Cancers, Volume 15, Issue 23 (December-1 2023) – 213 articles

CD73 and adenosine have gained prominence in lung cancer research. The NT5E gene encodes CD73, known as an ectonucleotidase, which plays a crucial role within tumor cells, with immune-suppressive properties. Beyond cancer, CD73 exerts an influence on cardiac, neural, and renal functions, affecting cardiac, neural, and renal functions. CD73’s significance lies in its production of extracellular adenosine. It is notably expressed across diverse cell types within the immune and stromal lung microenvironment. CD73 expression amplifies in lung tumors, especially non-small cell lung cancer (NSCLC), often aligned with key oncogenic drivers like mutant EGFR and KRAS. CD73/adenosine pathway seems to be involved in tumoral immunoevasion, hampering the use of the immune checkpoint inhibitor (ICI) and correlating with therapy resistance. Despite the partial success of current ICI therapies, the CD73/adenosine pathway offers promise in enhancing their effectiveness. This comprehensive review explores recent insights into lung cancer’s CD73/adenosine pathway. It explores roles within tumor cells, the lung’s stromal environment, and the immune system. Ranging from pre-clinical models to clinical trials, potential therapies targeting the adenosine pathway for lung cancer treatment are discussed below. Full article

Despite advances in head and neck cancer treatment, virtually all patients experience chemoradiation-induced toxicities. Oral mucositis (OM) and dysphagia are among the most prevalent and have a systemic impact on patients, hampering treatment outcome and harming quality of life. Accurate prediction of severe cases is crucial for improving management strategies and, ultimately, patient outcomes. This scoping review comprehensively maps the reported predictors and critically evaluates the performance, methodology, and reporting of predictive models for these conditions. A total of 174 studies were identified from database searches, with 73 reporting OM predictors, 97 reporting dysphagia predictors, and 4 reporting both OM and dysphagia predictors. These predictors included patient demographics, tumor classification, chemoradiotherapy regimen, radiation dose to organs-at-risk, genetic factors, and results of clinical laboratory tests. Notably, many studies only conducted univariate analysis or focused exclusively on certain predictor types. Among the included studies, numerous predictive models were reported: eight for acute OM, five for acute dysphagia, and nine for late dysphagia. The area under the receiver operating characteristic curve (AUC) ranged between 0.65 and 0.81, 0.60 and 0.82, and 0.70 and 0.85 for acute oral mucositis, acute dysphagia, and late dysphagia predictive models, respectively. Several areas for improvement were identified, including the need for external validation with sufficiently large sample sizes, further standardization of predictor and outcome definitions, and more comprehensive reporting to facilitate reproducibility. Full article

Secreted phosphoprotein-1 (SPP1) expression is differentially altered in many malignancies and could serve as a potential prognostic biomarker. Recent findings indicated that SPP1 possesses a broader role in bladder cancer (BC) pathogenesis than previously envisioned; however, the underlying mechanisms governing its expression, cellular localization, prognostic value and immune-related role in bladder cancer remain poorly understood. The expression and the prognosis value of SPP1 were assessed using immunohistochemistry (IHC) staining on a tissue microarray. SPP1 expression was correlated with the clinicopathological parameters, and survival analysis was calculated using a Kaplan–Meier plotter. Bioinformatics analysis of TCGA data was queried using UALCAN, CIBERSORT and TIMER datasets to decipher the biological processes enrichment pattern, protein–protein interactions and characterize tumor-infiltrating immune cells, respectively. IHC revealed that SPP1 expression is significantly associated with tumor type, stage, grade and smoking status. The Kaplan–Meier survival curve showed that low SPP1 expression is an unfavorable prognostic indicator in bladder cancer patients (p = 0.02, log-rank). The significant increased expression of the SPP1 level is associated with evident hypomethylation of the gene promoter in cancer compared to normal tissues in the TCGA-bladder dataset. Missense mutation is the most frequent genetic alteration of the SPP1 gene. Protein–protein interactions demonstrated that SPP1 shares the same network with many important genes and is involved in many signaling pathways and biological processes. TIMER reported a significant correlation between SPP1 expression and multiple immune cells infiltration. Furthermore, the expression of SPP1 was found to be positively correlated with a number of immune checkpoint genes such as PD-1 and CTLA4. The current investigation indicates that the SPP1 protein could serve as a prognostic biomarker and merit further investigation to validate its clinical usefulness in patients with bladder cancer. Full article

Background: As recommended in the European Society for Medical Oncology (ESMO) guidelines, assessment of health-related quality of life (HRQoL) should be a relevant endpoint in randomized controlled trials (RCTs) testing new anticancer therapies. However, previous publications by our group and others revealed a frequent underestimation and underreporting of HRQoL results in publication of RCTs in oncology. Herein, we systematically reviewed HRQoL reporting in RCTs testing new treatments in advanced prostate, kidney and urothelial cancers and published between 2010 and 2022. Methods: We searched PubMed RCTs testing novel therapies in genitourinary (GU) cancers and published in fifteen selected journals (Annals of Oncology, BMC Cancer, British Journal of Cancer, Cancer Discovery, Clinical Cancer Research, Clinical Genitourinary cancer, European Journal of Cancer, European Urology, European Urology Oncology, JAMA, JAMA Oncology, Journal of clinical Oncology, Lancet, Lancet Oncology and The New England Journal of Medicine). We excluded trials investigating exclusively best supportive care or behavioral intervention, as well as subgroup or post hoc analyses of previously published trials. For each RCT, we investigated whether HRQoL assessment was performed by protocol and if results were reported in the primary manuscript or in a secondary publication. Results: We found 85 eligible trials published between 2010 and 2022. Only 1/85 RCTs (1.2%) included HRQoL among primary endpoints. Of note, 25/85 (29.4%) RCTs did not include HRQoL among study endpoints. HRQoL results were non-disclosed in 56/85 (65.9%) primary publications. Only 18/85 (21.2%) publications fulfilled at least one item of the CONSORT-PRO checklist. Furthermore, 14/46 (30.4%) RCTs in prostate cancer, 12/25 (48%) in kidney cancer and 3/14 (21.4%) in urothelial cancer reported HRQoL data in primary publications. Next, HRQoL data were disclosed in primary manuscripts of 12/32 (37.5%), 5/13 (38.5%), 5/16 (31.3%) and 5/15 (33.3%) trials evaluating target therapies, chemotherapy, immunotherapy and new hormonal agents, respectively. Next, we found that HRQoL data were reported in 16/42 (38%) and in 13/43 (30.2%) positive and negative trials, respectively. Finally, the rate of RCTs reporting HRQoL results in primary or secondary publications was 55.3% (n = 47/85). Conclusions: Our analysis revealed a relevant underreporting of HRQoL in RCTs in advanced GU cancers. These results highlight the need to dedicate more attention to HRQoL in RCTs to fully assess the value of new anticancer treatments. Full article

Background: Despite the feasibility and promising activity data on intensity-modulated RT and simultaneous integrated boost (IMRT-SIB) dose escalation in preoperative chemoradiation (CRT) for locally advanced rectal cancer (LARC), few data are currently available on long-term outcomes. Patients and Methods: A cohort of 288 LARC patients with cT3-T4, cN0-2, cM0 treated with IMRT-SIB and capecitabine from March 2013 to December 2019, followed by a total mesorectal excision (TME) or an organ-preserving strategy, was collected from a prospective database of 10 Italian institutions. A dose of 45 Gy in 25 fractions was prescribed to the tumor and elective nodes, while the SIB dose was prescribed according to the clinical practice of each institution on the gross tumor volume (GTV). Concurrent capecitabine was administered at a dose of 825 mg/m² twice daily, 7 days a week. The primary objective of the study was to evaluate long-term outcomes in terms of local control (LC), progression-free survival (PFS) and overall survival (OS). The secondary objective was to confirm the previously reported feasibility, safety and efficacy (pCR, TRG1-2 and downstaging rates) of the treatment in a larger patient population. Results: All patients received a dose of 45 Gy to the tumor and elective nodes, while the SIB dose ranged from 52.5 Gy to 57.5 Gy (median 55 Gy). Acute gastrointestinal and hematologic toxicity rates of grade 3–4 were 5.7% and 1.8%, respectively. At preoperative restaging, 36 patients (12.5%) with complete or major clinical responses (cCR or mCR) were offered an organ-preserving approach with local excision (29 patients) or a watch and wait strategy (7 patients). The complete pathologic response rate (pCR) in radically operated patients was 25.8%. In addition, 4 TME patients had pT0N1 and 19 LE patients had pT0Nx, corresponding to an overall pT0 rate of 31.3%. Of the 36 patients selected for organ preservation, 7 (19.5%) required the completion of TME due to unfavorable pathologic features after LE or tumor regrowth during W-W resulting in long-term rectal preservation in 29 of 288 (10.1%) of the total patient population. Major postoperative complications occurred in 14.2% of all operated patients. At a median follow-up of 50 months, the 5-year PFS and OS rates were 72.3% (95% CI: 66.3–77.4) and 85.9% (95% CI: 80.2–90.1), respectively. The 5-year local recurrence (LR) rate was 9.2% (95% CI: 6.0–13.2), while the distant metastasis (DM) rate was 21.3% (95% CI: 16.5–26.5). The DM rate was 24.5% in the high-risk subset compared to 16.2% in the low-intermediate risk group (p = 0.062) with similar LR rates (10% and 8%, respectively). On multivariable analysis, cT4 and TRG3–5 were significantly associated with worse PFS, OS and metastasis-free survival. Conclusions: Preoperative IMRT-SIB with the moderate dose intensification of 52.5–57.5 Gy (median 55 Gy) and the full dose of concurrent capecitabine confirmed to be feasible and effective in our real-life clinical practice. Organ preservation was shown to be feasible in carefully selected, responsive patients. The favorable long-term survival rates highlight the efficacy of this intensified treatment program. The incorporation of IMRT-SIB with a more effective systemic therapy component in high-risk patients could represent a new area of investigational interest. Full article

(1) Background: The aim of our research was to systematically review papers specifically focused on the hepatocellular carcinoma (HCC) diagnostic performance of DL methods based on medical images. (2) Materials: To identify related studies, a comprehensive search was conducted in prominent databases, including Embase, IEEE, PubMed, Web of Science, and the Cochrane Library. The search was limited to studies published before 3 July 2023. The inclusion criteria consisted of studies that either developed or utilized DL methods to diagnose HCC using medical images. To extract data, binary information on diagnostic accuracy was collected to determine the outcomes of interest, namely, the sensitivity, specificity, and area under the curve (AUC). (3) Results: Among the forty-eight initially identified eligible studies, thirty studies were included in the meta-analysis. The pooled sensitivity was 89% (95% CI: 87–91), the specificity was 90% (95% CI: 87–92), and the AUC was 0.95 (95% CI: 0.93–0.97). Analyses of subgroups based on medical image methods (contrast-enhanced and non-contrast-enhanced images), imaging modalities (ultrasound, magnetic resonance imaging, and computed tomography), and comparisons between DL methods and clinicians consistently showed the acceptable diagnostic performance of DL models. The publication bias and high heterogeneity observed between studies and subgroups can potentially result in an overestimation of the diagnostic accuracy of DL methods in medical imaging. (4) Conclusions: To improve future studies, it would be advantageous to establish more rigorous reporting standards that specifically address the challenges associated with DL research in this particular field. Full article

Tuberculum sellae meningioma (TSM) is a challenging tumor that grows close to several crucial structures, such as the optic nerve, arteries, and pituitary. Surgical treatment is currently evolving from a transcranial microsurgical resection to a transsphenoidal approach. This study examined the clinical profile of patients with tuberculum sellae meningioma and explored its relationship with scoring systems. This retrospective observational study included patients with TSM who underwent surgery at the Department of Neurosurgery at our hospital between 2017 and 2022. The patients were excluded if their data required completion. The clinical profiles of the patients were counted and transformed into a scoring system using several variables such as size, vascular, and canal invasion. We then analyzed the relationship between the clinical signs and symptoms to determine the efficacy of this scoring system. Thirty-six patients were included in the study. Most of our patients had a high score for tumor diameter, bilateral canal invasion, and vascular invasion (2-2-2). Moreover, when related to clinical signs, there was no relationship between the canal and vascular invasion and decreased visual acuity. Tuberculum sellae meningioma mostly causes visual impairment and several other symptoms, such as hemianopsia and parasellar extension. Several factors in the scoring system should also be considered to predict outcomes, such as the onset of visual symptoms, peritumoral edema, and grade of excision. Full article

Background: Germline pathogenic variants (PV) in BRCA1 and BRCA2 genes, which account for 20% of familial breast cancer (BC) cases, are highly penetrant and are associated with Hereditary Breast/Ovarian Cancer Syndrome. Previous studies, mostly including higher numbers of BRCA1 BC patients, yielded conflicting results regarding BRCA1/2 BC outcomes. In the Portuguese population, BRCA2 BC is diagnosed more frequently than BRCA1 BC. We aimed to compare clinicopathological characteristics and prognosis between BC patients with BRCA1 and BRCA2 mutations and a control group without germline PV (BRCA-wt). Furthermore, we explored the frequency and outcomes of risk-reducing surgeries in BRCA-mutated patients. Methods: Prospective follow-up was proposed for patients with a diagnosed BRCA1/2 PV. For this study, a matched control group (by age at diagnosis, by decade, and by stage at diagnosis) included BC patients without germline PV. We compared overall survival (OS) and invasive disease-free survival (iDFS) within the three groups, and the use of risk-reducing surgeries among the BRCA cohort. Results: For a mean follow-up time of 113.0 months, BRCA-wt patients showed longer time to recurrence (p = 0.002) and longer OS (p < 0.001). Among patients with BRCA mutations, no statistical differences were found, although patients with BRCA2 BC had longer iDFS and OS. Uptake of risk-reducing surgeries (contralateral prophylactic mastectomy and salpingo-oophorectomy) were negative predictors of invasive disease and death, respectively. Conclusions: Testing positive for a BRCA PV is associated with a higher risk of relapse and death in patients with BC in the Portuguese population. Risk-reducing mastectomy and salpingo-oophorectomy were associated with lower incidence of relapse and longer median iDFS and OS, respectively. Full article

Background: This study aimed to assess the relative efficacy of modern radiotherapy strategies in patients with newly diagnosed glioblastoma. Method: A comprehensive literature review was conducted through MEDLINE, Embase and the Cochrane Central Registry of Controlled Trials of studies focused on newly diagnosed glioblastoma published up to and counting 15 September 2022. We included randomized controlled trials (RCTs) and comparative nonrandomized studies (NRSs) of radiotherapy for newly diagnosed glioblastoma. Eligible studies included patients treated with three-dimensional conformal radiation therapy, intensity-modulated radiation therapy, volumetric modulated arc therapy or proton therapy reporting either overall survival, progression-free survival or both. The impact of different radiotherapy modalities on survival was evaluated by direct comparisons of indirect evidence and estimated hazard ratios in terms of a Bayesian network meta-analysis. Results: A total of six RCTs or NRSs comprising 816 glioblastoma patients with modern radiotherapy strategies were reviewed, yielding improved overall survival by proton therapy over all other regimens. The network meta-analysis also indicated a significant advantage of proton therapy compared with other radiotherapy strategies in regard to progression-free survival. Conclusion: Our findings suggested PT as a standard RT regime with possibly superior survival outcomes for selected patients with GBM. Full article

Introduction: Head and neck squamous cell carcinoma (HNSCC) treatment includes surgery, radiotherapy, and immunotherapy with the aim of eradicating cancer cells without affecting normal tissues. HNSCC expresses epidermal growth factor receptor (EGFR) and cetuximab, an IgG1 monoclonal antibody targeting epidermal growth factor receptor, has been approved for the treatment of HNSCC. However, cetuximab has low reactivity and induces serious side effects. Gold nanoparticles (AuNPs) were reported to enhance the local antitumor effects of radiotherapy without damaging normal cells. Methods and Results: This study investigated the in vitro effects of single and combination therapy with AuNPs (1.0 nM), cetuximab (30 nM), and radiotherapy (4 Gy) on a human HNSCC cell line, HSC-3. Combination treatment of AuNPs + cetuximab + radiotherapy markedly reduced HSC-3 numbers and proliferation and enhanced apoptosis compared with single and double combination treatments. Furthermore, the in vivo combination treatment (AuNPs + cetuximab + radiotherapy) of a xenograft model of HSC-3 cells transplanted into nude mice (BALB/cAJcl-nu/nu) reduced the tumor volume compared with the controls. Scanning electron microscopy demonstrated the presence of AuNPs in tumor tissues and toxicity analysis indicated that AuNPs had no toxic effect on normal tissues. Conclusions: This study showed that AuNPs alone do not have a tumor-suppressing effect, but they sensitize tumors to radiotherapy and bind to cetuximab, leading to enhanced antitumor effects. Full article

Chronic Myelogenous Leukemia (CML) is a prevalent hematologic malignancy characterized by the malignant transformation of myeloid cells and their proliferation in the peripheral blood. The management of CML poses significant challenges, particularly in detecting and eradicating minimal residual disease, which is crucial for preventing relapse and improving survival outcomes. Traditional minimal residual disease detection methods, such as bone marrow aspiration, are invasive and have limitations which include the potential for sampling errors and false negatives. This study introduces a novel label-free microfluidic chip designed for the segregation and recovery of circulating leukemia cells, offering a non-invasive liquid biopsy approach with potential applications in precision medicine. Over July 2021 to October 2023, we recruited 56 CML patients across various disease stages and collected blood samples for analysis using our microfluidic device. The device demonstrated high efficacy in isolating circulating leukemia cells, with an optimal capture efficiency of 78% at a sample flow rate of 3 mL/h. Our results indicate that the microfluidic device can efficiently segregate and quantify circulating leukemia cells, providing a detailed understanding of CML progression and treatment response. The significant reduction in circulating leukemia cell counts in patients in complete remission highlights the device’s potential in monitoring treatment efficacy. Furthermore, the device’s sensitivity in detecting minimal residual disease could offer a more reliable prognostic tool for therapeutic decision-making in CML management. Full article

Recent studies have shed light on alterations to the proinflammatory tumor microenvironment as a significant carcinogenic mechanism. Despite previous studies on associations between proinflammatory cytokines and lung cancer risk, few studies have been conducted in Asian populations. This study aimed to investigate associations between proinflammatory cytokines and lung cancer risk, considering histological types, in the Korean general population. We carried out a case-cohort study on the Korean National Cancer Center Community (KNCCC) cohort (lung cancer cases: 136, subcohort: 822). Pre-diagnostic serum levels of proinflammatory cytokines (i.e., IL-6, TNF-α, IL-1β, IFN-γ, and IL-10) were measured using Quantikine^® ELISA. A Cox proportional-hazards regression analysis was conducted. In this study, serum levels of IL-6, IL-1β, and IFN-γ were associated with lung cancer risk. IL-6 was associated with lung cancer, regardless of the histological type. IL-1β had an association only with adenocarcinoma, while IFN-γ had an association only with squamous-cell carcinoma. This study shows associations between serum levels of IL-6, IL-1β, and IFN-γ and lung cancer risk, underscoring the potential of these cytokines to act as risk biomarkers. The utilization of these biomarkers for risk prediction may hold the promise of facilitating the identification of the high-risk population. Full article

Epithelial ovarian cancer (EOC) is the most lethal gynecologic cancer. The disease is often diagnosed after wide-spread dissemination, and the standard treatment combines aggressive surgery with platinum-based chemotherapy; however, most patients experience relapse in the form of peritoneal carcinomatosis, resulting in a 5-year mortality below 45%. There is clearly a need for the development of novel treatments and cancer immunotherapies offering a different approach. Immunotherapies have demonstrated their efficacy in many types of cancers; however, only <15% of EOC patients show any evidence of response. One of the main barriers behind the poor therapeutic outcome is the reduced expression of Major Histocompatibility Complexes class I (MHC I) which occurs in approximately 60% of EOC cases. This review aims to gather and enhance our current understanding of EOC, focusing on its distinct cancer characteristics related to MHC I expression, immunogenicity, antigen presentation, epithelial-to-mesenchymal transition, and various ongoing immunotherapeutic strategies designed to stimulate antitumor immunity. Full article

Background: Oral squamous cell carcinoma (OSCC) is characterized by an immunosuppressive tumor microenvironment. Their plasma-derived exosomes deliver immunomodulatory molecules and cargo that correlate significantly with clinical parameters. This study aims to assess the exosomal profile as a potential tool for early detection of relapse and long-term outcomes in OSCC patients undergoing conventional therapy. Methods: 27 OSCC patients with a median 38-month follow-up were included in this study. The relationship between NTA-derived parameters and clinical pathological parameters was examined, and receiver operating characteristic (ROC) curves were utilized to evaluate the diagnostic efficacy of these values in detecting cancer relapse. Results: Plasmatic levels of exosomes prior to surgery showed a drastic reduction after surgical intervention (8.08E vs. 1.41 × 10⁹ particles/mL, p = 0.006). Postsurgical concentrations of exosomes were higher in patients who experienced relapse compared to those who remained disease-free (2.97 × 10⁹ vs. 1.11 × 10⁹ particles/mL, p = 0.046). Additionally, patients who relapsed exhibited larger exosome sizes after surgery (141.47 vs. 132.31 nm, p = 0.03). Patients with lower concentrations of exosomes prior to surgery demonstrated better disease-free survival compared to those with higher levels (p = 0.012). ROC analysis revealed an area under the curve of 0.82 for presurgical exosome concentration in identifying relapse. Conclusions: Presurgical exosomal plasmatic levels serve as independent predictors of early recurrence and survival in OSCC. All in all, our findings indicate that the detection of peripheral exosomes represents a novel tool for the clinical management of OSCC, with potential implications for prognosis assessment. Full article

The application of artificial intelligence to improve the access of cancer patients to high-quality medical care is one of the goals of modern medicine. Pathology constitutes the foundation of modern oncologic treatment, and its role has expanded far beyond diagnosis into predicting treatment response and overall survival. However, the funding of pathology is often an afterthought in resource-scarce medical systems. The increased digitalization of pathology has paved the way towards the potential use of artificial intelligence tools for improving pathologist efficiency and extracting more information from tissues. In this review, we provide an overview of the main research directions intersecting with artificial intelligence and pathology in relation to oncology, such as tumor classification, the prediction of molecular alterations, and biomarker quantification. We then discuss examples of tools that have matured into clinical products and gained regulatory approval for clinical use. Finally, we highlight the main hurdles that stand in the way of the digitalization of pathology and the application of artificial intelligence in pathology while also discussing possible solutions. Full article

Aberrant estrogen receptor (ER) signaling is a major driver of breast tumor growth and progression. Sigma 2 receptor has long been implicated in breast carcinogenesis based on pharmacological studies, but its molecular identity had been elusive until TMEM97 was identified as the receptor. Herein, we report that the TMEM97/sigma 2 receptor is highly expressed in ER-positive breast tumors and its expression is strongly correlated with ERs and progesterone receptors (PRs) but not with HER2 status. High expression levels of TMEM97 are associated with reduced overall survival of patients. Breast cancer cells with increased expression of TMEM97 had a growth advantage over the control cells under both nutrition-limiting and sufficient conditions, while the knockdown of TMEM97 expression reduced tumor cell proliferations. When compared to their vector control cells, MCF7 and T47D cells with increased TMEM97 expression presented increased resistance to tamoxifen treatment and also grew better under estrogen-depleted conditions. The TMEM97/sigma 2 receptor enhanced the ERα transcriptional activities and increased the expression of genes responsive to estrogen treatment. Increased TMEM97 also stimulated the mTOR/S6K1 signaling pathways in the MCF7 and T47D cells. The increased level of active, phosphorylated ERα, and the enhanced resistance to tamoxifen treatment with increased TMEM97, could be blocked by an mTOR inhibitor. The knockdown of TMEM97 expression reduced the ERα and mTOR/S6K1 signaling activities, rendering the cells with an increased sensitivity to tamoxifen. The observations suggest that the TMEM97/sigma 2 receptor is a novel regulator of ERα activities in breast tumor cell growth. Full article

The aim of this study was to examine the cytogenetic profiles of plasma cell neoplasms (PCNs) at various disease stages, encompassing 1087 patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), newly diagnosed multiple myeloma (NDMM), and refractory/relapsed multiple myeloma (RRMM). Fluorescence in situ hybridization (FISH) analyses were conducted on highly purified plasma cell samples, revealing that 96% of patients exhibited at least one cytogenetic abnormality. The genomic complexity escalated from MGUS to SMM and further to NDMM and RRMM, largely driven by 1q gain, del(17p), MYC-rearrangement (MYC-R), del(1p), and tetraploidy. Elevated frequencies of high-risk cytogenetics (59%), 1q gain (44%), and del(17p) (23%), as well as the presence of subclones (48%), were particularly notable in RRMM cases. IGH::CCND1 was observed in 26% of the cases, with no apparent variations across races, ages, or disease groups. Concurrent chromosomal analysis with FISH revealed that the incidence of abnormal karyotypes was strongly correlated with the extent of neoplastic plasma cell infiltration, genomic complexity, and the presence of specific abnormalities like del(17p) and MYC-R. Approximately 98% of the cases with abnormal karyotypes were complex, with most featuring five or more abnormalities. Chromosome 1 structural abnormalities were the most prevalent, found in 65% of cases. The frequent presence of subclones and composite karyotypes underscored the genomic heterogeneity and instability in this cohort. Full article

Alternative splicing can produce transcripts that affect cancer development and thus shows potential for cancer diagnosis and treatment. However, intron retention (IR), a type of alternative splicing, has been studied less in cancer biology research. Here, we generated a pan-cancer IR landscape for more than 10,000 samples across 33 cancer types from The Cancer Genome Atlas (TCGA). We characterized differentially retained introns between tumor and normal samples and identified retained introns associated with survival. We discovered 988 differentially retained introns in 14 cancers, some of which demonstrated diagnostic potential in multiple cancer types. We also inferred a large number of prognosis-related introns in 33 cancer types, and the associated genes included well-known cancer hallmarks such as angiogenesis, metastasis, and DNA mutations. Notably, we discovered a novel intron retention inside the 5′UTR of STN1 that is associated with the survival of lung cancer patients. The retained intron reduces translation efficiency by producing upstream open reading frames (uORFs) and thereby inhibits colony formation and cell migration of lung cancer cells. Besides, the IR-based prognostic model achieved good stratification in certain cancers, as illustrated in acute myeloid leukemia. Taken together, we performed a comprehensive IR survey at a pan-cancer level, and the results implied that IR has the potential to be diagnostic and prognostic cancer biomarkers, as well as new drug targets. Full article

Addressing the persistent challenges in treating metastatic neuroendocrine tumors (NETs) demands ongoing refinement and innovation in therapeutic strategies. This study investigates the potential advantages of combining metronomic temozolomide (mTMZ) with bevacizumab for patients diagnosed with metastatic NETs, particularly focusing on those with a Ki-67 index under 55%. Data from 30 patients were analyzed, using key performance indicators such as progression-free survival (PFS), overall survival (OS), and response rates to therapy, to gauge the treatment’s efficacy. The results were encouraging: the median PFS recorded was 16.3 months, and the OS was 25.9 months. The disease control rate (DCR) reached an impressive 86.7%, and the objective response rate (ORR) stood at 63.3%. The treatment regimen was well-tolerated, with no reported instances of grade 4 toxicities. Such a safety profile indicates that this regimen may be particularly advantageous for older, fragile patients who might struggle with conventional dosage levels. These initial findings suggest that the mTMZ and bevacizumab combination could potentially rival the conventional temozolomide–capecitabine therapy in managing metastatic NETs. We aimed to meticulously assess the efficacy of the mTMZ and bevacizumab combination in treating metastatic NETs. Given the initial promising results, a more conclusive understanding of its efficacy will require further research through larger, multicenter prospective clinical trials. Full article

[Proposal] Here, we retrospectively evaluate risk factors for radiation necrosis and local recurrence after PBT for skull base chordoma or chondrosarcoma. [Patients and Methods] We analyzed 101 patients who received PBT for skull base chordomas and chondrosarcomas from January 1989 to February 2021. Multivariable logistic regression models were applied for local recurrence, temporal lobe radiation necrosis rates, and temporal lobe radiation necrosis. [Results] In multivariate analysis, chordoma and large tumor size were independent significant factors for local recurrence. The 1-, 2-, 3-, 4- and 5-year local recurrence rates were 3.9%, 16.9%, 20.3%, 28.5% and 44.0% for chordoma and 0%, 0%, 0%, 0% and 7.1% for chondrosarcoma, respectively. The local recurrence rates of small tumors (<30 mm) were 4.3%, 14.7%, 17.7%, 17.7% and 25.9%, and those for large tumors were 3.6%, 15.1%, 19.2%, 32.7% and 59.6%, respectively. In multivariate analysis, BED Gy₁₀ and total dose were risk factors for radiation necrosis. [Conclusions] For skull base chordoma and chondrosarcoma, the risk factors of local recurrence were chordoma and large tumor size, and those of radiation necrosis were BED Gy₁₀ and total dose, respectively. DVH analysis is needed to investigate the risk factors for brain necrosis in more detail. Full article

The early events that lead to the inflammatory and immune-modulatory effects of radiation therapy (RT) in the tumor microenvironment (TME) after its DNA damage response activating the innate DNA-sensing pathways are largely unknown. Neutrophilic infiltration into the TME in response to RT is an early innate inflammatory response that occurs within 24–48 h. Using two different syngeneic murine tumor models (RM-9 and MC-38), we demonstrated that CXCR2 blockade significantly reduced RT-induced neutrophilic infiltration. CXCR2 blockade showed the same effects on RT-induced tumor inhibition and host survival as direct neutrophil depletion. Neutrophils highly and preferentially expressed CXCR2 compared to other immune cells. Importantly, RT induced both gene and protein expression of CXCLs in the TME within 24 h, attracting neutrophils into the tumor. Expectedly, RT also upregulated the gene expression of both cGAS and AIM2 DNA-sensing pathways in cGAS-positive MC-38 tumors but not in cGAS-negative RM-9 tumors. Activation of these pathways resulted in increased IL-1β, which is known to activate the CXCLs/CXCR2 axis. Gene ontology analysis of mRNA-Seq supported these findings. Taken together, the findings suggest that the CXCLs/CXCR2 axis mediates the RT-induced innate inflammatory response in the TME, likely translating the effects of innate DNA-sensing pathways that are activated in response to RT-induced DNA damage. Full article

The most common genetic drivers of pituitary neuroendocrine tumors (PitNETs) lie within mutational hotspots, which are genomic regions where variants tend to cluster. Some of these hotspot defects are unique to PitNETs, while others are associated with additional neoplasms. Hotspot variants in GNAS and USP8 are the most common genetic causes of acromegaly and Cushing’s disease, respectively. Although it has been proposed that these genetic defects could define specific clinical phenotypes, results are highly variable among studies. In contrast, DICER1 hotspot variants are associated with a familial syndrome of cancer predisposition, and only exceptionally occur as somatic changes. A small number of non-USP8-driven corticotropinomas are due to somatic hotspot variants in USP48 or BRAF; the latter is a well-known mutational hotspot in cancer. Finally, somatic variants affecting a hotspot in SF3B1 have been associated with multiple cancers and, more recently, with prolactinomas. Since the associations of BRAF, USP48, and SF3B1 hotspot variants with PitNETs are very recent, their effects on clinical phenotypes are still unknown. Further research is required to fully define the role of these genetic defects as disease biomarkers and therapeutic targets. Full article

Purpose: This systematic review aims to identify, evaluate, and summarize the findings of the literature on existing computational models for radiofrequency and microwave thermal liver ablation planning and compare their accuracy. Methods: A systematic literature search was performed in the MEDLINE and Web of Science databases. Characteristics of the computational model and validation method of the included articles were retrieved. Results: The literature search identified 780 articles, of which 35 were included. A total of 19 articles focused on simulating radiofrequency ablation (RFA) zones, and 16 focused on microwave ablation (MWA) zones. Out of the 16 articles simulating MWA, only 2 used in vivo experiments to validate their simulations. Out of the 19 articles simulating RFA, 10 articles used in vivo validation. Dice similarity coefficients describing the overlap between in vivo experiments and simulated RFA zones varied between 0.418 and 0.728, with mean surface deviations varying between 1.1 mm and 8.67 mm. Conclusion: Computational models to simulate ablation zones of MWA and RFA show considerable heterogeneity in model type and validation methods. It is currently unknown which model is most accurate and best suitable for use in clinical practice. Full article

Previous work has reported the design of a novel thermobrachytherapy (TBT) balloon implant to deliver magnetic nanoparticle (MNP) hyperthermia and high-dose-rate (HDR) brachytherapy simultaneously after brain tumor resection, thereby maximizing their synergistic effect. This paper presents an evaluation of the robustness of the balloon device, compatibility of its heat and radiation delivery components, as well as thermal and radiation dosimetry of the TBT balloon. TBT balloon devices with 1 and 3 cm diameter were evaluated when placed in an external magnetic field with a maximal strength of 8.1 kA/m at 133 kHz. The MNP solution (nanofluid) in the balloon absorbs energy, thereby generating heat, while an HDR source travels to the center of the balloon via a catheter to deliver the radiation dose. A 3D-printed human skull model was filled with brain-tissue-equivalent gel for in-phantom heating and radiation measurements around four 3 cm balloons. For the in vivo experiments, a 1 cm diameter balloon was surgically implanted in the brains of three living pigs (40–50 kg). The durability and robustness of TBT balloon implants, as well as the compatibility of their heat and radiation delivery components, were demonstrated in laboratory studies. The presence of the nanofluid, magnetic field, and heating up to 77 °C did not affect the radiation dose significantly. Thermal mapping and 2D infrared images demonstrated spherically symmetric heating in phantom as well as in brain tissue. In vivo pig experiments showed the ability to heat well-perfused brain tissue to hyperthermic levels (≥40 °C) at a 5 mm distance from the 60 °C balloon surface. Full article

This study investigates the effect of fractionated (two-part) PDT on the long-term local control rate (LCR) using the concentration of reactive oxygen species ([ROS]_rx) as a dosimetry quantity. Groups with different fractionation schemes are examined, including a 2 h interval between light delivery sessions to cumulative fluences of 135, 180, and 225 J/cm². While the total treatment time remains constant within each group, the division of treatment time between the first and second fractionations are explored to assess the impact on long-term survival at 90 days. In all preclinical studies, Photofrin is intravenously administered to mice at a concentration of 5 mg/kg, with an incubation period between 18 and 24 h before the first light delivery session. Fluence rate is fixed at 75 mW/cm². Treatment ensues via a collimated laser beam, 1 cm in diameter, emitting light at 630 nm. Dosimetric quantities are assessed for all groups along with long-term (90 days) treatment outcomes. This study demonstrated a significant improvement in long-term survival after fractionated treatment schemes compared to single-fraction treatment, with the optimal 90-day survival increasing to 63%, 86%, and 100% vs. 20%, 25%, and 50%, respectively, for the three cumulative fluences. The threshold [ROS]_rx for the optimal scheme of fractionated Photofrin-mediated PDT, set at 0.78 mM, is significantly lower than that for the single-fraction PDT, at 1.08 mM. Full article

The tongue is the most common site for oral cavity carcinoma. It typically has male predominance. However, several studies have documented an increasing number of incidences among the younger population, with female predominance, which is unusual. In this study, we aimed to determine current trends in tongue cancer regarding age and gender. Data from 197 tongue cancer patients were extracted from The Oncology Center, Mansoura University (OCMU) database from 2006 to 2021. The patients were divided into two time periods: (2006–2013) and (2014–2021). We computed counts and proportions of tongue cancer for demographic and tumor characteristics. The data were analyzed using SPSS. Gender showed no statistically significant difference in both groups, while the percentages of diagnosed females were 52.7% and 52%, respectively. The percentages of males were 47.3% and 48%, p-value = 0.927. There was a statistically significant difference in the number of patients aged 20 to 39 years old and ≥60 years old in both periods. The p-values were 0.039 and 0.011, respectively. Although tongue cancer is typically more common in males, our results showed no significant difference in the gender of diagnosed patients. In addition, our results showed that the number of younger patients significantly increased in the period from 2014 to 2021. However, we encourage further investigations involving larger populations. Full article

A definitive surgical resection is the preferred treatment for early-stage non-small cell lung cancer (NSCLC). Research on genetic alterations, including epidermal growth factor receptor (EGFR) mutations, in early-stage NSCLC remains insufficient. We investigated the prevalence of genetic alterations in early-stage NSCLC and the association between EGFR mutations and recurrence after a complete resection. Between January 2019 and December 2021, 659 patients with NSCLC who underwent curative surgical resections at a single regional cancer center in Korea were recruited. We retrospectively compared the clinical and pathological data between the recurrence and non-recurrence groups. Among the 659 enrolled cases, the median age was 65.86 years old and the most common histology was adenocarcinoma (74.5%), followed by squamous cell carcinoma (21.7%). The prevalence of EGFR mutations was 43% (194/451). Among them, L858R point mutations and exon 19 deletions were 52.3% and 42%, respectively. Anaplastic lymphoma kinase (ALK) rearrangement was found in 5.7% of patients (26/453) and ROS proto-oncogene 1 (ROS1) fusion was found in 1.6% (7/441). The recurrence rate for the entire population was 19.7%. In the multivariate analysis, the presence of EGFR mutations (hazard ratio (HR): 2.698; 95% CI: 1.458–4.993; p = 0.002), stage II (HR: 2.614; 95% CI: 1.29–5.295; p = 0.008) or III disease (HR: 9.537; 95% CI: 4.825–18.852; p < 0.001) (vs. stage I disease), and the presence of a pathologic solid type (HR: 2.598; 95% CI: 1.405–4.803; p = 0.002) were associated with recurrence. Among the recurrence group, 86.5% of the patients with EGFR mutations experienced distant metastases compared with only 66.7% of the wild type (p = 0.016), with no significant difference in median disease-free survival (52.21 months vs. not reached; p = 0.983). In conclusion, adjuvant or neoadjuvant targeted therapy could be considered more actively because EGFR mutations were identified as an independent risk factor for recurrence and were associated with systemic recurrence. Further studies on perioperative therapy for other genetic alterations are necessary. Full article

Background: Chronic cancer-related fatigue is difficult to manage in breast cancer survivors. The tango trial showed that a six-week tango Argentino program was effective in reducing fatigue and improving quality of life, and here we investigated the sustainability of this tango program for breast cancer survivors. Methods: Stage I–III breast cancer survivors with increased fatigue symptoms were analyzed. The fifty participants in the tango trial were compared with a control cohort (n = 108) who did not participate in the tango program. Using the European Organization for Research and Treatment of Cancer Questionnaire C30 (EORTC-QLQ-C30) and the German version of the cancer fatigue scale (CFS-D) self-reported quality of life parameters were assessed and longitudinal changes, correlations, and association factors were calculated. Results: Significant improvements in fatigue (p = 0.006), physical functioning (p = 0.01), and diarrhea (p = 0.04) persisted in the 50 Tango participants at 6 months, but not in the control cohort. Twelve months after joining the tango program, increased fatigue was associated with reduced sporting activities (p = 0.0005), but this was not the case for tango dancing. Conclusions: The present results suggest that tango may be appropriate as a component of early supportive and follow-up care programs, to promote health-related quality of life and physical activity and also eventually to improve long-term clinical outcomes of breast cancer survivors. Trial registration: Trial registration numbers DRKS00013335 on 27 November 2017 and DRKS00021601 on 21 August 2020 retrospectively registered. Full article

(1) Background: The purpose of this study was to evaluate the time toxicity, or time spent in health care, of immunotherapy- versus chemotherapy-based regimens for metastatic esophageal and gastric cancers. (2) Methods: A literature search was conducted, and 18 phase III clinical trials of immune checkpoint inhibitors were selected for analysis. Health care days were calculated based on the number of days associated with receiving therapy and the adverse events reported in the clinical trials. Both the number of health care days and the median overall survival were compared among chemotherapy-only, immunotherapy-only, and chemo-immunotherapy regimens across this cohort of drug registration trials. (3) Results: The estimated median number of health care days was 37 (range of 7–52) days, or 1.2 (range of 0.2–1.7) months, compared to a median survival of 10.2 months across these 18 studies. For the chemotherapy-only regimens, the median number of health care days was 39 (range of 21–51) days, and for chemo-immunotherapy, it was 39 (range of 30–52) days. The immunotherapy-only regimens had fewer days, a median of 28 (range of 24–41), p < 0.05, compared to the other two arms. (4) Conclusions: The chemo-immunotherapy regimens did not add time toxicity compared to chemotherapy alone. The immunotherapy-only regimens had lower time toxicity compared to chemotherapy alone. In the setting of decreased time toxicity and improved overall survival, further development of immunotherapy-based regimens could improve outcomes in advanced esophageal and gastric cancers. Full article