellbeing throughout the ALL treatment trajectory. Full article

Background and Objectives: Totally endophytic renal tumors are a unique subset that pose significant technical challenges during partial nephrectomy (PN). The aim of this study was to evaluate the perioperative, oncologic, and functional outcomes of PN in this particular setting. Materials and Methods: We retrospectively evaluated 4151 patients who had surgical treatment for renal tumors between January 2013 and December 2016 at 26 urological Italian Centers (RECORD 2 project). Only patients treated with PN for entirely endophytic renal tumor were considered for final analyses. Results: A total of 211 patients were included, with a median PADUA score of 10 (IQR 9-11). Open, laparoscopic, and robotic approaches were used in 94 (44.5%), 52 (24.6%), and 65 (30.8%) cases, respectively. While surgical approach did not impact complication rates, robotic PN had significantly lower median blood loss (100 vs. 185 vs. 175 cc, p = 0.04) and shorter operative time (126 vs. 140 vs. 160 min, p = 0.01) compared to open and laparoscopic PN. At a median follow-up of 36.3 months (IQR 21.9–49.2), recurrence-free survival was 93.8%. Median %eGFR drop at 24 months was 12.1 (IQR 5.1–21.9), with significant eGFR loss (≥25%) in 36 (17.1%) patients. The robotic approach was associated with a lower %eGFR drop at 1-month and 1-year evaluations, but the benefit diminished at 24 months. Multivariate analysis showed age and open surgery as independent predictors of renal function loss at 1 month and Trifecta failure. Conclusions: The conservative management of entirely endophytic renal tumors is associated with favorable functional and oncologic outcomes. Whenever technically feasible, conservative surgery should be prioritized to optimize early renal function recovery. Full article

Background: Treatment of lung adenocarcinoma has changed and now includes checkpoint inhibitors (CPIs) or, in the case of an EGFR mutation, third-generation EGFR TKI osimertinib. Few data compare the long-term overall survival (OS) of current and historic subgroups. Methods: This real-world analysis (KOMPASS study) included stage IV lung-adenocarcinoma patients with either EGFR, KRAS, or no mutation. Patients were assigned to the “current” EGFR, KRAS, or no-mutation cohort if they had mutation testing using NGS (n = 199; median date of diagnosis 2021). If they had an EGFR PCR test only, they were assigned to the “historic” EGFR or no-mutation cohort (n = 127; median date of diagnosis 2014). Results: Both the current and the historic EGFR cohorts had significantly longer OS than the respective no-mutation cohorts (HR 0.58 and 0.60, respectively). The current no-mutation and EGFR cohorts had a strong trend to longer OS than the respective historic cohorts. In the no-mutation cohorts, the improvement was due to an increase in long-term survivors (HR 0.71), whereas in the EGFR mutation cohorts, the median OS was improved without long-term survivors (HR 0.70). The KRAS cohort showed OS like the no-mutation cohort, with a plateau of long-term survivors around 20%. Conclusions: A comparison of our data with that of the phase III trials KEYNOTE-189 and FLAURA suggests that the improved outcomes are due to the use of CPIs or osimertinib. The clinical trial results are well translated into real-world clinical practice with comparable OS. KRAS patients benefit from CPI treatment like no-mutation patients. Full article

Background: Teclistamab (TEC) is the first B-cell maturation antigen-directed bispecific antibody approved in 2022 by the European Medicines Agency and Food and Drug Administration for triple-class exposed relapsed/refractory multiple myeloma (RRMM). Objectives: As TEC is increasingly used in real-world (RW) settings, this study seeks to gather existing RW evidence on effectiveness, safety, healthcare resource utilization, and clinical practices associated with TEC. Methods: A systematic literature review was performed to identify RW observational studies of TEC-treated adults with RRMM from 2023 to June 2024. Results: Sixty-one records representing 41 unique studies were included; sample sizes ranged from 8 to 572 patients. Where reported, median follow-up ranged from 2.3 to 33.6 months, and >65% of the patients would have been ineligible for the pivotal trial of TEC (MajesTEC-1) in all but one study. In eight studies with ≥50 patients and ≥3 months follow-up, overall response rates were 59–66% and cytokine release syndrome (CRS) rates were 18–64%. Tocilizumab use for CRS management was reported in 14 studies, with two indicating CRS rates of 13% and 26% when used prophylactically. Survival and infection outcomes showed wide variability due to short follow-up in most studies. Conclusions: Overall, early RW effectiveness and safety outcomes of TEC were comparable to findings from MajesTEC-1. Full article

Background/Objectives: The significance of cytokine signaling on cancer progression and metastasis has raised interest in cancer research over the last few decades. Here, we analyzed the effects of three cytokines that we previously reported are significantly upregulated rapidly after the surgical removal of primary breast, colorectal, and prostate cancer. We also investigated the regulation of their cognate receptors. Methods: All experiments were conducted using the PANC-1, SW620, and MCF-7 cell lines, treated with three different cytokines (TGF-β1, HGF, and IL-6). The effect of these cytokines on the expression of epithelial–mesenchymal transition (EMT) cell surface markers and neuraminidase-1 activity was measured via fluorescent microscopy and image analysis software. Results: The findings show that these cytokines increase the expression of mesenchymal markers while reducing epithelial markers, corresponding to the EMT process. A strong link between cytokine receptor signaling and the Neu-1-MMP-9-GPCR crosstalk was identified, suggesting that cytokine receptor binding leads to increased Neu-1 activity and subsequent signaling pathway activation. Oseltamivir phosphate (OP) prevented sialic acid hydrolysis by neuraminidase-1 (Neu-1), leading to the downregulation of these signaling cascades. Conclusions: In concert with the previous work revealing the role of Neu-1 in regulating other glycosylated receptors implicated in cancer cell proliferation and EMT, targeting Neu-1 may provide effective treatment against a variety of malignancies. Most significantly, the treatment of patients with specific inhibitors of Neu-1 soon after primary cancer surgery may improve our ability to cure early-stage cancer by inhibiting the EMT process and disrupting the ability of any residual cancer cell population to metastasize. Full article